Cardiac Electrophysiology

Cardiac Electrophysiology
Anatomy, Pathophysiology and Medical Intervention
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Contents
Articles
Introduction
Cardiac electrophysiology 1 1 3 3 6 12 16 23 26 27 30 32 34 34 36 49 51 52 56 60 61 63 66 70 70 77 80 84 87 89
Anatomy and Physiology

Electrical conduction system of the heart Cardiac action potential Cardiac muscle Vagus nerve Sinoatrial node Bachmann's bundle Atrioventricular node Bundle of His Purkinje fibers
Principles of Diagnostics
Clinical cardiac electrophysiology Electrocardiography Electrophysiology study P wave QRS complex QT interval ST segment T wave Tilt table test Holter monitor
Dysrythmia
Cardiac dysrhythmia Palpitation Tachycardia Bradycardia Proarrhythmia
Sinus Rhythms and Dysrythmias
Sinus rhythm Sinus tachycardia Inappropriate sinus tachycardia Sinus bradycardia Sick sinus syndrome
89 91 93 96 98 100 100 102 103 104 108 121 121 127 130 131 132 132 138 140 140 145 149 151 157 158 159 162 165 172 172 176 179 187
Atrial Dysrythmias
Premature atrial contraction Wandering pacemaker Multifocal atrial tachycardia Atrial flutter Atrial fibrillation
Junctional Dysrythmias
Supraventricular tachycardia AV nodal reentrant tachycardia Junctional rhythm Junctional tachycardia
Atrioventricular Node Dysrythmias

WolffParkinsonWhite syndrome LownGanongLevine syndrome
Ventricular Dysrythmias
Premature ventricular contraction Ventricular tachycardia Torsades de pointes Ventricular fibrillation Accelerated idioventricular rhythm First-degree atrioventricular block Second-degree atrioventricular block Third-degree atrioventricular block Long QT syndrome
Antiarrythmic Agents
Antiarrhythmic agent Sodium channel blocker Beta blocker Potassium channel blocker
Calcium channel blocker
189 193 193 196 200 203 203 209 215 217 217 223 226 228 228 236 238 242 247 252 258 258 266 269 272 275 277 277 282 288 288 294
Type Ia Antiarrythmics
Procainamide Quinidine Disopyramide
Type Ib Antiarrythmics
Lidocaine Phenytoin Mexiletine
Type Ic Antiarrythmics
Flecainide Propafenone Moricizine
Type II Antiarrythmics
Propranolol Esmolol Timolol Metoprolol Atenolol Bisoprolol
Type III Antiarrythmics

Amiodarone Sotalol Ibutilide Dofetilide E-4031
Type IV Antiarrythmics
Verapamil Diltiazem
Type V Antiarrythmics
Adenosine Digoxin
Artificial Pacemakers
Artificial pacemaker Implantable cardioverter-defibrillator Transcutaneous pacing Transvenous pacing Pacemaker syndrome Pacemaker failure Pacemaker crosstalk
301 301 312 317 318 319 325 326 327 327
Cardioversion
Cardioversion
References
Article Sources and Contributors Image Sources, Licenses and Contributors 329 335
Article Licenses
License 339
Introduction
Cardiac electrophysiology
Cardiac electrophysiology is the science of elucidating, diagnosing, and treating the electrical activities of the heart. The term is usually used to describe studies of such phenomena by invasive (intracardiac) catheter recording of spontaneous activity as well as of cardiac responses to programmed electrical stimulation (PES). These studies are performed to assess complex arrhythmias, elucidate symptoms, evaluate abnormal electrocardiograms, assess risk of developing arrhythmias in the future, and design treatment. These procedures increasingly include therapeutic methods (typically radiofrequency ablation) in addition to diagnostic and prognostic procedures. Other therapeutic modalities employed in this field include antiarrhythmic drug therapy and implantation of pacemakers and automatic implantable cardioverter-defibrillators (AICD).[1]
Drawing of the ECG, with labels of intervals
The cardiac electrophysiology study (EPS) typically measures the response of the injured or cardiomyopathic myocardium to PES on specific pharmacological regimens in order to assess the likelihood that the regimen will successfully prevent potentially fatal sustained ventricular tachycardia (VT) or ventricular fibrillation VF (VF) in the future. Sometimes a series of EPS drug trials must be conducted to enable the cardiologist to select the one regimen for long-term treatment that best prevents or slows the development of VT or VF following PES. Such studies may also be conducted in the presence of a newly-implanted or newly-replaced cardiac pacemaker or AICD.[1] A specialist in cardiac electrophysiology is known as a cardiac electrophysiologist, or (more commonly) simply an electrophysiologist. Cardiac electrophysiology is considered a subspecialty of cardiology in most countries and usually requires two or more years of fellowship training beyond a general cardiology fellowship. In early 2011, the Centers for Medicare and Medicaid Services (CMS) promoted cardiac electrophysiology to its own specialty category in the United States. Cardiac electrophysiologists are trained to perform interventional cardiac electrophysiology studies (EPS) as well as surgical device implantations.[1] Cardiac electrophysiology is a relatively young subdiscipline of cardiology and internal medicine. It was developed during the mid-1970s jointly by Mark E. Josephson, of the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, now of Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, Massachusetts, and Hein J. J. Wellens, of the Academic Hospital in Maastricht, Netherlands.[2]
Cardiac electrophysiology The Heart Rhythm Society, founded in 1979, promotes education and advocacy for cardiac arrhythmia professionals (including cardiac electrophysiologists) and patients. It is the largest society of its kind.
References
[1] Fauci, Anthony, et al. Harrison's Textbook of Medicine. New York: McGraw Hill, 2009. [2] Josephson, Mark E. Clinical Cardiac Electrophysiology: Techniques and Interpretations, Fourth Edition. Philadelphia: Lippincott Williams and Wilkins, 2008.
External links
Cardiac Electrophysiology Society (http://www.cardiaceps.org/) Indian Heart Rhythm Society (http://www.ihrs.in/) Heart Rhythm Society (http://www.hrsonline.org/) Indian Pacing and Electrophysiology Journal (http://www.ipej.org/) International Winter Arrhythmia School (http://www.winterarrhythmia.com/) ECAS - European Cardiac Arrhythmia Society (http://www.ecas-congress.org/)
Anatomy and Physiology

Electrical conduction system of the heart
Isolated conduction system of the heart
Heart; conduction system 1. Sinoatrial node 2. Atrioventricular node 3. Bundle of His 4. Left bundle branch 5. left anterior fascicle Latin 6. left posterior fascicle 7. Left ventricle 8. Ventricular septum 9. Right ventricle 10. Right bundle branch
systema conducens cordis
The normal intrinsic electrical conduction of the heart allows electrical propagation to be transmitted from the Sinoatrial Node through both atria and forward to the Atrioventricular Node. Normal/baseline physiology allows further propagation from the AV node to the ventricle or Purkinje Fibers and respective bundle branches and subdivisions/fascicles. Both the SA and AV nodes stimulate the Myocardium. Time ordered stimulation of the myocardium allows efficient contraction of all four chambers of the heart, thereby allowing selective blood perfusion through both the lungs and systemic circulation.
Electrochemical mechanism
Cardiac neurons innervating the myocardium bear limited similarities to those of skeletal muscle as well as other important differences. Cardiac neurons are uniquely subject to influence by the sympathetic and parasympathetic influence of the autonomic nervous system unlike skeletal muscle.
Principle of ECG formation. Note that the red lines represent the depolarization wave, not blood flow.
Like a neuron, a given myocardial cell has a negative membrane potential when at rest. Stimulation above a threshold value induces the opening of voltage-gated ion channels with inducted flow of cations into the cell. The positively charged ions entering the cell cause the depolarization characteristic of an action potential. After depolarization, there's a brief repolarization that takes place with the eflux of potassium through fast acting potassium channels. Like skeletal muscle, depolarization causes the opening of voltage-gated calcium channels meanwhile potassium channels have closed - and are followed by a titrated release of Ca2+ from the t-tubules. This influx of calcium causes calcium-induced calcium release from the sarcoplasmic reticulum, and free Ca2+ causes muscle contraction. After a delay, slow acting Potassium channels reopen and the resulting flow of K+ out of the cell causes repolarization to the resting state. Note that there are important physiological differences between nodal cells and ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells, most importantly the spontaneous depolarizations necessary for the SA node pacemaker activity.
Conduction pathway
Action potentials arising in the SA node (and propagating to the left atrium via Bachmann's bundle) cause the atria to contract. In parallel, action potentials travel to the AV node via internodal pathways. After a delay, the stimulus is conducted through the bundle of His to the bundle branches and then to the purkinje fibers and the endocardium at the apex of the heart, then finally to the ventricular myocardium. The pathway of the nerve impulse pass through the heart muscles is ; SA node-> internodal pathway->transitional fibers->AV node->penetrating fibers->distal fibers->Bundle of his/AV bundle->right &left bundle branches->Purkinji fibers. the total time taken by the nerve impulse pass from SA node to the ventricular myocardium is 0.19 seconds. Microscopically, the wave of depolarization propagates to adjacent cells via gap junctions located on the intercalated disk. The heart is a functional syncytium (not to be confused with a true "syncytium" in which all the cells are fused together, sharing the same plasma membrane as in skeletal muscle). In a functional syncytium, electrical impulses propagate freely between communicating cells via gap junctions, so that the myocardium functions as a single contractile unit. This property allows rapid, synchronous depolarization of the myocardium. While normally
Electrical conduction system of the heart advantageous, this property can be detrimental as it potentially allows the propagation of incorrect electrical signals (e.g., via an ectopic pacemaker). Gap junctions can close, e.g., after a cardiac ischemic event such as myocardial infarction, thus isolating damaged or dying tissue in the myocardium, which then no longer participate in synchronous myocardial contractility.
Depolarization and the ECG

SA node: P wave
Under normal conditions, electrical activity is spontaneously generated by the SA node, the physiological pacemaker. This electrical impulse is propagated throughout the right atrium, and through Bachmann's bundle to the left atrium, stimulating the myocardium of both atria to contract. The conduction of the electrical impulse throughout the left and right atria is seen on the ECG as the P wave. As the electrical activity is spreading throughout the atria, it travels via specialized pathways, known as internodal tracts, from the SA node to the AV node.
Schematic diagram of normal sinus rhythm for a human heart as seen on ECG
AV node/Bundles: PR interval
The AV node functions as a critical delay in the conduction system. Without this delay, the atria and ventricles would contract at the same time, and blood wouldn't flow effectively from the atria to the ventricles. The delay in the AV node forms much of the PR segment on the ECG. Part of atrial repolarization can be represented by the PR segment. The distal portion of the AV node is known as the bundle of His. The bundle of His splits into two branches in the interventricular septum, the left bundle branch and the right bundle branch. The left bundle branch activates the left ventricle, while the right bundle branch activates the right ventricle. The left bundle branch is short, splitting into the left anterior fascicle and the left posterior fascicle. The left posterior fascicle is relatively short and broad, with dual blood supply, making it particularly resistant to ischemic damage. The left posterior fascicle transmits impulses to the papillary muscles, leading to mitral valve closure. As the left posterior fascicle is shorter and broader than the right, impulses reach the erection muscles just prior to depolarization, and therefore contraction, of the left ventricle myocardium. This allows pre-ejaculating
Electrical conduction system of the heart of the chordae tendinae, increasing the resistance to flow through the mitral valve during left ventricular contraction.
Purkinje fibers/ventricular myocardium: QRS complex

The two bundle branches taper out to produce numerous purkinje fibers, which stimulate individual groups of myocardial cells to contract. The spread of electrical activity (depolarization) through the ventricular myocardium produces the QRS complex on the ECG.
Ventricular repolarization: T wave

The last event of the cycle is the repolarization of the ventricles. The transthoracically measured PQRS portion of an electrocardiogram is chiefly influenced by the sympathetic nervous system. The T (and occasionally U) waves are chiefly influenced by the parasympathetic nervous system guided by integrated brainstem control from the vagus nerve and the thoracic spinal accessory ganglia. An impulse (action potential) that originates from the SA node at a relative rate of 60 - 100bpm is known as normal sinus rhythm. If SA nodal impulses occur at a rate less than 60bpm, the heart rhythm is known as bradycardiac sinus. If it occurs with a rate greater than 100bpm, it is called tachycardiac sinus.
Cardiac action potential

In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart.[1] The cardiac action potential differs significantly in different portions of the heart. This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized conduction tissue of the heart has the special property of depolarizing without any external influence. This is known as cardiac muscle automaticity. The electrical activity of the specialized conduction tissues are not apparent on the surface electrocardiogram (ECG or EKG - From German word). This is due to the relatively small mass of these tissues compared to the myocardium.
Overview
Ions transported through the transmembrane ion channels generate action potential. Rate dependence of action potential repolarization is a fundamental property of cardiac cells, and its modification by disease or drugs can bring about fatal arrhythmias.
Intra- and extracellular ion concentrations (mmol/L)

Element Sodium Potassium Chloride Calcium Na+ K+ ClCa2+ Ion Extracellular 135 - 145 3.5 - 5.0 95 - 110 2 10 155 10 - 20 104 Intracellular 14:1 1:30 4:1 2 x 104:1 Ratio
Although intracellular Ca2+ content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).
Cardiac action potential Cardiac muscle has some similarities to skeletal muscle, as well as important unique properties. Like skeletal myocytes (and axons for that matter), a given cardiac myocyte has a negative membrane potential when at rest. A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca2+ to induce contraction. When skeletal muscle is stimulated by somatic motor axons, influx of Na+ quickly depolarizes the skeletal myocyte and triggers calcium release from the sarcoplasmic reticulum. In cardiac myocytes, the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into the cell through voltage-gated calcium channels on the sarcolemma. This phenomenon is called calcium-induced calcium release and increases the myoplasmic free Ca2+ concentration causing muscle contraction. In both muscle types, after a delay (the absolute refractory period), potassium channels reopen and the resulting flow of K+ out of the cell causes repolarization to the resting state. The voltage-gated calcium channels in the cardiac sarcolemma are generally triggered by an influx in sodium during the "0" phase of the action potential (see below). Note that there are important physiological differences between nodal cells and ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells, most importantly the spontaneous depolarizations (cardiac muscle automaticity) necessary for the SA node's pacemaker activity.
Major currents
Major currents during the cardiac ventricular action potential
Ion Na+ Ca2+ K+ K+ K+ K+ Current (I) INa ICa(L) Ito1 IKs IKr IK1 subunit protein NaV1.5 CaV1.2 KV4.2/4.3 KV7.1 KV11.1 (hERG) Kir2.1/2.2/2.3 3Na+-1Ca2+-exchanger 3Na+-2K+-ATPase subunit gene SCN5A CACNA1C KCND2/KCND3 KCNQ1 KCNH2 0 0-2 1, notch 2,3 3 Phase / role
KCNJ2/KCNJ12/KCNJ4 3,4 NCX1 (SLC8A1) ATP1A ion homeostasis ion homeostasis ion homeostasis
Na+, Ca2+ INaCa Na+, K+ Ca2+ INaK IpCa
Ca2+-transporting ATPase ATP1B
Calcium channels
Two voltage-dependent calcium channels play critical roles in the physiology of cardiac muscle: L-type calcium channel ('L' for Long-lasting) and T-type calcium channels ('T' for Transient) voltage-gated calcium channels. These channels respond differently to voltage changes across the membrane: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels. Because of these properties, L-type channels are important in sustaining an action potential, while T-type channels are important in initiating them. Because of their rapid kinetics, T-type channels are commonly found in cells undergoing rhythmic electrical behavior. For example, T-type channels are commonly found in some neuron cell bodies involved in rhythmic activity such as walking and breathing. These T-type calcium channels are also found in pacemaker cells (i.e.
Cardiac action potential sinoatrial node and atrioventricular node) of the heart which control the heart beat. L-type channels are the targets of a class of drugs called dihydropyridines which block the currents produced by these channels.
Resting membrane potential

The resting membrane potential is caused by the difference in ionic concentrations and conductances across the membrane of the cell during phase 4 of the action potential. The normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV. This potential is determined by the selective permeability of the cell membrane to various ions. The membrane is most permeable to K+ and relatively impermeable to other ions. The resting membrane potential is therefore dominated by the K+ equilibrium potential according to the K+ gradient across the cell membrane. The membrane potential can be calculated using the Goldman-Hodgkin-Katz voltage equation. The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na+-K+ ion exchange pump, the Na+-Ca2+ exchanger current and the IK1 inwardly rectifying K+ current. I is the symbol for an electric current. Intracellularly (within the cell), K+ is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Extracellularly (outside the cell), Na+ and Cl- predominate.
Phases of the cardiac action potential

The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte. The action potential has 5 phases (numbered 0-4). Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated. Once the cell is electrically stimulated (typically by an electric current from an adjacent cell), it begins a sequence of actions involving the influx and efflux of multiple cations and anions that together produce the action potential of the cell, propagating the The cardiac action potential has five phases. electrical stimulation to the cells that lie adjacent to it. In this fashion, an electrical stimulation is conducted from one cell to all the cells that are adjacent to it, to all the cells of the heart.
Phase 4
Phase 4 is the resting membrane potential. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with diastole of the chamber of the heart. In addition to stimulus from adjacent cells, certain cells of the heart have the ability to undergo spontaneous depolarization, in which an action potential is generated without any influence from nearby cells. This is known as cardiac muscle automaticity.
Phase 0 ZIN
Phase 0 is the rapid depolarization phase. The slope of phase 0 represents the maximum rate of depolarization of the cell and is known as dV/dtmax. This phase is due to the opening of the fast Na+ channels causing a rapid increase in the membrane conductance to Na+ (GNa) and thus a rapid influx of Na+ ions (INa) into the cell; a Na+ current. The ability of the cell to open the fast Na+ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na+ channels are closed, and excitation will open them all, causing a large influx of Na+ ions. If, however, the membrane potential is less negative, some of the fast Na+ channels will be in an inactivated state insensitive to opening, thus causing a lesser response to excitation of the cell membrane and a lower Vmax. For this reason, if the resting membrane potential becomes too positive, the cell may not be excitable, and conduction through the heart may be delayed, increasing the risk for arrhythmias. The fast Na+ channel The fast sodium channel can be modeled as being controlled by a number of gates. Each gate (or gating variable) can attain a value between 1 (fully open) and 0 (fully closed). The product of all the gates denotes the percentage of channels available to conduct Na+. Following the model of Hodgkin and Huxley, the sodium channel contains three gates: m, h, and j. In the resting state, the m gate is closed (zero) and the h and j gates are open (one). Hence, the product denoting the percentage of conducting channels is also zero. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h and j gates close more slowly. For a brief period of time, all gates are open (i.e. non-zero) and Na+ can enter the cell following its electrochemical gradient. If, as above, the resting membrane potential is too positive, the h or j gates may be considerably less than one, such that the product of m, h and j becomes too small upon depolarization.
Phase 1
Phase 1 of the action potential occurs with the inactivation of the fast Na+ channels. The transient net outward current causing the small downward deflection of the action potential is due to the movement of K+ and Cl- ions, carried by the Ito1 and Ito2 currents, respectively. Particularly the Ito1 contributes to the "notch" of some ventricular cardiomyocyte action potentials. It has been suggested that Cl- ions movement across the cell membrane during Phase I is as a result of the change in membrane potential, from K+ efflux, and is not a contributory factor to the initial repolarization ("notch").
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Phase 2
This "plateau" phase of the cardiac action potential is sustained by a balance between inward movement of Ca2+ (ICa) through L-type calcium channels and outward movement of K+ through the slow delayed rectifier potassium channels, IKs. The sodium-calcium exchanger current, INa,Ca and the sodium/potassium pump current, INa,K also play minor roles during phase 2.
Phase 3
During phase 3 (the "rapid repolarization" phase) of the action potential, the L-type Ca2+ channels close, while the slow delayed rectifier (IKs) K+ channels are still open. This ensures a net outward current, corresponding to negative change in membrane potential, thus allowing more types of K+ channels to open. These are primarily the rapid delayed rectifier K+ channels (IKr) and the inwardly rectifying K+ current, IK1. This net outward, positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K+ channels close when the membrane potential is restored to about -80 to -85 mV, while IK1 remains conducting throughout phase 4, contributing to set the resting membrane potential.
Automaticity
In the myocardium, automaticity is the ability of the cardiac muscles to depolarize spontaneously, i.e. without external electrical stimulation from the nervous system. This spontaneous depolarization is due to the plasma membranes within the heart that have reduced permeability to potassium (K+) but still allow passive transfer of calcium ions, allowing a net charge to build. Automaticity is most often demonstrated in the sinoatrial node (SA node), the so called "Pacemaker of the Heart." Abnormalities in automaticity may result in rhythm changes.
Location
The cells that can undergo spontaneous depolarization the fastest are the primary pacemaker cells of the heart, and set the heart rate. Usually, these are cells in the SA node of the heart. Electrical activity that originates from the SA node is propagated to the rest of the heart. The fastest conduction of electrical activity is via the electrical conduction system of the heart.
Channels
The mechanism of automaticity involves the so-called pacemaker channels of the HCN family, Hyperpolarization-activated, Cyclic Nucleotide-gated channels (see Funny current). These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium ions. The activity of these channels in the SA node cells causes the membrane potential to slowly become more positive (depolarize). These "Funny" channels are responsible for the initial phase of the
Cardiac action potential "prepotential". The latter phase is due to the opening of "T" or "Transient" calcium channels. This further depolarizes the cell until, eventually, the "L" or "Long Lasting" calcium channels are activated and an action potential is initiated.
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Abnormal automaticity
The normal activity of the pacemaker cells of the heart is to spontaneously depolarize at a regular rhythm, generating the normal heart rate. Abnormal automaticity involves the abnormal spontaneous depolarization of cells of the heart. This typically causes arrhythmias (abnormal rhythms) in the heart. In cases of heart block, in which the activity of the primary pacemaker does not propagate to the rest of the heart, a latent pacemaker (also known as an escape pacemaker) will undergo spontaneous depolarization and create an action potential.
Regulation by the autonomic nervous system

The rate of depolarization and duration of the action potential in pacemaker cells is regulated by the parasympathetic and sympathetic fibres of the autonomic nervous system in addition to circulating catecholamines. Acetylcholine (ACh) binds to M2 (muscarinic) receptors and, via the subunit of a G protein, open a special set of potassium channels. The resulting increase in potassium efflux slows the depolarizing effect of the funny channels. In addition, activation of M2 receptors decreases cAMP in the cells and this slows the opening of the calcium "L" channels. The result is a decrease in the firing rate. Conversely, sympathetic stimulation via 1 receptors results in an increase in cAMP levels which facilitates the opening of calcium channels thereby increasing the rate of depolarization.
References
[1] Klabunde, R.E. (2005). "Electrical activity of the heart". Cardiovascular physiology concepts . Lippincott Williams & Wilkins. ISBN0-7817-5030-X.
2. Yoram Rudy (2008). "Control and Regulation of Transport Phenomena in the Cardiac System": Molecular Basis of Cardiac Action Potential Repolarization (1123): 113-118.
External links
Interactive animation (http://thevirtualheart.org/CAPindex.html) illustrating the generation of a cardiac action potential. Interactive mathematical models (http://thevirtualheart.org/APindex.html) of cardiac action potential and other generic action potentials.
Cardiac muscle
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Cardiac muscle
Cardiac muscle
Cardiac muscle
Dog Cardiac Muscle 400X Latin textus muscularis striatus cardiacus
Code TH H2.00.05.2.02001 [1]
Cardiac muscle (heart muscle) is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle. The cells that comprise cardiac muscle, called myocardiocyteal muscle cells, can be mononuclear or binuclear.[2] [3] [4] Coordinated contractions of cardiac muscle cells in the heart propel blood out of the atria and ventricles to the blood vessels of the left/body/systemic and right/lungs/pulmonary circulatory systems. This complex of actions makes up the systole of the heart. Cardiac muscle cells, like all tissues in the body, rely on an ample blood supply to deliver oxygen and nutrients and to remove waste products such as carbon dioxide. The coronary arteries fulfill this function.
Metabolism
Cardiac muscle is adapted to be highly resistant to fatigue: it has a large number of mitochondria, enabling continuous aerobic respiration via oxidative phosphorylation, numerous myoglobins (oxygen-storing pigment) and a good blood supply, which provides nutrients and oxygen. The heart is so tuned to aerobic metabolism that it is unable to pump sufficiently in ischaemic conditions. At basal metabolic rates, about 1% of energy is derived from anaerobic metabolism. This can increase to 10% under moderately hypoxic conditions, but, under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contractions.[5] Under basal aerobic conditions, 60% of energy comes from fat (free fatty acids and triglycerides), 35% from carbohydrates, and 5% from amino acids and ketone bodies. However, these proportions vary widely according to nutritional state. For example, during starvation, lactate can be recycled by the heart. This is very energy efficient, because one NAD+ is reduced to NADH and H+ (equal to 2.5 or 3 ATP) when lactate is oxidized to pyruvate, which can then be burned aerobically in the TCA cycle, liberating much more energy (ca 14 ATP per cycle).
Cardiac muscle In the condition of diabetes, more fat and less carbohydrate is used due to the reduced induction of GLUT4 glucose transporters to the cell surfaces. However, contraction itself plays a part in bringing GLUT4 transporters to the surface.[6] This is true of skeletal muscle as well, but relevant in particular to cardiac muscle due to its continuous contractions.
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Appearance
Striation
Cardiac muscle exhibits cross striations formed by alternating segments of thick and thin protein filaments. Like skeletal muscle, the primary structural proteins of cardiac muscle are actin and myosin. The actin filaments are thin causing the lighter appearance of the I bands in striated muscle, while the myosin filament is thicker lending a darker appearance to the alternating A bands as observed with electron microscopy. However, in contrast to skeletal muscle, cardiac muscle cells may be branched instead of linear and longitudinal.
T-Tubules
Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are larger, broader and run along the Z-Discs. There are fewer T-tubules in comparison with skeletal muscle. Additionally, cardiac muscle forms diads instead of the triads formed between the T-tubules and the sarcoplasmic reticulum in skeletal muscle. T-tubules play critical role in excitation-contraction coupling (ECC). Recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al.[7]
Intercalated discs
Intercalated discs (IDs) are complex adhering structures which connect single cardiac myocytes to an electrochemical syncytium (in contrast to the skeletal muscle, which becomes a multicellular syncytium during mammalian embryonic development) and are mainly responsible for force transmission during muscle contraction. Intercalated discs also support the rapid spread of action potentials and the synchronized contraction of the myocardium. IDs are described to consist of three different types of cell-cell junctions: the actin filament anchoring adherens junctions (fascia adherens), the intermediate filament anchoring desmosomes (macula adherens) and gap junctions. Gap junctions are responsible for electrochemical and metabolic coupling. They allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle. However, novel molecular biological and comprehensive studies unequivocally showed that IDs consist for the most part of mixed type adhering junctions named area composita (pl. areae compositae) representing an amalgamation of typical desmosomal and fascia adhaerens proteins (in contrast to various epithelia).[8] [9] [10] The authors discuss the high importance of these findings for the understanding of inherited cardiomyopathies (such as Arrhythmogenic Right Ventricular Cardiomyopathy, ARVC). Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells. The intercalated discs run perpendicular to the direction of muscle fibers. Under electron microscopy, an intercalated disc's path appears more complex. At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line. At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section.[11]
Cardiac muscle
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Role of calcium in contraction

In contrast to skeletal muscle, cardiac muscle requires extracellular calcium ions for contraction to occur. Like skeletal muscle, the initiation and upshoot of the action potential in ventricular muscle cells is derived from the entry of sodium ions across the sarcolemma in a regenerative process. However, an inward flux of extracellular calcium ions through L-type calcium channels sustains the depolarization of cardiac muscle cells for a longer duration. The reason for the calcium dependence is due to the mechanism of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum that must occur under normal excitation-contraction (EC) coupling to cause contraction. Once the intracellular concentration of calcium increases, calcium ions bind to the protein troponin, which initiate extracellular fluid and intracellular stores, and skeletal muscle, which is only activated by calcium stored in the sarcoplasmic reticulum.
Regeneration of heart muscle cells

Until recently, it was commonly believed that cardiac muscle cells could not be regenerated. However, a study reported in the April 3, 2009 issue of Science contradicts that belief.[12] Olaf Bergmann and his colleagues at the Karolinska Institute in Stockholm tested samples of heart muscle from people born before 1955 when nuclear bomb testing caused elevated levels of radioactive carbon 14 in the Earth's atmosphere. They found that samples from people born before 1955 did have elevated carbon 14 in their heart muscle cell DNA, indicating that the cells had divided after the person's birth. By using DNA samples from many hearts, the researchers estimated that a 20-year-old renews about 1% of heart muscle cells per year and about 45 percent of the heart muscle cells of a 50-year-old were generated after he or she was born.
References
[1] [2] [3] [4] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh200. html Pollard, Thomas D. and Earnshaw, William. C., "Cell Biology". Philadelphia: Saunders. 2007. http:/ / www. courseweb. uottawa. ca/ medicine-histology/ english/ ss_basictissues/ muscle_tissue. htm University of Guelph Developmental Biology ONLINE! web site (retrieved 2010-05-04) http:/ / www. uoguelph. ca/ zoology/ devobio/ 210labs/ muscle1. html [5] Ganong, Review of Medical Physiology, 22nd Edition.Specialized form of muscle that is peculiar to the vertebrate heart.p81 [6] S Lund, GD Holman, O Schmitz, and O Pedersen. Contraction Stimulates Translocation of Glucose Transporter GLUT4 in Skeletal Muscle Through a Mechanism Distinct from that of Insulin. PNAS 92: 5817-5821. [7] Guixue Bu, et al. Uniform action potential repolarization within the sarcolemma of in situ ventricular cardiomyocytes. Biophysical Journal, Vol.96, No.6, March 2009, pp.2532-2546. [8] Franke, W. W., Borrmann, C. M., Grund, C. and Pieperhoff, S. (2006). The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins. Eur J Cell Biol 85, 69-82. [9] Goossens, S., Janssens, B., Bonne, S., De Rycke, R., Braet, F., van Hengel, J. and van Roy, F. (2007). A unique and specific interaction between alphaT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs. J Cell Sci 120, 2126-36 [10] Pieperhoff, S., Barth, M., Rickelt, S. and Franke, W. W. (2010). Desmosomal molecules in and out of adhering junctions: normal and diseased states of epidermal, cardiac and mesenchymally derived cells. In Desmosomes and desmosomal cadherin function in skin and heart diseases advancements in basic and clinical research, (eds M. G. Mahoney E. J. Mller and P. J. Koch): Hindawi. [11] Histology at BU 22501loa (http:/ / www. bu. edu/ histology/ p/ 22501loa. htm) [12] Evidence for cardiomyocyte renewal in humans. PMID 19342590
Cardiac muscle
15
External links
Indiana State University, Muscle action (http://web.indstate.edu/thcme/mwking/muscle.html) Physiology at MCG 2/2ch7/2ch7line (http://www.lib.mcg.edu/edu/eshuphysio/program/section2/2ch7/ 2ch7line.htm)
Vagus nerve
16
Vagus nerve
Nerve: Vagus nerve
Plan of upper portions of glossopharyngeal, vagus, and accessory nerves.
Course and distribution of the glossopharyngeal, vagus, and accessory nerves. Latin Gray's Innervates MeSH nervus vagus subject #205 910
[1]
Levator veli palatini, Salpingopharyngeus, Palatoglossus, Palatopharyngeus, Superior pharyngeal constrictor, Middle pharyngeal constrictor, Inferior pharyngeal constrictor, viscera Vagus+Nerve
[2]
Cranial Nerves
CN I Olfactory CN II Optic CN III Oculomotor CN IV Trochlear CN V Trigeminal CN VI Abducens CN VII Facial CN VIII Vestibulocochlear CN IX Glossopharyngeal CN X Vagus
Vagus nerve
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CN XI Spinal Accessory CN XII Hypoglossal
The vagus nerve ( /ves/ USdict:vgs), also called pneumogastric nerve or cranial nerve X, is the tenth of twelve (excluding CN0) paired cranial nerves. Upon leaving the medulla between the olivary nucleus and the inferior cerebellar peduncle, it extends through the jugular foramen, then passing into the carotid sheath between the internal carotid artery and the internal jugular vein down below the head, to the neck, chest and abdomen, where it contributes to the innervation of the viscera. Besides output to the various organs in the body, the vagus nerve conveys sensory information about the state of the body's organs to the central nervous system. 80-90% of the nerve fibers in the vagus nerve are afferent (sensory) nerves communicating the state of the viscera to the brain.[3] The medieval Latin word vagus means literally "Wandering" (the words vagrant, vagabond, and vague come from the same root). Sometimes the branches are spoken of in the plural and are thus called vagi (/veda/, USdict:vj). The vagus is also called the pneumogastric nerve since it innervates both the lungs and the stomach. The motor division of the vagus nerve is derived from the basal plate of the embryonic medulla oblongata, while the sensory division originates from the cranial neural crest. The vagus nerve includes axons which emerge from or converge onto three nuclei of the medulla: 1. The Dorsal nucleus of vagus nerve - which sends parasympathetic output to the viscera esp intestines 2. The Nucleus ambiguus - which which sends parasympathetic output to the heart (slowing it down) and 3. The Solitary nucleus - which receives afferent taste information and primary afferents from visceral organs
Branches
Auricular nerve Pharyngeal nerve Superior laryngeal nerve Superior cervical cardiac branches of vagus nerve Inferior cervical cardiac branch Recurrent laryngeal nerve Thoracic cardiac branches Branches to the pulmonary plexus Branches to the esophageal plexus Anterior vagal trunk Posterior vagal trunk Hering-Breuer reflex in alveoli
The vagus runs posterior to the common carotid artery and internal jugular vein inside the carotid sheath.
Vagus nerve
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Innervation
Right and left vagus nerves descend from the cranial vault through the jugular foramena, penetrating the carotid sheath between the internal and external carotid arteries, then passing posterolateral to the common carotid artery. The cell bodies of visceral afferent fibers of the vagus nerve are located bilaterally in the inferior ganglion of the vagus nerve (nodose ganglia). The right vagus nerve gives rise to the right recurrent laryngeal nerve, which hooks around the right subclavian artery and ascends into the neck between the trachea and esophagus. The right vagus then crosses anteriorly to the right subclavian artery and runs posterior to the superior vena cava and descends posterior to the right main bronchus and contributes to cardiac, pulmonary, and esophageal plexuses. It forms the posterior vagal trunk at the lower part of the esophagus and enters the diaphragm through the esophageal hiatus. The left vagus nerve enters the thorax between left common carotid Vagus nerve - dissection artery and left subclavian artery and descends on the aortic arch. It gives rise to the left recurrent laryngeal nerve, which hooks around the aortic arch to the left of the ligamentum arteriosum and ascends between the trachea and esophagus. The left vagus further gives off thoracic cardiac branches, breaks up into pulmonary plexus, continues into the esophageal plexus, and enters the abdomen as the anterior vagal trunk in the esophageal hiatus of the diaphragm. The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, notable ones being: Cricothyroid muscle Levator veli palatini muscle Salpingopharyngeus muscle Palatoglossus muscle Palatopharyngeus muscle Superior, middle and inferior pharyngeal constrictors Muscles of the larynx (speech).
This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve) and keeping the larynx open for breathing (via action of the posterior cricoarytenoid muscle, the only abductor of the vocal folds). It also has some afferent fibers that innervate the inner (canal) portion of the outer ear, via the Auricular branch (also known as Alderman's nerve) and part of the meninges. This explains why a person may cough when tickled on the ear (such as when trying to remove ear wax with a cotton swab).
Vagus nerve
19
Vagus nerve
The vagus nerve and the heart

Parasympathetic innervation of the heart is controlled by the vagus nerve. To be specific, the vagus nerve acts to lower the heart rate. The right vagus innervates the sinoatrial node. Parasympathetic hyperstimulation predisposes those affected to bradyarrhythmias. The left vagus when hyperstimulated predisposes the heart to atrioventricular (AV) blocks. At this location, neuroscientist Otto Loewi first proved that nerves secrete substances called neurotransmitters, which have effects on receptors in target tissues. In his experiment, Loewi electrically Fibres of the vagus nerve (right/bottom of image) innervate the sinoatrial node tissue (central and left of stimulated the vagus nerve of a frog heart, which slowed the heart. image). H&E stain. Then he took the fluid from the heart and transferred it to a second frog heart without a vagus nerve. The second heart slowed down without an electrical stimulation. Loewi described the substance released by the vagus nerve as vagusstoff, which was later found to be acetylcholine. Drugs that inhibit the muscarinic cholinergic receptor (anticholinergics) such as atropine and scopolamine are called vagolytic because they inhibit the action of the vagus nerve on the heart, gastrointestinal tract, and other organs. Anticholinergic drugs increase heart rate and are used to treat bradycardia (slow heart rate) and asystole, which is when the heart has no electrical activity.
Vagus nerve
20
Medical treatment involving the vagus nerve

Vagus nerve stimulation (VNS) therapy using a pacemaker-like device implanted in the chest is a treatment used since 1997 to control seizures in epilepsy patients and has recently been approved for treating drug-resistant cases of clinical depression.[4] A non-invasive VNS device that stimulates an afferent branch of the vagus nerve is also being developed and will soon undergo trials. Clinical trials are currently underway in Antwerp, Belgium using VNS for the treatment of tonal tinnitus after a breakthrough study published in early 2011 by researchers at the University of Texas - Dallas showed successful tinnitus suppression in rats when tones were paired with brief pulses of stimulation of the vagus nerve. [5] VNS may also be achieved by one of the vagal maneuvers: holding the breath for a few seconds, dipping the face in cold water, coughing, or tensing the stomach muscles as if to bear down to have a bowel movement.[6] Patients with supraventricular tachycardia,[6] atrial fibrillation, and other illnesses may be trained to perform vagal maneuvers (or find one or more on their own). Vagus nerve blocking (VBLOC) therapy is similar to VNS but used only during the day. In a six-month open-label trial involving three medical centers in Australia, Mexico, and Norway, vagus nerve blocking has helped 31 obese participants lose an average of nearly 15 percent of their excess weight. A year-long 300-participant double-blind, phase II trial has begun.[7] Vagotomy (cutting of the vagus nerve) is a now-obsolete therapy that was performed for peptic ulcer disease. Vagotomy is currently being researched as a less invasive alternative weight-loss procedure to gastric bypass surgery.[8] The procedure curbs the feeling of hunger and is sometimes performed in conjunction with putting bands on patients' stomachs, resulting in average weight loss of 43% at six months with diet and exercise.[9] One serious side-effect of a Vagotomy is a Vitamin B-12 deficiency later in life - i.e., 10 years - that is similar to pernicious anemia. As one gets older, the stomach produces less acid. The acid, and one of its components called Intrinsic Factor, is needed to metabolize B-12 from food. The vagotomy reduces the acid that ultimately leads to the deficiency, which, if left untreated, causes nerve damage, tiredness, dementia, paranoia, and ultimately death.[10]
Physical and emotional effects

Activation of the vagus nerve typically leads to a reduction in heart rate, blood pressure, or both. This occurs commonly in the setting of gastrointestinal illness such as viral gastroenteritis or acute cholecystitis, or in response to other stimuli, including carotid sinus massage, Valsalva maneuver, or pain from any cause, in particular, having blood drawn. When the circulatory changes are great enough, vasovagal syncope results. Relative dehydration tends to amplify these responses. Excessive activation of the vagal nerve during emotional stress, which is a parasympathetic overcompensation of a strong sympathetic nervous system response associated with stress, can also cause vasovagal syncope because of a sudden drop in blood pressure and heart rate. Vasovagal syncope affects young children and women more than other groups. It can also lead to temporary loss of bladder control under moments of extreme fear. Research has shown that women having had complete spinal cord injury can experience orgasms through the vagus nerve, which can go from the uterus, cervix, and, it is presumed, the vagina to the brain.[11] [12] Liver - Insulin signaling activates the adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in the Arcuate nucleus, decreases AgRP release, and through the vagus nerve, leads to decreased glucose production by the liver by decreasing gluconeogenic enzymes : Phosphoenolpyruvate carboxykinase, Glucose 6-phosphatase)[13] [14]
Vagus nerve
21
Effects of vagus nerve lesions

The patient complains of hoarse voice, difficulty in swallowing (dysphagia), and choking when drinking fluid. There is also loss of gag reflex. Uvula deviates away from the side of lesion, and there is failure of palate elevation.
Additional images
Section of the neck at about the level of the sixth cervical vertebra
Transverse section of thorax, showing relations of pulmonary artery
The arch of the aorta, and its branches
Dura mater and its processes exposed by removing part of the right half of the skull, and the brain
The tracheobronchial lymph glands
Section of the medulla oblongata at about the middle of the olive
Hind- and mid-brains; postero-lateral view
Upper part of medulla spinalis and hind- and mid-brains; posterior aspect, exposed in situ
The right sympathetic chain and its connections with the thoracic, abdominal, and pelvic plexuses
The celiac ganglia with the sympathetic plexuses of the abdominal viscera radiating from the ganglia
The position and relation of the esophagus in the cervical region and in the posterior mediastinum, seen from behind
Vagus nerve
22
The thyroid gland and its relations
The thymus of a full-term fetus, exposed in situ
References
[1] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=205#p910 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Vagus+ Nerve [3] Functional and chemical anatomy of the afferent vagal system. Berthoud HR and Neuhuber WL (http:/ / www. sciencedirect. com/ science?_ob=ArticleURL& _udi=B6VT5-41TN409-2& _user=10& _coverDate=12/ 20/ 2000& _rdoc=2& _fmt=high& _orig=browse& _srch=doc-info(#toc#6281#2000#999149998#220094#FLA#display#Volume)& _cdi=6281& _sort=d& _docanchor=& view=c& _ct=23& _acct=C000050221& _version=1& _urlVersion=0& _userid=10& md5=540993eae7f65c7a08bcabc6693627c1) [4] Nemeroff C, Mayberg H, Krahl S, McNamara J, Frazer A, Henry T, George M, Charney D, Brannan S (2006). "VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms.". Neuropsychopharmacology 31 (7): 134555. doi:10.1038/sj.npp.1301082. PMID16641939. link (http:/ / www. nature. com/ npp/ journal/ v31/ n7/ abs/ 1301082a. html) [5] http:/ / www. utdallas. edu/ news/ 2011/ 1/ 13-8021_Findings-Show-Promise-in-Battle-Against-Tinnitus_article. html [6] Vibhuti N, Singh; Monika Gugneja (2005-08-22). "Supraventricular Tachycardia" (http:/ / www. emedicinehealth. com/ supraventricular_tachycardia/ page7_em. htm). eMedicineHealth.com. . Retrieved 2008-11-28. [7] Mayo Clinic. Device Blocking Stomach Nerve Signals Shows Promise in Obesity (http:/ / www. mayoclinic. org/ news2008-rst/ 4892. html) [8] Ulcer surgery may help treat obesity - Diet and nutrition - MSNBC.com (http:/ / www. msnbc. msn. com/ id/ 19563617/ ) [9] . http:/ / www. cnn. com/ 2007/ HEALTH/ conditions/ 07/ 09/ obesity. nerve. ap/ index. html. [10] http:/ / www. pernicious-anaemia-society. org [11] (http:/ / www. wired. com/ medtech/ health/ news/ 2007/ 01/ 72325) [12] Komisaruk, B.R, Whipple, B., Crawford, A., Grimes, S., Liu, W-C., Kalin, A., & Mosier, K. (2004). Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: MRI evidence of mediation by the Vagus nerves. (http:/ / psychology. rutgers. edu/ ~brk/ brainresearch04. pdf) [13] Pocai, A; TK Lam, Gutierrez-Juarez R (2005). "Hypothalamic K(ATP) channels control hepatic glucose production". Nature 434: 10261031. doi:10.1038/nature03439. [14] Pagotto, U. (2009). "Where does insulin resistance start? The brain.". Diabetes Care 32 (2): S174-S177.
External links
MedEd at Loyola grossanatomy/h_n/cn/cn1/cn10.htm (http://www.meddean.luc.edu/Lumen/MedEd/ grossanatomy/h_n/cn/cn1/cn10.htm) Cranial Nerves at Yale 10-1 (http://www.med.yale.edu/caim/cnerves/cn10/cn10_1.html) Human anatomy at Dartmouth figures/chapter_24/24-7.HTM (http://www.dartmouth.edu/~humananatomy/ figures/chapter_24/24-7.HTM) cranialnerves (http://mywebpages.comcast.net/wnor/cranialnerves.htm) at The Anatomy Lesson (http:// home.comcast.net/~wnor/homepage.htm) by Wesley Norman (Georgetown University) ( X (http:// mywebpages.comcast.net/wnor/X.jpg))
Sinoatrial node
23
Sinoatrial node
Sinoatrial node
Low magnification micrograph of a sinoatrial node (center-right on image) and its surrounding tissue. The SA node surrounds the (sinuatrial) nodal artery (on lumen in the image), a branch of the right coronary artery, abuts cardiac myocytes (of the right atrium) on its deep aspect (left of image) and adipose tissue on its superficial (epicardial) aspect (right of image). H&E stain.
Isolated Heart conduction system, showing SA node Latin Artery MeSH nodus sinuatrialis sinuatrial nodal artery Sinoatrial+Node
[1]
The sinoatrial node (also commonly spelled sinuatrial node, abbreviated SA node or SAN, also called the sinus node) is the impulse-generating (pacemaker) tissue located in the right atrium of the heart, and thus the generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava. These cells are modified cardiac myocytes. Though they possess some contractile filaments, they do not contract. It was first described in 1907 by Arthur Keith and Martin Flack.[2]
Role as a pacemaker
Although all of the heart's cells have the ability to generate the electrical impulses (or action potentials) that trigger cardiac contraction, the sinoatrial node normally initiates it, simply because it generates impulses slightly faster than the other areas with pacemaker potential. Cardiac myocytes, like all muscle cells, have refractory periods following contraction during which additional contractions cannot be triggered; their pacemaker potential is overridden by the sinoatrial or atrioventricular nodes. In the absence of extrinsic neural and hormonal control, cells in the sinoatrial node (SA node), situated in the upper right corner of the heart, will naturally discharge (create action potentials) at about 60-100 beats/minute.[3] Because the sinoatrial node is responsible for the rest of the heart's electrical activity, it is sometimes called the primary pacemaker. If the SA node does not function, or the impulse generated in the SA node is blocked before it travels down the electrical conduction system, a group of cells further down the heart will become the heart's pacemaker.[4] These
Sinoatrial node cells form the atrioventricular node (AV node), which is an area between the atria and ventricles, within the atrial septum. If the AV node also fails, Purkinje fibers (or known by some as the bundle of His) are capable of acting as the pacemaker. The reason Purkinje cells do not normally control the heart rate is that they generate action potentials at a lower frequency than the AV or SA nodes.
24
Histology
The sinoatrial node is submyocardial at the lateral aspect of the junction of the superior vena cava and right atrium. Its deep aspect abuts cardiac myocytes belonging to the right atrium. Its superficial aspect is covered by adipose tissue. The SA node fibres vaguely resemble cardiac myocytes; however, they are measurably thinner, more tortuous and stain less intensely (on H&E) than cardiac myocytes.
Innervation
The SA node is richly innervated by parasympathetic nervous system fibers (CN X: Vagus Nerve) and by sympathetic nervous system fibers (T1-4, Spinal Nerves). This unique anatomical arrangement makes the SA node susceptible to distinctly paired and opposed autonomic influences. Stimulation of the vagus nerves (the parasympathetic fibers) causes a decrease in the SA node rate (thereby decreasing the heart rate). Parasympathetic fibers cannot change the force of contraction, however,because they only innervate the SA node and AV node (which control heart rate only)***(NOTE: This statement is not entirely accurate. The following study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2278718/demonstrates how the parasympathetic nervous system, through the action of vagus nerve, exerts a negative inotropic effect upon the heart) Stimulation via sympathetic fibers causes an increase in the SA node rate (thereby increasing the heart rate and force of contraction). Sympathetic fibers can increase the force of contraction because in addition to innervating the SA and AV nodes, they innervate the atria and ventricles themselves.
High magnification micrograph of sinoatrial node tissue and an adjacent nerve fibre. H&E stain.
Blood supply
In the majority of individuals, the SA node receives blood from the right coronary artery, meaning that a myocardial infarction occluding it will cause ischaemia in the SA node unless there is a sufficiently good anastomosis from the left coronary artery. If not, death of the affected cells will stop the SA node from triggering the heartbeat, and pacemaker function will be manifest more distal in the cardiac system (e.g. AV node).
Sinus node dysfunction

Sinus node dysfunction describes an irregular heartbeat caused by faulty electrical signals of the heart. When the heart's sinoatrial node is defective, the hearts rhythms become abnormal either too fast, too slow, or a combination.[5]
Sinoatrial node
25
Additional images
Heart; conduction system
Schematic representation of the atrioventricular bundle
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Sinoatrial+ Node [2] Boyett MR, Dobrzynski H (June 2007). "The sinoatrial node is still setting the pace 100 years after its discovery" (http:/ / circres. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=17556667). Circ. Res. 100 (11): 15435. doi:10.1161/CIRCRESAHA.107.101101. PMID17556667. . [3] AnatomySAnode (http:/ / sprojects. mmi. mcgill. ca/ cardiophysio/ AnatomySAnode. htm) [4] (http:/ / emedicine. medscape. com/ article/ 155146-overview) [5] Sinus node dysfunction (http:/ / www. mountsinai. org/ Patient Care/ Service Areas/ Heart/ Diseases and Conditions?citype=Disease& ciid=Sinus node dysfunction) Mount Sinai Hospital, New York
External links
sinuatrial+node (http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=sinuatrial+node) at eMedicine Dictionary SUNY Figs 20:06-01 (http://ect.downstate.edu/courseware/haonline/figs/l20/200601.htm) - "The conduction system of the heart." Diagram at gru.net (http://user.gru.net/clawrence/vccl/chpt2/adlt46.gif) thoraxlesson4 (http://mywebpages.comcast.net/wnor/thoraxlesson4.htm) at The Anatomy Lesson (http:// home.comcast.net/~wnor/homepage.htm) by Wesley Norman (Georgetown University) ( thoraxheartinternalner (http://mywebpages.comcast.net/wnor/thoraxheartinternalner.jpg)) http://www.healthyheart.nhs.uk/heart_works/heart03.shtml
Bachmann's bundle
26
Bachmann's bundle
Bachmann's bundle, also known as the anterior interatrial band, is a broad band of atrial muscle that runs just behind the ascending aorta and connects the top of the right atrium with the top of the left atrium. Bachmann's bundle is, during normal sinus rhythm, the preferential path for electrical activation of the left atrium. It is therefore considered as part of the atrial conduction system of the heart.
Image showing Bachmann's bundle
Interatrial conduction
The normal cardiac rhythm originates in the sinoatrial node, which is located in the right ventricle near the superior caval vein. From there, the electrical activation spreads over the right atrium. There are at least four different locations where the activation can pass to the left atrium. Apart from Bachmann's bundle these are the anterior interatrial septum, posterior interatrial septum, and the coronary sinus.[1] . Because it originates close to the sinoatrial node and consists of long parallel fibers, Bachmann's bundle is, during sinus rhythm, the first of these connections to activate the left atrium.
Bachmann's bundle and the atrial conduction system

Besides Bachmann's bundle, the other three conduction tracts that constitute the atrial conduction system are known as the anterior, middle, and posterior tracts, which run from the sinoatrial node to the atrioventricular node, converging in the region near the coronary sinus. Atrial automaticity foci are within the atrial conduction system. The concentration of converging conduction tracts near the coronary sinus results in considerable automaticity activity originating in that area.
References
[1] Sakamoto, S-I, et al. (2005). "Interatrial Electrical Connections: The Precise Location and Preferential Conduction". Journal of Cardiovascular Electrophysiology 16: 10771086. doi:10.1111/j.1540-8167.2005.40659.x.
Atrioventricular node
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Isolated Heart conduction system showing AV node
Heart; conduction system Latin Artery nodus atrioventricularis atrioventricular nodal branch
The atrioventricular node (abbreviated AV node) is a part of the electrical control system of the heart that coordinates heart rate. It electrically connects atrial and ventricular chambers.[1] The AV node is an area of specialized tissue between the atria and the ventricles of the heart, specifically in the posteroinferior region of the interatrial septum near the opening of the coronary sinus, which conducts the normal electrical impulse from the atria to the ventricles. The AV node is quite compact (~1 x 3 x 5mm).[2] It is located at the center of Koch's Trianglea triangle enclosed by the septal leaflet of the tricuspid valve, the coronary sinus, and the membraneous part of the interatrial septum.[3] The AV node may also be (rarely) referred to as the Aschoff-Tawara node named so after Ludwig Aschoff and Sunao Tawara.[4]
Function
Contraction of myocytes (heart muscle cells) requires depolarization and repolarization of their cell membranes. Movement of ions across cell membranes causes these events. The cardiac conduction system (and AV node part of it) coordinates myocyte mechanical activity. A wave of excitation spreads out from the sinoatrial node through the atria along specialized conduction channels. This activates the AV node.[1] The atrioventricular node delays impulses by approximately 0.12s. This delay in the cardiac pulse is extremely important: It ensures that the atria have ejected their blood into the ventricles first before the ventricles contract.[5] This also protects the ventricles from excessively fast rate response to atrial arrhythmias (see below).[6] The AV node receives two inputs from the atria: posteriorly, via the crista terminalis, and anteriorly, via the interatrial septum.[7] AV conduction during normal cardiac rhythm occurs through two different pathways: the first pathway has a slow conduction velocity but shorter refractory period
Atrioventricular node the second pathway has a faster conduction velocity but longer refractory period.[8] An important property that is unique to the AV node is decremental conduction,[9] in which the more frequently the node is stimulated the slower it conducts. This is the property of the AV node that prevents rapid conduction to the ventricle in cases of rapid atrial rhythms, such as atrial fibrillation or atrial flutter. The AV node's normal intrinsic firing rate without stimulation (like from the SA node) is 40-60 times/minute.[10]
28
Blood supply
The blood supply can vary.[11] The blood supply of the AV node is from the posterior interventricular artery, which is a branch of the right coronary artery in right-dominant individuals. In the remainder of individuals, the AV node is still supplied by the posterior interventricular artery, but that artery is a branch of the left circumflex artery; the coronary circulation of these individuals is considered left-dominant.
Disorders
Atrioventricular (AV) conduction disease (AV block) describes impairment of the electrical continuity between the atria and ventricles. It occurs when the atrial depolarization fail to reach the ventricles or is conducted with a delay. It can result from an injury or be a genetically inherited disorder.[12] Atrioventricular nodal re-entry tachycardia[8] Cystic tumour of atrioventricular nodal region (CTAVN) CTAVN is of endodermal origin and occurs exclusively in the area of the AV node, tricuspid valve, and interatrial septum.[13]
Development
BMP (Bone morphogenetic protein) cell signaling plays a key role in diverse aspects of cardiac differentiation and morphogenesis. (BMPs) are multifunctional signaling molecules critical for the development of AV node. BMP influences AV node development through Alk3 receptor (Activin receptor-like kinase 3). Abnormalities seen in BMP and Alk3 are associated with some cardiovascular diseases like Ebsteins anomaly and AV conduction disease.[14]
References
[1] Gray, Huon H.; Keith D. Dawkins, Iain A. Simpson and John M. Morgan (2002). Lecture Notes on Cardiology. Boston: Blackwell Science. p.135. ISBN978-0-86542-864-5. [2] Full Size Picture triangle of-Koch.jpg (http:/ / medical-dictionary. thefreedictionary. com/ _/ viewer. aspx?path=dorland& name=triangle_of-Koch. jpg). Retrieved on 2008-12-22 [3] Harrison's Principles of Internal Medicine, 17e Section 3: Disorders of Rhythm (http:/ / www. accessmedicine. com/ content. aspx?aID=2874462) [4] synd/454 (http:/ / www. whonamedit. com/ synd. cfm/ 454. html) at Who Named It? [5] Campbell, N., & Reece, J. (2002). Biology. 6th ed. San Francisco: Benjamin Cummings [6] Gray, Huon H.; Keith D. Dawkins, Iain A. Simpson and John M. Morgan (2002). Lecture Notes on Cardiology. Boston: Blackwell Science. p.136. ISBN978-0-86542-864-5. [7] Fuster V, Rydn LE, Asinger RW, et al. (October 2001). "ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation" (http:/ / www. americanheart. org/ downloadable/ heart/ 222_ja20017993p_1. pdf). Journal of the American College of Cardiology 38 (4): 123166. doi:10.1016/S0735-1097(01)01587-X. PMID11583910. . [8] Gray, Huon H.; Keith D. Dawkins, Iain A. Simpson and John M. Morgan (2002). Lecture Notes on Cardiology. Boston: Blackwell Science. p.157. ISBN978-0-86542-864-5. [9] Patterson E, Scherlag BJ (October 2002). "Decremental conduction in the posterior and anterior AV nodal inputs". Journal of Interventional Cardiac Electrophysiology 7 (2): 13748. doi:10.1023/A:1020833604423. PMID12397223.
[10] Guyton, Arthur C.; John E. Hall (2006). Textbook of Medical Physiology (11 ed.). Philadelphia: Elsevier Saunders. p.120. ISBN0721602401. [11] Van der Hauwaert LG, Stroobandt R, Verhaeghe L (October 1972). "Arterial blood supply of the atrioventricular node and main bundle". British Heart Journal 34 (10): 104551. doi:10.1136/hrt.34.10.1045. PMC458545. PMID5086972. [12] Benson DW (October 2004). "Genetics of atrioventricular conduction disease in humans". The Anatomical Record. Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology 280 (2): 9349. doi:10.1002/ar.a.20099. PMID15372490. [13] Sharma G, Linden MD, Schultz DS, Inamdar KV (January 2009). "Cystic tumor of the atrioventricular node: an unexpected finding in an explanted heart". Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology 19 (3): e758. doi:10.1016/j.carpath.2008.10.011. PMID19144541. [14] Stroud DM, Gaussin V, Burch JB, et al. (November 2007). "Abnormal Conduction and Morphology in the Atrioventricular Node of Mice With Atrioventricular CanalTargeted Deletion of Alk3/Bmpr1a Receptor". Circulation 116 (22): 253543. doi:10.1161/CIRCULATIONAHA.107.696583. PMC2947829. PMID17998461.
29
External links
SUNY Figs 20:06-02 (http://ect.downstate.edu/courseware/haonline/figs/l20/200602.htm) - "The conduction system of the heart." thoraxlesson4 (http://mywebpages.comcast.net/wnor/thoraxlesson4.htm) at The Anatomy Lesson (http:// home.comcast.net/~wnor/homepage.htm) by Wesley Norman (Georgetown University) ( thoraxheartinternalner (http://mywebpages.comcast.net/wnor/thoraxheartinternalner.jpg)) http://www.healthyheart.nhs.uk/heart_works/heart03.shtml
Bundle of His
30
Bundle of His
Bundle of His
Isolated Heart conduction system showing Bundle of His
Heart cut away showing Bundle of His Schematic representation of the atrioventricular bundle of His. The bundle, represented in red, originates near the orifice of the coronary sinus, undergoes slight enlargement to form the AV node. The AV node tapers down into the bundle of His, which passes into the ventricular septum and divides into two bundle branches, the left and right bundles. Sometimes the 'left and right bundles of His' are called Purkyn or Purkinje fibres. The ultimate distribution cannot be completely shown in this diagram. Latin fasciculus atrioventricularis
The bundle of His, known as the AV bundle or atrioventricular bundle, is a collection of heart muscle cells specialized for electrical conduction that transmits the electrical impulses from the AV node (located between the atria and the ventricles) to the point of the apex of the fascicular branches. The fascicular branches then lead to the Purkinje fibers which provide electrical conduction to the ventricles, causing the cardiac muscle of the ventricles to contract at a paced interval.
Etymology
These specialized muscle fibres in the heart were named after the Swiss cardiologist Wilhelm His, Jr., who discovered them in 1893.[1] [2]
Function
This bundle is an important part of the electrical conduction system of the heart as it transmits the impulse from the sinoatrial (SA) node (pacemaker) located in the right atrium to the rest of the heart. The intrinsic rate of the Bundle of His is between 40 - 60 bpm.[3] The bundle of His branches into the three bundle branches: the right, left anterior and left posterior bundle branches that run along the interventricular septum. The bundles give rise to thin filaments known as Purkinje fibers. These fibers distribute the impulse to the ventricular muscle. Together, the bundle branches and Purkinje network comprise the ventricular conduction system. It takes about 0.03-0.04s for the impulse to travel from the bundle of His to the ventricular muscle.
Bundle of His
31
Pathology
If the Bundle of His is blocked, it will result in dissociation between the activity of the atria and that of the ventricles, otherwise called a third degree heart block. The other cause of a third degree block would be a block of the right, left anterior, and left posterior bundle branches. A third degree block is a very serious medical condition that will most likely require an artificial pacemaker.
His Bundle Pacing

Direct His-Bundle pacing has produced synchronous ventricular depolarization and improved cardiac function relative to apical pacing.[4] In some patients with atrial fibrillation and a fast ventricular rate, as a last ditch effort to control the heart rate, electrophysiologists perform AV node modification / ablation following a pacemaker placement.
References
[1] synd/3490 (http:/ / www. whonamedit. com/ synd. cfm/ 3490. html) at Who Named It? [2] W. His, Jr. Die Thtigkeit des embryonalen Herzens und deren Bedeutung fr die Lehre von der Herzbewegung beim Erwachsenen. Arbeiten aus der medizinischen Klinik zu Leipzig, Jena, 1893: 14-50. [3] AnatomyBundleHis (http:/ / sprojects. mmi. mcgill. ca/ cardiophysio/ anatomybundlehis. htm) [4] Pramod Deshmukh, MD; David A. Casavant, MS; Mary Romanyshyn, CRNP; Kathleen Anderson, BSN (29 February 2000). "Permanent, direct His-bundle pacing: a novel approach to cardiac pacing in patients with normal His-Purkinje activation." (http:/ / www. circ. ahajournals. org/ cgi/ content/ abstract/ 101/ 8/ 869). Circulation 101 (8): 8367. PMID10694526. . Retrieved 2008-10-08.
External links
-1469382599 (http://www.gpnotebook.co.uk/simplepage.cfm?ID=-1469382599) at GPnotebook Atlas of anatomy at UMich ht_rt_vent (http://www.med.umich.edu/lrc/coursepages/M1/anatomy/html/ atlas/ht_rt_vent.html) - "Right atrioventricular bundle branch, anterior view" atrioventricular+bundle (http://www.emedicinehealth.com/script/main/srchcont_dict. asp?src=atrioventricular+bundle) at eMedicine Dictionary Scheinman MM, Saxon LA (2000). "Long-term His-bundle pacing and cardiac function" (http://circ. ahajournals.org/cgi/content/full/101/8/836). Circulation 101 (8): 8367. PMID10694517. thoraxlesson4 (http://mywebpages.comcast.net/wnor/thoraxlesson4.htm) at The Anatomy Lesson (http:// home.comcast.net/~wnor/homepage.htm) by Wesley Norman (Georgetown University) ( thoraxheartinternalner (http://mywebpages.comcast.net/wnor/thoraxheartinternalner.jpg)) http://www.healthyheart.nhs.uk/heart_works/heart03.shtml
Purkinje fibers
32
Purkinje fibers
Purkinje fibers
Isolated Heart conduction system showing purkinje fibers
The QRS complex is the large peak.
For the nervous cells, see Purkinje cell Purkinje fibers (Purkyne tissue or Subendocardial branches) are located in the inner ventricular walls of the heart, just beneath the endocardium. These fibers are specialized myocardial fibers that conduct an electrical stimulus or impulse that enables the heart to contract in a coordinated fashion.
Histology
Purkinje fibers are a unique end-organ cardiac extension of the Autonomic Nervous System. Further histologic examination reveals that these fibers are split into left and right trees as well as atrial and ventricular contributions. The electrical origin of atrial Purkinje fibers arrives from the Sinoatrial Node. The following electrical origin of the ventricular Purkinje fibers arrives from the Atrioventricular Node. Given no aberrant channels, the atrial and ventricular Purkinje trees are distinctly shielded from each other by collagen or the cardiac skeleton. The Purkinje fibers are uniquely dedicated to sympathetic electrical depolarization of the right and left atria and ventricles. The Purkinje fibers are further specialized to rapidly conduct impulses (numerous sodium ion channels and mitochondria, fewer myofibrils than the surrounding muscle tissue). Purkinje fibers take up stain differently than the surrounding muscle cells, and, on a slide, they often appear lighter and larger than their neighbours. They are binucleated.
Purkinje fibers
33
Function
Heart rate is governed by many influences from the Autonomic Nervous System. The Purkinje Fibers do not have any known role in setting heart rate, but are influenced by Sympathetic discharge from the Sinoatrial node and thoracic Spinal Accessory Ganglia . During the ventricular contraction portion of the cardiac cycle, the Purkinje fibers carry the contraction impulse from both the left and right bundle branch to the myocardium of the ventricles. This causes the muscle tissue of the ventricles to contract, thus enabling a force to eject blood out of the heart; either to the Pulmonary circulation from the right ventricle or to the Systemic circulation from the left ventricle. Atrial and ventricular discharge through the Purkinje trees is assigned on a standard Electrocardiogram as the P Wave and QRS complex, respectively. Purkinje fibers also have the ability of automaticity,[1] firing at a rate of 15-40 beats per minute if left to their own devices. In contrast, the SA node outside of parasympathetic control can fire a a rate of almost 100 beats per minute. - in short, they generate action potentials, but at a slower rate than sinoatrial node and other atrial ectopic pacemakers. Thus they serve as the last resort when other pacemakers fail. When a pukinje fiber does fire, it is called a premature ventricular contraction or PVC. Another name given is ventricular escape. It plays a vital role in the circulatory system.
Etymology
They were discovered in 1839 by Jan Evangelista Purkyn, who gave them his name.
References
[1] [biomed.engr.sc.edu/bme_lab/lab%20reports/36)%20ECG%20I.pdf ]
External links
subendocardial+branches+of+atrioventricular+bundles (http://www.emedicinehealth.com/script/main/ srchcont_dict.asp?src=subendocardial+branches+of+atrioventricular+bundles) at eMedicine Dictionary Organology at UC Davis Circulatory/heart/purkinje/purkinje1 (http://trc.ucdavis.edu/mjguinan/apc100/ modules/Circulatory/heart/purkinje/purkinje1.html) - "Mammal heart, purkinje fibers (LM, Medium)" Anatomy Atlases - Microscopic Anatomy, plate 05.78 (http://www.anatomyatlases.org/MicroscopicAnatomy/ Section05/Plate0578.shtml) MedEd at Loyola Histo/practical/cardio/hp8-21.html (http://www.meddean.luc.edu/Lumen/MedEd/Histo/ practical/cardio/hp8-21.html) Histology at ucsd.edu (http://meded.ucsd.edu/hist-img-bank/chapter_3/Slides_43_44_45_cardiac/pages/d.2. 44.1.2.htm) Histology at nhmccd.edu (http://science.nhmccd.edu/Biol/cardio/purkinje.htm)
34
Principles of Diagnostics
Clinical cardiac electrophysiology
Cardiac Electrophysiology (also referred to as clinical cardiac electrophysiology , Arrhythmia Services , or electrophysiology), is a branch of the medical specialty of clinical cardiology and is concerned with the study and treatment of rhythm disorders of the heart. Cardiologists with expertise in this area are usually referred to as electrophysiologists. Electrophysiologists are trained in the mechanism, function, and performance of the electrical activities of the heart. Electrophysiologists work closely with other cardiologists and cardiac surgeons to assist or guide therapy for heart rhythm disturbances (arrhythmias).They are trained to perform interventional and surgical procedures to treat cardiac arrhythmia. The training required to became an electrophysiologist is long and requires 7 to 8 years after medical school (in the U.S.). Three years of Internal Medicine residency, three years of Clinical Cardiology fellowship, and one to two (in most instances) years of Clinical Cardiac Electrophysiology. An electrophysiology study is a term used to describe a number of invasive (intracardiac) and non-invasive recording of spontaneous electrical activity as well as of cardiac responses to programmed electrical stimulation. These studies are performed to assess arrhythmias, elucidate symptoms, evaluate abnormal electrocardiograms, assess risk of developing arrhythmias in the future, and design treatment. In addition to diagnostic testing of the electrical properties of the heart, electrophysiologists are trained in therapeutic and surgical methods to treat many of the rhythm disturbances of the heart. Therapeutic modalities employed in this field include antiarrhythmic drug therapy and surgical implantation of pacemakers and implantable cardioverter-defibrillators.
Scope of practice, tests and procedures

Diagnostic testing
Ambulatory electrocardiographic monitoring - Holter recording and interpretation, loop recording and interpretation; Tilt table testing; T-wave alternans testing; Signal-averaged electrocardiogram (SAECG) interpretation, also referred to as "late potentials" reading; Electrophysiology study (EPS) consists in the insertion of pacing and recording electrodes either in the oesophagus (intra-oesophageal EPS) or, through blood vessels, directly into the heart chambers (intra-cardiac EPS) in order to measure electrical properties of the heart and, in the case of intra-cardiac EPS, to electrically stimulate it in the attempt to induce arrhythmias for diagnostic purposes ("programmed electrical stimulation").
Clinical cardiac electrophysiology
35
Medical treatment
Initital administration and monitoring of the effect of drugs for treatment of heart rhythm disorders. Electrophysiologists are often involved when severe or life threatening arrhythmias are being treated, or when multiple drugs must be used to treat an arrhythmia.
Catheter ablation
Ablation therapy - Catheter based creation of lesions in the heart (with radiofrequency energy, cryotherapy (destructive freezing), or ultrasound energy) to cure or control arrhythmias (see radiofrequency ablation). Ablation is usually performed during the same procedure as the electrophysiology study which induces and confirms the diagnosis of the arrhythmia for which ablation therapy is sought. "Non-complex" ablations include ablation for arrhythmias such as: AV nodal reentrant tachycardia, Accessory pathway mediated tachycardia, atrial flutter. These procedures are usually performed using intracardiac catheters (as are used during an electrophysiology study), fluoroscopy (a real-time X-ray camera), and electrical recordings from the inside of the heart. "Complex" ablations include ablation for arrhythmias such as multifocal atrial tachycardia, atrial fibrillation, and ventricular tachycardia. In addition to the apparatus used for a "non-complex" ablation, these procedures often make use of sophisticated computer mapping systems to localize the source of the abnormal rhythm and to direct delivery of ablation lesions.
Surgical Procedures: Pacemaker and Defibrillator implantation and follow up

Implantation of single and dual chamber pacemakers and defibrillators Implantation of "biventricular" pacemakers and defibrillators for patients with congestive heart failure Implantation of loop recorders (implanted ECG recorders for long term monitoring of ECG to allow for diagnosis of an arrhythmia) Clinical follow up and reprogramming of implanted devices
External links
Canadian Heart Rhythm Society [1] Heart Rhythm Society [2] International Winter Arrhythmia School [3]
References
[1] http:/ / www. chrsonline. ca [2] http:/ / www. hrsonline. org [3] http:/ / www. winterarrhythmia. com
Electrocardiography
36
Electrocardiography
Electrocardiography
Intervention
Image showing a patient connected to the 10 electrodes necessary for a 12-lead ECG ICD-9-CM MeSH 89.52 D004562 [1]
Electrocardiography (ECG or EKG from the German Elektrokardiogramm) is a transthoracic (across the thorax or chest) interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body.[2] The 12 Lead EKG of a 26-year-old male. recording produced by this noninvasive procedure is termed as electrocardiogram (also ECG or EKG). An electrocardiogram (ECG) is a test that records the electrical activity of the heart. ECG is used to measure the rate and regularity of heartbeats as well as the size and position of the chambers, the presence of any damage to the heart, and the effects of drugs or devices used to regulate the heart (such as a pacemaker). See also stress test and Holter monitor (24h). The etymology of the word is derived from the Greek electro, because it is related to electrical activity, kardio, Greek for heart, and graph, a Greek root meaning "to write". In English speaking countries, medical professionals often use "EKG" (the abbreviation for the German word Elektrokardiogramm) in order to avoid confusion with EEG in emergency situations where background noise is high. Most EKGs are performed for diagnostic or research purposes on human hearts, but may also be performed on animals, usually for research.
Electrocardiography
37
Function
The ECG device detects and amplifies the tiny electrical changes on the skin that are caused when the heart muscle depolarizes during each heartbeat. At rest, each heart muscle cell has a negative charge (membrane potential) across its outer wall (or cell membrane). Increasing this negative charge towards zero (via the influx of the positive ions, Na+ and Ca++) is called depolarization, which activates the mechanisms in the cell that cause it to contract. During each heartbeat a healthy heart will have an orderly progression of a wave of depolarisation that is triggered by the cells in the sinoatrial node, spreads out through the atrium, passes through "intrinsic conduction pathways" and then spreads all over the ventricles. This is detected as tiny rises and falls in the voltage between two electrodes placed either side of the heart which is displayed as a wavy line either on a screen or on paper. This display indicates the overall rhythm of the heart and weaknesses in different parts of the heart muscle. Usually more than 2 electrodes are used and they can be combined into a number of pairs (For example: Left arm (LA), right arm (RA) and left leg (LL) electrodes form the three pairs LA+RA, LA+LL, and RA+LL). The output from each pair is known as a lead. Each lead is said to look at the heart from a different angle. Different types of EKGs can be referred to by the number of leads that are recorded, for example 3-lead, 5-lead or 12-lead EKGs (sometimes simply "a 12-lead"). A 12-lead EKG is one in which 12 different electrical signals are recorded at approximately the same time and will often be used as a one-off recording of an EKG, traditionally printed out as a paper copy. 3- and 5-lead EKGs tend to be monitored continuously and viewed only on the screen of an appropriate monitoring device, for example during an operation or whilst being transported in an ambulance. There may or may not be any permanent record of a 3- or 5-lead EKG, depending on the equipment used. It is the best way to measure and diagnose abnormal rhythms of the heart,[3] particularly abnormal rhythms caused by damage to the conductive tissue that carries electrical signals, or abnormal rhythms caused by electrolyte imbalances.[4] In a myocardial infarction (MI), the EKG can identify if the heart muscle has been damaged in specific areas, though not all areas of the heart are covered.[5] The EKG cannot reliably measure the pumping ability of the heart, for which ultrasound-based (echocardiography) or nuclear medicine tests are used. It is possible for a human or other animal to be in cardiac arrest but still have a normal EKG signal (a condition known as pulseless electrical activity).
History
Alexander Muirhead is reported to have attached wires to a feverish patient's wrist to obtain a record of the patient's heartbeat while studying for his Doctor of Science (in electricity) in 1872 at St Bartholomew's Hospital.[6] This activity was directly recorded and visualized using a Lippmann capillary electrometer by the British physiologist John Burdon Sanderson.[7] The first to systematically approach the heart from an electrical point-of-view was Augustus Waller, working in St Mary's Hospital in Paddington, London.[8] His electrocardiograph machine consisted of a Lippmann capillary electrometer fixed to a projector. The trace from the heartbeat was projected onto a photographic plate which was itself fixed to a toy train. This allowed a heartbeat to be recorded in real time. In 1911 he still saw little clinical application for his work.
Electrocardiography
38 An initial breakthrough came when Willem Einthoven, working in Leiden, Netherlands, used the string galvanometer that he invented in 1903.[9] This device was much more sensitive than both the capillary electrometer that Waller used and the string galvanometer that had been invented separately in 1897 by the French engineer Clment Ader.[10] Rather than using today's self-adhesive electrodes Einthoven's subjects would immerse each of their limbs into containers of salt solutions from which the EKG was recorded.
Einthoven assigned the letters P, Q, R, S and T to the various Einthoven's ECG device deflections, Naming of the Waves in the ECG [11] and described the electrocardiographic features of a number of cardiovascular disorders. In 1924, he was awarded the Nobel Prize in Medicine for his discovery.[12] Though the basic principles of that era are still in use today, there have been many advances in electrocardiography over the years. The instrumentation, for example, has evolved from a cumbersome laboratory apparatus to compact electronic systems that often include computerized interpretation of the electrocardiogram.[13]
EKG graph paper

The output of an ECG recorder is a graph (or sometimes several graphs, representing each of the leads) with time represented on the x-axis and voltage represented on the y-axis. A dedicated ECG machine would usually print onto graph paper which has a background pattern of 1mm squares (often in red or green), with bold divisions every 5mm in both vertical and horizontal directions. It is possible to change the output of most ECG devices but it is standard to represent each mV on the y axis as 1cm and each second as 25mm on the x-axis (that is a paper speed of 25mm/s). Faster paper One second of ECG graph paper speeds can be used, for example, to resolve finer detail in the ECG. At a paper speed of 25mm/s, one small block of ECG paper translates into 40ms. Five small blocks make up one large block, which translates into 200ms. Hence, there are five large blocks per second. A calibration signal may be included with a record. A standard signal of 1mV must move the stylus vertically 1cm, that is, two large squares on ECG paper.
Layout
By definition, a 12-lead ECG will show a short segment of the recording of each of the 12-leads. This is often arranged in a grid of 4 columns by three rows, the first columns being the limb leads (I,II and III), the second column the augmented limb leads (aVR, aVL and aVF) and the last two columns being the chest leads (V1-V6). It is usually possible to change this layout so it is vital to check the labels to see which lead is represented. Each column will usually record the same moment in time for the three leads and then the recording will switch to the next column which will record the heart beats after that point. It is possible for the heart rhythm to change between the columns of leads. Each of these segments is short, perhaps 1g-3 heart beats only, depending on the heart rate and it can be difficult to analyse any heart rhythm that shows changes between heart beats. To help with the analysis it is common to print one or two "rhythm strips" as well. This will usually be lead II (which shows the electrical signal from the atrium, the P-wave, well) and shows the rhythm for the whole time the ECG was recorded (usually 56 seconds). Some ECG machines will print a second lead II along the very bottom of the paper in addition to the output described
Electrocardiography above. This printing of Lead II is continuous from start to finish of the process. The term "rhythm strip" may also refer to the whole printout from a continuous monitoring system which may show only one lead and is either initiated by a clinician or in response to an alarm or event.
39
Leads
The term "lead" in electrocardiography causes much confusion because it is used to refer to two different things. In accordance with common parlance the word lead may be used to refer to the electrical cable attaching the electrodes to the ECG recorder. As such it may be acceptable to refer to the "left arm lead" as the electrode (and its cable) that should be attached at or near the left arm. There are usually ten of these electrodes in a standard "12-lead" ECG. Alternatively (and some would say properly, in the context of electrocardiography) the word lead may refer to the tracing of the voltage difference between two of the electrodes and is what is actually produced by the ECG recorder. Each will have a specific name. For example "Lead I" (lead one) is the voltage between the right arm electrode and the left arm electrode, whereas "Lead II" (lead two) is the voltage between the right limb and the feet. (This rapidly becomes more complex as one of the "electrodes" may in fact be a composite of the electrical signal from a combination of the other electrodes (see later). Twelve of this type of lead form a "12-lead" ECG To cause additional confusion the term "limb leads" usually refers to the tracings from leads I, II and III rather than the electrodes attached to the limbs.
Placement of electrodes
Ten electrodes are used for a 12-lead ECG. The electrodes usually consist of a conducting gel, embedded in the middle of a self-adhesive pad onto which cables clip. Sometimes the gel also forms the adhesive.[14] They are labeled and placed on the patient's body as follows:[15] [16] . * Note that when exercise stress tests are performed, limb leads may be placed on the trunk to avoid artifacts while ambulatory (arm leads moved sub-clavicularly and leg leads medial to and above the iliac crest).
Proper placement of the limb electrodes, color coded as recommended by the American Heart Association (a different colour scheme is used in Europe). Note that the limb electrodes can be far down on the limbs or close to the hips/shoulders, [17] but they must be even (left vs right).
12 leads
Electrocardiography
40
Electrode label (in the USA) RA LA RL LL V1 V2 V3 V4 V5 On the right arm, avoiding thick muscle.
Electrode placement
In the same location that RA was placed, but on the left arm. On the right leg, lateral calf muscle In the same location that RL was placed, but on the left leg. In the fourth intercostal space (between ribs 4 & 5) just to the right of the sternum (breastbone). In the fourth intercostal space (between ribs 4 & 5) just to the left of the sternum. Between leads V2 and V4. In the fifth intercostal space (between ribs 5 & 6) in the mid-clavicular line (the imaginary line that extends down from the midpoint of the clavicle (collarbone)). Horizontally even with V4, but in the anterior axillary line. (The anterior axillary line is the imaginary line that runs down from the point midway between the middle of the clavicle and the lateral end of the clavicle; the lateral end of the collarbone is the end closer to the arm.) Horizontally even with V4 and V5 in the midaxillary line. (The midaxillary line is the imaginary line that extends down from the middle of the patient's armpit.)
V6
Additional electrodes The classical 12-lead ECG can be extended in a number of ways in an attempt to improve its sensitivity in detecting myocardial infarction involving territories not normally "seen" well. This includes an rV4 lead which uses the equivalent landmarks to the V4 but on the right side of the chest wall and extending the chest leads onto the back with a V7, V8 and V9.
Limb leads
In both the 5- and 12-lead configuration, leads I, II and III are called limb leads. The electrodes that form these signals are located on the limbsone on each arm and one on the left leg.[18] [19] [20] The limb leads form the points of what is known as Einthoven's triangle.[21] Lead I is the voltage between the (positive) left arm (LA) electrode and right arm (RA) electrode:
Lead II is the voltage between the (positive) left leg (LL) electrode and the right arm (RA) electrode:
Lead III is the voltage between the (positive) left leg (LL) electrode and the left arm (LA) electrode:
Simplified electrocardiograph sensors designed for teaching purposes at e.g. high school level are generally limited to three arm electrodes serving similar purposes.[22]
Unipolar vs. bipolar leads

There are two types of leads: unipolar and bipolar. Bipolar leads have one positive and one negative pole.[23] In a 12-lead ECG, the limb leads (I, II and III) are bipolar leads. Unipolar leads also have two poles, as a voltage is measured; however, the negative pole is a composite pole (Wilson's central terminal, or WCT) made up of signals from lots of other electrodes.[24] In a 12-lead ECG, all leads besides the limb leads are unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, and V6).
Electrocardiography Wilson's central terminal VW is produced by connecting the electrodes, RA; LA; and LL, together, via a simple resistive network, to give an average potential across the body, which approximates the potential at infinity (i.e. zero):
41
Augmented limb leads

Leads aVR, aVL, and aVF are augmented limb leads (after their inventor Dr. Emanuel Goldberger known collectively as the Goldberger's leads). They are derived from the same three electrodes as leads I, II, and III. However, they view the heart from different angles (or vectors) because the negative electrode for these leads is a modification of Wilson's central terminal. This zeroes out the negative electrode and allows the positive electrode to become the "exploring electrode". This is possible because Einthoven's Law states that I + (II) + III = 0. The equation can also be written I + III = II. It is written this way (instead of I II + III = 0) because Einthoven reversed the polarity of lead II in Einthoven's triangle, possibly because he liked to view upright QRS complexes. Wilson's central terminal paved the way for the development of the augmented limb leads aVR, aVL, aVF and the precordial leads V1, V2, V3, V4, V5 and V6. Lead augmented vector right (aVR) has the positive electrode (white) on the right arm. The negative electrode is a combination of the left arm (black) electrode and the left leg (red) electrode, which "augments" the signal strength of the positive electrode on the right arm:
Lead augmented vector left (aVL) has the positive (black) electrode on the left arm. The negative electrode is a combination of the right arm (white) electrode and the left leg (red) electrode, which "augments" the signal strength of the positive electrode on the left arm:
Lead augmented vector foot (aVF) has the positive (red) electrode on the left leg. The negative electrode is a combination of the right arm (white) electrode and the left arm (black) electrode, which "augments" the signal of the positive electrode on the left leg:
The augmented limb leads aVR, aVL, and aVF are amplified in this way because the signal is too small to be useful when the negative electrode is Wilson's central terminal. Together with leads I, II, and III, augmented limb leads aVR, aVL, and aVF form the basis of the hexaxial reference system, which is used to calculate the heart's electrical axis in the frontal plane. The aVR, aVL, and aVF leads can also be represented using the I and II limb leads:
Electrocardiography
42
Precordial leads
The electrodes for the precordial leads (V1, V2, V3, V4, V5 and V6) are placed directly on the chest. Because of their close proximity to the heart, they do not require augmentation. Wilson's central terminal is used for the negative electrode, and these leads are considered to be unipolar (recall that Wilson's central terminal is the average of the three limb leads. This approximates common, or average, potential over the body). The precordial leads view the heart's electrical activity in the so-called horizontal plane. The heart's electrical axis in the horizontal plane is referred to as the Z axis.
Waves and intervals

A typical ECG tracing of the cardiac cycle (heartbeat) consists of a P wave, a QRS complex, a T wave, and a U wave which is normally visible in 50 to 75% of ECGs.[25] The baseline voltage of the electrocardiogram is known as the isoelectric line. Typically the isoelectric line is measured as the portion of the tracing following the T wave and preceding the next P wave.
Schematic representation of normal ECG
Animation of a normal ECG wave.
Electrocardiography
43
Detail of the QRS complex, showing ventricular activation time (VAT) and amplitude.
Feature RR interval P wave
Description The interval between an R wave and the next R wave . Normal resting heart rate is between 60 and 100 bpm
Duration 0.6 to 1.2s
During normal atrial depolarization, the main electrical vector is directed from the SA node towards the AV node, and spreads from the right atrium to the left atrium. This turns into the P wave on the ECG. The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. The PR interval reflects the time the electrical impulse takes to travel from the sinus node through the AV node and entering the ventricles. The PR interval is therefore a good estimate of AV node function.
80ms
PR interval
120 to 200ms
PR segment
The PR segment connects the P wave and the QRS complex. This coincides with the electrical conduction from the AV 50 to node to the bundle of His to the bundle branches and then to the Purkinje Fibers. This electrical activity does not produce a 120ms contraction directly and is merely traveling down towards the ventricles and this shows up flat on the ECG. The PR interval is more clinically relevant. The QRS complex reflects the rapid depolarization of the right and left ventricles. They have a large muscle mass compared to the atria and so the QRS complex usually has a much larger amplitude than the P-wave. The point at which the QRS complex finishes and the ST segment begins. Used to measure the degree of ST elevation or depression present. The ST segment connects the QRS complex and the T wave. The ST segment represents the period when the ventricles are depolarized. It is isoelectric. The T wave represents the repolarization (or recovery) of the ventricles. The interval from the beginning of the QRS complex to the apex of the T wave is referred to as the absolute refractory period. The last half of the T wave is referred to as the relative refractory period (or vulnerable period). The ST interval is measured from the J point to the end of the T wave. 80 to 120ms N/A
QRS complex J-point
ST segment T wave
80 to 120ms 160ms
ST interval
320ms
Electrocardiography
44
QT interval
The QT interval is measured from the beginning of the QRS complex to the end of the T wave. A prolonged QT interval is 300 to a risk factor for ventricular tachyarrhythmias and sudden death. It varies with heart rate and for clinical relevance requires a 430ms correction for this, giving the QTc. The U wave is hypothesized to be caused by the repolarization of the interventricular septum. They normally have a low amplitude, and even more often completely absent. They always follow the T wave and also follow the same direction in [26] amplitude. If they are too prominent we suspect hypokalemia, hypercalcemia or hyperthyroidism usually. The J wave, elevated J-Point or Osborn Wave appears as a late delta wave following the QRS or as a small secondary R [27] wave . It is considered pathognomonic of hypothermia or hypocalcemia.
U wave
J wave
There were originally four deflections, but after the mathematical correction for artifacts introduced by early amplifiers, five deflections were discovered. Einthoven chose the letters P, Q, R, S, and T to identify the tracing which was superimposed over the uncorrected labeled A, B, C, and D.[28] In intracardiac electrocardiograms, such as can be acquired from pacemaker sensors, an additional wave that can be seen is the H deflection, which reflects the depolarization of the bundle of His.[29] The H-V interval, in turn, is the duration from the beginning of the H deflection to the earliest onset of ventricular depolarization recorded in any lead.[30]
Vectors and views

Interpretation of the ECG relies on the idea that different leads (by which we mean the ECG leads I,II,III, aVR, aVL, aVF and the chest leads) "view" the heart from different angles. This has two benefits. Firstly, leads which are showing problems (for example ST segment elevation) can be used to infer which region of the heart is affected. Secondly, the overall direction of travel of the wave of depolarisation can also be inferred which can reveal other problems. This is termed the cardiac axis . Determination of the cardiac axis relies on the concept of a vector which describes the motion of the depolarisation wave. This vector can then be described in terms of its components in relation to the direction of the lead considered. One component will be in the direction of the lead and this will be revealed in the behaviour of Graphic showing the relationship between the QRS complex and one component will be at 90 degrees to this positive electrodes, depolarization wavefronts (or mean electrical vectors), and complexes (which will not). Any net positive deflection of the QRS complex (i.e. displayed on the ECG. height of the R-wave minus depth of the S-wave) suggests that the wave of depolarisation is spreading through the heart in a direction that has some component (of the vector) in the same direction as the lead in question.
Electrocardiography
45
Axis
The heart's electrical axis refers to the general direction of the heart's depolarization wavefront (or mean electrical vector) in the frontal plane. With a healthy conducting system the cardiac axis is related to where the major muscle bulk of the heart lies. Normally this is the left ventricle with some contribution from the right ventricle. It is usually Diagram showing how the polarity of the QRS oriented in a right shoulder to left leg direction, which corresponds to complex in leads I, II, and III can be used to the left inferior quadrant of the hexaxial reference system, although estimate the heart's electrical axis in the frontal 30 to +90 is considered to be normal. If the left ventricle increases plane. its activity or bulk then there is said to be "left axis deviation" as the axis swings round to the left beyond -30, alternatively in conditions where the right ventricle is strained or hypertrophied then the axis swings round beyond +90 and "right axis deviation" is said to exist. Disorders of the conduction system of the heart can disturb the electrical axis without necessarily reflecting changes in muscle bulk.
Normal 30 to 90 Normal Normal
Left axis deviation 30 to 90 Right axis deviation Extreme right axis deviation +90 to +180 +180 to 90
May indicate left anterior fascicular block or Q waves from inferior MI. May indicate left posterior fascicular block, Q waves from high lateral MI, or a right ventricular strain pattern. Is rare, and considered an 'electrical no-man's land'.
Left axis deviation is considered normal in pregnant women and those with emphysema. Right deviation is considered normal in children and is a standard effect of dextrocardia.
In the setting of right bundle branch block, right or left axis deviation may indicate bifascicular block.
Clinical lead groups

There are twelve leads in total, each recording the electrical activity of the heart from a different perspective, which also correlate to different anatomical areas of the heart for the purpose of identifying acute coronary ischemia or injury. Two leads that look at neighbouring anatomical areas of the heart are said to be contiguous (see color coded chart). The relevance of this is in determining whether an abnormality on the ECG is likely to represent true disease or a spurious finding.
The hexaxial reference system showing the orientation of each lead. For example, if the bulk of heart muscle is oriented at +60 degrees with respect to the SA node, lead II will show the greatest deflection and aVL the least.
Electrocardiography
46
Diagram showing the contiguous leads in the same color
Category
Color on chart Yellow
Leads
Activity
Inferior leads Lateral leads
Leads II, III and aVF I, aVL, V5 and V6
Look at electrical activity from the vantage point of the inferior surface (diaphragmatic surface of heart). Look at the electrical activity from the vantage point of the lateral wall of left ventricle. The positive electrode for leads I and aVL should be located distally on the left arm and because of which, leads I and aVL are sometimes referred to as the high lateral leads. Because the positive electrodes for leads V5 and V6 are on the patient's chest, they are sometimes referred to as the low lateral leads.
Green
Septal leads Orange
V1 and V2 V3 and V4
Look at electrical activity from the vantage point of the septal wall of the ventricles (interventricular septum). Look at electrical activity from the vantage point of the anterior surface of the heart (sternocostal surface of heart).
Anterior leads
Blue
In addition, any two precordial leads that are next to one another are considered to be contiguous. For example, even though V4 is an anterior lead and V5 is a lateral lead, they are contiguous because they are next to one another. Lead aVR offers no specific view of the left ventricle. Rather, it views the inside of the endocardial wall to the surface of the right atrium, from its perspective on the right shoulder.
Filter selection
Modern ECG monitors offer multiple filters for signal processing. The most common settings are monitor mode and diagnostic mode. In monitor mode, the low frequency filter (also called the high-pass filter Wiggers diagram, showing a normal ECG curve because signals above the threshold are allowed to pass) is set at either synchronized with other major events during the 0.5Hz or 1Hz and the high frequency filter (also called the low-pass cardiac cycle. filter because signals below the threshold are allowed to pass) is set at 40Hz. This limits artifact for routine cardiac rhythm monitoring. The high-pass filter helps reduce wandering baseline and the low-pass filter helps reduce 50 or 60Hz power line noise (the power line network frequency differs between 50 and 60Hz in different countries). In diagnostic mode, the high-pass filter is set at 0.05Hz, which allows accurate ST segments to be recorded. The low-pass filter is set to 40, 100, or 150Hz. Consequently, the monitor mode ECG display is more filtered than diagnostic mode, because its passband is narrower.[31]
Electrocardiography
47
Indications
Symptoms generally indicating use of electrocardiography include: Cardiac murmurs [32] Syncope or collapse[32] Seizures[32] Perceived cardiac dysrhythmias[32] Symptoms of myocardial infarction. See Electrocardiography in myocardial infarction
It is also used to assess patients with systemic disease as well as monitoring during anesthesia and critically ill patients.[32]
Some pathological entities which can be seen on the ECG

Shortened QT interval Prolonged QT interval Flattened or inverted T waves Hyperacute T waves Hypercalcemia, some drugs, certain genetic abnormalities. Hypocalcemia, some drugs, certain genetic abnormalities. Coronary ischemia, hypokalemia, left ventricular hypertrophy, digoxin effect, some drugs.
Possibly the first manifestation of acute myocardial infarction, where T waves become more prominent, symmetrical, and pointed. Hypokalemia.
Prominent U waves
Electrocardiogram heterogeneity
Electrocardiogram (ECG) heterogeneity is a measurement of the amount of variance between one ECG waveform and the next. This heterogeneity can be measured by placing multiple ECG electrodes on the chest and by then computing the variance in waveform morphology across the signals obtained from these electrodes. Recent research suggests that ECG heterogeneity often precedes dangerous cardiac arrhythmias. In the future, implantable devices may be programmed to measure and track heterogeneity. These devices could potentially help ward off arrhythmias by stimulating nerves such as the vagus nerve, by delivering drugs such as beta-blockers, and if necessary, by defibrillating the heart.[33]
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D004562 [2] "ECG- simplified. Aswini Kumar M.D" (http:/ / www. lifehugger. com/ doc/ 120/ ecg-100-steps). LifeHugger. . Retrieved 2010-02-11. [3] Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997. ISBN 0-7216-5666-8. [4] Van Mieghem, C; Sabbe, M; Knockaert, D (2004). "The clinical value of the EKG in noncardiac conditions". Chest 125 (4): 156176. doi:10.1378/chest.125.4.1561. PMID15078775. [5] "2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care - Part 8: Stabilization of the Patient With Acute Coronary Syndromes." Circulation 2005; 112: IV-89 - IV-110. [6] Ronald M. Birse, rev. Patricia E. Knowlden (http:/ / www. oxforddnb. com/ view/ article/ 37794) Oxford Dictionary of National Biography 2004 (Subscription required) - (original source is his biography written by his wife - Elizabeth Muirhead. Alexandernn Muirhead 1848 - 1920. Oxford, Blackwell: privately printed 1926.) [7] Burdon Sanderson J; Page, F. J. M. (1878). "Experimental results relating to the rhythmical and excitatory motions of the ventricle of the frog heart". Proc Roy Soc Lond 27 (185189): 41014. doi:10.1098/rspl.1878.0068. [8] Waller AD (1887). "A demonstration on man of electromotive changes accompanying the heart's beat". J Physiol (Lond) 8: 22934. [9] Rivera-Ruiz, M; Cajavilca, C; Varon, J (1927-09-29). "Einthoven's String Galvanometer: The First Electrocardiograph". Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital (Pubmedcentral.nih.gov) 35 (2): 1748. PMC2435435. PMID18612490. [10] Interwoven W. Un nouveau galvanometre. Arch Neerl Sc Ex Nat 1901; 6:625
Electrocardiography
[11] http:/ / circ. ahajournals. org/ content/ 98/ 18/ 1937. full [12] Cooper J (1986). "Electrocardiography 100 years ago. Origins, pioneers, and contributors". N Engl J Med 315 (7): 4614. doi:10.1056/NEJM198608143150721. PMID3526152. [13] Mark, Jonathan B. (1998). Atlas of cardiovascular monitoring. New York: Churchill Livingstone. ISBN0443088918. [14] See images of ECG electrodes here: http:/ / www. superboverseas. com/ show_product. asp?id=104 or here: http:/ / images. google. com/ images?q=ecg+ electrode& oe=UTF-8& rls=org. mozilla:en-US:official& client=firefox-a& um=1& ie=UTF-8& sa=N& tab=wi& ei=IOEHSqCELp3ItgeY8_2HBw& oi=property_suggestions& resnum=0& ct=property-revision& cd=1) [15] "lead_dia" (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson1/ lead_dia. html). Library.med.utah.edu. . Retrieved 2009-08-15. [16] http:/ / www. welchallyn. com/ documents/ Cardiopulmonary/ Electrocardiographs/ PC-Based%20Exercise%20Stress%20ECG/ poster_110807_pcexerecg. pdf [17] (http:/ / www. scst. org. uk/ coleman/ resting. htm) [18] "Univ. of Maryland School of Medicine Emergency Medicine Interest Group" (http:/ / davidge2. umaryland. edu/ ~emig/ ekgtu03. html). Davidge2.umaryland.edu. . Retrieved 2009-08-15. [19] "Limb Leads - ECG Lead Placement - Normal Function of the Heart - Cardiology Teaching Package - Practice Learning - Division of Nursing - The University of Nottingham" (http:/ / www. nottingham. ac. uk/ nursing/ practice/ resources/ cardiology/ function/ limb_leads. php). Nottingham.ac.uk. . Retrieved 2009-08-15. [20] "Lesson 1: The Standard 12 Lead ECG" (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson1/ index. html#orientation). Library.med.utah.edu. . Retrieved 2009-08-15. [21] http:/ / nobelprize. org/ medicine/ educational/ ecg/ images/ triangle. gif [22] e.g. Pasco Pasport EKG Sensor PS-2111, Sciencescope ECG Sensor, etc. [23] http:/ / academic. cuesta. edu/ fjohnson/ PowerPoint_PDF/ 12leadecg. pdf [24] "Electrocardiogram Leads" (http:/ / www. cvphysiology. com/ Arrhythmias/ A013. htm). CV Physiology. 2007-03-26. . Retrieved 2009-08-15. [25] Watch a movie by the National Heart Lung and Blood Institute explaining the connection between an ECG and the electricity in your heart at this site http:/ / www. nhlbi. nih. gov/ health/ dci/ Diseases/ hhw/ hhw_electrical. html [26] Making sense of the ECG 3rd edition p214 [27] Gan-Xin Yan; Charles Antzelevitch. Cellular Basis for the Electrocardiographic J Wave. Circulation. 1996;93:372-379. http:/ / circ. ahajournals. org/ cgi/ content/ full/ circulationaha;93/ 2/ 372 pmid=8548912 [28] Hurst JW. Current Perspective: Naming of the Waves in the ECG, With a Brief Account of Their Genesis. Circulation. 1998;98:1937-1942. http:/ / www. circ. ahajournals. org/ cgi/ content/ full/ 98/ 18/ 1937 [29] thefreedictionary.com > H deflection (http:/ / medical-dictionary. thefreedictionary. com/ H+ deflection) Citing: Mosby's Medical Dictionary, 8th edition. 2009 [30] thefreedictionary.com > H-V interval (http:/ / medical-dictionary. thefreedictionary. com/ H-V+ interval) Citing: McGraw-Hill Concise Dictionary of Modern Medicine. 2002 [31] Mark JB "Atlas of Cardiovascular Monitoring." p. 130. New York: Churchill Livingstone, 1998. ISBN 0-443-08891-8. [32] Page 244 (http:/ / books. google. se/ books?id=K1I8aTnBe5sC) in: Masters, Jo; Bowden, Carole; Martin, Carole (2003). Textbook of veterinary medical nursing. Oxford: Butterworth-Heinemann. ISBN0-7506-5171-7. [33] Verrier, Richard L. "Dynamic Tracking of ECG Heterogeneity to Estimate Risk of Life-threatening Arrhythmias." CIMIT Forum. September 25, 2007.
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External links
Electrocardiogram, EKG, or ECG (http://www.nhlbi.nih.gov/health/dci/Diseases/ekg/ekg_what.html) Explanation of what an ECG is, who needs one, what to expect during one, etc. Written by the National Heart Lung and Blood Institute (a division of the NIH) University of Maryland School of Medicine Emergency Medicine Interest Group (http://davidge2.umaryland. edu/~emig/ekgtu01.html) Introduction to EKGs as written by a medical student and a cardiologist ECG in 100 steps: Slideshow (http://www.lifehugger.com/doc/120/ecg-100-steps) ECG Lead Placement (https://www.nottingham.ac.uk/nursing/practice/resources/cardiology/function/ placement_of_leads.php) A teaching guide "designed for student nurses who know nothing at all about Cardiology" ECGpedia: Course for interpretation of ECG (http://en.ecgpedia.org) 12-lead ECG library (http://www.ecglibrary.com) Simulation tool to demonstrate and study the relation between the electric activity of the heart and the ECG (http:/ /www.ecgsim.org) Minnesota ECG Code (http://www.sph.umn.edu/epi/ecg/)
Electrocardiography openECGproject - help develop an open ECG solution (http://www.open-ecg-project.org/) EKG Review: Arrhythmias (http://www.gwc.maricopa.edu/class/bio202/cyberheart/ekgqzr0.htm) A guide to reading ECGs not written for a university biology (anatomy and physiology) course. AME ECG - Advanced PC Based Electrocardiograph solution (http://www.advancedmedicalengineering.com/ electrocardiograph.html)
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Electrophysiology study
An electrophysiology study (EP test or EP study) is a minimally invasive procedure which tests the electrical conduction system of the heart to assess the electrical activity and conduction pathways of the heart. The study is indicated to investigate the cause, location of origin, and best treatment for various abnormal heart rhythms. This type of study is performed by a specialist (an electrophysiologist) and is performed using a single or multiple catheters situated within the heart through a vein or artery.
Preparation
It is important for patients not to eat or drink for up to 12 hours before the procedure. This is to prevent vomiting, which can result in aspiration, and even cause severe bleed from the insertion site of the catheter. Failure to follow this simple preparation may result in dangerous consequences. Generally small amounts of water can be consumed up to 2 hours before the exam. Patients should try to schedule the exam at a time when they will be having symptoms and will not need to drive for 2 to 3 days.
Procedure
This procedure is performed in a cath lab which is a specially equipped operating room. More modern cath labs contain a video X-ray machine and large magnets (2-3 tesla, 2ft. diameter) for manipulating the electrodes, in addition to other necessary equipment. An IV tube is generally inserted to keep the patient hydrated and to allow for the administration of sedatives, anesthesia, or drugs. In order to reach the heart with a catheter, a site will be prepared that will allow access to the heart via an artery or vein, usually in the wrist or groin. This site is then described as the insertion point. A metal plate is placed underneath the patient between the shoulder blades, directly under the heart. An automated blood pressure cuff is placed on the arm which periodically measures the patient's blood pressure. A pulse oximeter is placed on one of the patient's fingers which steadily monitors the patient's pulse and oxygen saturation of the blood. The insertion point is cleanly shaved and sterilized. A local anesthetic is injected into the skin to numb the insertion point. A small puncture is then made with a needle in either the femoral vein in the groin or the radial vein in the wrist, before a guide wire is inserted into the venous puncture. A plastic sheath (with a stiffer plastic introducer inside) is then threaded over the wire and pushed into the vein (the Seldinger technique). The wire is then removed and the side-port of the sheath is aspirated to ensure venous blood flows back. It is then flushed with saline. Catheters are inserted using a long guide wire and moved towards the heart. Once in position the guide wire is then removed. NOTE It is standard procedure to use the venous system, and place the catheter's tip in the right atrium at the beginning of the procedure. The advantage of this that the SA node is in the right atrium, which is the place where the procedure will start testing the pacing system of the heart.
Electrophysiology study
50
EP Study
Once the catheter is in and all preparations are complete elsewhere in the lab, the EP study begins. The two large magnets are brought in on either side of the patient. They are large and looming and will sandwich the patient, but are able to precisely control the position of the electrodes that are on the end of the catheters. The X-ray machine will give the doctor a view of the heart and the position of the electrodes, and the magnets will allow the doctor to guide the electrodes through the heart. The magnets are controlled with either a joystick or game controller. The electrophysiologist begins by moving the electrodes along the conduction pathways and along the inner walls of the heart, measuring the electrical activity along the way. The next step is pacing the heart, this means he/she will speed up or slow down the heart by placing the electrode at certain points along the conductive pathways of the heart and literally controlling the depolarization rate of the heart. The doctor will pace each chamber of the heart one by one, looking for any abnormalities. Then the electrophysiologist tries to provoke arrhythmias and reproduce any conditions that have resulted in the patient's placement in the study. This is done by injecting electric current into the conductive pathways and into the endocardium at various places. Lastly, the electrophysioligst may administer various drugs (proarrhythmic agents) to induce arrhythmia. If the arrhythmia is reproduced by the drugs, the electrophysiologist will search out the source of the abnormal electrical activity. The entire procedure can take several hours.
Ablation
If at any step during the EP study the electrophysiologist finds the source of the abnormal electrical activity, he/she may try to ablate the cells that are misfiring. This is done using high energy radio frequencies (similar to microwaves) to effectively "cook" the abnormal cells.
Recovery
When the necessary procedures are complete, the catheter is removed. Firm pressure is applied to the site to prevent bleeding. This may be done by hand or with a mechanical device. Other closure techniques include an internal suture and plug. If the femoral artery was used, the patient will probably be asked to lie flat for several hours (3 to 6) to prevent bleeding or the development of a hematoma. Trying to sit up or even lift the head is strongly discouraged until an adequate clot has formed. The patient will be moved to a recovery area where he/she will be monitored. For patients who had a catheterization at the femoral artery or vein (and even some of those with a radial insertion site), generally recovery is fairly quick as the only damage is at the insertion site. The patient will probably feel fine within 8 to 12 hours after the procedure, but may feel a small pinch at the insertion site. After a short period of general rest, the patient may resume some minor activity such as gentle, short, slow walks after the first 24 hours. If stairs must be climbed, they should be taken one step at a time and very slowly. All vigorous activity must be postponed until approved by an physician. It is also important to note that unless directed by a doctor, some patients should avoid taking blood thinners and foods that contain salicylates, such as cranberry containing products until the clot has healed. (12 weeks)
Complications
As with any surgical procedure, cardiac catheterizations come with a generic list of possible complications. One of the complications that is sometimes reported involves some temporary nerve involvement. Some times a small amount of swelling occurs that can put pressure on nerves in the area of the incision. There have been reports of patients feeling like they have hot fluid like blood or urine running down their leg for up to a month or two after the incision has healed. This usually passes with time, but patients should tell their doctor if they have these symptoms and if they last.
Electrophysiology study More severe but relatively rare complications include: damage or trauma to a blood vessel, which could require repair; infection from the skin puncture or from the catheter itself; cardiac perforation, causing blood to leak into the sac around the heart and compromising the heart's pumping action, requiring removal using a needle under the breast bone (pericardiocentesis); hematoma at the site(s) of the puncture(s); induction of a dangerous cardiac rhythm requiring an external shock(s); a clot may be dislodged, which may travel to a distant organ and impede blood flow or cause a stroke; myocardial infarction; unanticipated reactions to the medications used during the procedure; damage to the conduction system, requiring a permanent pacemaker; death.
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References
P wave
In electrocardiography, during normal atrial depolarization, the main electrical vector is directed from the SA node towards the AV node, and spreads from the right atrium to the left atrium. This turns into the P wave on the ECG. The P wave is upright in II, III, and aVF (since the general electrical activity is going toward the positive electrode in those leads), and inverted in aVR (since it is going away from the positive electrode for that lead). A P wave must be upright in leads II and aVF and inverted in lead aVR to designate a cardiac rhythm as sinus rhythm.
P wave
52
Clinical significance
With mild to moderate hyperkalemia, there is reduction of the size of the P wave The relationship between P waves and QRS complexes helps distinguish various cardiac arrhythmias: A prolonged P wave may indicate left atrial enlargement.[1] Left atrial enlargement can accompany mitral stenosis.[2] A P wave with increased amplitude can indicate hypokalemia.[3] It can also indicate right atrial enlargement.[4] A P wave with decreased amplitude can indicate hyperkalemia. Absence of the P wave may indicate atrial fibrillation. A saw tooth formed P wave may indicate atrial flutter. If P waves are not clearly delineated in the surface ECG, Lewis lead may be used to better visualize P waves.
References
[1] http:/ / www. uab. edu/ emig/ yellow_book/ yb_reading_ekg. htm [2] http:/ / emedicine. medscape. com/ article/ 155724-diagnosis [3] http:/ / www. uhmc. sunysb. edu/ internalmed/ nephro/ webpages/ Part_D. htm [4] http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson7/ index. html
Electrocardiography showing precordial leads in hyperkalemia, with small or indiscernible P waves.
QRS complex
The QRS complex is a name for the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the right and left ventricles of the human heart. In adults, it normally lasts 0.06 - 0.10 s; in children and during physical activity, it may be shorter. Typically an ECG has five deflections, arbitrarily named "P" to "T" waves. The Q, R, and S waves occur in rapid succession, do not all appear in all leads, and reflect a single event, and thus are usually considered together. A Q wave is any downward deflection after the P wave. An R wave follows as an upward deflection, and the S wave is any downward deflection after the R wave. The T wave follows the S wave, and in some cases an additional U wave follows the T wave.
Etiology
The His/Purkinje specialized muscle cells coordinate the depolarization of both ventricles, and if they are working efficiently the QRS complex is 80 to 120 ms in duration (represented by three small squares or less
QRS complex
53
at the standard paper speed of 25mm/s). Any abnormality of conduction takes longer and causes "widened" QRS complexes. In bundle branch block there can be an abnormal second upward deflection within the QRS complex, and in this case the second upward deflection is referred to as R' (pronounced "R prime"). This would be described as an RSR' pattern.
Diagram showing how the polarity of the QRS complex in leads I, II, and III can be used to estimate the heart's electrical axis in the frontal plane.
Ventricles contain more muscle mass than the atria; therefore the QRS complex is considerably larger than the P wave. The QRS complex is often used to determine the axis of the electrocardiogram (although it is also possible to determine a separate P wave axis). The duration, amplitude, and morphology of the QRS complex are useful in diagnosing cardiac arrhythmias, conduction abnormalities, ventricular hypertrophy, myocardial infarction, electrolyte derangements, and other disease states.
Parameters
Schematic representation of the QRS complex.
QRS complex
54
Parameter QRS duration QRS amplitude 0.06 - 0.10 sec
Normal value [1]
Value comments Shorter in children and in [2] tachycardia
Clinical significance Prolonged duration indicates e.g. hyperkalemia. or bundle branch block [3]
S amplitude in V1 + R amplitude in V5 < [2] 3.5 millivolt (mV) [2] R+S in a precordial lead < 4.5 mV R in V5 or V6 < 2.6 mV < 0.05sec in V5 or V6 [2] < 0.03sec in V1 [2]
Increased amplitude indicated cardiac hypertrophy
Ventricular activation time (VAT) Q wave
Measured in increased QRS amplitude
[2]
Duration less than 0.04 secs in leads other [4] than III and AVR [4] Amplitude less than 1/3 QRS amplitude (R+S) [4] Amplitude less than 1/4 of R wave
Abnormality indicates presence of infarction
[4]
The QRS complex is also included in estimating the QT interval.
Q wave
Normal Q waves, when present, represent depolarization of the interventricular septum. For this reason, they are referred to as septal Q waves and can be appreciated in the lateral leads I, aVL, V5 and V6.
R wave progression
Looking at the precordial leads, the r wave usually progresses from showing a rS-type complex in V1 with an increasing R and a decreasing S wave when moving towards the left side. There is usually an qR-type of complex in V5 and V6 with the R-wave amplitude usually taller in V5 than in V6. It is normal to have a narrow QS and rSr' patterns in V1, and so is also the case for qRs and R patterns in V5 and V6. The transition zone is where the QRS complex changes from predominately negative to predominately positive (R/S ratio becoming >1), and this usually occurs at V3 or V4. It is normal to have the transition zone at V2 (called "early transition"), and at V5 (called "delayed transition").[5] The definition of poor R wave progression (PRWP) varies in the literature, but a common one is when the R wave is less than 24mm in leads V3 or V4 and/or there is presence of a reversed R wave progression, which is defined as R in V4 < R in V3 or R in V3 < R in V2 or R in V2 < R in V1, or any combination of these.[5] Poor R wave progression is commonly attributed to anterior myocardial infarction, but it may also be caused by left bundle branch block, WolffParkinsonWhite syndrome, right and left ventricular hypertrophy as well as by faulty ECG recording technique.[5]
J-point
The point at which the QRS complex meets the ST segment is known as the J-point. The J-point is easy to identify when the ST segment is horizontal and forms a sharp angle with the last part of the QRS complex. However, when the ST segment is sloped or the QRS complex is wide, the two features do not form a sharp angle and the location of the J-point is less clear. There is no consensus on the precise location of the J-point in these circumstances.[6] Two possible definitions are: The "first point of inflection of the upstroke of the S wave" [6] The point at which the ECG trace becomes more horizontal than vertical.[7]
QRS complex
55
Monomorphic or polymorphic
Monomorphic refers to all QRS waves in a single lead being similar in shape. Polymorphic means that the QRS change from complex to complex.[8] These terms are used in the description of ventricular tachycardia.
Terminology
Not every QRS complex contains a Q wave, an R wave, and an S wave. By convention, any combination of these waves can be referred to as a QRS complex. However, correct interpretation of difficult ECGs requires exact labeling of the various waves. Some authors use lowercase and capital letters, depending on the relative size of each wave. For example, an Rs complex would be positively deflected, while an rS complex would be negatively deflected. If both complexes were labeled RS, it would be impossible to appreciate this distinction without viewing the actual ECG.
Various QRS complexes with nomenclature.
References
[1] III. Characteristics of the Normal ECG (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson3/ index. html) Frank G. Yanowitz, MD. Professor of Medicine. University of Utah School of Medicine. Retrieved on April 14, 2010 [2] Compendium for interpretation of ECG at Uppsala Institution for Clinical Physiology. Year 2010 [3] http:/ / www. umm. edu/ altmed/ drugs/ potassium-gluconate-104100. htm [4] Loyola University Chicago Stritch School of Medicine. > EKG Interpretive skills (http:/ / www. meddean. luc. edu/ lumen/ MedEd/ MEDICINE/ skills/ ekg/ les1prnt. htm) Retrieved on April 22, 2010 [5] Poor R-Wave Progression. By: Ross MacKenzie, MD. J Insur Med 2005;37:5862 (http:/ / www. aaimedicine. org/ journal-of-insurance-medicine/ jim/ 2005/ 037-01-0058. pdf) [6] Brownfield, J; Herbert, M (2008 Jan). "EKG Criteria for Fibrinolysis: What's Up with the J Point?". The western journal of emergency medicine 9 (1): 402. PMC2672223. PMID19561701. [7] http:/ / www. monroecc. edu/ depts/ PSTC/ backup/ parasec1. htm#JPT [8] Kenneth M Sutin; Marino, Paul L. (2007). The ICU book. Hagerstwon, MD: Lippincott Williams & Wilkins. pp.356. ISBN0-7817-4802-X.
QT interval
56
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles. A prolonged QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death.
Schematic representation of normal ECG trace (sinus rhythm), with waves, segments, and intervals labeled.
Correction for heart rate

The QT interval is dependent on the heart rate in an obvious way (the faster the heart rate the shorter the QT interval) and may be adjusted to The qt-time is normal, when it is less than half the rr-time. improve the detection of patients at increased risk of ventricular arrhythmia. Modern computer-based ECG machines can easily calculate a corrected QT, but this correction may not aid in the detection of patients at increased risk of arrhythmia. The standard clinical correction is to use Bazett's formula,[1] named after physiologist Henry Cuthbert Bazett, calculating the heart rate-corrected QT interval QTc. Bazett's formula is as follows: QTcB=QTRR where QTc is the QT interval corrected for heart rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds, often derived from the heart rate (HR) as 60/HR (here QT is measured in milliseconds). However, this nonlinear formula, obtained from data in only 39 young men, is not accurate, and over-corrects at high heart rates and under-corrects at low heart rates.[2] Fridericia[3] has published an alternative correction using the cuberoot of RR. QTcF=QT3RR There are several other methods as well. For example a regression-based approach that had been developed by Sagie et al.,[4] as follows: QTcL= QT + 0.154(1000-RR)
QT interval
57
Definitions of normal QTc varies around being equal to or less than 0.40 s (400ms),[5] 0.41s (410ms),[6] 0.42s (420ms)[7] or 0.44s (440ms).[8] For risk of sudden cardiac death "Borderline QTc" in males is 431-450 ms, and in females 451-470 ms. An "abnormal" QTc in males is a QTc above 450 ms, and in females, above 470 ms.[9] If there is not a very high or low heart rate, the upper limits of QT can Upper limit of normal QT interval, corrected for heart rate according to Bazett's [1] [3] formula , Fridericia's formula and subtracting 0.02s from QT for every 10bpm roughly be estimated by taking [5] increase in heart rate. Up to 0.42s (420ms) is chosen as normal QTc of QTf in this QT=QTc at a heart rate of 60 beats per diagram. minute (bpm), and subtracting 0.02s from QT for every 10bpm increase in heart rate. For example, taking normal QTc 0.42s, QT would be expected to be 0.42s or less at a heart rate of 60bpm. For a heart rate of 70 bpm, QT would roughly be expected to be equal to or below 0.40s. Likewise, for 80 bpm, QT would roughly be expected to be equal to or below 0.38s.[5]
Measurement
The QT interval is an important ECG parameter and the identification of ECGs with long QT syndrome is of clinical importance. Considering the required standards for precision, the measurement of QT interval is subjective.[10] This is because the end of the T wave is not always clearly defined and usually merges gradually with the baseline. QT interval in an ECG complex can be measured manually by different methods such as the threshold method, in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline or the tangent method, in which the end of the T wave is determined by the intersection of a line extrapolated from the isoelectric baseline and the tangent line, which touches the terminal part of the T wave at the point of maximum downslope.[11] With the increased availability of digital ECGs with simultaneous 12-channel recording, QT measurement may also done by the 'superimposed median beat' method. In the superimposed median beat method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset...[12]
QT interval
58
Abnormal intervals
If abnormally prolonged or shortened, there is a risk of developing ventricular arrhythmias.
Genetic causes
An abnormal prolonged QT interval could be due to Long QT syndrome, whereas an abnormal shortened QT interval could be due to Short QT syndrome. The length of the interval was found to associate with variations in NOS1AP gene.[13]
Due to adverse drug reactions

Prolongation of the QT interval may be due to an adverse drug reaction.[14] Many drugs such as haloperidol[15] and methadone can prolong the QT interval. Some antiarrhythmic drugs, like amiodarone or sotalol work by getting a pharmacological QT prolongation. Additionally, some second generation of antihistamines, such as astemizole, have this effect. Additionally, alcohol in high blood concentrations prolong the QT interval.[16]
Due to pathological conditions

Hypothyroidism, a condition of low function of the thyroid gland, can give QTc prolongation at the electrocardiogram. Acute hypocalcemia causes prolongation of the QT interval, which may lead to ventricular dysrhythmias. A shortened QT can be associated with hypercalcemia.[17]
Use in drug studies for FDA approval

Since 2005, the FDA and European regulators have required that nearly all new molecular entities are evaluated in a Thorough QT (TQT) study to determine a drug's effect on the QT interval.[18] The TQT study serves to assess the potential arrhythmia liability of a drug. Traditionally, the QT interval has been evaluated by having individual human readers measure approximately nine cardiac beats per clinical timepoint. However, a number of recent drug approvals have used a highly automated approach, blending automated software algorithms with expert human readers reviewing a portion of the cardiac beats, to enable the assessment of significantly more beats per timepoint in order to improve precision and reduce cost.[19] As the pharmaceutical industry has gained experience in performing TQT studies, it has also become evident that traditional QT correction formulas such as QTcF, QTcB, and QTcI may not always be suitable for evaluation of drugs impacting autonomic tone.[20] Current efforts are underway by industry and regulators to consider alternative methods to help evaluate QT liability in drugs affecting autonomic tone, such as QT beat-to-beat and Holter-bin methodologies.[21]
References
[1] Bazett HC. (1920). "An analysis of the time-relations of electrocardiograms". Heart (7): 353370. [2] Salvi V, Karnad DR, Panicker GK, Kothari S. (2010). "Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development". Br J Pharmacol. 159 (1): 3448. doi:10.1111/j.1476-5381.2009.00427.x. PMC2823350. PMID19775279. [3] Fridericia LS (1920). "The duration of systole in the electrocardiogram of normal subjects and of patients with heart disease". Acta Medica Scandinavica (53): 469486. [4] Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D (1992). "An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study)". Am J Cardiol 70 (7): 797801. doi:10.1016/0002-9149(92)90562-D. PMID1519533. [5] Lesson III. Characteristics of the Normal ECG (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson3/ index. html) Frank G. Yanowitz, MD. Professor of Medicine. University of Utah School of Medicine. Retrieved on Mars 23, 2010 [6] Loyola University Chicago Stritch School of Medicine > Medicine I (http:/ / www. meddean. luc. edu/ lumen/ MedEd/ MEDICINE/ skills/ ekg/ les1prnt. htm) By Matthew Fitz, M.D. Retrieved on Mars 23, 2010 [7] ecglibrary.com > A normal adult 12-lead ECG (http:/ / www. ecglibrary. com/ norm. html) Retrieved on Mars 23, 2010
QT interval
[8] Image for Cardiovascular Physiology Concepts > Electrocardiogram (EKG, ECG) (http:/ / www. cvphysiology. com/ Arrhythmias/ A009. htm) By Richard E Klabunde PhD [9] medscape.com > QTc Prolongation and Risk of Sudden Cardiac Death: Is the Debate Over? (http:/ / www. medscape. com/ viewarticle/ 522879) February 3, 2006 [10] Panicker GK, Karnad DR, Joshi R, Shetty S, Vyas N, Kothari S, Narula D (2009). "Z-score for benchmarking reader competence in a central ECG laboratory". Ann Noninvasive Electrocardiol 14 (14(1)): 1925. doi:10.1111/j.1542-474X.2008.00269.x. PMID19149789. [11] Panicker GK, Karnad DR, Natekar M, Kothari S, Narula D, Lokhandwala Y (2009). "Intra- and interreader variability in QT interval measurement by tangent and threshold methods in a central electrocardiogram laboratory". J Electrocardiol 42 (42(4)): 34852. doi:10.1016/j.jelectrocard.2009.01.003. PMID19261293. [12] Salvi V, Karnad DR, Panicker GK, Natekar M, Hingorani P, Kerkar V, Ramasamy A, de Vries M, Zumbrunnen T, Kothari S, Narula D (2011). "Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers". J Electrocardiol 44 (44(2)): 96104. doi:10.1016/j.jelectrocard.2010.11.010. PMID21238976. [13] Arking DE, Pfeufer A, Post W, Kao WH, Newton-Cheh C, Ikeda M, West K, Kashuk C, Akyol M, Perz S, Jalilzadeh S, Illig T, Gieger C, Guo CY, Larson MG, Wichmann HE, Marbn E, O'Donnell CJ, Hirschhorn JN, Kb S, Spooner PM, Meitinger T, Chakravarti A (June 2006). "A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization". Nat. Genet. 38 (6): 64451. doi:10.1038/ng1790. PMID16648850. [14] Leitch A, McGinness P, Wallbridge D (September 2007). "Calculate the QT interval in patients taking drugs for dementia". BMJ 335 (7619): 557. doi:10.1136/bmj.39020.710602.47. PMC1976518. PMID17855324. [15] "Information for Healthcare Professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate)" (http:/ / web. archive. org/ web/ 20071011025019/ http:/ / www. fda. gov/ cder/ drug/ InfoSheets/ HCP/ haloperidol. htm). Archived from the original (http:/ / www. fda. gov/ cder/ drug/ InfoSheets/ HCP/ haloperidol. htm) on 2007-10-11. . Retrieved 2007-09-18. [16] Willy Aaseb, Jan Erikssen, Jrgen Jonsbu and Knut Stavem. ECG changes in patients with acute ethanol intoxication. Scand Cardiovasc J, 41 (2) 79-84 (2007) [17] http:/ / www. clevelandclinicmeded. com/ medicalpubs/ diseasemanagement/ endocrinology/ hypercalcemia/ [18] http:/ / www. fda. gov/ downloads/ RegulatoryInformation/ Guidances/ UCM129357. pdf [19] http:/ / appliedclinicaltrialsonline. findpharma. com/ appliedclinicaltrials/ News/ iCardiac-Applies-Automated-Approach-to-Thorough-QT/ ArticleStandard/ Article/ detail/ 560528?contextCategoryId=44906& ref=25 [20] http:/ / thew-project. org/ document/ 2009%20THEW%20meeting/ Garnett. pdf [21] http:/ / thew-project. org/ document/ FDA%20CPI%20project. pdf
59
External links
Cardiac safety section in the Biopharmaceutical network (http://www.biopharmnet.com/cardiac.html)
ST segment
60
ST segment
In electrocardiography, the ST segment connects the QRS complex and the T wave and has a duration of 0.08 to 0.12 sec (80 to 120 ms). It starts at the J point (junction between the QRS complex and ST segment) and ends at the beginning of the T wave. However, since it is usually difficult to determine exactly where the ST segment ends and the T wave begins, the relationship between the RT segment and T wave should be examined together. The typical ST segment duration is usually around 0.08 sec (80 ms). It should be essentially level with the PR and TP segment. The ST segment represents the period when the ventricles are depolarized. It is isoelectric.
Interpretation
The normal ST segment has a slight upward concavity. Flat, downsloping, or depressed ST segments may indicate coronary ischemia. ST elevation may indicate myocardial infarction. An elevation of >1mm and longer than 80 milliseconds following the J-point. This measure has a false positive rate of 15-20% (which is slightly higher in women than men) and a false negative rate of 20-30%.[1] ST depression may be associated with hypokalemia or digitalis toxicity.[2]
References
[1] Sabatine MS (2000). Pocket Medicine (Pocket Notebook). Lippincott Williams & Wilkins. ISBN0-7817-1649-7. [2] http:/ / www. uab. edu/ emig/ yellow_book/ yb_reading_ekg. htm
T wave
61
T wave
In electrocardiography, the T wave represents the repolarization (or recovery) of the ventricles. The interval from the beginning of the QRS complex to the apex of the T wave is referred to as the absolute refractory period. The last half of the T wave is referred to as the relative refractory period (or vulnerable period). The T wave contains more information than the QT interval. The T wave can be described by its symmetry, skewness, slope of ascending and descending limbs, amplitude and subintervals like the TpeakTend interval [1] In most leads, the T wave is positive. However, a negative T wave is normal in lead aVR. Lead V1 may have a positive, negative, or biphasic (positive followed by negative, or vice versa) T wave. In addition, it is not uncommon to have an isolated negative T wave in lead III, aVL, or aVF.
Clinical significance
T-wave inversion (negative T waves) can be a sign of coronary ischemia, Wellens' syndrome, left ventricular hypertrophy, or CNS disorder. A periodic beat-to-beat variation in the amplitude or shape of the T wave may be termed T wave alternans. Tall and narrow ("peaked" or "tented") symmetrical T waves may indicate hyperkalemia.[2] Flat T waves (less than 1 mV in the limb leads and less than 2 mV in the precordial leads)[3] may indicate coronary ischemia or hypokalemia[3] The earliest electrocardiographic finding of ST-elevation MI (STEMI) acute myocardial infarction is sometimes the hyperacute T wave, which can be distinguished from hyperkalemia by the broad base and slight asymmetry. This may also be seen in Prinzmetal angina. When left bundle branch block is present, the T wave should be deflected opposite the terminal deflection of the QRS complex. This is known as appropriate T wave discordance.
Frequency of inverted T-waves in precordial leads (lead V1 to V6) according to gender and age
Numbers from Lepeschkin E in [4]
Age (ethnicity) Children 1 week - 1 y 1y-2y 2y-5y 5y-8y 8 y - 16 y Males 12 y - 13 y 209 47% 7% 0% 0% 0% 0% 210 92% 74% 154 96% 85% 202 98% 50% 94 90 91% 25% 62% 7% 27% 39% 22% 14% 2% 20% 10% 7% 5% 0% 0.5% 0% 0.7% 0% 1% 1% 0% 0% 1% 0% n V1 V2 V3 V4 V5 V6
T wave
62
13 y - 14 y 260 35% 4.6% 0.8% 0% 32% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%
16 y - 19 y (whites) 50
16 y - 19 y (blacks) 310 46% 7% 20 - 30 y (whites) 20 - 30 y (blacks) Females 12 y - 13 y 13 y - 14 y 174 69% 11% 285 41% 0% 295 37% 0%
2.9% 1.3% 0% 0% 0% 0% 0% 0% 0%
1.2% 0%
0% 0% 0%
0% 0% 0% 0% 0% 0%
154 52% 8.4% 1.4% 0% 66% 0% 0% 0%
16 y - 19 y (whites) 50 16 - 19 y (blacks) 20 - 30 y (whites) 20 - 30 y (blacks)
310 73% 9% 280 55% 0%
1.3% 0.6% 0% 0% 0% 0% 0% 0%
330 55% 2.4% 1%
References
[1] Haarmark C, Graff C, Andersen MP, et al. (2010). "Reference values of electrocardiogram repolarization variables in a healthy population". Journal of Electrocardiology 43 (1): 319. PMID19740481. [2] http:/ / www. uhmc. sunysb. edu/ internalmed/ nephro/ webpages/ Part_D. htm [3] Loyola University Chicago Stritch School of Medicine. > EKG Interpretive skills (http:/ / www. meddean. luc. edu/ lumen/ MedEd/ MEDICINE/ skills/ ekg/ les1prnt. htm) Retrieved on April 22, 2010 [4] Antaloczy, Z (1978). Modern Electrocardiology. Amsterdam: Excerpta Medica. pp.401.
Tilt table test
63
Tilt table test

Tilt table test
Intervention MeSH D018667 [1]
A tilt table test, occasionally called upright tilt testing,[2] is a medical procedure often used to diagnose dysautonomia or syncope. Patients with symptoms of dizziness or lightheadedness, with or without a loss of consciousness (fainting), suspected to be associated with a drop in blood pressure or positional tachycardia are good candidates for this test. The procedure tests for causes of syncope by attempting to cause syncope by having the patient lie flat on a special table or bed while connected to ECG and blood pressure monitors. The table then creates a change in posture from lying to standing.[2] [3]
Preparations
Before taking the test, the patient may be instructed to fast for a period before the test will take place and to stop taking any medications. On the day of the tilt table test, an intravenous line may be placed in case the patient needs to be given medication quickly; however, this may influence the results of the test and may only be indicated in particular circumstances. More recently, most investigators monitor cerebral perfusion using mean flow velocity recording with transcranial doppler ultrasound in supine horizontal position, during and after head-up tilt. An 18MHz ultrasound transducer is placed on the temporal bone above the cheekbone, using headgear to hold the probe in place.
Procedure
A tilt table test can be done in different ways and be modified for individual circumstances. In some cases, the patient will be strapped to a tilt table lying flat and then tilted or suspended completely or almost completely upright (as if standing). Most of the time, a patient is suspended at an angle of 60 to 80 degrees. Sometimes, the patient will be given a drug, such as glyceryl trinitrate or isoproterenol, to create further susceptibility to the test. In all cases, the patient is instructed not to move. Symptoms, blood pressure, pulse, electrocardiogram, and sometimes blood oxygen saturation are recorded. The test either ends when the patient faints or develops other significant symptoms, or after a set period (usually from 20 to 45 minutes, depending on the facility or individualized protocol).
Diagnostic symptoms
A tilt table test is considered positive if the patient experiences symptoms associated with a drop in blood pressure or cardiac arrhythmia. A normal person's blood pressure will not drop dramatically while standing, because the body will compensate for this posture with a slight increase in heart rate and constriction of the blood vessels in the legs. If this process does not function normally in the patient, the test could provoke signs and symptoms ranging from minor lightheadedness to a very severe cardiac episode, depending on the person. A common side effect during tilt table testing is a feeling of heaviness and warmth in the lower extremities. This is due to blood pooling in the legs and, to onlookers, the patient's lower extremities may appear blotchy, pink, or red. Dizziness or lightheadedness are also likely to occur in susceptible patients. Tilt table testing could provoke fainting or syncope; in fact, this is the purpose of the test. It may not be appropriate, or indeed even possible, to stop the test before this occurs, as the drop in blood pressure or pulse rate associated with fainting can come on in seconds. This
Tilt table test is why the patient's blood pressure and ECG should be continuously monitored during the test. In extreme cases, tilt table testing could provoke seizures or even cause the heart to stop. The heart resumes beating normally upon being returned to a flat or head-down position. If at any time in tilt table testing a patient loses consciousness, he or she will be returned to a supine or head down position and will be given immediate medical attention, which could include being given fluids or perhaps atropine or adrenaline.
64
Applications
These findings suggest a positive induced cardiovascular training effect in the fighter pilots group. Repetitive exposure to higher G forces results in an increased resting mean arterial pressure and an elevated heart rate response to tilt table tests, which may provide benefits to operational fighter pilots.[4] Head-up tilt table testing can be used to evaluate autonomic dysfunction and is frequently helpful for the work-up of fibromyalgia (FM) complaints, including fatigue, dizziness, and palpitations. One of the most common events experienced by FM patients during tilt table testing is postural orthostatic tachycardia syndrome (POTS) which is defined as a heart rate increase of more than 30 beats per minute after more than three minutes of standing upright.[5] In a study of adolescents, chronic fatigue syndrome (CFS) subjects were more susceptible to orthostatic intolerance (OI) than controls, the cardiovascular response predominantly manifest as POTS without hypotension, a response unique to CFS suggesting further investigation is warranted with respect to the pathophysiologic mechanisms involved.[6] It has recently shown that CFS is associated with a short corrected electrocardiographic QT interval (QTc). A relatively short QTc and positive HIS distinguish CFS patients from FM patients. These data may support the contention that FM and CFS are separate disorders.[7] The head-up tilt table test reveals a particular dysautonomia in CFS patients that differs from other conditions and is useful in supporting the diagnosis of CFS. Furthermore, these studies indicate that the test is an objective means of monitoring the course and management of CFS.[8] [9]
References
[1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D018667 http:/ / www. rush. edu/ rumc/ page-P06558. html http:/ / www. metrohealth. org/ body. cfm?id=282 Newman DG, Callister R (August 2008). "Cardiovascular training effects in fighter pilots induced by occupational high G exposure". Aviat Space Environ Med 79 (8): 7748. doi:10.3357/ASEM.1575.2008. PMID18717117. Staud R (December 2008). "Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia". Curr Rheumatol Rep 10 (6): 4636. doi:10.1007/s11926-008-0076-8. PMID19007537. Galland BC, Jackson PM, Sayers RM, Taylor BJ (February 2008). "A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome". Pediatr. Res. 63 (2): 196202. doi:10.1203/PDR.0b013e31815ed612. PMID18091356. Naschitz JE, Slobodin G, Sharif D, et al. (May 2008). "Electrocardiographic QT interval and cardiovascular reactivity in fibromyalgia differ from chronic fatigue syndrome". Eur. J. Intern. Med. 19 (3): 18791. doi:10.1016/j.ejim.2007.08.003. PMID18395162. Naschitz JE, Sabo E, Dreyfuss D, Yeshurun D, Rosner I (November 2003). "The head-up tilt test in the diagnosis and management of chronic fatigue syndrome". Isr. Med. Assoc. J. 5 (11): 80711. PMID14650107. Naschitz JE, Rosner I, Rozenbaum M, et al. (February 2003). "The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome" (http:/ / qjmed. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=12589011). QJM 96 (2): 13342. doi:10.1093/qjmed/hcg018. PMID12589011. .
Tilt table test
65
External links
2004 European Society of Cardiology Guidelines on Management (Diagnosis and Treatment) of Syncope. (http:// www.escardio.org/guidelines-surveys/esc-guidelines/Pages/syncope.aspx) University of Michigan: Tilt Table Testing (http://www.med.umich.edu/1libr/chheart/noninv13.htm) Head-Upright Tilt Table Testing (http://www.postgradmed.com/issues/1998/01_98/grubb.htm) Tilt Table Testing (http://heartdisease.about.com/cs/syncope/a/tilttabltesting.htm) Tilt Table Test information (http://heartcenter.seattlechildrens.org/what_to_expect/tilt_table_test.asp) from Children's Hospital Heart Center, Seattle
Holter monitor
66
Holter monitor
Holter monitor
Holter monitor Inventor Norman Holter
In medicine, a Holter monitor (often simply "Holter" or occasionally ambulatory electrocardiography device) is a portable device for continuously monitoring various electrical activity of the cardiovascular system for at least 24 hours (often for two weeks at a time). The Holter's most common use is for monitoring heart activity (electrocardiography or ECG), but it can also be used for monitoring brain activity (electroencephalography or EEG). Its extended recording period is sometimes useful for observing occasional cardiac arrhythmias or epileptic events which would be difficult to identify in a shorter period of time. For patients having more transient symptoms, a cardiac event monitor which can be worn for a month or more can be used. The Holter monitor is named for physicist Norman J. Holter who invented telemetric cardiac monitoring in 1949.[1] Clinical use started in the early 1960s.[1] When used for the heart, much like standard electrocardiography the Holter monitor records electrical signals from the heart via a series of electrodes attached to the chest. Electrodes are placed over bones to minimize artifacts from muscular activity. The number and position of electrodes varies by model, but most Holter monitors employ between three and eight. These electrodes are connected to a small piece of equipment that is attached to the patient's belt or hung around the neck, and is responsible for keeping a log of the heart's electrical activity throughout the recording period. Older devices used reel to reel tapes or a standard C90 or C120 audio cassette and ran at a 1.7mm or 2mm/second speed to record the data. Once a recording was made, it could be played back and analysed at 60x speed so 24 hours of recording could be analysed in 24 minutes. More modern units record onto digital flash memory devices. The data are uploaded into a computer which then automatically analyzes the input, counting ECG complexes, calculating summary statistics such as average heart rate, minimum and maximum heart rate, and finding candidate areas in the recording worthy of further study by the technician.
Holter monitor
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Recorder
Each Holter system consists of two basic parts the hardware (called monitor or recorder) for recording the signal and software for review and analysis of the record. Advanced Holter recorders are able to display the signal, which is very useful for checking the signal quality. Very often there is also a patient button located on the front site allowing the patient to press it in specific cases such as sickness, going to bed, taking pills. A special mark will be then placed into the record so that the doctors or technicians can quickly pinpoint these areas when analyzing the signal. More modern devices also have the ability to record a vocal patient diary entry. Size of recorder differs depending on manufacturer of the device. The average dimensions of todays Holter monitors are about 110x70x30 mm. Most of the devices operate with two AA batteries. In case the batteries are depleted, some Holters allow their replacement even during monitoring. Most of the Holters monitor the ECG just in two or three channels. Depending on the model (manufacturer), different count of leads and lead systems are used. Todays trend is to minimize such number to insure the patients comfort during recording. Although 2/3 channel recording has been used for a long time in the Holter monitoring history, recently 12 channel Holters have appeared. These systems use the classic Mason-Likar lead system, thus producing the signal in the same representation as during the common rest ECG and/or stress test measurement. These Holters then allow to substitute stress test examination in cases the stress test is not possible for the current patient. They are also suitable when analyzing patients after myocardial infarction. Recordings from these 12-lead monitors are of a significantly lower resolution than those from a standard 12-lead ECG and in some cases have been shown to provide misleading ST segment representation, even though some device allow to set the sampling frequency up to 1000 Hz for special purposes exams like the late potential. Another interesting innovation is the presence of a triaxial movement sensor, which record the patient physical activity, and later show in the software three different status: sleep, stand-up, walking. This helps the cardiologist to better analyze the recorded events belong to the patient activity and diary.
Analysing software
When the recording of ECG signal is finished (usually after 24 or 48 hours), it is up to the physician to perform the signal analysis. Since it would be extremely time demanding to browse through such a long signal, there is an integrated automatic analysis process in each Holter software which automatically determines different sorts of heart beats, rhythms, etc. However the success of the automatic analysis is very closely associated with the signal quality. The quality itself mainly depends on the attachment of the electrodes to the patient body. If these are not properly attached, the electromagnetic disturbance surrounding us will influence the ECG signal resulting thus in a very noisy record. If the patient moves rapidly, the distortion will be even bigger. Such record is then very difficult to process. Besides the attachment and quality of electrodes, there are other factors affecting the signal quality, such as muscle tremors, sampling rate and resolution of the digitized signal (high quality devices offer 2000Hz and 16 bits or higher). The automatic analysis commonly provides the physician with information about heart beat morphology, beat interval measurement, heart rate variability, rhythm overview and patient diary (moments when the patient pressed the patient button). Advanced systems also perform spectral analysis, ischemic burden evaluation, graph of patients activity or PQ segment analysis. Another requirement is the ability of pacemaker detection and analysis. Such ability is useful when one wants to check the correct pacemaker function.
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68
Screenshot of Holter ECG software.
Wearing the monitor

Although some patients may feel uncomfortable about a Holter examination, there is nothing to worry about. No hazards are involved, and it should have little effect on one's normal daily life. The recording device can be worn in a case on a belt or on a strap across the chest. The device may be visible under light clothing, and those wearing a Holter monitor may wish to avoid shirts with a low neckline. Persons being monitored should not limit normal daily activities,since its purpose is to record how a heart works under various actual conditions over an extended period. It is an electrical device, however, and should be kept dry; showering or swimming should probably be avoided. Monitors can be removed for a few minutes without invalidating collected data, but proper reattachment is critical to avoid degradation of its signals. Beyond changing batteries, one should leave its handling to trained personnel.
Gallery
A Holter monitor can be worn for many days without causing significant discomfort.
Canine Holter Monitor with DogLeggs Vest
A Holter monitor with a US quarter dollar coin to show scale
Holter monitor can be worn with bra on woman, with no discomfort.
Holter monitor
69
References
[1] Hilbel, Thomas; Thomas M Helms, Gerd Mikus, Hugo A Katus, Christian Zugck (01/10/2008). "Telemetry in the clinical setting" (https:/ / www. researchgate. net/ publication/ 23423927_Telemetry_in_the_clinical_setting). Herzschrittmachertherapie & Elektrophysiologie 19 (3): 14664. ISSN0938-7412. . Retrieved 2009-Aug-04.
External links
Holter monitor - MedLine Plus (http://www.nlm.nih.gov/medlineplus/ency/article/003877.htm) Holter monitor - Texas Heart Institute (http://www.texasheart.org/HIC/Topics/Diag/diholt.cfm) Holter Monitor information (http://heart.seattlechildrens.org/what_to_expect/holter_monitor.asp) from Children's Hospital Heart Center, Seattle.
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Dysrythmia
Cardiac dysrhythmia
Cardiac dysrhythmia
Classification and external resources
Ventricular fibrillation (V-Fib or VF) an example of cardiac arrhythmia. ICD-10 ICD-9 DiseasesDB MedlinePlus MeSH I47 427 [1] [3] [4] [5] [6] - I49 [2]
15206
001101
D001145
Cardiac dysrhythmia (also known as arrhythmia and irregular heartbeat) is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular. Some arrhythmias are life-threatening medical emergencies that can result in cardiac arrest and sudden death. Others cause symptoms such as an abnormal awareness of heart beat (palpitations), and may be merely annoying. These palpitations have also been known to be caused by atrial/ventricular fibrillation, wire faults, and other technical or mechanical issues in cardiac pacemakers/defibrillators. Still others may not be associated with any symptoms at all, but may predispose the patient to potentially life threatening stroke or embolism. Some arrhythmias are very minor and can be regarded as normal variants. In fact, most people will on occasion feel their heart skip a beat, or give an occasional extra strong beat; neither of these is usually a cause for alarm.[7] Proarrhythmia is a new or more frequent occurrence of pre-existing arrhythmias, paradoxically precipitated by antiarrhythmic therapy, which means it is a side effect associated with the administration of some existing antiarrhythmic drugs, as well as drugs for other indications. In other words, it is a tendency of antiarrhythmic drugs to facilitate emergence of new arrhythmias. The term sinus arrhythmia refers to a normal phenomenon of mild acceleration and slowing of the heart rate that occurs with breathing in and out. It is usually quite pronounced in children, and steadily decreases with age. This can also be present during meditation breathing exercises that involve deep inhaling and breath holding patterns.
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Classification
Arrhythmia may be classified by rate (normal, tachycardia, bradycardia), or mechanism (automaticity, reentry, fibrillation). It is also appropriate to classify by site of origin:
Atrial
Premature Atrial Contractions (PACs) Wandering Atrial Pacemaker Multifocal atrial tachycardia Atrial flutter Atrial fibrillation (Afib)
Junctional arrhythmias
Supraventricular tachycardia (SVT) AV nodal reentrant tachycardia is the most common cause of Paroxysmal Supra-ventricular Tachycardia (PSVT) Junctional rhythm Junctional tachycardia Premature junctional complex
Ventricular
Premature Ventricular Contractions (PVC) sometimes called Ventricular Extra Beats (VEBs) Premature Ventricular beats occurring after every normal beat are termed "ventricular bigeminy" PVCs that occur at intervals of 2 normal beats to 1 PVC are termed "PVCs in trigeminy" Three premature ventricular grouped together is termed a "run of PVCs"; runs lasting longer than three beats are generally referred to as ventricular tachycardia Accelerated idioventricular rhythm Monomorphic Ventricular tachycardia Polymorphic ventricular tachycardia Ventricular fibrillation
Heart blocks
These are also known as AV blocks, because the vast majority of them arise from pathology at the atrioventricular node. They are the most common causes of bradycardia: First degree heart block, which manifests as PR prolongation Second degree heart block Type 1 Second degree heart block, also known as Mobitz I or Wenckebach Type 2 Second degree heart block, also known as Mobitz II Third degree heart block, also known as complete heart block.
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SADS
SADS, or sudden arrhythmic death syndrome, is a term used to describe sudden death due to cardiac arrest brought on by an arrhythmia in the absence of any structural heart disease on autopsy. The most common cause of sudden death in the US is coronary artery disease. Approximately 300,000 people die suddenly of this cause every year in the US. SADS occurs from other causes. There are many inherited conditions and heart diseases that can affect young people and subsequently cause sudden death. Many of these victims have no symptoms before dying suddenly. Causes of SADS in young people include viral myocarditis, long QT syndrome, Brugada syndrome, Catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia.
Signs and symptoms

The term cardiac arrhythmia covers a very large number of very different conditions. The most common symptom of arrhythmia is an abnormal awareness of heartbeat, called palpitations. These may be infrequent, frequent, or continuous. Some of these arrhythmias are harmless (though distracting for patients) but many of them predispose to adverse outcomes. Some arrhythmias do not cause symptoms, and are not associated with increased mortality. However, some asymptomatic arrhythmias are associated with adverse events. Examples include a higher risk of blood clotting within the heart and a higher risk of insufficient blood being transported to the heart because of weak heartbeat. Other increased risks are of embolisation and stroke, heart failure and sudden cardiac death. If an arrhythmia results in a heartbeat that is too fast, too slow or too weak to supply the body's needs, this manifests as a lower blood pressure and may cause lightheadedness or dizziness, or fainting. Some types of arrhythmia result in cardiac arrest, or sudden death. Medical assessment of the abnormality using an electrocardiogram is one way to diagnose and assess the risk of any given arrhythmia.
Differential diagnosis
Normal electrical activity
Each heart beat originates as an electrical impulse from a small area of tissue in the right atrium of the heart called the sinus node or Sino-atrial node or SA node. The impulse initially causes both atria to contract, then activates the atrioventricular (or AV) node which is normally the only electrical connection between the atria and the ventricles (main pumping chambers). The impulse then spreads through both ventricles via the Bundle of His and the Purkinje fibres causing a synchronised contraction of the heart muscle and, thus, the pulse. In adults the normal resting heart rate ranges from 60 to 80 beats per minute. The resting heart rate in children is much faster.
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Bradycardias
A slow rhythm (less than 60 beats/min), is labelled bradycardia. This may be caused by a slowed signal from the sinus node (sinus bradycardia), a pause in the normal activity of the sinus node (sinus arrest), or by blocking of the electrical impulse on its way from the atria to the ventricles (AV block or heart block). Heart block comes in varying degrees and severity. It may be caused by reversible poisoning of the AV node (with drugs that impair conduction) or by irreversible damage to the node. Bradycardias may also be present in the normally functioning heart of endurance athletes or other well-conditioned persons.
Tachycardias
Normal sinus rhythm, with solid black arrows pointing to normal P waves representative of normal sinus node function, followed by a pause in sinus node activity (resulting in a transient loss of heart beats). Note that the P wave that disrupts the pause (indicated by the dashed arrow) does not look like the previous (normal) P waves this last P wave is arising from a different part of the atrium, representing an escape rhythm.
In adults and children over 15, resting heart rate faster than 100 beats/minute is labelled tachycardia. Tachycardia may result in palpitation; however, tachycardia is not necessarily an arrhythmia. Increased heart rate is a normal response to physical exercise or emotional stress. This is mediated by the sympathetic nervous system on the sinus node and called sinus tachycardia. Other things that increase sympathetic nervous system activity in the heart include ingested or injected substances, such as caffeine or amphetamines, and an overactive thyroid gland (hyperthyroidism). Tachycardia that is not sinus tachycardia usually results from the addition of abnormal impulses to the normal cardiac cycle. Abnormal impulses can begin by one of three mechanisms: automaticity, reentry or triggered activity. A specialised form of re-entry problem is termed fibrillation.
Automaticity
Automaticity refers to a cardiac muscle cell firing off an impulse on its own. All of the cells in the heart have the ability to initiate an action potential; however, only some of these cells are designed to routinely trigger heart beats. These cells are found in the conduction system of the heart and include the SA node, AV node, Bundle of His and Purkinje fibers. The sinoatrial node is a single specialized location in the atrium which has a higher automaticity (a faster pacemaker) than the rest of the heart and, therefore, is usually responsible for setting the heart rate and initiating each heart beat. Any part of the heart that initiates an impulse without waiting for the sinoatrial node is called an ectopic focus and is, by definition, a pathological phenomenon. This may cause a single premature beat now and then, or, if the ectopic focus fires more often than the sinoatrial node, it can produce a sustained abnormal rhythm. Rhythms produced by an ectopic focus in the atria, or by the atrioventricular node, are the least dangerous dysrhythmias; but they can still produce a decrease in the heart's pumping efficiency, because the signal reaches the various parts of the heart muscle with different timing to usual and can be responsible for poorly coordinated contraction. Conditions that increase automaticity include sympathetic nervous system stimulation and hypoxia. The resulting heart rhythm depends on where the first signal begins: If it is the sinoatrial node, the rhythm remains normal but rapid; if it is an ectopic focus, many types of dysrhythmia may ensue.
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Re-entry
Re-entry arrhythmias occur when an electrical impulse recurrently travels in a tight circle within the heart, rather than moving from one end of the heart to the other and then stopping.[8] Every cardiac cell is able to transmit impulses in every direction but will only do so once within a short time. Normally, the action potential impulse will spread through the heart quickly enough that each cell will only respond once. However, if conduction is abnormally slow in some areas (for example in heart damage) so the myocardial cells are unable to activate the fast sodium channel, part of the impulse will arrive late and potentially be treated as a new impulse. Depending on the timing, this can produce a sustained abnormal circuit rhythm. Re-entry circuits are responsible for atrial flutter, most paroxysmal supraventricular tachycardia, and dangerous ventricular tachycardia. These types of re-entry circuits are different from WPW syndromes in which the real pathways existed.
Fibrillation
When an entire chamber of the heart is involved in a multiple micro-reentry circuits and, therefore, quivering with chaotic electrical impulses, it is said to be in fibrillation. Fibrillation can affect the atrium (atrial fibrillation) or the ventricle (ventricular fibrillation); ventricular fibrillation is imminently life-threatening. Atrial fibrillation affects the upper chambers of the heart, known as the atria. Atrial fibrillation may be due to serious underlying medical conditions and should be evaluated by a physician. It is not typically a medical emergency. Ventricular fibrillation occurs in the ventricles (lower chambers) of the heart; it is always a medical emergency. If left untreated, ventricular fibrillation (VF, or V-fib) can lead to death within minutes. When a heart goes into V-fib, effective pumping of the blood stops. V-fib is considered a form of cardiac arrest. An individual suffering from it will not survive unless cardiopulmonary resuscitation (CPR) and defibrillation are provided immediately. CPR can prolong the survival of the brain in the lack of a normal pulse, but defibrillation is the only intervention that can restore a healthy heart rhythm. Defibrillation is performed by applying an electric shock to the heart, which resets the cells, permitting a normal beat to re-establish itself.
Triggered beats
Triggered beats occur when problems at the level of the ion channels in individual heart cells result in abnormal propagation of electrical activity and can lead to sustained abnormal rhythm. They are relatively rare and can result from the action of anti-arrhythmic drugs.
Diagnostic approach
Cardiac dysrhythmias are often first detected by simple but nonspecific means: auscultation of the heartbeat with a stethoscope, or feeling for peripheral pulses. These cannot usually diagnose specific dysrhythmias, but can give a general indication of the heart rate and whether it is regular or irregular. Not all the electrical impulses of the heart produce audible or palpable beats; in many cardiac arrhythmias, the premature or abnormal beats do not produce an effective pumping action and are experienced as "skipped" beats. The simplest specific diagnostic test for assessment of heart rhythm is the electrocardiogram (abbreviated ECG or EKG). A Holter monitor is an EKG recorded over a 24-hour period, to detect dysrhythmias that may happen briefly and unpredictably throughout the day. A more advanced study of the heart's electrical activity can be performed to assess the source of the aberrant heart beats. This can be accomplished in an Electrophysiology study. A minimally invasive procedure that uses a catheter to "listen" to the electrical activity from within the heart, additionally if the source of the arrhythmias is found, often the abnormal cells can be ablated and the arrhythmia can be permanently corrected.
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Management
The method of cardiac rhythm management depends firstly on whether or not the affected person is stable or unstable. Treatments may include physical maneuvers, medications, electricity conversion, or electro or cryo cautery.
Physical maneuvers
A number of physical acts can increase parasympathetic nervous supply to the heart, resulting in blocking of electrical conduction through the AV node. This can slow down or stop a number of arrhythmias that originate above or at the AV node (see main article: supraventricular tachycardias). Parasympathetic nervous supply to the heart is via the vagus nerve, and these maneuvers are collectively known as vagal maneuvers.
Antiarrhythmic drugs
There are many classes of antiarrhythmic medications, with different mechanisms of action and many different individual drugs within these classes. Although the goal of drug therapy is to prevent arrhythmia, nearly every antiarrhythmic drug has the potential to act as a pro-arrhythmic, and so must be carefully selected and used under medical supervision.
Other drugs
A number of other drugs can be useful in cardiac arrhythmias. Several groups of drugs slow conduction through the heart, without actually preventing an arrhythmia. These drugs can be used to "rate control" a fast rhythm and make it physically tolerable for the patient. Some arrhythmias promote blood clotting within the heart, and increase risk of embolus and stroke. Anticoagulant medications such as warfarin and heparins, and anti-platelet drugs such as aspirin can reduce the risk of clotting.
Electricity
Dysrhythmias may also be treated electrically, by applying a shock across the heart either externally to the chest wall, or internally to the heart via implanted electrodes. Cardioversion is either achieved pharmacologically or via the application of a shock synchronised to the underlying heartbeat. It is used for treatment of supraventricular tachycardias. In elective cardioversion, the recipient is usually sedated or lightly anesthetized for the procedure. Defibrillation differs in that the shock is not synchronised. It is needed for the chaotic rhythm of ventricular fibrillation and is also used for pulseless ventricular tachycardia. Often, more electricity is required for defibrillation than for cardioversion. In most defibrillation, the recipient has lost consciousness so there is no need for sedation. Defibrillation or cardioversion may be accomplished by an implantable cardioverter-defibrillator (ICD). Electrical treatment of dysrhythmia also includes cardiac pacing. Temporary pacing may be necessary for reversible causes of very slow heartbeats, or bradycardia, (for example, from drug overdose or myocardial infarction). A permanent pacemaker may be placed in situations where the bradycardia is not expected to recover.
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Electrical cautery
Some cardiologists further sub-specialise into electrophysiology. In specialised catheter laboratories, they use fine probes inserted through the blood vessels to map electrical activity from within the heart. This allows abnormal areas of conduction to be located very accurately, and subsequently destroyed with heat, cold, electrical or laser probes. This may be completely curative for some forms of arrhythmia, but for others, the success rate remains disappointing. AV nodal reentrant tachycardia is often curable. Atrial fibrillation can also be treated with this technique (e.g. pulmonary vein isolation), but the results are less reliable.
References
[1] [2] [3] [4] [5] [6] [7] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I47 http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I49 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427 http:/ / www. diseasesdatabase. com/ ddb15206. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001101. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D001145 familydoctor.org (http:/ / familydoctor. org/ online/ famdocen/ home/ articles/ 286. html)
[8] Allessie MA, Bonke FI, Schopman FJ (August 1976). "Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes". Circ. Res. 39 (2): 16877. PMID939001.
External links
Cardiac dysrhythmia (http://www.dmoz.org/Health/Conditions_and_Diseases/Cardiovascular_Disorders/ Heart_Disease/Arrhythmia//) at the Open Directory Project
Palpitation
77
Palpitation
Palpitation
ICD-10 ICD-9 DiseasesDB R00.2 785.1 29231 [1] [2] [3]
MedlinePlus 003081 [4] eMedicine aaem/337 [5]
A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating,[6] whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself.[7] It can be caused by (but should not be confused with) ectopic beat, which is a more specific diagnosis. The difference between an abnormal awareness and a normal awareness is that the former interrupts other thoughts, whereas the latter is almost always caused by a concentration on the beating of one's heart. Palpitations may be brought on by overexertion, adrenaline, alcohol, nicotine, caffeine, cocaine, amphetamines, and other drugs, disease (such as hyperthyroidism and pheochromocytoma) or as a symptom of panic disorder. More colloquially, it can also refer to a shaking motion. It can also happen in mitral stenosis. Nearly everyone experiences an occasional awareness of their heart beating, but when it occurs frequently, it can indicate a problem. Palpitations may be associated with heart problems, but also with anemias and thyroid malfunction. Attacks can last for a few seconds or hours, and may occur very infrequently, or more than daily. Palpitations alongside other symptoms, including sweating, faintness, frequent headaches, chest pain or dizziness, indicate irregular or poor heart function and should be investigated. Palpitations may also be associated with anxiety and panic attacks, in which case psychological assessment is recommended. This is a common disorder associated with many common medications such as anti-depressants. Palpitations can also occur from blood loss, excessive pain, or lack of oxygen.
Causes
Palpitations can be attributed to one of three main causes: 1. Hyperdynamic circulation (valvular incompetence, thyrotoxicosis, hypercapnia, pyrexia, anemia, pregnancy). 2. Sympathetic overdrive (panic disorders, hypoglycemia, hypoxia, levocetirizine antihistamines, anemia, heart failure, mitral valve prolapse).[8] 3. Cardiac dysrhythmias (premature atrial contraction, junctional escape beat, premature ventricular contraction, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, heart block). Anxiety can also cause palpitations in that the heart muscles are affected by the state of one's mind. Psychological problems can thus induce one to palpitate. Clinicians should therefore consider the psycho-social aspect before diagnosis.
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78
Symptoms
Many times, the person experiencing palpitations may not be aware of anything apart from the abnormal heart rhythm itself. But palpitations can be associated with other things such as tightness in the chest, shortness of breath, dizziness or light-headedness. Depending on the type of rhythm problem, these symptoms may be just momentary or more prolonged. Actual blackouts or near blackouts, associated with palpitations, should be taken seriously because they often indicate the presence of important underlying heart disease. Another symptom is pain in arms or legs sometimes lasting through the night after the palpitation.
Diagnosis
The most important initial clue to the diagnosis is one's description of the palpitations. The approximate age of the person when first noticed and the circumstances under which they occur are important, as is information about caffeine intake (tea or coffee drinking). It is also very helpful to know how they start and stop (abruptly or not), whether or not they are regular, and approximately how fast the pulse rate is during an attack. If the person has discovered a way of stopping the palpitations, that is also helpful information. The diagnosis is usually not made by a routine medical examination and electrical tracing of the heart's activity (ECG), because most people cannot arrange to have their symptoms while visiting the doctor. Nevertheless, findings such as a heart murmur or an abnormality of the ECG, which could point to the probable diagnosis, may be discovered. In particular, ECG changes that can be associated with specific disturbances of the heart rhythm may be picked up; so routine physical examination and ECG remain important in the assessment of palpitations. Blood tests, particularly tests of thyroid gland function are also important baseline investigations (an overactive thyroid gland is a potential cause for palpitations; the treatment in that case is to treat the thyroid gland over-activity). The next level of diagnostic testing is usually 24 hour (or longer) ECG monitoring, using a form of tape recorder called a Holter monitor, which can record the ECG continuously during a 24-hour period. If symptoms occur during monitoring it is a simple matter to examine the ECG recording and see what the cardiac rhythm was at the time. For this type of monitoring to be helpful, the symptoms must be occurring at least once a day. If they are less frequent, the chances of detecting anything with continuous 24, or even 48-hour monitoring, are substantially lowered. Other forms of monitoring are available, and these can be useful when symptoms are infrequent. A continuous-loop event recorder monitors the ECG continuously, but only saves the data when the wearer activates it. Once activated, it will save the ECG data for a period of time before the activation and for a period of time afterwards - the cardiologist who is investigating the palpitations can program the length of these periods. A new type of continuous-loop recorder has been developed recently that may be helpful in people with very infrequent, but disabling symptoms. This recorder is implanted under the skin on the front of the chest, like a pacemaker. It can be programmed and the data examined using an external device that communicates with it by means of a radio signal. Investigation of heart structure can also be important. The heart in most people with palpitations is completely normal in its physical structure, but occasionally abnormalities such as valve problems may be present. Usually, but not always, the cardiologist will be able to detect a murmur in such cases, and an ultrasound scan of the heart (echocardiogram) will often be performed to document the heart's structure. This is a painless test performed using sound waves and is virtually identical to the scanning done in pregnancy to look at the fetus.
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79
References
[1] [2] [3] [4] [5] [6] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ R00. 2 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=785. 1 http:/ / www. diseasesdatabase. com/ ddb29231. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003081. htm http:/ / www. emedicine. com/ aaem/ topic337. htm " palpitation (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ six/ 000077604. htm)" at Dorland's Medical Dictionary [7] (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003081. htm) [8] MedlinePlus Medical Encyclopedia: Heart palpitations (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003081. htm)
External links
Medic8 Family Health Guide (http://www.medic8.com/healthguide/articles/palpitations.html) MedlinePlus Medical Encyclopedia, NIH (http://www.nlm.nih.gov/medlineplus/ency/article/003081.htm) Arrhythmia (palpitations) (http://hcd2.bupa.co.uk/fact_sheets/html/arrhythmia.html) Heart Palpitations (http://health.nytimes.com/health/guides/symptoms/heart-palpitations/overview.html) Irregular heartbeat (http://www.medicinenet.com/arrhythmia_irregular_heartbeat/article.htm)
Abnormal Heart Rhythm (Arrhythmia) (http://www.webmd.com/heart-disease/guide/ heart-disease-abnormal-heart-rhythm)
Tachycardia
80
Tachycardia
Tachycardia
ECG showing sinus tachycardia with a rate of about 100 beats per minute. ICD-10 ICD-9 MeSH I47 427 [1] -I49 [2] , R00.0 [2] [1]
[3]
, 785.0 [3]
D013610
Tachycardia comes from the Greek words tachys (rapid or accelerated) and kardia (of the heart). Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate (heart rate in an inactive or sleeping individual). It can be dangerous depending on the speed and type of rhythm.
Definition
The upper threshold of a normal human heart rate is based upon age. Tachycardia for different age groups is as listed below:[4] 12 days: >159 beats per minute (bpm) 36 days: >166 bpm 13 weeks: >182 bpm 12 months: >179 bpm 35 months: >186 bpm 611 months: >169 bpm 12 years: >151 bpm 34 years: >137 bpm 57 years: >133 bpm 811 years: >130 bpm 1215 years: >119 bpm >15 years adult: >100 bpm
When the heart beats excessively rapidly, the heart pumps less efficiently and provides less blood flow to the rest of the body, including the heart itself. The increased heart rate also leads to increased work and oxygen demand by the heart, which can lead to rate related ischemia.[5]
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Differential diagnosis
An electrocardiogram (ECG) is used to classify the type of tachycardia. They may be classified into narrow and wide complex based on the QRS complex.[6] Presented in the order of most to least common they are:[6] Narrow complex Sinus tachycardia, which originates from the sino-atrial (SA) node, near the base of the superior vena cava. Atrial fibrillation Atrial flutter AV nodal reentrant tachycardia Accessory pathway mediated tachycardia Atrial tachycardia Multifocal atrial tachycardia Junctional tachycardia
12 lead electrocardiogram showing a ventricular tachycardia (VT)
Wide complex Ventricular tachycardia, any tachycardia which originates in the ventricles. Tachycardias may be classified as either narrow complex tachycardias (supraventricular tachycardias) or wide complex tachycardias. Narrow and widerefer to the width of the QRS complex on the ECG. Narrow complex tachycardias tend to originate in the atria, while wide complex tachycardias tend to originate in the ventricles. Tachycardias can be further classified as either regular or irregular.
Sinus
The body has several feedback mechanisms to maintain adequate blood flow and blood pressure. If blood pressure decreases, the heart beats faster in an attempt to raise it. This is called reflex tachycardia. This can happen in response to a decrease in blood volume (through dehydration or bleeding), or an unexpected change in blood flow. The most common cause of the latter is orthostatic hypotension (also called postural hypotension). Fever, hyperventilation and severe infections can also cause tachycardia, primarily due to increase in metabolic demands. An increase in sympathetic nervous system stimulation causes the heart rate to increase, both by the direct action of sympathetic nerve fibers on the heart and by causing the endocrine system to release hormones such as epinephrine (adrenaline), which have a similar effect. Increased sympathetic stimulation is usually due to physical or psychological stress. This is the basis for the so-called "Fight or Flight" response, but such stimulation can also be induced by stimulants such as ephedrine, amphetamines or cocaine. Certain endocrine disorders such as pheochromocytoma can also cause epinephrine release and can result in tachycardia independent nervous system stimulation. Hyperthyroidism can also cause tachycardia.[7]
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Ventricular
Ventricular tachycardia (VT or V-tach) is a potentially life-threatening cardiac arrhythmia that originates in the ventricles. It is usually a regular, wide complex tachycardia with a rate between 120 and 250 beats per minute. Ventricular tachycardia has the potential of degrading to the more serious ventricular fibrillation. Ventricular tachycardia is a common, and often lethal, complication of a myocardial infarction (heart attack). Exercise-induced ventricular tachycardia is a phenomenon related to sudden deaths, especially in patients with severe heart disease (ischemia, acquired valvular heart and congenital heart disease) accompanied with left ventricular dysfunction.[8] Both of these rhythms normally last for only a few seconds to minutes (paroxysmal tachycardia), but if VT persists it is extremely dangerous, often leading to ventricular fibrillation.
Supraventricular
This is a type tachycardia that originates from above the ventricles, such as the atria. It is sometimes known as paroxysmal atrial tachycardia (PAT). Several types of supraventricular tachycardia are known to exist. Atrial fibrillation Atrial fibrillation is one of the most common cardiac arrhythmias. It is generally an irregular, narrow complex rhythm. However, it may show wide QRS complexes on the ECG if a bundle branch block is present. At high rates, the QRS complex may also become wide due to the Ashman phenomenon. It may be difficult to determine the rhythm's regularity when the rate exceeds 150 beats per minute. Depending on the patient's health and other variables such as medications taken for rate control, atrial fibrillation may cause heart rates that span from 50 to 250 beats per minute (or even higher if an accessory pathway is present). However, new onset atrial fibrillation tends to present with rates between 100 and 150 beats per minute. This also induces massive Diarrhea. AV nodal reentrant tachycardia AV nodal reentrant tachycardia (AVNRT) is the most common reentrant tachycardia. It is a regular narrow complex tachycardia that usually responds well to the Valsalva maneuver or the drug adenosine. However, unstable patients sometimes require synchronized cardioversion. Definitive care may include catheter ablation. AV reentrant tachycardia AV reentrant tachycardia (AVRT) requires an accessory pathway for its maintenance. AVRT may involve orthodromic conduction (where the impulse travels down the AV node to the ventricles and back up to the atria through the accessory pathway) or antidromic conduction (which the impulse travels down the accessory pathway and back up to the atria through the AV node). Orthodromic conduction usually results in a narrow complex tachycardia, and antidromic conduction usually results in a wide complex tachycardia that often mimics ventricular tachycardia. Most antiarrhythmics are contraindicated in the emergency treatment of AVRT, because they may paradoxically increase conduction across the accessory pathway.
Tachycardia Junctional tachycardia Junctional tachycardia is an automatic tachycardia originating in the AV junction. It tends to be a regular, narrow complex tachycardia and may be a sign of digitalis toxicity.
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Management
The management of tachycardia depends on its type (wide complex versus narrow complex), whether or not the person is stable or unstable, and if the instability is due to the tachycardia.[6] Unstable means that either important organ functions are affected or cardiac arrest is about to occur.[6]
Stable
In those who are stable treatment is determined by the exact ECG findings: wide versus narrow complex, regular versus irregular heart rate, and whether the QRS is monomorphic or polymorphic.
Unstable
In those who are unstable with a narrow complex tachycardia, intravenous adenosine may be attempted.[6] In all others immediate cardioversion is recommended.[6]
References
[1] [2] [3] [4] [5] [6] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ R00. 0 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=785. 0 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?field=uid& term=D013610 Custer JW, Rau RE, eds. Johns Hopkins: The Harriet Lane Handbook. 18th ed. Philadelphia, PA: Mosby Elsevier Inc; 2008. Data also available through eMedicine: Pediatrics, Tachycardia (http:/ / emedicine. medscape. com/ article/ 804613-overview). Harrison's Principles of Internal Medicine, 17th Edition Neumar RW, Otto CW, Link MS, et al. (November 2010). "Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation 122 (18 Suppl 3): S72967. doi:10.1161/CIRCULATIONAHA.110.970988. PMID20956224. Barker RL, Burton JR, Zieve, PD eds. Principles of Ambulatory Medicine. Sixth Edition. Philadelphia, PA: Lippinocott, Wilkins & Williams 2003 "Ventricular tachycardia and ST segment elevation during Exercise" (http:/ / web. archive. org/ web/ 20071014054004/ http:/ / medinet. hochiminhcity. gov. vn/ medic/ nckh/ nhthat/ e_nhthat. htm). Archived from the original (http:/ / www. medinet. hochiminhcity. gov. vn/ medic/ nckh/ nhthat/ e_nhthat. htm) on 2007-10-14. . Retrieved 2007-07-21.
[7] [8]
External links
Dysautonomia Youth Network of America, Inc. (http://www.dynakids.org) Postural Orthostatic Tachycardia Syndrome - overview from Dysautonomia Information Network (http://www. dinet.org/pots_an_overview.htm) Heart Arrhythmias Respond to Ablation (http://www.uclahealth.org/body.cfm?xyzpdqabc=0&id=502& action=detail&ref=179&start=3&issueref=65) UCLA Healthcare Heart Rate Calculator (http://www.etoolsage.com/Calculator/Heart_Rate_Calculator.asp?toolsort=1500) Heart Rate Calculator for Diagnosis of Tachycardia Drugs most commonly reported to the FDA with the adverse event Tachycardia in AERS (http://www.drugcite. com/indi/?i=TACHYCARDIA)
Bradycardia
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Bradycardia
Bradycardia
Sinus bradycardia seen in lead II with a heart rate of about 50. ICD-10 ICD-9 MeSH R00.1 [1] [2] , 659.7 [3] , 785.9 [4] , 779.81 [5]
427.81
D001919
[6]
Bradycardia (Greek , bradykarda, "heart slowness"), in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart. It sometimes results in fainting, shortness of breath, and if severe enough, death.[7] [8] Trained athletes or young healthy individuals may also have a slow resting heart rate (e.g. professional cyclist Miguel Indurain had a resting heart rate of 28 beats per minute).[9] Resting bradycardia is often considered normal if the individual has no other symptoms such as fatigue, weakness, dizziness, lightheadedness, fainting, chest discomfort, palpitations or shortness of breath associated with it. The term relative bradycardia is used in explaining a heart rate which although not actually below 60 beats per minute still is considered too slow for the individual's current medical condition.
Definition
Bradycardia in an adult is any heart rate less than 60 beatsperminute, although symptoms usually manifest only for heart rates less than 50.[10]
Classification
Atrial
Atrial bradycardias come in three different types. The first is respiratory sinus arrhythmia.. This is usually found in young and healthy adults. Heart rate increases during inhalation and decreases during exhalation. This is thought to be caused by changes in the vagal tone during respiration.[11] If the decrease during exhalation drops the heart rate below 60bpm on each breath, this type of bradycardia is usually deemed benign and a sign of good autonomic tone. Sinus bradycardia is a sinus rhythm of less than 60 bpm. It is a common condition found in both healthy individuals and those who are considered well conditioned athletes. Studies have found that 50 - 85 percent of conditioned athletes have benign sinus bradycardia, as compared to 23 percent of the general population studied.[12] The reason for this is that their heart muscle has become conditioned to have a higher stroke volume and therefore requires fewer contractions to circulate the same volume of blood.[11]
Bradycardia Sick sinus syndrome covers conditions that include severe sinus bradycardia, sinoatrial block, sinus arrest, and bradycardi-tachycardia syndrome (atrial fibillation, flutter, and paroxysmal supraventricular tachycardia).[11]
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Atrioventricular nodal
An atrioventricular nodal bradycardia or AV junction rhythm is usually caused by the absence of the electrical impulse from the sinus node. This usually appears on an EKG with a normal QRS complex accompanied with an inverted P wave either before, during, or after the QRS complex.[11] An AV junctional escape is a delayed heartbeat originating from an ectopic focus somewhere in the AV junction. It occurs when the rate of depolarization of the SA node falls below the rate of the AV node.[11] This dysrhythmia also may occur when the electrical impulses from the SA node fail to reach the AV node because of SA or AV block.[13] This is a protective mechanism for the heart, to compensate for a SA node that is no longer handling the pacemaking activity, and is one of a series of backup sites that can take over pacemaker function when the SA node fails to do so. This would present with a longer PR interval. A junctional escape complex is a normal response that may result from excessive vagal tone on the SA node. Pathological causes include sinus bradycardia, sinus arrest, sinus exit block, or AV block.[11]
Ventricular
A ventricular bradycardia, also known as ventricular escape rhythm or idioventricular rhythm, is a heart rate of less than 50 beats a minute. This is a safety mechanism that arises when there is lack of electrical impulse or stimuli from the atrium.[11] Impulses originating from or below the His bundle, also known as ventricular, will produce a wide QRS complex with heart rates between 20 and 40 beats a minute. Those above the His bundle, also known as junctional, will typically range between 40 and 60 bpm with a narrow QRS complex.[14] [15] In a third degree heart block, approximately 61% take place at the bundle branch-Purkinje system, 21% at the AV node, and 15% at the His bundle.[15] AV block maybe ruled out with an EKG indicating "a 1:1 relationship between P waves and QRS complexes."[14] Ventricular bradycardias occurs with sinus bradycardia, sinus arrest, and AV block. Treatment often consist of the administration of atropine and cardiac pacing.[11]
Infantile
For infants, bradycardia is defined as a heart rate of less than 100 beats per minute. (Normal is around 120-160 beats per minute.) Premature babies are more likely than full-term babies to have apnea and bradycardia spells; their cause is not clearly understood. Some researchers think the spells are related to centers inside the brain that regulate breathing and that may not be fully developed. Touching the baby gently or rocking the incubator slightly will almost always get the baby to start breathing again, which increases the heart rate. Medications (theophylline or caffeine) can be used to treat these spells in babies if necessary. NICU standard practice is to electronically monitor the heart and lungs for this reason.
Causes
This cardiac arrhythmia can be underlain by several causes, which are best divided into cardiac and non-cardiac causes. Non-cardiac causes are usually secondary, and can involve drug use or abuse; metabolic or endocrine issues, especially in the thyroid; an electrolyte imbalance; neurologic factors; autonomic reflexes; situational factors such as prolonged bed rest; and autoimmunity. Cardiac causes include acute or chronic ischemic heart disease, vascular heart disease, valvular heart disease, or degenerative primary electrical disease. Ultimately, the causes act by three mechanisms: depressed automaticity of the heart, conduction block, or escape pacemakers and rhythms. There are generally two types of problems that result in bradycardias: disorders of the sinoatrial node (SA node), and disorders of the atrioventricular node (AV node).
Bradycardia With sinus node dysfunction (sometimes called sick sinus syndrome), there may be disordered automaticity or impaired conduction of the impulse from the sinus node into the surrounding atrial tissue (an "exit block"). Only second degree sinostrial blocks can be detected by use of a 12-lead EKG.[16] It is difficult and sometimes impossible to assign a mechanism to any particular bradycardia, but the underlying mechanism is not clinically relevant to treatment, which is the same in both cases of sick sinus syndrome: a permanent pacemaker. Atrioventricular conduction disturbances (aka: AV block; 1o AV block, 2o type I AV block, 2o type II AV block, 3o AV block) may result from impaired conduction in the AV node, or anywhere below it, such as in the Bundle of His. The clinical relevance pertaining to AV blocks is greater than that of sinoatrial blocks.[16] Patients with bradycardia have likely acquired it, as opposed to having it congenitally. Bradycardia is more common in older patients.
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Diagnosis
A diagnosis of bradycardia in adults is based on a heart rate less than 60. This is determined usually either via palpation or an ECG. If symptoms occur, a determination of electrolytes may be helpful in determining the underlying cause.
Management
The treatment of bradycardia is dependent on whether or not the person is stable or unstable.[10] If oxygen saturations are low supplemental oxygen should be provided.[10]
Stable
Emergent treatment is not needed if the person is asymptomatic or minimally symptomatic.[10]
Unstable
If a person is unstable the initial recommended treatment is intravenous atropine.[10] Doses less than 0.5mg should not be used as this may further decrease the rate.[10] If this is not effective intravenous inotrope infusion (dopamine, epinephrine) or transcutaneous pacing should be used.[10] Transvenous pacing may be required if the cause of the bradycardia is not rapidly reversible.[10]
References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ R00. 1 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 81 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=659. 7 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=785. 9 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=779. 81 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?field=uid& term=D001919 Sinus Bradycardia (http:/ / www. emedicine. com/ emerg/ topic534. htm) eMedicine Bradycardia (http:/ / www. mountsinai. org/ Patient Care/ Service Areas/ Heart/ Diseases and Conditions?citype=Disease& ciid=Bradycardia) at Mount Sinai Hospital [9] L'quipe, France, 2 July 2004 [10] Neumar RW, Otto CW, Link MS, et al. (November 2010). "Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation 122 (18 Suppl 3): S72967. doi:10.1161/CIRCULATIONAHA.110.970988. PMID20956224. [11] Allan B. Wolfson, ed (2005). Harwood-Nuss' Clinical Practice of Emergency Medicine (4th ed.). p.260. ISBN0-7817-5125-X. [12] Ward, Bryan G.; Rippe, JM (1992). "11". Athletic Heart Syndrome. Clinical Sports Medicine. p.259. [13] "AV Junctional Rhythm Disturbances (for Professionals)" (http:/ / www. americanheart. org/ presenter. jhtml?identifier=746). American Heart Association. 2008-12-04. . Retrieved 15 December 2009.
Bradycardia
[14] "Arrhythmias and Conduction Disorders" (http:/ / www. merck. com/ mmpe/ sec07/ ch075/ ch075a. html). The merck Manuals: Online Medical Library. Merck Sharp and Dohme Corp. 2008-01. . Retrieved 16 December 2009. [15] Adams, Mary; Pelter, M (2003). "Ventricular Escape Rhythms" (http:/ / ajcc. aacnjournals. org/ cgi/ content/ full/ 12/ 5/ 477). American Journal of Critical Care. pp. 12: 477478. . Retrieved 15 December 2009. [16] Ufberg, JW; Clark JS. (2006-02). "Bradydysrhythmias and atrioventricular conduction blocks". Emergency Medicine Clininics of North America (National Center for Biotechnology Information): 24(1):19, v.. PMID16308110.
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Proarrhythmia
Proarrhythmia is a new or more frequent occurrence of pre-existing arrhythmias, paradoxically precipitated by antiarrhythmic therapy, which means it is a side effect associated with the administration of some existing antiarrhythmic drugs, as well as drugs for other indications. In other words, it is a tendency of antiarrhythmic drugs to facilitate emergence of new arrhythmias.
Types of proarrhythmia
According to the Vaughan Williams classification (VW) of antiarrhythmic drugs, there are 3 main types of Proarrhythmia during treatment with various antiarrhythmic drugs for Atrial Fibrillation or Atrial flutter:
Ventricular proarrhythmia
Torsade de pointes (VW type IA and type III drugs) Sustained monomorphic ventricular tachycardia (usually VW type IC drugs) Sustained polymorphic ventricular tachycardia/ventricular fibrillation without long QT (VQ types IA, IC, and III drugs)
Atrial proarrhythmia
Conversion of atrial fribrillation to flutter (usually VW type IC drugs or amiodarone). May be a desired effect. Increase of defibrillation threshold (a potential problem with VW type IC drugs) Provocation of recurrence (probably VW types IA, IC and III drugs). It is rare.
Abnormalities of conduction or impulse formation

Sinus node dysfunction, atrioventricular block (almost all drugs) Accelerate conduction over accessory pathway (digoxin, intravenous verapamil, or diltiazem) Acceleration of ventricular rate during atrial fibrillation (VW type IA and type IC drugs).
Increased risk
Presence of structural heart disease, especially LV systolic dysfunction. Class IC agents. Increased age. Females.
Proarrhythmia
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Clinical pointers
Class IA drugs
Dose independent, occurring at normal levels. Follow QT interval, keep ms.
Class IC drugs
May be provoked by increased heart rate. Exercise stress tests after loading.
Class III drugs

Dose dependent. Follow bradycardia, prolonged QT closely.
External links
Roden DM (August 1998). "Mechanisms and management of proarrhythmia". Am. J. Cardiol. 82 (4A): 49I57I. doi:10.1016/S0002-9149(98)00472-X. PMID9737654.
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Sinus Rhythms and Dysrythmias

Sinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram (ECG). It has certain generic features that serve as hallmarks for comparison with normal ECGs.
ECG structure
There are typically six distinct waves (identified by the letters P, Q, R, S, T, and U) in a single beat of the heart in sinus rhythm, and they occur in a specific order, over specific periods of time, with specific relative sizes. While there is a significant range within which variations in rhythm are considered normal, anything that deviates from sinus rhythm by more than a certain amount may be indicative of heart disease. See also Heart rate variability.
Schematic representation of normal sinus rhythm showing standard waves, segments, and intervals
Cardiac Conduction System and Pathway

The cardiac conduction system is a pathway that consists of specialized cells, known as myocytes (cardiac cells), which create the natural electrical impulse that informs the heart when it needs to pump. The location within the conduction system that gives rise to electrical impulses is known as the pacemaker. The initial impulse originates in the sinoatrial (SA) node, or sinus node, which is located in the upper right atrium of the heart. The SA node is designated as the pacemaker of the heart. From the SA node, the electrical impulse spreads through interatrial tracts that spread the electrical impulse through the right and left atria's and therefore cause atrial depolarization. As a result, a P wave is observed. After the atria's depolarize, the electrical impulse spreads through the internodal tracts and reach the atrioventricular (AV) node. The AV node has its own pacing rhythm that serves as a back up pacemaker in case the SA node fails to initiate an electrical impulse. Consequently, the AV node slows down the electrical impulse to allow the atria to project their blood into the ventricles. From the AV node, the impulse travels through the bundle of His, which bifurcate into the left and right bundle branches. From the branches, the impulse travels through the Purkinje fibers and allows the electrical impulse to end in the ventricles to initiate ventricular depolarization. Consequently, a QRS complex is observed.
Sinus rhythm
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Sinus rhythm on ECG

Sinus rhythm, more commonly referred to as Normal Sinus Rhythm, is designated as the normal rhythm of the heart. Several requirements must be met for an electrocardiogram to be classified as normal sinus rhythm. Criteria for a Normal Sinus Rhythm include: 1. 2. 3. 4. 5. 6. 1. A heart rate between 60-100 beats per minute. 2. The SA node pacing the heart. 3. Regularity- Regular 4. A "P" wave must be present for every "QRS" complex in a ratio of 1:1. 5. PR interval is between .12 second and .20 second. 6. QRS complex width should be less than .12 second.
External links
Normal Sinus Rhythm [1]
References
[1] http:/ / pediatriccardiology. uchicago. edu/ PP/ abnl%20rhythm%20for%20parents%20body. htm
Sinus tachycardia
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Sinus tachycardia
Sinus tachycardia
ECG readout of an individual with sinus tachycardia. Here the heart rate is around 150. ICD-9 DiseasesDB MeSH 427.81 12135 [2] [1] [2]
D013616
Sinus tachycardia (also colloquially known as sinus tach or sinus tachy) is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60100 beats/min. Note that the normal heart rate varies with age, with infants having normal heart rate of 110150 bpm to the elderly, who have slower normals.
Etiology
Sinus tachycardia is usually a response to normal physiological situations, such as exercise and an increased sympathetic tone with increased catecholamine releasestress, fright, flight, anger. Other causes include: Fever Anxiety Dehydration Malignant hyperthermia Hypovolemia with hypotension and shock Anemia Heart failure Hyperthyroidism Mercury poisoning Kawasaki disease Pheochromocytoma Sepsis Pulmonary embolism Acute coronary ischemia and myocardial infarction Chronic pulmonary disease Hypoxia Intake of stimulants such as caffeine, nicotine, cocaine, or amphetamines
Hyperdynamic circulation Electric shock
Sinus tachycardia Drug Withdrawal
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Symptoms
Tachycardia is often asymptomatic. If the heart rate is too high, cardiac output may fall due to the markedly reduced ventricular filling time. Rapid rates, though they may be compensating for ischemia elsewhere, increase myocardial oxygen demand and reduce coronary blood flow, thus precipitating an ischemia heart or valvular disease. Sinus tachycardia accompanying a myocardial infarction may be indicative of cardiogenic shock.
ECG characteristics
Rate: Greater than or equal to 100. Rhythm: Regular. P waves: Upright, consistent, and normal in morphology (if no atrial disease) PR interval: Between 0.120.20 seconds and shortens with increasing heart rate QRS complex: Less than 0.12 seconds, consistent, and normal in morphology.
Diagnosis and differentials

Usually apparent on the EKG, but if heart rate is above 140 bpm the P wave may be difficult to distinguish from the previous T wave and one may confuse it with a paroxysmal supraventricular tachycardia or atrial flutter with a 2:1 block. Ways to distinguish the three are: Vagal maneuvers (such as carotid sinus massage or Valsalva's maneuver) to slow the rate and identification of P waves administer AV blockers (e.g., adenosine, verapamil) to identify atrial flutter with 2:1 block
Inappropriate sinus tachycardia (IST)

Also known as chronic nonparoxysmal sinus tachycardia, patients have elevated resting heart rate and/or exaggerated heart rate in response to exercise. These patients have no apparent heart disease or other causes of sinus tachycardia. IST is thought to be due to abnormal autonomic control..
Postural orthostatic tachycardia syndrome (POTS)

Usually in women with no heart problems, this syndrome is characterized by normal resting heart rate but exaggerated postural sinus tachycardia with or without orthostatic hypotension.
Treatment
Not required for physiologic sinus tachycardia. Underlying causes are treated if present. Acute myocardial infarction. Sinus tachycardia can present in more than a third of the patients with AMI but this usually decreases over time. Patients with sustained sinus tachycardia reflects a larger infarct that are more anterior with prominent left ventricular dysfunction, associated with high mortality and morbidity. Tachycardia in the presence of AMI can reduce coronary blood flow and increase myocardial oxygen demand, aggravating the situation. Beta blockers can be used to slow the rate, but most patients are usually already treated with beta blockers as a routine regimen for AMI. Practically, many studies showed that there is no need for any treatment. IST and POTS. Beta blockers are useful if the cause is sympathetic overactivity. If the cause is due to decreased vagal activity, it is usually hard to treat and one may consider radiofrequency catheter ablation.
Sinus tachycardia
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References
1. Guyton text book of physiology 2. Harrison's principles of internal medicine 3. Pediatr Surg Int. 2005 Feb;21(2):127-8. Epub 2005 Jan 15. Inappropriate sinus node tachycardia following gastric transposition surgery in children. Choudhury SR, Sharma A, Kohli V.
References
[1] http:/ / www. diseasesdatabase. com/ ddb12135. htm [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D013616
Inappropriate sinus tachycardia

Inappropriate Sinus Tachycardia (IST) is a rare type of cardiac arrhythmia, within the category of supraventricular tachycardia (SVT), although doctors believe it stems from dysautonomia, a disturbance and/or failure of the autonomic nervous system. The mechanism and primary etiology of Inappropriate Sinus Tachycardia has not been fully elucidated. The mechanism of the arrhythmia primarily involves the sinus node and peri-nodal tissue[1] and does not require the AV node for maintenance. Treatments in the form of pharmacological therapy or catheter ablation are available, although it is currently difficult to treat successfully.
Symptoms
Symptoms reported by patients vary in frequency and severity. Symptoms associated with IST include: Frequent palpitations Dyspnea (shortness of breath) and palpitations on exertion Pre-syncope (feeling as if about to faint) Fatigue (physical) Dizziness Exercise intolerance Occasional paresthesia and cramping Symptoms associated with autonomic nervous system disturbance, including GI disturbance
Diagnosis
No formal diagnostic criteria exist. A diagnosis of Inappropriate sinus tachycardia is primarily one of exclusion and the following may be observed: Exclusion of all other causes of sinus tachycardia Common forms of supraventricular tachycardia (SVT) must be excluded Normal P wave morphology A resting sinus tachycardia is usually (but not always) present Nocturnal dip in heart rate
Inappropriate heart rate response on exertion Mean heart rate in 24hrs >95bpm
Inappropriate sinus tachycardia Symptoms are documented to be due to tachycardia Hypotension is occasionally observed Syncope (fainting) is occasionally reported
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Treatment
IST has been treated both pharmacologically and invasively, with varying degrees of success. Some types of medication tried by cardiologists and other physicians include: beta blockers, selective sinus node If channel inhibitors (ivabradine)[2] , calcium channel blockers and antiarrhythmic agents. Some SSRI drugs are also occasionally tried and also treatments more commonly used to treat postural orthostatic tachycardia syndrome such as fludrocortisone. This approach is very much "trial-and-error". Patients with IST are often intolerant to beta blockers. A new selective sinus node inhibitor ivabradine is also being used to treat IST. Invasive treatments include forms of catheter ablation such as sinus node modification[3] (selective ablation of the sinus node), complete sinus node ablation (with associated implantation of a permanent artificial pacemaker) and AV node ablation in very resistant cases (creation of iatrogenic complete heart block, necessitating implantation of a permanent artificial pacemaker).
References
[1] Sato T, Mitamura H, Murata M, et al. (October 2000). "Electrophysiologic findings of a patient with inappropriate sinus tachycardia cured by selective radiofrequency catheter ablation" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0022073600288730). J Electrocardiol 33 (4): 3816. doi:10.1054/jelc.2000.9648. PMID11099363. . [2] Zellerhoff S, Hinterseer MIvabradine in patients with inappropriate sinus tachycardia. Naunyn Schmiedebergs Arch Pharmacol. 2010 Sep 22. http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 20859616 [3] Lee RJ, Kalman JM, Fitzpatrick AP, et al. (November 1995). "Radiofrequency catheter modification of the sinus node for "inappropriate" sinus tachycardia" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=7586260). Circulation 92 (10): 291928. PMID7586260. .
External links
Inappropriate sinus tachycardia by Dr Richard N. Fogoros (http://heartdisease.about.com/cs/arrhythmias/a/ IST.htm) Arrhythmia Alliance (http://www.arrhythmiaalliance.org.uk/)
Literature
Yusuf S, Camm AJ (June 2005). "Deciphering the sinus tachycardias". Clin Cardiol 28 (6): 26776. doi:10.1002/clc.4960280603. PMID16028460. Still AM, Raatikainen P, Ylitalo A, et al. (March 2005). "Prevalence, characteristics and natural course of inappropriate sinus tachycardia" (http:/ / europace. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=15763524). Europace 7 (2): 10412. doi:10.1016/j.eupc.2004.12.007. PMID15763524. Leon H, Guzman JC, Kuusela T, Dillenburg R, Kamath M, Morillo CA (January 2005). "Impaired baroreflex gain in patients with inappropriate sinus tachycardia" (http:/ / www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed& issn=1045-3873& date=2005& volume=16& issue=1& spage=64). J. Cardiovasc. Electrophysiol. 16 (1): 648. doi:10.1046/j.1540-8167.2005.04441.x. PMID15673390. Snchez-Quintana D, Cabrera JA, Farr J, Climent V, Anderson RH, Ho SY (February 2005). "Sinus node revisited in the era of electroanatomical mapping and catheter ablation" (http:/ / heart. bmj. com/ cgi/ pmidlookup?view=long& pmid=15657230). Heart 91 (2): 18994. doi:10.1136/hrt.2003.031542. PMC1768731. PMID15657230.
Inappropriate sinus tachycardia Cruz Filho FE, Maia IG, Fagundes ML, Boghossian S, Ribeiro JC (March 1998). "[Sinus node modification by catheter using radiofrequency current in a patient with inappropriate sinus tachycardia. Evaluation of early and late results]" (in Portuguese). Arq. Bras. Cardiol. 70 (3): 1736. PMID9674178. Lee SH, Cheng JJ, Kuan P, Hung CR (1997). "Radiofrequency Catheter Modification of Sinus Node for Inappropriate Sinus Tachycardia: A Case Report" (http:/ / www. vghtpe. gov. tw/ ~cmj/ 6002/ 600210. htm). Chin Med J (Taipei) 60: 11723.
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Sinus bradycardia
96
Sinus bradycardia
Sinus bradycardia
Sinus bradycardia seen in lead II with a heart rate of about 50. ICD-9 MeSH 427.81 [2] [1]
D001146
Sinus bradycardia is a heart rhythm that originates from the sinus node and has a rate of under 60 beats per minute.
Signs and symptoms

The decreased heart rate can cause a decreased cardiac output resulting in symptoms such as lightheadedness, dizziness, hypotension, vertigo, and syncope. The slow heart rate may also lead to atrial, junctional, or ventricular ectopic rhythms. Bradycardia is not necessarily problematic. People who regularly practice sports may have sinus bradycardia, because their trained hearts can pump enough blood in each contraction to allow a low resting heart rate. Sinus Bradycardia can aid in the sport of Freediving, which includes any of various aquatic activities that share the practice of breath-hold underwater diving. Bradycardia aids in this process due to drop in blood rate pulse. These adaptations enable the human body to endure depth and lack of oxygen far beyond what would be possible without the mammalian diving reflex. Sinus bradycardia is a sinus rhythm of less than 60 bpm. It is a common condition found in both healthy individuals and those who are considered well conditioned athletes. Studies have found that 50 - 85 percent of conditioned athletes have benign sinus bradycardia, as compared to 23 percent of the general population studied. Trained athletes or young healthy individuals may also have a slow resting heart rate.
Cause
This rhythm may be caused by one of the following: Increased vagal tone. Sleep Hypothermia Hypothyroidism Intrinsic disease of the SA node (Eg. sick sinus syndrome). An effect of drugs, such as the use of digitalis, beta-blockers, or quinidine. Seizure. It could also be a normal finding in a healthy, well-conditioned person. It may be secondary to infections like Diphtheria, acute rheumatic fever, viral myocarditis. It is physiologic in trained athletes.
Sinus bradycardia Increased intracranial pressure.
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Diagnosis
ECG Characteristics Rate: Less than 60 beats per minute. Rhythm: Regular. P waves: Upright, consistent, and normal in morphology and duration. P-R Interval: Between 0.12-0.20 seconds in duration. QRS Complex: Less than 0.12 seconds in width, and consistent in morphology.
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?field=uid& term=D001146
Sick sinus syndrome
98
Sick sinus syndrome

Sick sinus syndrome
Classification and external resources ICD-10 ICD-9 I49.5 427.81 [2]
Sick sinus syndrome, also called sinus node dysfunction, is a group of abnormal heart rhythms (arrhythmias) presumably caused by a malfunction of the sinus node, the heart's primary pacemaker.[1] Bradycardia-tachycardia syndrome is a variant of sick sinus syndrome in which slow arrhythmias and fast arrhythmias alternate.
Causes
Sick sinus syndrome is a relatively uncommon syndrome. It can result in many abnormal heart rhythms (arrhythmias), including sinus arrest, sinus node exit block, sinus bradycardia, and other types of bradycardia (slow heart rate). Sick sinus syndrome may also be associated with tachycardias (fast heart rate) such as paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation. Tachycardias that occur with sick sinus syndrome are characterized by a long pause after the tachycardia. Abnormal rhythms are often caused or worsened by medications such as digitalis, calcium channel blockers, beta-blockers, sympatholytic medications, and anti-arrhythmics. Disorders that cause scarring, degeneration, or damage to the conduction system can cause sick sinus syndrome, including sarcoidosis, amyloidosis, Chagas' disease,[2] and cardiomyopathies. Sick sinus syndrome is more common in elderly adults, where the cause is often a non-specific, scar-like degeneration of the cardiac conduction system. Cardiac surgery, especially to the atria, is a common cause of sick sinus syndrome in children.
This ECG from the same patient shows atrial fibrillation at around 126 beats per minute. Electrocardiogram from a man with bradycardia-tachycardia syndrome following mitral valvuloplasty, resection of the left atrial appendage and maze procedure. The ECG shows AV-junctional rhythm resulting in bradycardia at around 46 beats per minutes. The second beat is most likely an atrial extrasystole, given the atypical P wave (negative in I, positive in aVR).
Coronary artery disease, high blood pressure, and aortic and mitral valve diseases may be associated with sick sinus syndrome, although this association may only be incidental. The mechanism is related to delayed escape. Congenital SSS is due to mutations of gene responsible for formation of Alpha subunit of sodium channel. A Russian study showed that the heterozygous variant of connexin 40 polymorphism gene variant is more frequent among patients with sick sinus node syndrome and their healthy relatives than in persons of control group, suggesting a link between the gene and the disease.[3]
Sick sinus syndrome
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Symptoms
Even though many types of sick sinus syndrome produce no symptoms, patients may present with: Stokes-Adams attacks - fainting due to asystole or ventricular fibrillation Dizziness or light-headedness Palpitations Chest pain or angina Shortness of breath Fatigue Headache Nausea Fainting
Diagnosis
Ambulatory monitoring of the electrocardiogram (ECG) may be necessary because arrhythmias are transient.[4] The ECG may show any of the following Inappropriate sinus bradycardia Sinus arrest Sinoatrial block Atrial fibrillation with slow ventricular response A prolonged asystolic period after a period of tachycardias Atrial flutter Ectopic atrial tachycardia Sinus node reentrant tachycardia
Electrophysiologic tests are no longer used for diagnostic purposes because of their low specificity and sensitivity. Cardioinhibitory n vasodepressor forms of sick sinus syndrome may be revealed by tilt table testing.
Treatment
Artificial pacemakers have been used in the treatment of sick sinus syndrome.[5] Bradyarrhythmias are well controlled with pacemakers, while tachyarrhythmias respond well to medical therapy. However, because both bradyarrhythmias and tachyarrhythmias may be present, drugs to control tachyarrhythmia may exacerbate bradyarrhythmia. Therefore, a pacemaker is implanted before drug therapy is begun for the tachyarrhythmia.
References
[1] Dobrzynski H, Boyett MR, Anderson RH (April 2007). "New insights into pacemaker activity: promoting understanding of sick sinus syndrome" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=17420362). Circulation 115 (14): 192132. doi:10.1161/CIRCULATIONAHA.106.616011. PMID17420362. . [2] Keller KB, Lemberg L (March 2006). "The sick sinus syndrome" (http:/ / ajcc. aacnjournals. org/ cgi/ pmidlookup?view=long& pmid=16501143). Am. J. Crit. Care 15 (2): 2269. PMID16501143. . [3] Chernova, AA. [Polymorphism of Connexin 40 Gene a Novel Genetic Marker of the Sick Sinus Node Syndrome.]. PMID21649591. [4] Adn V, Crown LA (April 2003). "Diagnosis and treatment of sick sinus syndrome". Am Fam Physician 67 (8): 172532. PMID12725451. [5] Drago F, Silvetti MS, Grutter G, De Santis A (July 2006). "Long term management of atrial arrhythmias in young patients with sick sinus syndrome undergoing early operation to correct congenital heart disease" (http:/ / europace. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=16798761). Europace 8 (7): 48894. doi:10.1093/europace/eul069. PMID16798761. .
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Atrial Dysrythmias
Premature atrial contraction
Classification and external resources ICD-10 ICD-9 MeSH I49.1 [1] [2] [3]
427.61
D018880
Premature atrial contractions (PACs), also known as atrial premature complexes (APC) or atrial premature beats (APB), are a common cardiac arrhythmia characterized by premature heartbeats originating in the atria. While the sinoatrial node typically regulates the heartbeat during normal sinus rhythm, PACs occur when another region of the atria depolarizes before the sinoatrial node and thus triggers a premature heartbeat. The exact cause of PACs is unclear; while several predisposing conditions exist, PACs commonly occur in healthy young and elderly people without heart disease, and by themselves are not considered an abnormal finding.[4] [5] PACs are often completely asymptomatic and may be noted only with Holter monitoring, but occasionally they cause a sensation of palpitations. In most cases, no treatment other than reassurance is needed for PACs, although medications such as beta blockers can reduce the frequency of symptomatic PACs.
Diagnosis
Premature atrial contractions are typically diagnosed with an electrocardiogram, Holter monitor, or cardiac event monitor.
Prognosis
In otherwise healthy patients, occasional premature atrial contractions are a common and normal finding and do not indicate any particular health risk. Rarely, in patients with other underlying structural heart problems, PACs can trigger a more serious arrhythmia such as atrial flutter or atrial fibrillation.
Electrocardiogram
On an electrocardiogram (EKG), PACs are characterized by an abnormally shaped P wave. Since the premature beat initiates outside the sinoatrial node, the associated P wave appears different from those seen in normal sinus rhythm. Typically, the atrial impulse propagates normally through the atrioventricular node and into the cardiac ventricles, resulting in a normal, narrow QRS complex. However, if the atrial beat is premature enough, it may reach the atrioventricular node during its refractory period, in which case it will not be conducted to the ventricle and there will be no QRS complex following the P wave.
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References
[1] [2] [3] [4] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I49. 1 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 61 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D018880 Brodsky M, Wu D, Denes P, Kanakis C, Rosen KM (March 1977). "Arrhythmias documented by 24 hour continuous electrocardiographic monitoring in 50 male medical students without apparent heart disease". Am. J. Cardiol. 39 (3): 3905. doi:10.1016/S0002-9149(77)80094-5. PMID65912. [5] Folarin VA, Fitzsimmons PJ, Kruyer WB (September 2001). "Holter monitor findings in asymptomatic male military aviators without structural heart disease". Aviat Space Environ Med 72 (9): 8368. PMID11565820.
Wandering pacemaker
102
Wandering pacemaker
Wandering pacemaker
Classification and external resources ICD-9 427.89 [1]
In cardiology, a wandering pacemaker is an atrial arrhythmia that occurs when the natural cardiac pacemaker site shifts between the SA node, the atria, and/or the AV node. This shifting of the pacemaker from the SA node to adjacent tissues is identifiable on ECG Lead II by morphological changes in P waves; sinus beats have smooth upright P waves, while atrial beats have flattened, notched, or diphasic P-waves. Ventricular conduction is normal with wandering pacemaker, and thus the QRS is normal. Wandering pacemaker is usually caused by varying vagal tone. With increased vagal tone the SA Node slows,allowing a pacemaker in the atria or AV Nodal area,which may become slightly faster briefly. After vagal tone decreases the SA Node assumes its natural pace. It is often seen in the very young, very old and in athletes, and rarely causes symptoms or requires treatment.
External links
Cleveland Clinic Atrial Fibrillation Management [2] CEUFast ECG Interpretation Course [3] RnCeus Health Interactive [4] RN.ORG Nursing Resources [5]
References
[1] [2] [3] [4] [5] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 89 http:/ / www. clevelandclinicmeded. com/ medicalpubs/ diseasemanagement/ cardiology/ atrial-fibrillation/ http:/ / www. ceufast. com/ courses/ viewcourse. asp?id=239& nurse-ce-course-title=ECG+ Interpretation#Wandering_Pacemaker http:/ / rnceus. com/ ekg/ ekgwap. html http:/ / www. rn. org/ courses/ coursematerial-187. pdf
Multifocal atrial tachycardia
103

Classification and external resources ICD-9 eMedicine 427.89 article/759135 [1]
Multifocal atrial tachycardia (MAT) is a cardiac arrhythmia,[2] specifically a type of supraventricular tachycardia. "Multifocal atrial rhythm" is the condition in the absence of tachycardia.[3]
Causes and epidemiology

It is more common in the elderly.[4] It is mostly common in patients with lung disorders, but it can be occur after acute MI, hypokalemia, and hypomagnesemia. It is sometimes associated with digitalis toxicity in patients with heart disease. It is most commonly associated with hypoxia and COPD
Presentation and pathophysiology

It is characterized by an electrocardiogram (ECG) strip with 3 or more P-waves of variable morphology and varying PR intervals, plus tachycardia, which is a heart rate exceeding 100 beats per minute. Narrow QRS complexes are visible as well. The P-waves and PR intervals are variable due to a phenomenon called wandering atrial pacemaker (WAP). The electrical impulse is generated at a different focus within the atria of the heart each time. WAP is positive once the heart generates at least three different P-wave formations from the same ECG lead. Then, if the heart rate exceeds 100 beats per minute, the phenomenon is called multifocal atrial tachycardia.
Treatment
Its rate may in some cases be reduced by administering verapamil. Administration of oxygen may play a role in the treatment of some patients.[5]
References
[1] http:/ / emedicine. medscape. com/ article/ 759135-overview [2] Bradley DJ, Fischbach PS, Law IH, Serwer GA, Dick M (August 2001). "The clinical course of multifocal atrial tachycardia in infants and children" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0735-1097(01)01390-0). J. Am. Coll. Cardiol. 38 (2): 4018. doi:10.1016/S0735-1097(01)01390-0. PMID11499730. . [3] http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson5/ supra. html#multifocal [4] McCord J, Borzak S (January 1998). "Multifocal atrial tachycardia" (http:/ / www. chestjournal. org/ cgi/ pmidlookup?view=long& pmid=9440591). Chest 113 (1): 2039. doi:10.1378/chest.113.1.203. PMID9440591. . [5] American College of Physicians; Acp (15 June 2008). MKSAP for students four (http:/ / books. google. com/ books?id=jgjGG5SLSS4C& pg=PA37). ACP Press. pp.37. ISBN9781934465035. . Retrieved 11 November 2010.
Atrial flutter
104
Atrial flutter
Atrial flutter
Atrial flutter with variable block ( between 3 and 4 to 1 ) ICD-10 ICD-9 DiseasesDB MedlinePlus eMedicine MeSH I48 [1] [2]
427.32 1072
[3] [4] [5] [6]
000184
med/185 D001282
Atrial flutter (AFL) is an abnormal heart rhythm that occurs in the atria of the heart.[7] When it first occurs, it is usually associated with a fast heart rate or tachycardia (beats over 100 per minute),[8] and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with cardiovascular disease (e.g. hypertension, coronary artery disease, and cardiomyopathy), it may occur spontaneously in people with otherwise normal hearts. It is typically not a stable rhythm, and frequently degenerates into atrial fibrillation (AF). However, it does rarely persist for months to years. Atrial flutter was first identified as an independent medical condition in 1920 by the British physician Sir Thomas Lewis (18811945) and colleagues.[9]
Signs and symptoms

While atrial flutter can sometimes go unnoticed, its onset is often marked by characteristic sensations of regular palpitations. Such sensations usually last until the episode resolves, or until the heart rate is controlled. Atrial flutter is usually well tolerated initially (a high heart rate is for most people just a normal response to exercise), however, people with other underlying heart disease or poor exercise tolerance may rapidly develop symptoms, which can include shortness of breath, chest pains, lightheadedness or dizziness, nausea and, in some patients, nervousness and feelings of impending doom. Prolonged fast flutter may lead to decompensation with loss of normal heart function (heart failure). This may manifest as effort intolerance (exertional breathlessness), nocturnal breathlessness, or swelling of the legs or abdomen.
Atrial flutter
105
Pathophysiology
Atrial flutter is caused by a reentrant rhythm in either the right or left atrium. Typically initiated by a premature electrical impulse arising in the atria, atrial flutter is propagated due to differences in refractory periods of atrial tissue. This creates electrical activity that moves in a localized self-perpetuating loop. For each cycle around the loop, there results an electric impulse that propagates through the atria. The impact and symptoms of atrial flutter depend on the heart rate of the patient. Heart rate is a measure of the ventricular rather than atrial activity. Impulses from the atria are conducted to the ventricles through the atrio-ventricular node. Due primarily to its longer refractory period, the AV node exerts a protective effect on heart rate by blocking atrial impulses in excess of about 180 beats/minute, for the example of a resting heart rate. (This block is dependent on the age of the patient, and can be calculated roughly by subtracting patient age from 220). If the flutter rate is 300/minute only half of these impulses will be conducted, giving a ventricular rate of 150/minute, or a 2:1 heart block. The addition of rate-controlling drugs or conduction system disease can increase this block substantially (see image below).
Classification
There are two types of atrial flutter, the common type I and rarer type II.[10] Most individuals with atrial flutter will manifest only one of these. Rarely someone may manifest both types; however, they can only manifest one type at a time.
Type I
Type I atrial flutter, also known as common atrial flutter or typical atrial flutter, has an atrial rate of 240 to 340 beats/minute. However, this rate may be slowed by antiarrhythmic agents. The reentrant loop circles the right atrium, passing through the cavo-tricuspid isthmus a body of fibrous tissue in the lower atrium between the inferior vena cava, and the tricuspid valve. Type I flutter is further divided into two subtypes, known as counterclockwise atrial flutter and clockwise atrial flutter depending on the direction of current passing through the loop.
Type I atrial flutter, counterclockwise rotation with 3:1 and 4:1 AV nodal block.
Counterclockwise atrial flutter (known as cephalad-directed atrial flutter) is more commonly seen. The flutter waves in this rhythm are inverted in ECG leads II, III, and aVF. The re-entry loop cycles in the opposite direction in clockwise atrial flutter, thus the flutter waves are upright in II, III, and aVF. Catheter ablation of the isthmus is a procedure usually available in the electrophysiology laboratory. Eliminating conduction through the isthmus prevents reentry, and if successful, prevents the recurrence of the atrial flutter.
Atrial flutter
106
Type II
Type II flutter follows a significantly different re-entry pathway to type I flutter, and is typically faster, usually 340-440 beats/minute.[11] Left atrial flutter is common after incomplete left atrial ablation procedures.
Treatment
In general, atrial flutter should be treated the same as atrial fibrillation. Because both rhythms can lead to the formation of thrombus in the atria, individuals with atrial flutter usually require some form of anticoagulation or anti-platelet agent. Both rhythms can be associated with dangerously fast heart rate and thus require medication for rate and or rhythm control. Additionally, there are some specific considerations particular to treatment of atrial flutter.
Cardioversion
Atrial flutter is considerably more sensitive to electrical direct-current cardioversion than atrial fibrillation, and usually requires a lower energy shock. 20-50J is commonly enough to revert to sinus rhythm. Conversely, it is relatively resistant to chemical cardioversion, and often deteriorates into atrial fibrillation prior to spontaneous return to sinus rhythm.
Ablation
Because of the reentrant nature of atrial flutter, it is often possible to ablate the circuit that causes atrial flutter. This is done in the electrophysiology lab by causing a ridge of scar tissue that crosses the path of the circuit that causes atrial flutter. Ablation of the isthmus, as discussed above, is a common treatment for typical atrial flutter.
Complications
Although often regarded as a relatively benign rhythm problem, atrial flutter shares the same complications as the related condition atrial fibrillation. There is paucity of published data directly comparing the two, but overall mortality in these conditions appears to be very similar.[12]
Rate Related
Rapid heart rates may produce significant symptoms in patients with pre-existing heart disease. Even in patients whose hearts are normal to start with, prolonged tachycardia tends to produce ventricular decompensation and heart failure.
Clot formation
Because there is little if any effective contraction of the atria there is stasis (pooling) of blood in the atria. Stasis of blood in susceptible individuals can lead to formation of thrombus (blood clots) within the heart. Thrombus is most likely to form in the atrial appendages. Clot in the left atrial appendage is particularly important since the left side of the heart supplies blood to the entire body. Thus, any thrombus material that dislodges from this side of the heart can embolize to the brain, with the potentially devastating consequence of a stroke. Thrombus material can of course embolize to any other portion of the body, though usually with a less severe outcome.
Atrial flutter
107
Sudden cardiac death

Sudden death is not directly associated with atrial flutter. However, in individuals with a pre-existing accessory conduction pathway, such as the bundle of Kent in Wolff-Parkinson-White syndrome, the accessory pathway may conduct activity from the atria to the ventricles at a rate that the AV node would usually block. Bypassing the AV node, the atrial rate of 300 beats/minute leads to a ventricular rate of 300 beats/minute (1:1 conduction). Even if the ventricles are able to sustain a cardiac output at such a high rates, 1:1 flutter with time may degenerate into ventricular fibrillation, causing hemodynamic collapse and death.
References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I48 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 32 http:/ / www. diseasesdatabase. com/ ddb1072. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000184. htm http:/ / www. emedicine. com/ med/ topic185. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D001282 Atrial flutter (http:/ / www. mountsinai. org/ patient-care/ health-library/ diseases-and-conditions/ atrial-flutter) at Mount Sinai Hospital " atrial flutter (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ three/ 000041158. htm)" at Dorland's Medical Dictionary
[9] Lewis T, Feil HS, Stroud WD (1920). "Observations upon flutter, fibrillation, II: the nature of auricular flutter". Heart 7: 191. [10] Surawicz, Borys; Knilans, Timothy K.; Chou, Te-Chuan (2001). Chou's electrocardiography in clinical practice: adult and pediatric. Philadelphia: Saunders. ISBN0-7216-8697-4. [11] "Atrial Flutter: Overview - eMedicine Cardiology" (http:/ / emedicine. medscape. com/ article/ 151210-overview). . Retrieved 2009-03-06. [12] Vidaillet H, Granada JF, Chyou PH, Maassen K, Ortiz M, Pulido JN, et al., "A Population-Based Study of Mortality among Patients with Atrial Fibrillation or Flutter" The American Journal of Medicine 2002 Oct 1;113(5):365-70. PMID 12401530. doi:10.1016/S0002-9343(02)01253-6
Atrial fibrillation
108
Atrial fibrillation
Atrial fibrillation
The P waves, which represent depolarization of the atria, are absent during atrial fibrillation. ICD-10 ICD-9 DiseasesDB MedlinePlus eMedicine MeSH I48 [1] [1]
427.31 1065
[2] [4] [3] [5] emerg/46 [4]
000184
med/184 D001281
Atrial fibrillation (AF or A-fib) is the most common cardiac arrhythmia (abnormal heart rhythm). It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers (atria) of the heart result in the muscle fibrillating (i.e., quivering), instead of achieving coordinated contraction. The presence of AF can be confirmed with an electrocardiogram (ECG or EKG) by the absence of P waves and an irregular ventricular rate. Presence of AF in a population increases with age, with 8% of people over 80 having AF. In AF, the normal electrical impulses that are generated by the sinoatrial node are suddenly or gradually overwhelmed by disorganized electrical impulses that often originate in the roots of the pulmonary veins, leading to irregular conduction of impulses to the ventricles which generate the heartbeat. AF may occur in episodes lasting from minutes to weeks, or be permanent in nature. The natural tendency of AF over time is to become a chronic condition. Chronic AF leads to a small increase in the risk of death.[6] [7] Some people are asymptomatic despite having frequent episodes, while others experience symptoms that are troubling or incapacitating. Whilst AF is not immediately life-threatening, it may result in palpitations, fainting, chest pain, or congestive heart failure. People with AF have an increased risk of stroke because blood tends to form clots in the poorly contracting atria - especially in the left atrial appendage (LAA). The degree of stroke risk can be up to seven times that of the average population, depending on the presence of additional risk factors[8] . In the absence of other risk factors, the risk of stroke in AF patients is similar to that of the general population.[9]
Atrial fibrillation Atrial fibrillation may be treated with medications to either slow the heart rate or revert the heart rhythm back to normal. Synchronized electrical cardioversion can be used to convert AF to a normal heart rhythm. Surgical and catheter-based therapies may be used to prevent recurrence of AF in certain individuals. People with AF often take anticoagulants such as warfarin to protect them from stroke.
109
Classification
Classification system
AF Category First detected Paroxysmal Persistent Permanent Defining Characteristics only one diagnosed episode recurrent episodes that self-terminate in less than 7 days. recurrent episodes that last more than 7 days an ongoing long-term episode
The American College of Cardiology (ACC), American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend in their guidelines the following classification system based on simplicity and clinical relevance.[10] All atrial fibrillation patients are initially in the category called first detected AF. These patients may or may not have had previous undetected episodes. If a first detected episode self-terminates in less than 7days and then another episode begins later on, the case has moved into the category of paroxysmal AF. Although patients in this category have episodes lasting up to 7days, in most cases of paroxysmal AF the episodes will self-terminate in less than 24hours. If instead the episode lasts for more than 7days, it is unlikely to self-terminate,[11] and it is called persistent AF. In this case, the episode may be still terminated by cardioversion. If cardioversion is unsuccessful or it is not attempted, and the episode is ongoing for a long time (e.g. a year or more), the patient's AF is called permanent. Episodes that last less than 30seconds are not considered in this classification system. Also, this system does not apply to cases where the AF is a secondary condition that occurs in the setting of a primary condition that may be the cause of the AF. Using this classification system, it's not always clear what an AF case should be called. For example, a case may fit into the paroxysmal AF category some of the time, while other times it may have the characteristics of persistent AF. One may be able to decide which category is more appropriate by determining which one occurs most often in the case under consideration. In addition to the above four AF categories, which are mainly defined by episode timing and termination, the ACC/AHA/ESC guidelines describe additional AF categories in terms of other characteristics of the patient.[10] Lone atrial fibrillation (LAF) - absence of clinical or echocardiographic findings of other cardiovascular disease (including hypertension), related pulmonary disease, or cardiac abnormalities such as enlargement of the left atrium, and age under 60years Nonvalvular AF - absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair Secondary AF - occurs in the setting of a primary condition which may be the cause of the AF, such as acute myocardial infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or other acute pulmonary disease
Atrial fibrillation
110
Signs and symptoms

Atrial fibrillation is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as palpitations, exercise intolerance, and occasionally produce angina (if the rate is faster and puts the heart under strain) and congestive symptoms of shortness of breath or edema. Sometimes the arrhythmia will be identified only with the onset of a stroke or a transient ischemic attack (TIA). It is not uncommon for a patient to first become aware of AF from a routine physical examination or ECG, as it may be asymptomatic in many cases.[10] As most cases of atrial fibrillation are secondary to other medical problems, the presence of chest pain or angina, symptoms of hyperthyroidism (an overactive thyroid gland) such as weight loss and diarrhea, and symptoms suggestive of lung disease would indicate an underlying cause. A history of stroke or TIA, as well as hypertension (high blood pressure), diabetes, heart failure and rheumatic fever, may indicate whether someone with AF is at a higher risk of complications.[10]
Rapid heart rate

Presentation is similar to other forms of rapid heart rate (tachycardia), and in some cases may actually be asymptomatic. The patient may complain of palpitations or chest discomfort. The rapid heart rate may result in the heart being unable to provide adequate blood flow and oxygen delivery to the rest of the body. Therefore, common symptoms may include shortness of breath which often worsens with exertion (dyspnea on exertion), shortness of breath when lying flat (orthopnea), and sudden onset of shortness of breath during the night (paroxysmal nocturnal dyspnea), and may progress to swelling of the lower extremities (peripheral edema). Owing to inadequate blood flow, patients may also complain of light-headedness, may feel like they are about to faint (presyncope), or may actually lose consciousness (syncope). The patient may be in significant respiratory distress. Because of inadequate oxygen delivery, the patient may appear blue (cyanosis). By definition, the heart rate will be greater than 100 beats per minute. Blood pressure will be variable, and often difficult to measure as the beat-by-beat variability causes problems for most digital (oscillometric) non-invasive blood pressure monitors. It is most concerning if consistently lower than usual (hypotension). Respiratory rate will be increased in the presence of respiratory distress. Pulse oximetry may confirm the presence of hypoxia related to any precipitating factors such as pneumonia. Examination of the jugular veins may reveal elevated pressure (jugular venous distention). Lung exam may reveal rales or crackles, which are suggestive of pulmonary edema. Heart exam will reveal an irregular but rapid rhythm.
Association with other conditions

Central sleep apnea (CSA) A study found that the prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively). There was a total of 180 subjects with 60 people in each of the 3 groups. Possible explanations for the association between CSA and AF are a causal relationship between the two conditions, or an abnormality of central cardiorespiratory regulation.[12] Left atrial enlargement Mitral stenosis
Diagnosis
The evaluation of atrial fibrillation involves diagnosis, determination of the etiology of the arrhythmia, and classification of the arrhythmia. The minimal evaluation of atrial fibrillation is a history and physical examination, ECG, transthoracic echocardiogram, and case specific bloodwork. Depending upon given resources, afflicted individuals may benefit from an in-depth evaluation which may include correlation of the heart rate response to exercise, exercise stress testing, chest X-ray, trans-esophageal echocardiography, and other studies.
Atrial fibrillation If a patient presents with a sudden onset of severe symptoms other forms of tachyarrhythmia must be ruled-out, as some may be immediately life threatening, such as ventricular tachycardia. While most patients will be placed on continuous cardiorespiratory monitoring, an electrocardiogram is essential for diagnosis. Provoking causes should be sought out. A common cause of any tachycardia is dehydration, as well as other forms of hypovolemia. Acute coronary syndrome should be ruled out. Intercurrent illness such as pneumonia may be present.
111
Screening
Screening for atrial fibrillation is not generally performed, although a study of routine pulse checks or ECGs during routine office visits found that the annual rate of detection of AF in elderly patients improved from 1.04% to 1.63%; selection of patients for prophylactic anticoagulation would improve stroke risk in that age category.[13] This estimated sensitivity of the routine primary care visit is 64%. This low result probably reflects the pulse not being checked routinely or carefully.[13] When ECGs are used for screening, the SAFE trial found that electronic software, primary care physicians and the combination of the two had the following sensitivities and specificities:[14] Interpreted by software: sensitivity = 83%, specificity = 99% Interpreted by a primary care physician: sensitivity = 80%, specificity = 92% Interpreted by a primary care physician with software: sensitivity = 92%, specificity = 91%
Minimal evaluation
The minimal evaluation of atrial fibrillation should generally be performed in all individuals with AF. The goal of this evaluation is to determine the general treatment regimen for the individual. If results of the general evaluation warrant it, further studies may then be performed. History and physical examination The history of the individual's atrial fibrillation episodes is probably the most important part of the evaluation. Distinctions should be made between those who are entirely asymptomatic when they are in AF (in which case the AF is found as an incidental finding on an ECG or physical examination) and those who have gross and obvious symptoms due to AF and can pinpoint whenever they go into AF or revert to sinus rhythm. Routine bloodwork While many cases of AF have no definite cause, it may be the result of various other problems (see below). Hence, renal function and electrolytes are routinely determined, as well as thyroid-stimulating hormone (commonly suppressed in hyperthyroidism and of relevance if amiodarone is administered for treatment) and a blood count.[10] In acute-onset AF associated with chest pain, cardiac troponins or other markers of damage to the heart muscle may be ordered. Coagulation studies (INR/aPTT) are usually performed, as anticoagulant medication may be commenced.[10]
Atrial fibrillation Electrocardiogram Atrial fibrillation is diagnosed on an electrocardiogram (ECG), an investigation performed routinely whenever an irregular heart beat is suspected. Characteristic findings are the absence of P waves, with unorganized electrical activity in their place, and irregular R-R intervals due to irregular conduction of impulses to the ventricles.[10] However, irregular R-R intervals may be difficult to determine if the rate is extremely rapid.[15]
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ECG of atrial fibrillation (top) and normal sinus rhythm (bottom). The purple arrow indicates a P wave, which is lost in atrial fibrillation.
QRS complexes should be narrow, signifying that they are initiated by normal conduction of atrial electrical activity through the intraventricular conduction system. Wide QRS complexes are worrisome for ventricular tachycardia, although in cases where there is disease of the conduction system, wide complexes may be present in A-Fib with rapid ventricular response. If paroxysmal AF is suspected but an ECG during an office visit only shows a regular rhythm, AF episodes may be detected and documented with the use of ambulatory Holter monitoring (e.g. for a day). If the episodes are too infrequent to be detected by Holter monitoring with reasonable probability, then the patient can be monitored for longer periods (e.g. a month) with an ambulatory event monitor.[10] Echocardiography A non-invasive transthoracic echocardiogram (TTE) is generally performed in newly diagnosed AF, as well as if there is a major change in the patient's clinical state. This ultrasound-based scan of the heart may help identify valvular heart disease (which may greatly increase the risk of stroke), left and right atrial size (which indicates likelihood that AF may become permanent), left ventricular size and function, peak right ventricular pressure (pulmonary hypertension), presence of left atrial thrombus (low sensivity), presence of left ventricular hypertrophy and pericardial disease.[10] Significant enlargement of both the left and right atria is associated with long-standing atrial fibrillation and, if noted at the initial presentation of atrial fibrillation, suggests that the atrial fibrillation is likely to be of a longer duration than the individual's symptoms.
Extended evaluation
An extended evaluation is generally not necessary in most individuals with atrial fibrillation, and is only performed if abnormalities are noted in the limited evaluation, if a reversible cause of the atrial fibrillation is suggested, or if further evaluation may change the treatment course. Chest X-ray A chest X-ray is generally only performed if a pulmonary cause of atrial fibrillation is suggested, or if other cardiac conditions are suspected (particularly congestive heart failure.) This may reveal an underlying problem in the lungs or the blood vessels in the chest.[10] In particular, if an underlying pneumonia is suggested, then treatment of the pneumonia may cause the atrial fibrillation to terminate on its own.
Atrial fibrillation Transesophageal echocardiogram A normal echocardiography (transthoracic or TTE) has a low sensitivity for identifying thrombi (blood clots) in the heart. If this is suspected - e.g. when planning urgent electrical cardioversion - a transesophageal echocardiogram (TEE or TOE where British spelling is used) is preferred.[10] The TEE has much better visualization of the left atrial appendage than transthoracic echocardiography. This structure, located in the left atrium, is the place where thrombus is formed in more than 90% of cases in non-valvular (or non-rheumatic) atrial fibrillation or flutter.[16] TEE has a high sensitivity for locating thrombi in this area[17] and can also detect sluggish bloodflow in this area that is suggestive of thrombus formation.[18] If no thrombus is seen on TEE, the incidence of stroke, (immediately after cardioversion is performed), is very low. Ambulatory Holter monitoring A Holter monitor is a wearable ambulatory heart monitor that continuously monitors the heart rate and heart rhythm for a short duration, typically 24 hours. In individuals with symptoms of significant shortness of breath with exertion or palpitations on a regular basis, a holter monitor may be of benefit to determine if rapid heart rates (or unusually slow heart rates) during atrial fibrillation are the cause of the symptoms. Exercise stress testing Some individuals with atrial fibrillation do well with normal activity but develop shortness of breath with exertion. It may be unclear if the shortness of breath is due to a blunted heart rate response to exertion caused by excessive AV node blocking agents, a very rapid heart rate during exertion, or due to other underlying conditions such as chronic lung disease or coronary ischemia. An exercise stress test will evaluate the individual's heart rate response to exertion and determine if the AV node blocking agents are contributing to the symptoms.
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Cause
AF is linked to several cardiac causes, but may occur in otherwise normal hearts. Known associations include: Hypertension (High blood pressure) Primary heart diseases including coronary artery disease, mitral stenosis (e.g. due to rheumatic heart disease or mitral valve prolapse), mitral regurgitation, hypertrophic cardiomyopathy (HCM), pericarditis, congenital heart disease, previous heart surgery Lung diseases (such as pneumonia, lung cancer, pulmonary embolism, sarcoidosis) Excessive alcohol consumption ("binge drinking" or "holiday heart syndrome"). Even otherwise healthy middle-aged women who consumed more than 2 drinks daily were 60% more likely to develop AF.[19] Hyperthyroidism Carbon monoxide poisoning Dual-chamber pacemakers in the presence of normal atrioventricular conduction.[20] A family history of AF may increase the risk of AF. A study of more than 2,200 AF patients found that 30 per cent had parents with AF.[21] Various genetic mutations may be responsible.[22] [23] Friedreich's ataxia
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Pathophysiology
Morphology
The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. This fibrosis is primarily due to atrial dilation, however genetic causes and inflammation may have a cause in some individuals. One study found that atrial dilation can occur as a consequence of AF,[24] although another study found that AF by itself does not cause it.[25] Dilation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the intra-cardiac pressures. This includes valvular heart disease (such as mitral stenosis, mitral regurgitation, and tricuspid regurgitation), hypertension, and congestive heart failure. Any inflammatory state that affects the heart can cause fibrosis of the atria. This is typically due to sarcoidosis but may also be due to autoimmune disorders that create autoantibodies against myosin heavy chains. Mutation of the lamin AC gene is also associated with fibrosis of the atria that can lead to atrial fibrillation. Once dilation of the atria has occurred, this begins a chain of events that leads to the activation of the renin aldosterone angiotensin system (RAAS) and subsequent increase in matrix metaloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. This process is not immediate, and experimental studies have revealed patchy atrial fibrosis may precede the occurrence of atrial fibrillation and may progress with prolonged durations of atrial fibrillation. Fibrosis is not limited to the muscle mass of the atria, and may occur in the sinus node (SA node) and atrioventricular node (AV node), correlating with sick sinus syndrome. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time,[10] [26] [27] suggesting that dysfunction of the SA node is progressive with prolonged episodes of atrial fibrillation.
Electrophysiology
Conduction Sinus rhythm Atrial fibrillation
The normal electrical conduction system of the heart allows the impulse that is generated by the sinoatrial node (SA node) of the heart to be propagated to and stimulate the myocardium (muscle of the heart). When the myocardium is stimulated, it contracts. It is the ordered stimulation of the myocardium that allows efficient contraction of the heart, thereby allowing blood to be pumped to the body.
Atrial fibrillation There are multiple theories about the etiology of atrial fibrillation. An important theory is that in atrial fibrillation, the regular impulses produced by the sinus node for a normal heartbeat, are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. Sources of these disturbances are either automatic foci, often localized at one of the pulmonary veins, or a small number of reentrant sources (rotors) harbored by the posterior wall of the left atrium near the junctions with the pulmonary veins. The pathology progresses from paroxysmal to persistent AF as the sources multiply and localize anywhere in the atria. Because recovery of the atria from excitation is heterogeneous, the electrical waves generated by the AF sources undergo repetitive, spatially distributed breakup and fragmentation in a process known as "fibrillatory conduction". Another theory is the multiple wavelet theory first formulated by Moe,[28] which was experimentally proven by Allessie et al. AF can be distinguished from atrial flutter (AFL), which appears as an organized electrical circuit usually in the right atrium. AFL produces characteristic saw-toothed F-waves of constant amplitude and frequency on an ECG whereas AF does not. In AFL, the discharges circulate rapidly at a rate of 300beats per minute (bpm) around the atrium. In AF, there is no regularity of this kind, except at the sources where the local activation rate can exceed 500 bpm. Although the electrical impulses of AF occur at a high rate, most of them do not result in a heart beat. A heart beat results when an electrical impulse from the atria passes through the atrioventricular (AV) node to the ventricles and causes them to contract. During AF, if all of the impulses from the atria passed through the AV node, there would be severe ventricular tachycardia resulting in severe reduction of cardiac output. This dangerous situation is prevented by the AV node since its limited conduction velocity reduces the rate at which impulses reach the ventricles during AF.[29]
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Management
The main goals of treatment are to prevent circulatory instability and stroke. Rate or rhythm control are used to achieve the former, while anticoagulation is used to decrease the risk of the latter.[30] If cardiovascularly unstable due to uncontrolled tachycardia, immediate cardioversion is indicated.[10]
Anticoagulation
Anticoagulation can be achieved through a number of means including the use of aspirin, heparin, warfarin, and dabigatran. Which method is used depends on a number issues including: cost, risk of stroke, risk of falls, compliance, and speed of desired onset of anticoagulation.
Rate control versus rhythm control using drugs

AF can cause disabling and bothersome symptoms. Palpitations, chest discomfort, anxiety, and decreased exercise tolerance are related to rapid heart rate and inefficient cardiac output caused by AF. Furthermore, AF with a persistent rapid rate can cause a form of heart failure called tachycardia induced cardiomyopathy. This can significantly increase mortality and morbidity, which can be prevented by early and adequate treatment of the AF. There are two ways to approach these symptoms using drugs: rate control and rhythm control. Rate control lowers the heart rate closer to normal, usually 60 to 100bpm, without trying to convert to a regular rhythm. Rhythm control restores normal heart rhythm in a process called cardioversion and maintains the normal rhythm with drugs. Studies suggest that rhythm control is most important in the acute setting AF, while rate control is more important in the chronic phase. As far as mortality is concerned, the AFFIRM trial showed that there is lower mortality using rate control with anticoagulation treatment versus rhythm control treatment and the difference increases up to 5 years (end of study).[31] The AFFIRM study also showed no difference in risk of stroke in patients who have converted to a normal rhythm with anti-arrhythmic treatment, compared to those who have only rate control.[31] AF is associated with a reduced quality of life, and while some studies indicate that rhythm control leads to a higher quality of life, the AFFIRM
Atrial fibrillation study did not find a difference.[32] A further study focused on rhythm control in patients with AF with concomitant heart failure, based on the hypothesis that AF confers a higher mortality risk in heart failure. In this setting, rhythm control offered no advantage compared to rate control.[33] However, the diagnosis and progression of atrial fibrillation and other cardiovascular disease requires further investigation. In patients with a fast ventricular response, intravenous magnesium significantly increases the chances of successful rate and rhythm control in the urgent setting without major side-effects.[34] A patient with fluctuating vital signs, mental status changes, preexcitation, or chest pain often will go to immediate treatment with synchronized DC cardioversion.[10] Otherwise the decision of rate control versus rhythm control using drugs is made. This is based on a number of criteria that includes whether or not symptoms persist with rate control.
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Rate control
Rate control is achieved with medications that work by increasing the degree of block at the level of the AV node, effectively decreasing the number of impulses that conduct into the ventricles. This can be done with:[10] [35] Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, atenolol, bisoprolol, nebivolol) Non-dihydropyridine calcium channel blockers (i.e. diltiazem or verapamil) Cardiac glycosides (i.e. digoxin) - have limited use, apart from in the sedentary elderly patient In addition to these agents, amiodarone has some AV node blocking effects (particularly when administered intravenously), and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension). Diltiazem has been shown to be more effective than either digoxin or amiodarone.[36]
Cardioversion
Cardioversion is a noninvasive conversion of an irregular heartbeat to a normal heartbeat using electrical or chemical means:[10] Electrical cardioversion involves the restoration of normal heart rhythm through the application of a DC electrical shock. Chemical cardioversion is performed with drugs, such as amiodarone, dronedarone,[37] procainamide, dofetilide, ibutilide, propafenone or flecainide. Vernakalant has been found to safely and rapidly convert new onset atrial fibrillation.[38]
Ablation
If rhythm control is desired and cannot be maintained by medication or cardioversion then catheter ablation may be attempted.[10]
Prognosis
Thromboembolism
In atrial fibrillation, the lack of an organized atrial contraction can result in some stagnant blood in the left atrium (LA) or left atrial appendage (LAA). This lack of movement of blood can lead to thrombus formation (blood clotting). If the clot becomes mobile and is carried away by the blood circulation, it is called an embolus. An embolus proceeds through smaller and smaller arteries until it plugs one of them and prevents blood from flowing through the artery. This process results in end-organ damage due to loss of nutrients, oxygen, and removal of cellular waste products. Thrombus can form anywhere in the body, while emboli follow the blood circulation to specific points in the body. Emboli in the brain may results in a ischemic stroke or transient ischemic attack (TIA).
Atrial fibrillation More than 90% of cases of thrombi associated with non-valvular atrial fibrillation evolve in the left atrial appendage.[16] However, the LAA lies in close relation to the free wall of the left ventricle and thus the LAA's emptying and filling, which determines its degree of blood stagnation, may be helped by the motion of the wall of the left ventricle, if there is good ventricular function.[39] If the LA is enlarged, there is an increased risk of thrombi that originate in the LA. Moderate to severe, non-rheumatic, mitral regurgitation (MR) reduces this risk of stroke.[40] This risk reduction may be due to a beneficial stirring effect of the MR blood flow into the LA.[41]
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Mitral valve
Atrial fibrillation and a corresponding enlargement of the left atrium may cause an increase in the perimeter of the mitral valve. The somewhat circular perimeter of the mitral valve is defined by the mitral annulus.[42] With a normal sinus rhythm, the mitral annulus undergoes dynamic changes during the cardiac cycle. For example, at the end of diastole the annular area is smaller than at the end of systole. A possible reason for this dynamic size difference is that the coordinated contraction of the left atrium acts like a sphincter about the mitral annulus and reduces its size. This may be important for mitral valve competence so that it does not leak when the left ventricle pumps blood. However, when the left atrium fibrillates, this sphincter action is not possible and may contribute to, or result in, mitral regurgitation in some cases.[42]
Epidemiology
Atrial fibrillation is the most common arrhythmia found in clinical practice.[10] It also accounts for 1/3 of hospital admissions for cardiac rhythm disturbances,[10] and the rate of admissions for AF has risen in recent years.[43] Strokes from AF account for 6-24% of all ischemic strokes.[44] Between 3-11% of those with AF have structurally normal hearts.[24] Approximately 2.2million individuals in the United States and 4.5million in the European Union have AF.[10] [45] The incidence of atrial fibrillation increases with age. The prevalence in individuals over the age of 80 is about 8%.[46] In developed countries, the number of patients with atrial fibrillation is likely to increase during the next 50years, owing to the growing proportion of elderly individuals.[47]
History
Because the diagnosis of atrial fibrillation requires measurement of the electrical activity of the heart, atrial fibrillation was not truly described until 1874, when Edm Flix Alfred Vulpian observed the irregular atrial electrical behavior that he termed "fremissement fibrillaire" in dog hearts.[48] In the mid-eighteenth century, Jean-Baptiste de Snac made note of dilated, irritated atria in people with mitral stenosis.[49] The irregular pulse associated with AF was first recorded in 1876 by Carl Wilhelm Hermann Nothnagel and termed "delirium cordis", stating that "[I]n this form of arrhythmia the heartbeats follow each other in complete irregularity. At the same time, the height and tension of the individual pulse waves are continuously changing".[50] Correlation of delirium cordis with the loss of atrial contraction as reflected in the loss of a waves in the jugular venous pulse was made by Sir James MacKenzie in 1904.[51] Willem Einthoven published the first ECG showing AF in 1906.[52] The connection between the anatomic and electrical manifestations of AF and the irregular pulse of delirium cordis was made in 1909 by Carl Julius Rothberger, Heinrich Winterberg, and Sir Thomas Lewis.[53] [54] [55]
Atrial fibrillation
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References
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[35] "Atrial fibrillation: national clinical guideline for management in primary and secondary care" (http:/ / www. nice. org. uk/ nicemedia/ pdf/ cg036fullguideline. pdf) (PDF). National Collaborating Centre for Chronic Conditions. London: Royal College of Physicians. 2006. . Retrieved 2009-05-05. [36] Siu CW, Lau CP, Lee WL, Lam KF, Tse HF (July 2009). "Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation". Crit. Care Med. 37 (7): 21749; quiz 2180. doi:10.1097/CCM.0b013e3181a02f56. PMID19487941. [37] Singh BN, Connolly SJ, Crijns HJ et al. (2007). "Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter". N. Engl. J. Med. 357 (10): 98799. doi:10.1056/NEJMoa054686. PMID17804843. [38] Finnin M (July 2010). "Vernakalant: A novel agent for the termination of atrial fibrillation". Am J Health Syst Pharm 67 (14): 115764. doi:10.2146/ajhp080501. PMID20592320. [39] Al-Saady, N. M.; O. A. Abel, A. J. Camm (1999). "Left atrial appendage: structure, function, and role in thromboembolism". Heart 82 (5): 54755. PMC1760793. PMID10525506. [40] Nakagami H, Yamamoto K, Ikeda U, Mitsuhashi T, Goto T, Shimada K (1998). "Mitral regurgitation reduces the risk of stroke in patients with nonrheumatic atrial fibrillation" (http:/ / www. ahjonline. com/ article/ S0002-8703(98)70231-5/ abstract). Americal Heart Journal 136 (3): 52832. doi:10.1016/S0002-8703(98)70231-5. PMID9736148. . Retrieved 2010-02-23. [41] Cheng, TO (1999-11). "Reduced risk for thromboembolism in atrial fibrillation and mitral regurgitation". American Heart Journal 138 (5 Pt 1): 9989. doi:10.1016/S0002-8703(99)70045-1. PMID10539836. [42] Pai, RG; Varadarajan, P; Tanimoto, M (2003-01). "Effect of Atrial Fibrillation on the Dynamics of Mitral Annular Area" (http:/ / www. icr-heart. com/ journal/ content/ 2003/ jan/ abstracts/ article. php?id=135). The Journal of Heart Valve Disease 12 (1): 317. PMID12578332. . Retrieved 2009-12-20. [43] Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. (2003). "Rising rates of hospital admissions for atrial fibrillation". Epidemiology 14 (6): 66672. doi:10.1097/01.ede.0000091649.26364.c0. PMID14569181. [44] Narumiya T, Sakamaki T, Sato Y, Kanmatsuse K (2003 January). "Relationship between left atrial appendage function and left atrial thrombus in patients with nonvalvular chronic atrial fibrillation and atrial flutter". Circulation Journal 67 (1): 6872. doi:10.1253/circj.67.68. PMID12520155. [45] Go AS, Hylek EM, Phillips KA et al. (2001). "Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study". JAMA 285 (18): 23705. doi:10.1001/jama.285.18.2370. PMID11343485. [46] Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM (1994). "Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study)". Am. J. Cardiol. 74 (3): 23641. doi:10.1016/0002-9149(94)90363-8. PMID8037127. [47] Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (2001). "Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study". JAMA 285 (18): 23705. doi:10.1001/jama.285.18.2370. PMID11343485. [48] Vulpian A. (1874). "Note sur les effets de la faradisation directe des ventricules du coeur chez le chien". Archives de Physiologie Normale et Pathologique 6: 975.
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Atrial fibrillation
[49] McMichael J. (1982). "History of atrial fibrillation 1628-1819 Harvey - de Senac - Lannec". Br Heart J 48 (3): 1937. doi:10.1136/hrt.48.3.193. PMC481228. PMID7049202. [50] Nothnagel H. (1876). "Ueber arythmische Herzthatigkeit". Deutsches Archiv fur Klinische Medizin 17: 190220. [51] MacKenzie J. (1904). "Observations on the Inception of the Rhythm of the Heart by the Ventricle: As the cause of Continuous Irregularity of the Heart". Br Med J 1 (2253): 52936. doi:10.1136/bmj.1.2253.529. PMC2353402. PMID20761393. [52] Einthoven W. (1906). "Le telecardiogramme". Archives Internationales de Physiologie 4: 13264. [53] Rothberger CJ, Winterberg H. (1909). "Vorhofflimmern und Arhythmia perpetua". Wiener Klinische Wochenschrift 22: 83944. [54] Lewis T (1909). "Auricular fibrillation: a common clinical condition". Br Med J 2: 1528. [55] Flegel KM (1995). "From delirium cordis to atrial fibrillation: historical development of a disease concept". Ann. Intern. Med. 122 (11): 86773. PMID7741373.
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External links
American Heart Association (http://www.americanheart.org/presenter.jhtml?identifier=4451) page on atrial fibrillation
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Junctional Dysrythmias
Supraventricular tachycardia
Lead II electrocardiogram strip showing SVT with a heart rate of about 150. ICD-10 ICD-9 MeSH I47.1 [1] [1] , 427.0 [2]
427.89
D013617
[3]
Supraventricular tachycardia (SVT) is a general term that refers to any rapid heart rhythm originating above the ventricular tissue. Supraventricular tachycardias can be contrasted to the potentially more dangerous ventricular tachycardias - rapid rhythms that originate within the ventricular tissue. Although technically an SVT can be due to any supraventricular cause, the term is often used by clinicians to refer to one specific cause of SVT, namely Paroxysmal supraventricular tachycardia (PSVT) which is due to AV nodal reentrant tachycardia.
A 12 lead ECG showing PSVT
Terminology
The term supraventricular tachycardia is often used differently in different settings. Theoretically, it refers to any tachycardia that is not ventricular in origin. This definition includes physiological sinus tachycardia which can be a normal reaction to stress and a variety of non-cardiac conditions such as fever and hyperthyroidism. In the widest useful sense supraventricular tachycardia includes abnormal sinus tachycardia, ectopic atrial tachycardia (that is, not from the sinoatrial node), atrial fibrillation/atrial flutter (though if identified these are usually considered separately) and junctional tachycardia.[4] Often, however, in a clinical setting, it is used practically as a synonym for paroxysmal supraventricular tachycardia (PSVT). This term refers to those SVTs that have a sudden, almost immediate onset [5] and are regular. A person experiencing PSVT may feel their heart rate go from 60 to 200 beats per minute
Supraventricular tachycardia instantaneously, often in response to a quick movement such as picking something up from the floor. Because physiological sinus tachycardias have a gradual (i.e. non-immediate) onset and AF is usually obviously irregular they are excluded from the PSVT category. PSVTs are most commonly AV nodal reentrant tachycardias or part of Wolff-Parkinson-White syndrome (WPW) - which may be "concealed", i.e. not evident on the resting electrocardiogram.
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Types
The following are types of supraventricular tachycardias, each with a different mechanism of impulse maintenance. It should be noted that whilst all of the below terms are technically causes of SVT, clinicians usually use the specific term/diagnosis, when possible: SVTs from a sinoatrial source: Inappropriate sinus tachycardia (IST) Sinoatrial nodal reentrant tachycardia (SNRT) SVTs from an atrial source: Ectopic (unifocal) atrial tachycardia (EAT) Multifocal atrial tachycardia (MAT) Atrial fibrillation with a rapid ventricular response Atrial flutter with a rapid ventricular response Without rapid ventricular response, fibrillation and flutter are usually not classified as SVT SVTs from an atrioventricular source (junctional tachycardia): AV nodal reentrant tachycardia (AVNRT) or junctional reciprocating tachycardia (JRT) Permanent (or persistent) junctional reciprocating tachycardia (PJRT), a form of JRT which occurs predominantly in infants and children but can occasionally occur in adults AV reentrant tachycardia (AVRT) - visible or concealed (including Wolff-Parkinson-White syndrome) Junctional ectopic tachycardia (JET)
Signs and symptoms

Symptoms can come on suddenly and may go away without treatment. Stress, exercise, and emotion can all result in a normal or physiological increase in heart rate, but can also, though more rarely, precipitate SVT. Episodes can last a few minutes or as long as 1 or 2 days, sometimes persisting until treated. The rapid beating of the heart during SVT can make the heart a less-effective pump, decreasing cardiac output and blood pressure. The following symptoms are typical with a rapid pulse of 150270 or more beats per minute: Pounding heart Shortness of breath Chest pain Rapid breathing Dizziness Loss of consciousness (in serious cases) Numbness of various body parts
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Diagnosis
The individual subtypes of SVT can be usually be distinguished from each other by the physiological and electrical characteristics that are present in the patient's electrocardiogram (ECG).
Holter monitor-Imaging with start (red arrow) and end (blue arrow) of a SV-tachycardia
Most supraventricular tachycardias with a pulse frequency of about 128/min. have a narrow QRS complex on ECG, but supraventricular tachycardia with aberrant conduction (SVTAC) can produce a wide-complex tachycardia that may mimic ventricular tachycardia (VT). In the clinical setting, it is important to determine whether a wide-complex tachycardia is an SVT or a ventricular tachycardia, since they are treated differently. Ventricular tachycardia has to be treated appropriately, since it can quickly degenerate to ventricular fibrillation and death. A number of different algorithms have been devised to determine whether a wide-complex tachycardia is supraventricular or ventricular in origin.[6] In general, a history of structural heart disease dramatically increases the likelihood that the tachycardia is ventricular in origin. Sinus tachycardia is considered physiological or "appropriate" when a reasonable stimulus, such as the catecholamine surge associated with fright, stress, or physical activity, provokes the tachycardia. It is distinguished by a presentation identical to a normal sinus rhythm except for its fast rate (>100 beats per minute in adults). Sinoatrial node reentrant tachycardia (SANRT) is caused by a reentry circuit localised to the SA node, resulting in a normal morphology P-wave that falls before a regular, narrow QRS complex. It is therefore impossible to distinguish on the ECG from physiological sinus tachycardia unless the sudden onset is observed (or recorded on Holter monitor. It may sometimes be distinguished by its prompt response to vagal manoeuvres. Ectopic (unifocal) atrial tachycardia is tachycardia resultant from one ectopic focus within the atria, distinguished by a consistent P-wave of abnormal morphology that falls before a narrow, regular QRS complex. Multifocal atrial tachycardia (MAT) is tachycardia resultant from at least three ectopic foci within the atria, distinguished by P-waves of at least three different morphologies that all fall before irregular, narrow QRS complexes. Atrial fibrillation is not, in itself, a tachycardia, but when it is associated with a rapid ventricular response greater than 100 beats per minute, it becomes a tachycardia. A-fib is characteristically an "irregularly irregular rhythm" both in its atrial and ventricular depolarizations. It is distinguished by fibrillatory P-waves that, at some point in their chaos, stimulate a response from the ventricles in the form of irregular, narrow QRS complexes. Atrial flutter, is caused by a re-entry rhythm in the atria, with a regular rate of about 300 beats per minute. On the ECG, this appears as a line of "sawtooth" P-waves. The AV node will not usually conduct such a fast rate, and so the P:QRS usually involves a 2:1 or 4:1 block pattern, (though rarely 3:1, and sometimes 1:1 in the setting of class IC antiarrhythmic drug use). Because the ratio of P to QRS is usually consistent, A-flutter is often regular in comparison to its irregular counterpart, A-fib. Atrial Flutter is also not necessarily a tachycardia unless the AV node permits a ventricular response greater than 100 beats per minute. AV nodal reentrant tachycardia (AVNRT) is also sometimes referred to as junctional reciprocating tachycardia (JRT), since the atrioventricular junction (AV junction) includes the AV node. It involves a reentry circuit forming just next to or within the AV node itself. The circuit most often involves two tiny pathways one faster than the other, within the AV node. Because the AV node is immediately between the atria and the ventricle, the re-entry circuit often stimulates both, meaning that a retrogradely conducted P-wave is buried within or occurs just after the regular, narrow QRS complexes.
Supraventricular tachycardia Atrioventricular reentrant tachycardia (AVRT), also known as circus movement tachycardia (CMT), also results from a reentry circuit, although one physically much larger than AVNRT. One portion of the circuit is usually the AV node, and the other, an abnormal accessory pathway from the atria to the ventricle. Wolff-Parkinson-White syndrome is a relatively common abnormality with an accessory pathway, the Bundle of Kent crossing the AV valvular ring. In orthodromic AVRT, atrial impulses are conducted down through the AV node and retrogradely re-enter the atrium via the accessory pathway. A distinguishing characteristic of orthodromic AVRT can therefore be a P-wave that follows each of its regular, narrow QRS complexes, due to retrograde conduction. In antidromic AVRT, atrial impulses are conducted down through the accessory pathway and re-enter the atrium retrogradely via the AV node. Because the accessory pathway initiates conduction in the ventricles outside of the bundle of His, the QRS complex in antidromic AVRT is often wider than usual, with a delta wave. Finally, junctional ectopic tachycardia (JET) is a rare tachycardia caused by increased automaticity of the AV node itself initiating frequent heart beats. On the ECG, junctional tachycardia often presents with abnormal morphology P-waves that may fall anywhere in relation to a regular, narrow QRS complex. It is often due to drug toxicity.
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Treatment
In general, SVT is rarely life threatening, but episodes can be treated or prevented. While some treatment modalities can be applied to all SVTs with impunity, there are specific therapies available to cure some of the different sub-types. Cure requires intimate knowledge of how and where the arrhythmia is initiated and propagated. The SVTs can be separated into two groups, based on whether they involve the AV node for impulse maintenance or not. Those that involve the AV node can be terminated by slowing conduction through the AV node. Those that do not involve the AV node will not usually be stopped by AV nodal blocking maneuvers. These maneuvers are still useful however, as transient AV block will often unmask the underlying rhythm abnormality. AV nodal blocking can be achieved in at least three different ways:
Physical maneuver
A number of physical maneuvers cause increased AV nodal block, principally through activation of the parasympathetic nervous system, conducted to the heart by the vagus nerve. These manipulations are therefore collectively referred to as vagal maneuvers. The Valsalva maneuver should be the first vagal maneuver tried.[7] It works by increasing intra-thoracic pressure and affecting baro-receptors (pressure sensors) within the arch of the aorta. It is carried out by asking the patient to hold their breath and try to exhale forcibly as if straining during a bowel movement, or by getting them to hold their nose and blow out against it.[8] There are many other vagal maneuvers including: holding ones breath for a few seconds, coughing, plunging the face into cold water,[8] (via the diving reflex[9] ), drinking a glass of ice cold water, and standing on one's head. Carotid sinus massage, carried out by firmly pressing the bulb at the top of one of the carotid arteries in the neck, is effective but is often not recommended due to risks of stroke in those with plaque in the carotid arteries.
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Medications
Adenosine, an ultra short acting AV nodal blocking agent, is indicated if vagal maneuvers are not effective.[10] If this works, followup therapy with diltiazem, verapamil or metoprolol may be indicated. SVT that does not involve the AV node may respond to other anti-arrhythmic drugs such as sotalol or amiodarone.
Termination of PSVT following adenosine
In pregnancy, adenosine is the treatment of choice as recommended by the ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias.[11]
Cardioversion
If the patient is unstable or other treatments have not been effective, cardioversion may be used, and is almost always effective.
Prevention
Once the acute episode has been terminated, ongoing treatment may be indicated to prevent a recurrence of the arrhythmia. Patients who have a single isolated episode, or infrequent and minimally symptomatic episodes usually do not warrant any treatment except observation. Patients who have more frequent or disabling symptoms from their episodes generally warrant some form of preventive therapy. A variety of drugs including simple AV nodal blocking agents like beta-blockers and verapamil, as well as anti-arrhythmics may be used, usually with good effect, although the risks of these therapies need to be weighed against the potential benefits. A limited study has demonstrated that acupuncture can also be effective in preventing paroxysmal supraventricular tachycardia[12] . Radiofrequency ablation has revolutionized the treatment of tachycardia caused by a re-entrant pathway. This is a low risk procedure that uses a catheter inside the heart to deliver radio frequency energy to locate and destroy the abnormal electrical pathways. Ablation has been shown to be highly effective: around 90% effective in eliminating AVNRT. Similar high rates of success are achieved with radio frequency ablation in eliminating AVRT and typical Atrial Flutter. There is a newer treatment for SVT involving the AV node directly. This treatment is called Cryoablation. SVT involving the AV node is often a contraindication for using radiofrequency ablation due to the small (1%) incidence of injuring the AV node requiring a permanent pacemaker. With Cryoablation, a supercooled catheter is used (cooled by nitrous oxide gas), and the tissue is frozen to -10C. This provides the same result as radiofrequency ablation but does not carry the same risk. If you freeze the tissue and then realize you are in a dangerous spot, you can halt freezing the tissue and allow the tissue to spontaneously rewarm and the tissue is the same as if you never touched it. If after freezing the tissue to -10C, you get the desired result, then you freeze the tissue down to a temperature of -73C and you permanently ablate the tissue. This therapy has further improved the treatment options for people with AVNRT (and other SVTs with pathways close to the AV node), widening the application of curative ablation to young patients with relatively mild but still troublesome symptoms who would not have accepted the risk of requiring a pacemaker.
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Notable cases
After being successfully diagnosed and treated, Bobby Julich went on to place third in the 1998 Tour de France and win a Bronze Medal in the 2004 Summer Olympics.[13] Women's Olympic volleyball player Tayyiba Haneef-Park underwent an ablation for SVT just two months before competing in the 2008 Summer Olympics.[14] Tony Blair, former PM of the UK, was also operated on for atrial flutter. Anastacia was diagnosed with the disease.[15] Women's Olympic gold medalist swimmer, Rebecca Soni has had SVT and has had heart surgery for it. In addition, Neville Fields had corrective surgery for SVT in early 2006.
References
[1] [2] [3] [4] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I47. 1 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 0 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D013617 " supraventricular tachycardia (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ nine/ 000957470. htm)" at Dorland's Medical Dictionary [5] " paroxysmal supraventricular tachycardia (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ nine/ 000957466. htm)" at Dorland's Medical Dictionary [6] Lau EW, Ng GA (2002). "Comparison of the performance of three diagnostic algorithms for regular broad complex tachycardia in practical application". Pacing and clinical electrophysiology : PACE 25 (5): 8227. doi:10.1046/j.1460-9592.2002.00822.x. PMID12049375. [7] "BestBets: Comparing Valsalva manoeuvre with carotid sinus massage in adults with supraventricular tachycardia" (http:/ / www. bestbets. org/ bets/ bet. php?id=930). . [8] Vibhuti N, Singh; Monika Gugneja (2005-08-22). "Supraventricular Tachycardia" (http:/ / www. emedicinehealth. com/ supraventricular_tachycardia/ page7_em. htm). eMedicineHealth.com. . Retrieved 2008-11-28. [9] Mathew PK (January 1981). "Diving reflex. Another method of treating paroxysmal supraventricular tachycardia". Arch. Intern. Med. 141 (1): 223. doi:10.1001/archinte.141.1.22. PMID7447580. [10] "Adenosine vs Verapamil in the acute treatment of supraventricular tachycardias" (http:/ / www. bestbets. org/ bets/ bet. php?id=996). . [11] Blomstrm-Lundqvist ET AL., MANAGEMENT OF PATIENTS WITH Supraventricular Arrhythmias. J Am Coll Cardiol 2003;42:1493531 (http:/ / www. acc. org/ qualityandscience/ clinical/ guidelines/ arrhythmias/ VI_special. htm) [12] Wu RD, Lin LF. Clinical observation on wrist-ankle acupuncture for treatment of paroxysmal supraventricular tachycardia (PSVT). Zhongguo Zhen Jiu. 2006 Dec;26(12):854-6. (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 17313005) [13] An athlete's experience with Re-entrant Supraventricular Tachycardia (http:/ / www. bobbyjulich. com/ julich/ ?page_id=46) [14] USA Volleyball 2008 Olympic Games Press Kit (http:/ / www. usavolleyball. org/ media/ national/ 08WNTOlympicPressKit. pdf) [15] "Anastacia delays heart surgery" (http:/ / www. nowmagazine. co. uk/ celebrity-news/ 279923/ anastacia-delays-heart-surgery/ 1/ ). News of the World (http:/ / www. nowmagazine. co. uk). 3 Nov 2008. . Retrieved 30 Apr 2010.
External links
Supraventricular Tachycardia information (http://heartcenter.seattlechildrens.org/conditions_treated/ supraventricular_tachycardia.asp) from Seattle Children's Hospital Heart Center
AV nodal reentrant tachycardia
127

AV nodal reentrant tachycardia. In yellow, is evidenced the P wave that falls after the QRS complex. ICD-10 ICD-9 eMedicine MeSH I47.1 [1] [1] , 427.0 [2] [2] [3]
426.89
med/2955 D013611
ped/2535
[4]
AV nodal reentrant tachycardia (AVNRT), or atrioventricular nodal reentrant tachycardia, is a type of tachycardia (fast rhythm) of the heart. It is a type of supraventricular tachycardia (SVT), meaning that it originates from a location within the heart above the bundle of His. AV nodal reentrant tachycardia is the most common regular supraventricular tachycardia. It is more common in women than men (approximately 75% of cases occurring in females). The main symptom is palpitations. Treatment may be with specific physical maneuvers, medication, or rarely Synchronized cardioversion. Frequent attacks may require radiofrequency ablation, in which the abnormally conducting tissue in the heart is destroyed. AVNRT occurs when a reentry circuit forms within or just next to the atrioventricular node. The circuit usually involves two anatomical pathways: the fast pathway and the slow pathway, which are both in the right atrium. The slow pathway (which is usually targeted for ablation) is located inferiorly and slightly posterior to the AV node, often following the anterior margin of the coronary sinus. The fast pathway is usually located just superior and posterior to the AV node. These pathways are formed from tissue that behaves very much like the AV node, and some authors regard them as part of the AV node. The fast and slow pathways should not be confused with the accessory pathways that give rise to Wolff-Parkinson-White syndrome (WPW syndrome) or atrioventricular re-entrant tachycardia (AVRT). In AVNRT, the fast and slow pathways are located within the right atrium in close proximity to or within the AV node and exhibit electrophysiologic properties similar to AV nodal tissue. Accessory pathways that give rise to WPW syndrome and AVRT are located in the atrioventricular valvular rings. They provide a direct connection between the atria and ventricles, and have electrophysiologic properties similar to ventricular myocardium.
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Signs and symptoms

The main symptom is the sudden development of rapid regular palpitations. Often, no precipitant is present, although some report development of symptoms in stressful situations, consumption of alcohol or caffeine, or other factors. In some cases, the onset of the tachycardia is associated with a brief drop in blood pressure. When this happens, the patient may experience dizziness or rarely syncope (fainting). If the heart rate is very fast, and the patient has underlying coronary artery disease (obstruction of the arteries of the heart by atherosclerosis), chest pain similar to angina may be experienced; this pain is band- or pressure-like around the chest and often radiates to the left arm and angle of the left jaw. AVNRT is rarely life-threatening.
Diagnosis
If the symptoms are present while the patient is attending medical care (e.g. emergency department), an electrocardiogram (ECG/EKG) may show typical changes that confirm the diagnosis. If the palpitations are recurrent, a doctor may request a Holter monitor (24 hour or longer portable ECG) recording. Again, this will show the diagnosis if the recorder is attached at the time of the symptoms. Rarely, disabling but infrequent episodes of palpitations may require the insertion of a small microchip-based device (e.g. Reveal Plus) under the skin that continuously record heart activity, and can be read through the skin after an episode. All these ECG-based technologies also enable the distinction between AVNRT and other tachycardias such as atrial fibrillation, atrial flutter, sinus tachycardia, ventricular tachycardia and tachyarrhythmias related to Wolff-Parkinson-White syndrome, all of which may have symptoms that are similar to AVNRT. Blood tests commonly performed in people with palpitations are: thyroid function tests (TFTs) - an overactive thyroid increases the risk of AVNRT electrolytes - disturbances in potassium, calcium and magnesium may predispose to AVNRT cardiac markers - if there is a concern that myocardial infarction (heart attack) has occurred either as a cause or as a result of the AVNRT; this is usually only the case if the patient has experienced chest pain
Classification
There are several types of AVNRT. The "common form" or "usual" AVNRT utilizes the slow AV nodal pathway as the anterograde limb of the circuit and the fast AV nodal pathway as the retrograde limb. The reentry circuit can be reversed such that the fast AV nodal pathway is the anterograde limb and the slow AV nodal pathway is the retrograde limb. This, not surprisingly, is referred to as the "uncommon form" of AVNRT. However, there is also a third type of AVNRT that utilizes the slow AV nodal pathway as the anterograde limb and left atrial fibers that approach the AV node from the left side of the inter-atrial septum as the retrograde limb. This is known as atypical, or Slow-Slow AVNRT. [5]
Common AVNRT
In common AVNRT, the anterograde conduction is via the slow pathway and the retrograde conduction is via the fast pathway ("slow-fast" AVNRT). Because the retrograde conduction is via the fast pathway, stimulation of the atria (which produces the inverted P wave) will occur at the same time as stimulation of the ventricles (which causes the QRS complex). As a result, the inverted P waves may not be seen on the surface ECG since they are buried with the QRS complexes. Often the retrograde p-wave is visible, but also in continuity with the QRS complex, appearing as a "pseudo R prime" wave in lead V1 or a "pseudo S" wave in the inferior leads.
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Uncommon AVNRT
In uncommon AVNRT, the anterograde conduction is via the fast pathway and the retrograde conduction is via the slow pathway ("fast-slow" AVNRT). Multiple slow pathways can exist so that both anterograde and retrograde conduction are over slow pathways. ("slow-slow" AVNRT). Because the retrograde conduction is via the slow pathway, stimulation of the atria will be delayed by the slow conduction tissue and will typically produce an inverted P wave that falls after the QRS complex on the surface ECG.
Treatment
An episode of supraventricular tachycardia (SVT) due to AVNRT can be terminated by any action that transiently blocks the AV node. Various methods are possible.
Vagal maneuvers
Some people with known AVNRT may be able to stop their attack by using various tricks to activate the vagus nerve. This includes carotid sinus massage (pressure on the carotid sinus in the neck) or the Valsalva maneuver (increasing the pressure in the chest by attempting to exhale against a closed airway).
Medication
Medical therapy can be initiated with AV nodal slowing drugs such as adenosine (which is a pharmacologic cardioversion), beta blockers or calcium channel blockers (such as verapamil). Numerous other antiarrhythmic drugs may be effective if the more commonly used medications have not worked; these include flecainide or amiodarone. Both adenosine and beta blockers may cause tightening of the airways, and are therefore used with caution in people who are known to have asthma.
Cardioversion
In very rare instances, cardioversion (the electrical restoration of a normal heart rhythm) is needed in the treatment of AVNRT. This would normally only happen if all other treatments have been ineffective, or if the fast heart rate is poorly tolerated (e.g. the development of heart failure symptoms, low blood pressure or coma).
Electrophysiology
After being diagnosed with AVNRT, patients can also undergo an electrophysiology (EP) study to confirm the diagnosis. Catheter ablation of the slow pathway, if successfully carried out, can potentially cure the patient of AVNRT.
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Pacemaker-mediated Tachycardia
A separate form of AV nodal reentrant tachycardia is pacemaker-mediated tachycardia (PMT), a possible complication of dual-chamber artificial pacemakers is. In PMT, the artificial pacemaker forms the anterograde (atrium to ventricle) limb of the circuit and the atrioventricular (AV) node forms the retrograde limb (ventricle to atrium) of the circuit.[6] Treatment of PMT typically involves reprogramming the pacemaker.[6]
References
[1] [2] [3] [4] [5] [6] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 89 http:/ / www. emedicine. com/ med/ topic2955. htm http:/ / www. emedicine. com/ ped/ topic2535. htm# http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D013611 http:/ / lifeinthefastlane. com/ 2009/ 09/ avnrt-ecg/ eMedicine > Pacemaker-Mediated Tachycardia (http:/ / emedicine. medscape. com/ article/ 159645-overview) Author: Brian Olshansky, MD. Coauthor(s): Chirag M Sandesara, MD; Noel G Boyle, MB, BCh, MD, PhD. Updated: Jun 17, 2008
External links
AVNRT Clinical Cases (http://lifeinthefastlane.com/2009/09/avnrt-ecg/) from Life in the Fast Lane Medical Blog Supraventricular Tachycardia: Diagnosis and Management (http://www.mayoclinicproceedings.com/content/ 83/12/1400.full) from Mayo Clinic Proceedings
Junctional rhythm
Junctional rhythm describes an abnormal heart rhythm resulting from impulses coming from a locus of tissue in the area of the atrioventricular node,[1] the "junction" between atria and ventricles. Under normal conditions, the heart's sinoatrial node determines the rate by which the organ beats - in other words, it is the heart's "pacemaker." The electrical activity of sinus rhythm originates in the sinoatrial node and depolarizes the atria. Current then passes from the atria through the bundle of His, from which it travels along Purkinje fibers to reach and depolarize the ventricles. This sinus rhythm is important because it ensures that the heart's atria reliably contract before the ventricles. In junctional rhythm, however, the sinoatrial node does not control the heart's rhythm - this can happen in the case of a block in conduction somewhere along the pathway described above. When this happens, the heart's atrioventricular node takes over as the pacemaker.[2] . In the case of a junctional rhythm, the atria will actually still contract before the ventricles; however, this does not happen by the normal pathway and instead is due to retrograde conduction (conduction comes from the ventricles or from the AV node into and through the atria).[3] . Junctional rhythm can be diagnosed by looking at an ECG: it usually presents without a P wave or with an inverted P wave. Occasionally the P wave will be retrograde, meaning appearing after the QRS complex. [4]
Junctional rhythm
131
References
[1] Merriam-Webster dictionary > Junctional rhythm (http:/ / www. merriam-webster. com/ medical/ junctional rhythm) Retrieved September 2010 [2] eMedicine:"Junctional Rhythms" http:/ / www. emedicine. com/ MED/ topic1212. htm [3] medical dictionary http:/ / medical-dictionary. thefreedictionary. com/ retrograde+ conduction [4] Abnormalities in the ECG measurement http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson4/ index. html#PRinterval
Junctional tachycardia
Junctional tachycardia is a form of supraventricular tachycardia characterized by involvement of the AV node.[1] It can be contrasted to atrial tachycardia. It is a tachycardia associated with the generation of impulses in a locus in the region of the atrioventricular node. It can be associated with digitalis toxicity.[2] It may be due to coronary artery disease and conduction system disease. It can appear similar to atrioventricular nodal reentrant tachycardia.[3] One form is junctional ectopic tachycardia.
References
[1] " junctional tachycardia (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ nine/ 000957463. htm)" at Dorland's Medical Dictionary [2] "Junctional Rhythm: Overview - eMedicine" (http:/ / emedicine. medscape. com/ article/ 155146-overview). . Retrieved 2008-12-21. [3] Srivathsan K, Gami AS, Barrett R, Monahan K, Packer DL, Asirvatham SJ (January 2008). "Differentiating atrioventricular nodal reentrant tachycardia from junctional tachycardia: novel application of the delta H-A interval" (http:/ / www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed& issn=1045-3873& date=2008& volume=19& issue=1& spage=1). J. Cardiovasc. Electrophysiol. 19 (1): 16. doi:10.1111/j.1540-8167.2007.00961.x. PMID17916156. .
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Atrioventricular Node Dysrythmias

WolffParkinsonWhite syndrome
A characteristic delta wave seen in a patient with WPW. Note short PR interval. ICD-10 ICD-9 OMIM DiseasesDB eMedicine MeSH I45.6 426.7 [1] [2] [3]
194200 14186
[4] [5] med/2417 [7] [6]
emerg/644
C14.280.067.780.977
WolffParkinsonWhite syndrome (WPW) is a disorder of the heart in which the ventricles of the heart contract prematurely due to an accessory pathway known as the bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles. WPW is a type of atrioventricular reentrant tachycardia. The incidence of WPW syndrome is between 0.1% and 0.3% of the general population.[8] [9] [10] While the majority of individuals with a bundle of Kent remain asymptomatic throughout their entire lives, there is a risk of sudden death associated with the syndrome. Sudden death due to WPW syndrome is rare (incidence of less than 0.6%[10] [11] ), and is due to the accessory pathway disrupting the flow of electricity during tachyarrhythmias.
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Signs and symptoms

Patients are usually asymptomatic. However, during supraventricular tachycardia the individual may have symptoms of palpitations (an awareness of one's own heart beating in the chest), dizziness, shortness of breath, and occasionally fainting/near fainting during episodes of supraventricular tachycardia. An ECG will show the telltale "Delta wave".
Pathophysiology
In normal individuals, electrical activity in the heart is initiated in the sinoatrial (SA) node (located in the right atrium), propagates to the atrioventricular (AV) node, and then through the bundle of His to the ventricles of the heart. (See electrical conduction system of the heart). The AV node acts as a gatekeeper, limiting the electrical activity that reaches the ventricles of the heart. This function of the AV node is important, because if the signals generated in the atria of the heart were to increase in rate (as they do during atrial fibrillation or atrial flutter), Graphical representation of the the AV node will limit the electrical activity that conducts to the Wolff-Parkinson-White Syndrome ventricles. For instance, if the atria are electrically activated at 300 beats per minute, half those electrical impulses are blocked by the AV node, so that the ventricles are activated at 150 beats per minute (giving a pulse of 150 beats per minute). Another important property of the AV node is that it slows down individual electrical impulses. This is manifest on the ECG as the PR interval, which lasts slightly less than 200 milliseconds, the time from activation of the atria (manifest as the P wave) and activation of the ventricles (manifest as the QRS complex). Individuals with WPW syndrome have an accessory pathway that connects the atria and the ventricles, in addition to the AV node. This accessory pathway is known as the bundle of Kent (see below). This accessory pathway does not share the rate-slowing properties of the AV node, and may conduct electrical activity at a significantly higher rate than the AV node. For instance, in the example above, if an individual had an atrial rate of 300 beats per minute, the accessory bundle may conduct all the electrical impulses from the atria to the ventricles, causing the ventricles to activate at 300 beats per minute. Extremely fast heart rates are potentially dangerous, and cause hemodynamic instability. In some cases, the combination of an accessory pathway and cardiac arrhythmias can trigger ventricular fibrillation, a leading cause of sudden cardiac death. WPW may be associated with PRKAG2.[12]
Bundle of Kent
The Bundle of Kent is an extra or accessory conduction pathway between the atria and ventricles in the heart. It is an abnormal pathway that is present in a small percentage of the general population. This pathway is a bundle of connecting tissue that may be either between the left atrium and the left ventricle, in which case it is termed a type A pre-excitation, or the right atrium and the right ventricle, in which case it is termed a type B pre-excitation.[13] Problems arise when this pathway creates an electrical circuit that bypasses the AV node. The AV node has rate-slowing electrical (regulation) properties, whereas the pathway via the Bundle of Kent does not. When an aberrant electrical connection is made via this bundle, tachyarrhythmia occurs. In order to treat persons with WPW, destruction of the Bundle of Kent is accomplished by radiofrequency catheter ablation. This procedure is performed almost exclusively by cardiac electrophysiologists.
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Diagnosis
WPW syndrome is commonly diagnosed on the basis of the surface ECG in an asymptomatic individual. In this case it is manifested as a delta wave, which is a slurred upstroke in the QRS complex that is associated with a short PR interval. The short PR interval and slurring of the QRS complex is actually the impulse making it through to the ventricles prematurely (across the accessory pathway) without the usual delay experienced in the AV node. If the patient experiences episodes of atrial fibrillation, the ECG will show a rapid polymorphic wide-complex tachycardia (without torsades de pointes). This combination of atrial fibrillation and WPW is considered dangerous, and most antiarrhythmic drugs are contraindicated. When an individual is in normal sinus rhythm, the ECG characteristics of WPW syndrome are a short PR interval, widened QRS complex (greater than 120ms in length) with slurred upstroke of the QRS complex, and secondary repolarization changes reflected in ST segment-T wave changes.
One beat from a rhythm strip in V2 demonstrating characteristic findings in WPW syndrome. Note the characteristic delta wave (above the blue bar), the short PR interval (red bar) of 0.08 seconds, and the long QRS complex (green) at 0.12 seconds.
In individuals with WPW syndrome, electrical activity that is initiated in the SA node travels through the accessory pathway as well as through the AV node to activate the ventricles via both pathways. Since the accessory pathway does not have the impulse slowing properties of the AV node, the electrical impulse first activates the ventricles via the accessory pathway, and immediately afterwards via the AV node. This gives the short PR interval and slurred upstroke to the QRS complex known as the delta wave. In case of type A pre-excitation (left atrioventricular connections), a positive R wave will be seen in V1 ("positive delta") on the precordial leads of the electrocardiogram, while in type B pre-excitation (right atrioventricular connections), a predominantly negative delta wave will be seen in lead V1 ("negative delta").[13] Patients with WPW often exhibit more than one accessory pathway, and in some patients as many as eight additional abnormal pathways can be found. This has been seen in individuals with Ebstein's anomaly. WolffParkinsonWhite syndrome is sometimes associated with Leber's hereditary optic neuropathy (LHON), a form of mitochondrial disease.[14]
Risk stratification
Treatment is based on risk stratification of the individual. Risk stratification is performed to determine which individuals with WPW syndrome are at risk for sudden cardiac death (SCD). Sudden cardiac death in these individuals is due to the propagation of an atrial arrhythmia to the ventricles at a very high rate. A good history should be taken to determine whether an individual has factors suggestive of a previous episode of unexplained syncope (fainting) or palpitations (sudden awareness of one's own, usually irregular, heartbeat). These may be due to earlier episodes of a tachycardia associated with the accessory pathway.
12 lead electrocardiogram of an individual with WPW syndrome.
Individuals with WPW syndrome in whom the delta waves disappear with increases in the heart rate are considered at lower risk of SCD. This is because the loss of the delta wave shows that the accessory pathway cannot conduct
WolffParkinsonWhite syndrome electrical impulses at a high rate (in the anterograde direction). These individuals will typically not have fast conduction down the accessory pathway during episodes of atrial fibrillation. Risk stratification is best performed via programmed electrical stimulation (PES) in the cardiac electrophysiology lab. This is an invasive procedure, in which the rate of impulse propagation via the accessory pathway is determined by stimulating the atria and by inducing transient atrial fibrillation. High risk features that may be present during PES include an effective refractory period of the accessory pathway less than 270 ms, multiple pathways, septal location of pathway, and inducibility of supraventricular tachycardia. Individuals with any of these high risk features are generally considered at increased risk for SCD and should be treated accordingly.[15] It is unclear whether invasive risk stratification (with programmed electrical stimulation) is necessary in the asymptomatic individual.[16] While some groups advocate PES for risk stratification in all individuals under 35 years old, others only offer it to individuals who have history suggestive of a tachyarrhythmia, since the incidence of sudden death is so low (less than 0.6 percent in some reports).[10] [11] [17]
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Treatment
Acutely, people with WPW who are experiencing tachyarrhythmias may require synchronized electrical cardioversion if their condition is critical (they are hypotensive or lethargic with altered mental status), or, if more stable, medical treatment may be used. Patients with atrial fibrillation and rapid ventricular response are often treated with amiodarone[18] or procainamide[19] to stabilize their heart rate. Procainamide, amiodarone, and cardioversion are now accepted treatments for conversion of tachycardia found with WPW.[20] Adenosine and other AV node blockers should be avoided in atrial fibrillation and atrial flutter with WPW or history of it; this includes adenosine, diltiazem, verapamil, other calcium channel blockers and beta blockers.[21] Beta-blockers and other pharmacological agents that slow the conduction through the AV pathway (such as digoxin) should be avoided, because they will exacerbate the syndrome, by blocking the normal heart's electrical pathway, therefore exaggerating the pre-excitation pathway (Bundle of Kent). Patients with a rapid heart beat with narrow QRS complexes (circus movement tachycardias) may also be cardioverted, alternatively, adenosine may be administered if equipment for cardioversion is immediately available as a backup. The definitive treatment of WPW syndrome is a destruction of the abnormal electrical pathway by radiofrequency catheter ablation. This procedure is performed almost exclusively by cardiac electrophysiologists. Radiofrequency catheter ablation is not performed in all individuals with WPW syndrome because there are inherent risks involved in the procedure. When performed by an experienced electrophysiologist, radiofrequency ablation has a high success rate.[22] Findings from 1994 indicate success rates of as high as 95% in patients treated with radiofrequency catheter ablation for WPW.[23] If radiofrequency catheter ablation is successfully performed, the patient is generally considered cured. Recurrence rates are typically less than 5% after a successful ablation.[22] The one caveat is that individuals with underlying Ebstein's anomaly may develop additional accessory pathways during progression of their disease.
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History
Cardiologists Louis Wolff, Sir John Parkinson and Paul Dudley White described the disorder in 1930.[24] [25] It had been described before by F.N.Wilson in 1915 [26] and A. M. Wedd in 1921.[27] The first ever diagnosed sufferer of this disease was a S.Singh in 1942, and was diagnosed by K.Bhainiawala a cardiologist at the time. [28]
Notable cases
Rock n' roll singer Meat Loaf[29] Portland Trail Blazers player LaMarcus Aldridge[30] Australian Rules Footballer for the Western Bulldogs Nathan Eagleton.[31] Former World Wrestling Entertainment wrestler Hassan Assad, also known as Montel Vontavious Porter[32] NY Rangers forward Mike Rupp.[33] Shock Rocker Marilyn Manson
References
[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I45. 6 [2] [3] [4] [5] [6] [7] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 7 http:/ / omim. org/ entry/ 194200 http:/ / www. diseasesdatabase. com/ ddb14186. htm http:/ / www. emedicine. com/ emerg/ topic644. htm http:/ / www. emedicine. com/ med/ topic2417. htm# http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Wolff-Parkinson-White+ Syndrome& field=entry#TreeC14. 280. 067. 780. 977 [8] Rosner MH, Brady WJ Jr, Kefer MP, Martin ML. (1999). "Electrocardiography in the patient with the WolffParkinsonWhite syndrome: diagnostic and initial therapeutic issues". American Journal of Emergency Medicine 17 (7): 70514. doi:10.1016/S0735-6757(99)90167-5. PMID10597097. [9] Sorbo MD, Buja GF, Miorelli M, Nistri S, Perrone C, Manca S, Grasso F, Giordano GM, Nava A. (1995). "The prevalence of the WolffParkinsonWhite syndrome in a population of 116,542 young males" (in Italian). Giornale Italiano di Cardiologia 25 (6): 6817. PMID7649416. [10] Munger TM, Packer DL, Hammill SC, Feldman BJ, Bailey KR, Ballard DJ, Holmes DR Jr, Gersh BJ. (1993). "A population study of the natural history of WolffParkinsonWhite syndrome in Olmsted County, Minnesota, 19531989". Circulation. 87 (3): 86673. PMID8443907. [11] Fitzsimmons PJ, McWhirter PD, Peterson DW, Kruyer WB (2001). "The natural history of WolffParkinsonWhite syndrome in 228 military aviators: a long-term follow-up of 22 years" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0002870301189404). American Heart Journal 142 (3): 5306. doi:10.1067/mhj.2001.117779. PMID11526369. . [12] Gollob MH (January 2008). "Modulating phenotypic expression of the PRKAG2 cardiac syndrome" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=18195183). Circulation 117 (2): 1345. doi:10.1161/CIRCULATIONAHA.107.747345. PMID18195183. . [13] americanheart.org > Atrial and Ventricular Depolarization Changes (http:/ / www. americanheart. org/ presenter. jhtml?identifier=563) Last updated 11/24/2008. [14] Mashima Y, Kigasawa K, Hasegawa H, Tani M, Oguchi Y. (1996). "High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy" (http:/ / gateway. ovid. com/ ovidweb. cgi?T=JS& PAGE=linkout& SEARCH=9147893. ui) (subscription required). Clinical Genetics 50 (6): 5357. PMID9147893. . [15] Pappone C, Santinelli V, Manguso F, Augello G, Santinelli O, Vicedomini G, Gulletta S, Mazzone P, Tortoriello V, Pappone A, Dicandia C, Rosanio S. (2003). "A randomized study of prophylactic catheter ablation in asymptomatic patients with the WolffParkinsonWhite syndrome" (http:/ / content. nejm. org/ cgi/ content/ full/ 349/ 19/ 1803) (free registration required). New England Journal of Medicine 349 (19): 180311. doi:10.1056/NEJMoa035345. PMID14602878. . [16] Campbell RM, Strieper MJ, Frias PA, Collins KK, Van Hare GF, Dubin AM (2003). "Survey of current practice of pediatric electrophysiologists for asymptomatic WolffParkinsonWhite syndrome" (http:/ / pediatrics. aappublications. org/ cgi/ content/ full/ 111/ 3/ e245). Pediatrics 111 (3): e2457. doi:10.1542/peds.111.3.e245. PMID12612279. . [17] John Kenyon. WolffParkinsonWhite Syndrome and the Risk of Sudden Cardiac Death. Doctors Lounge Website. Available at: http:/ / www. doctorslounge. com/ index. php/ blogs/ page/ 14613. Accessed October 07 2010. [18] "WolffParkinsonWhite Syndrome" (http:/ / www. patient. co. uk/ doctor/ Wolff-Parkinson-White-Syndrome. htm). 08 Dec, 2009. .
[19] Fengler BT, Brady WJ, Plautz CU (June 2007). "Atrial fibrillation in the WolffParkinsonWhite syndrome: ECG recognition and treatment in the ED" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0735-6757(06)00450-5). Am J Emerg Med 25 (5): 57683. doi:10.1016/j.ajem.2006.10.017. PMID17543664. . [20] Ritchie, James V; Juliano, Michael L; Thurman R. J. "Ch. 23. ECG Abnormalities" (http:/ / www. accessmedicine. com/ content. aspx?aID=6007764). In Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine, 3e. . [21] Wald DA (2009). "Resuscitation". In Lex J. Emergency Medicine Q&A (3rd ed.). McGrawHill. pp.4. ISBN0-7216-5944-6. [22] Pappone C, Lamberti F, Santomauro M, Stabile G, De Simone A, Turco P, Pannain S, Loricchio ML, Rotunno R, Chiariello M (1993). "Ablation of paroxysmal tachycardia in WolffParkinsonWhite syndrome" (in Italian). Cardiologia 38 (12 Suppl 1): 18997. PMID8020017. [23] Thakur RK, Klein GJ, Yee R (September 1994). "Radiofrequency catheter ablation in patients with Wolff-Parkinson-White syndrome". CMAJ 151 (6): 7716. PMC1337132. PMID8087753. [24] synd/1019 (http:/ / www. whonamedit. com/ synd. cfm/ 1019. html) at Who Named It? [25] Wolff L, Parkinson J, White PD (1930). "Bundle-branch block with short P-R interval in healthy young people prone to paroxysmal tachyardia". American Heart Journal (St. Louis) 5: 685. [26] Wilson FN (1915). "A case in which the vagus influenced the form of the ventricular complex of the electrocardiogram". Archives of Internal Medicine (Chicago) 16: 100827. [27] Wedd AM (1921). "Paroxysmal tachyardia". Archives of Internal Medicine (Chicago) 27: 571590. [28] Johnson FN (1942). "The history of Cardiology". Archives of Internal Medicine (Chicago) 20: 300. [29] "Meat Loaf recals stage collapse" (http:/ / news. bbc. co. uk/ 1/ hi/ england/ london/ 3247268. stm). BBC News. 2003-11-28. . Retrieved 2007-04-17. [30] Associated Press (2007-04-10). "Aldridge out with WolffParkinsonWhite Syndrome" (http:/ / sports. espn. go. com/ nba/ news/ story?id=2831364). ESPN.com. . Retrieved 2007-04-10. [31] Sam Landsberger (April 17, 2008). "Courageous dog all heart" (http:/ / www. westernbulldogs. com. au/ tabid/ 4112/ Default. aspx?newsid=58099). . Retrieved 2008-04-17. [32] "MVP Interview" (http:/ / sports. ign. com/ articles/ 791/ 791766p1. html). IGN. . Retrieved 2007-10-06. [33] Rich Chere (2008-09-25). "New Jersey Devils' Rupp has been in teammate Tallackson's shoes" (http:/ / www. nj. com/ devils/ index. ssf/ 2008/ 09/ _barry_tallackson_had_hoped. html). NJ.com. . Retrieved 2008-11-21.
137
LownGanongLevine syndrome
138
Classification and external resources ICD-10 ICD-9 OMIM DiseasesDB eMedicine MeSH I45.6 [1] [1] [2]
426.81 108950 7599
[3] [4]
med/2954 D008151
[5]
LownGanongLevine syndrome (LGL) is a syndrome of pre-excitation of the ventricles due to an accessory pathway providing an abnormal electrical communication from the atria to the ventricles. It is grouped with WolffParkinsonWhite syndrome as an atrioventricular re-entrant tachycardia (AVRT). The syndrome is named after Bernard Lown, William Francis Ganong, Jr., and Samuel A. Levine.[6] [7] A short PR is seen.[8]
Pathophysiology
In normal individuals, electrical activity in the heart is initiated in the sinoatrial (SA) node (located in the right atrium), propagates to the atrioventricular (AV) node, and then through the bundle of His to the ventricles of the heart. (See electrical conduction system of the heart). The AV node acts as a gatekeeper, limiting the electrical activity that reaches the ventricles of the heart. This is an important function of the AV node, because if the signals generated in the atria of the heart were to increase in rate (such as during atrial fibrillation or atrial flutter), the AV node will limit the electrical activity that conducts to the ventricles. For instance, if the atria are electrically activated at 300 beats per minute, half those electrical impulses are blocked by the AV node, so that the ventricles are activated at 150 beats per minute (giving a pulse of 150 beats per minute). Another important property of the AV node is that it slows down individual electrical impulses. This is manifest on the EKG as the PR interval, the time from activation of the atria (manifest as the P wave) and activation of the ventricles (manifest as the QRS complex). Individuals with LGL syndrome are thought to have an accessory pathway that connects the atria directly to the bundle of His. As in WPW syndrome, the accessory pathway does not share the rate-slowing properties of the AV node, and may conduct electrical activity at a significantly higher rate than the AV node. For instance, in the example above, if an individual had an atrial rate of 300 beats per minute, the accessory bundle may conduct all the electrical impulses from the atria to the ventricles, causing the ventricles to activate at 300 beats per minute. Because the ventricles are the main pumping chambers of the heart, the body depends on the proper filling and emptying (contraction) of them. When conducted too rapidly (i.e. 300 beats per minute), the body would become hemodynamically unstable. If not corrected quickly, the ventricles can fibrillate causing VF (ventricular fibrillation) leading to sudden cardiac death (SCD).
139
Diagnosis
LGL syndrome is commonly diagnosed on the basis of the surface EKG in an asymptomatic individual. In this case it is manifest as a PR interval less than or equal to 0.12 second (120 ms) with normal QRS complex duration. It can be distinguished from WPW syndrome because: The QRS complexes in LGL syndrome are normal because ventricular contraction is initiated in the normal manner. The broad complexes seen in the asymptomatic individual with WPW are not a feature of LGL. The delta waves seen in WPW syndrome are not seen in LGL syndrome as the accessory pathway does not connect to the ventricles and so ventricular contraction does not start early.
References
[1] [2] [3] [4] [5] [6] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 81 http:/ / omim. org/ entry/ 108950 http:/ / www. diseasesdatabase. com/ ddb7599. htm http:/ / www. emedicine. com/ med/ topic2954. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D008151 Rull G (2009). "LownGanongLevine Syndrome" (http:/ / www. patient. co. uk/ doctor/ Lown-Ganong-Levine-Syndrome. htm). Patient UK. EMIS. . Retrieved 2011-05-29.
[7] Lown B, Ganong WF, Levine SA (May 1952). "The syndrome of short P-R interval, normal QRS complex and paroxysmal rapid heart action". Circulation 5 (5): 693706. PMID14926053. [8] Eichholz A, Whiting RB, Artal R (December 2003). "LownGanongLevine syndrome in pregnancy" (http:/ / www. greenjournal. org/ cgi/ pmidlookup?view=long& pmid=14662232). Obstet Gynecol 102 (6): 13935. doi:10.1016/S0029-7844(03)00708-7. PMID14662232. .
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Ventricular Dysrythmias
Premature ventricular contraction
A premature ventricular contraction marked by the arrow. ICD-10 ICD-9 DiseasesDB eMedicine MeSH I49.3 [1] [2] [3] [4]
427.69 32412
emerg/773 D018879
[5]
A premature ventricular contraction (PVC), also known as a premature ventricular complex, ventricular premature contraction (or complex or complexes) (VPC), ventricular premature beat (VPB), or extrasystole, is a relatively common event where the heartbeat is initiated by the heart ventricles rather than by the sinoatrial node, the normal heartbeat initiator. The electrical events of the heart detected by the electrocardiogram allow a PVC to be easily distinguished from a normal heart beat. A PVC may be perceived as a "skipped beat" or felt as palpitations in the chest. In a normal heartbeat, the ventricles contract after the atria have helped to fill them by contracting; in this way the ventricles can pump a maximized amount of blood both to the lungs and to the rest of the body. In a PVC, the ventricles contract first, which means that circulation is inefficient. However, single beat PVC arrhythmias do not usually pose a danger and can be asymptomatic in healthy individuals.[6]
141
Causes
Premature ventricular contractions can occur in a healthy person of any age, but are more prevalent in the elderly and in men.[7] They frequently occur spontaneously with no known cause. Some possible causes include: Ischemia;[8] Certain medicines such as digoxin, which increases heart contraction[7] Myocarditis;[7] Cardiomyopathy, hypertrophic or dilated;[7] Myocardial contusion;[7] Hypoxia;[7] Hypercapnia (CO2 poisoning);[7] Sarcoidosis; Mitral valve prolapse;[7] Smoking;[8] Alcohol;[8] Drugs such as cocaine;[7] Caffeine;[7] Theobromine; Tricyclic antidepressants;[7] Magnesium and potassium deficiency;[7] Calcium excess;[7] Thyroid problems;[9] Chemical (electrolyte) problems in the blood;[10] Heart attack;[11] Adrenaline excess;[11] Lack of sleep/exhaustion;[12] Stress[12]
Premature ventricular contraction in an ECG (arrows)
Symptoms
A PVC may be perceived as a skipped heart beat, a strong beat, or a feeling of suction in the chest. They may also cause chest pain, a faint feeling, fatigue, or hyperventilation after exercise.[11] Several PVCs in a row becomes a form of ventricular tachycardia (VT), which is a dangerous rapid heartbeat.
Diagnosis
PVCs are usually diagnosed after the patient has described skipped beats, pauses or palpitations. Typically the palpitations felt by PVC patients are very irregular and less sustained than patients with other types of arrhythmia. They are likely to have flip flopping sensations where it feels like the heart is flipping over or pounding due to there being a pause after the premature contraction and then a powerful contraction after the pause. There is a possibility that they might feel a fluttering in their chest or a pounding in their neck but these two types of palpitations arent very common in PVC patients.[13] A physical examination should be conducted after a full history has been taken. This is useful in determining any possible heart defects that might be causing the palpitations. Most cases of premature ventricular contraction have a
Premature ventricular contraction mitral-valve prolapse which can be determined through the physical examination.[13] The next step in diagnosis is a 12 lead ECG which can be performed in the doctors office over a short period of time however this is often non-conclusive in diagnosis because it is not very sensitive and there is only a small chance of a premature ventricular contraction occurring in the short period of time. Holter monitoring is a far better method for diagnosis as it is continuous recording of the hearts rhythm over a period of 24 hours, or event monitoring which records noncontinuously for 30 days or indefinitely. This increases the likelihood of a premature ventricular contraction occurring during the recording period and is therefore more useful in diagnosis.[14] When looking at an electrocardiograph premature ventricular contractions are easily spotted and therefore a definitive diagnosis can be made. The QRS and T waves look very different to normal readings. The spacing between the PVC and the preceding QRS wave is a lot shorter than usual and the time between the PVC and the proceeding QRS is a lot longer. However, the time between the preceding and proceeding QRS waves stays the same as normal due to the compensatory pause.[15] PVCs can be distinguished from premature atrial contractions because the compensatory pause is longer following premature ventricular contractions.[16] There are four different named patterns of regularly occurring PVCs. Depending whether there are 1, 2, or 3 normal beats between each PVC, the rhythm is called bigeminy, trigeminy, or quadrigeminy. A unifocal PVC is where the depolarisation is triggered from the one site in the ventricle causing the peaks on the ECG to look the same. Multifocal PVCs arise when more than one site in the ventricles initiate depolarisation causing each peak on the ECG to have a different shape. If 3 or more PVCs occur in a row it may be called Ventricular tachycardia.[16]
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Treatment
Isolated PVCs with benign characteristics require no treatment. In healthy individuals, PVCs can often be resolved by restoring the balance of magnesium, calcium and potassium within the body. The most effective treatment is the elimination of triggers (particularly the cessation of the use of substances such as caffeine, and certain drugs.) Pharmacological agents Antiarrhythmics:[7] these agents alter the electrophysiologic mechanisms responsible for PVCs Beta blockers[11] Calcium channel blockers[11] Electrolytes replacement Magnesium supplements (e.g. magnesium citrate, orotate, Maalox, etc.) Potassium supplements Radiofrequency catheter ablation treatment[11] Lifestyle modification Frequently stressed individuals should consider therapy, or joining a support group. Heart attacks can increase the likelihood of having PVCs.[11] In the setting of existing cardiac disease, however, PVCs must be watched carefully, as they may cause a form of ventricular tachycardia (rapid heartbeat). Recent studies have shown that those subjects who have an extremely high occurrence of PVCs (several thousand a day) can develop dilated cardiomyopathy. In these cases, if the PVCs are reduced or removed (for example, via ablation therapy) the cardiomyopathy usually regresses.[17] [18]
143
Pathophysiology
Normally impulses pass through both ventricles almost simultaneously, the depolarisation waves of the two ventricles partially cancel each other out in the ECG. However, when a PVC occurs the impulse nearly always travels in one direction therefore there is no neutralisation effect which results in the high voltage QRS wave in the electrocardiograph. There are two main physiological explanations for premature ventricular contractions: re-entrant signalling and enhanced automaticity in some ectopic focus. The enhanced automaticity means that the ectopic centre fires more regularly than usual and is protected from depolarisation that results in premature contractions.[15]
Molecular Basis
There are a number of different molecular explanations for PVCs. One explanation is most basically due to an increased amount of cyclic AMP(cAMP) in the ventricular cardiac myocytes leading to increased flow of calcium ions into the cell. This may happen for the following reasons: Activation of the sympathetic nervous system, due to anxiety and/or physiological stress, for example hypovolemia caused by dehydration or hemorrhage. This activation can cause a release of catecholamines such as epinephrine (adrenaline) which can bind to beta-1 adrenergic receptor (1 receptors) on cardiac myocytes, activating a type of guanosine nucleotide-binding protein called Gs protein.[19] This type of protein stimulates the production of cAMP,[20] ultimately increasing the flow of calcium ions from the extracellular space and from the sarcoplasmic reticulum into the cytosol.[21] This has the effect of (1) increasing the strength of contraction (inotropy) and (2) depolarizing the myocyte more rapidly (chronotropy). The ventricular myocytes are therefore more irritable than usual, and may depolarize spontaneously before the SA node depolarizes. Other sympathomimetic molecules such as amphetamines and cocaine will also cause this effect. Phosphodiesterase inhibitors such as caffeine directly affect the G-coupled signal transduction cascade[22] by inhibiting the enzyme that catalyzes the breakdown of cAMP,[19] again leading to the increased concentration of calcium ions in the cytosol. Potassium ion concentrations are a major determinant in the magnitude of the electrochemical potential of cells, and hypokalemia makes it more likely that cells will depolarize spontaneously. Hypercalcemia has a similar effect, although clinically it is of less concern. Magnesium ions affect the flow of calcium ions, and they affect the function of the Na+/K+ ATPase, and are necessary for maintaining potassium levels. Hypomagnesemia therefore also makes spontaneous depolarization more likely. Existing damage to the myocardium can also provoke PVCs. The myocardial scarring that occurs in myocardial infarction and also in the surgical repair of congenital heart disease can disrupt the conduction system of the heart and may also irritate surrounding viable ventricular myocytes, make them more likely to depolarize spontaneously. Inflammation of the myocardium (as occurs in myocarditis) and systemic inflammation cause surges of cytokines, which can affect the electrical properties of myocytes and may be ultimately responsible for causing irritability of myocytes.
144
References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I49. 3 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 69 http:/ / www. diseasesdatabase. com/ ddb32412. htm http:/ / www. emedicine. com/ emerg/ topic773. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D018879 Stanfield, C.; Germann, W. (2008), Principles of Human Physiology (3rd ed.), Pearson International Edition, p.378, ISBN0321455061 Premature ventricular contraction (http:/ / emedicine. medscape. com/ article/ 761148-overview) at eMedicine Emilsson K (June 2008), "Suspected association of ventricular arrhythmia with air pollution in a motorbike rider: a case report", J Med Case Reports 2: 192, doi:10.1186/1752-1947-2-192, PMC2427047, PMID18522736 [9] Health encyclopedia diseases and conditions. The heathcentral network. Accessed Feb 8th 2009. (http:/ / www. healthcentral. com/ encyclopedia/ 408/ 643. html#causes,) [10] MedlinePlus Encyclopedia Ectopic heartbeat (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001100. htm) [11] [Leonard I Ganz, MD, http:/ / www. uptodate. com/ patients/ content/ topic. do?topicKey=hrt_dis/ 11733, Up-to-date patient information, Updated Sep 11th 2007, reviewed Oct 2008, Accessed Feb 9th 2009.] [12] Guyton MD, Arthur C.; Hall, John E. (2006), Textbook of medical physiology (11th ed.), p.151, ISBN0721602401 [13] Zimetbaum P, Josephson ME (May 1998), "Evaluation of patients with palpitations" (http:/ / content. nejm. org/ cgi/ content/ full/ 338/ 19/ 1369), N. Engl. J. Med. 338 (19): 136973, doi:10.1056/NEJM199805073381907, PMID9571258, [14] Meurs KM, Spier AW, Wright NA, Hamlin RL (January 2001), "Comparison of in-hospital versus 24-hour ambulatory electrocardiography for detection of ventricular premature complexes in mature Boxers", J. Am. Vet. Med. Assoc. 218 (2): 2224, doi:10.2460/javma.2001.218.222, PMID11195827 [15] Levy 2007, pp.4950 [16] Haist, Steven A.; Gomella, Leonard G. (2004), "19 Basic ECG Reading: Ventricular Arrhythmias" (http:/ / books. google. com/ books?id=KaegPx6LK2sC& pg=PA390& dq=unifocal+ premature+ ventricular+ contraction& client), Clinician's pocket reference (10th ed.), New York: McGraw-Hill, p.390, ISBN0-07-140255-1, [17] Belhassen B (April 2005), "Radiofrequency ablation of "benign" right ventricular outflow tract extrasystoles: a therapy that has found its disease?" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0735-1097(05)00234-2), J. Am. Coll. Cardiol. 45 (8): 12668, doi:10.1016/j.jacc.2005.01.028, PMID15837260, [18] Shiraishi, Hirokazu; Ishibashi, Kazuya; Urao, Norifumi; Tsukamoto, Masaki; Hyogo, Masayuki; Keira, Natsuya; Hirasaki, Satoshi; Shirayama, Takeshi et al. (2002), "A case of cardiomyopathy induced by premature ventricular complexes", Circulation 66 (11): 10657, doi:10.1253/circj.66.1065 [19] Nelson 2008, p.424 [20] Levy 2007, p.62 [21] Levy 2007, p.24 [22] Nelson 2008, p.430
Further reading
Levy, M.N.; Pappano, A.J. (2007), Cardiovascular physiology (9th ed.), Mosby Elsevier, ISBN0323034462 Nelson, D.L.; Cox, M.M. (2008), Lehninger Principles of Biochemistry (5th ed.), WH Freeman, ISBN071677108X
Ventricular tachycardia
145
ICD-10 ICD-9 DiseasesDB eMedicine MeSH
I47.2 427.1
[1] [2] [3] [4] med/2367 [5] ped/2546 [6]
13819
emerg/634 D017180
[7]
Ventricular tachycardia (V-tach or VT) is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart. This is a potentially life-threatening arrhythmia because it may lead to ventricular fibrillation, asystole, and sudden death.
Classification
Ventricular tachycardia can be classified based on its morphology: Monomorphic ventricular tachycardia means that the appearance of all the beats match each other in each lead of a surface electrocardiogram (ECG). RVOT tachycardia is a type of monomorphic ventricular tachycardia originating in the right ventricular outflow tract. RVOT morphology refers to the characteristic pattern of this type of tachycardia on an ECG.
12 lead electrocardiogram showing a run of monomorphic ventricular tachycardia (VT)
Polymorphic ventricular tachycardia, on the other hand, has beat-to-beat variations in morphology. This most commonly appears as a cyclical progressive change in cardiac axis, previously referred to by its French name torsades de pointes ("twisting of the points"). However, currently the term torsades is reserved for polymorphic VT occurring in the context of a prolonged resting QT interval. Another way to classify ventricular tachycardias is the duration of the episodes: Three or more beats in a row on an ECG that originate from the ventricle at a rate of more than 100 beats per minute constitute a ventricular tachycardia. If the fast rhythm self-terminates within 30 seconds, it is considered a non-sustained ventricular tachycardia. If the rhythm lasts more than 30 seconds, it is known as a sustained ventricular tachycardia (even if it terminates on its own after 30 seconds). A third way to classify ventricular tachycardia is on the basis of its symptoms: Pulseless VT is associated with no effective cardiac output, hence, no effective pulse, and is a cause of cardiac arrest. In this circumstance, it is best treated the same way as ventricular fibrillation (VF), and is recognized as one of the shockable rhythms on the cardiac arrest protocol. Some VT is associated with reasonable cardiac output and may even be asymptomatic. The heart usually tolerates this rhythm poorly in the medium to long term, and patients may certainly deteriorate to
Ventricular tachycardia pulseless VT or to VF. Less common is ventricular tachycardia which occurs in individuals with structurally normal hearts. This is known as idiopathic ventricular tachycardia and in the Monomorphic form appears with little or no incidence of increased risk of sudden cardiac death. In general, idiopathic ventricular tachycardia occurs in younger individuals diagnosed with VT. While the causes of idiopathic VT are not known, it is generally presumed to be congenital, and can be brought on by any number of diverse factors.
146
Pathophysiology
The morphology of the tachycardia depends on its cause. In monomorphic ventricular tachycardia, all the beats look the same because the impulse is either being generated from increased automaticity of a single point in either the left or right ventricle, or due to a reentry circuit within the ventricle. The most common cause of monomorphic ventricular tachycardia is myocardial scarring from a previous myocardial infarction (heart attack). This scar cannot conduct electrical activity, so there is a potential circuit around the scar that results in the tachycardia. This is similar to the re-entrant circuits that are the cause of atrial flutter and the re-entrant forms of supraventricular tachycardia. Other rarer congenital causes of monomorphic VT include right ventricular dysplasia, and right and left ventricular outflow tract VT. Polymorphic ventricular tachycardia, on the other hand, is most commonly caused by abnormalities of ventricular muscle repolarization. The predisposition to this problem usually manifests on the ECG as a prolongation of the QT interval. QT prolongation may be congenital or acquired. Congenital problems include Long QT syndrome and Catecholaminergic polymorphic ventricular tachycardia. Acquired problems are usually related to drug toxicity or electrolyte abnormalities, but can occur as a result of myocardial ischemia. Class III anti-arrhythmic drugs such as sotalol and amiodarone prolong the QT interval and may in some circumstances be pro-arrhythmic. Other relatively common drugs including some antibiotics and antihistamines may also be a danger, particularly in combination with one another. Problems with blood levels of potassium, magnesium and calcium may also contribute. High dose magnesium is often used as an antidote in cardiac arrest protocols.
Diagnosis
The diagnosis of ventricular tachycardia is made based on the rhythm seen on either a 12 lead EKG or a telemetry rhythm strip. It may be very difficult to differentiate between ventricular tachycardia and a wide-complex supraventricular tachycardia in some cases. In particular, supraventricular tachycardias with aberrant conduction from pre-existing bundle branch block are commonly misdiagnosed as ventricular tachycardia. Other rarer phenomena include ashman beats and antedromic atrioventricular re-entry tachcyardias. Various diagnostic criteria have been developed to determine whether a wide complex tachycardia is ventricular tachycardia or a more benign rhythm.[8] [9] In addition to these diagnostic criteria, if the individual has a past history of a myocardial infarction, congestive heart failure, or recent angina, the wide complex tachycardia is much more likely to be ventricular tachycardia.[10] The proper diagnosis is important, as the misdiagnosis of supraventricular tachycardia when ventricular tachycardia is present is associated with worse prognosis. This is particularly true if calcium channel blockers, such as verapamil, are used to attempt to terminate a presumed supraventricular tachycardia.[11] It is therefore wisest to assume that all wide complex tachycardia is VT until proven otherwise.
147
Treatment
Therapy may be directed at either terminating an episode of the arrhythmia or for suppressing a future episode from occurring. The treatment for stable VT is tailored to the specific patient, with regard to how well the individual tolerates episodes of ventricular tachycardia, how frequently episodes occur, their comorbidities, and their wishes. Patients suffering from pulseless VT or unstable VT are hemodynamically compromised and require immediate cardioversion.
Synchronized electrical cardioversion

If the patient still has a pulse, it is usually possible to terminate a VT episode with a direct current shock across the heart. This is ideally synchronized to the patient's heartbeat. As this is quite uncomfortable, shocks should be delivered only to an unconscious or sedated patient. As a reminder, this is different from defibrillating the patient. If the patient still had a pulse, defibrillating the patient could potentially send him into asystole.
Defibrillation
A patient with pulseless VT or a ventricular fibrillation will be unconscious and treated as an emergency on an ACLS protocol, given high energy (360J with a monophasic defibrillator, or 200J with a biphasic defibrillator) unsynchronised cardioversion (defibrillation). The shock may be delivered to the outside of the chest using an external defibrillator, or internally to the heart by an implantable cardioverter-defibrillator (ICD) if one has previously been inserted. An ICD may also be set to attempt to overdrive pace the ventricle. Pacing the ventricle at a rate faster than the underlying tachycardia can sometimes be effective in terminating the rhythm. If this fails after a short trial, the ICD will usually stop pacing, charge up and deliver a defibrillation grade shock.
Cardiac ablation
Catheter ablation is a key therapeutic modality for patients with recurrent VT. A task force consisting of the European Heart Rhythm Association (EHRA) in conjunction with the Heart Rhythm Society (HRS) developed an expert consensus paper that carefully defines the indications, techniques, and outcomes of this procedure.[12] There was consensus among the task force members that catheter ablation for VT should generally be considered early in the treatment of patients with recurrent VT. In the past, ablation was often not considered until pharmacological options had been exhausted, often after the patient had suffered substantial morbidity from recurrent episodes of VT and ICD shocks. Antiarrhythmic medications can reduce the frequency of ICD therapies, but have disappointing efficacy and side effects. Advances in technology and understanding of VT substrates now allow ablation of multiple and unstable VTs with acceptable safety and efficacy, even in patients with advanced heart disease. Remote magnetic navigation is recognized as an important method for delivery of ablation therapy for these patients due to the ability of the flexible magnetic catheter to carefully map the diseased tissue without inadvertently inducing abnormal ventricular rhythms. In a series of 110 patients that included all morphologies of VT, 85% of patients treated with magnetic ablation were free from VT at one year after the intervention and were exposed to statistically reduced levels of radiation when compared to non-magnetic VT ablations at the same center.[13] In patients with myocardial scarring from a previous heart attack who were receiving excessive shocks from an ICD, magnetic ablation was shown to be successful in reducing these shocks and demonstrated a 67% reduction in imaging radiation needed to complete the procedure compared to a historical non-magnetic group.[14] For monomorphic idiopathic VT which may originate in thin-walled tissues, magnetic ablation offers catheter flexibility, steering accuracy and reproducibility to navigate to a desired location with a low probability of perforating the myocardium.[15]
148
Antiarrhythmic drug therapy

Drugs such as amiodarone or procainamide may be used in addition to defibrillation to terminate VT while the underlying cause of the VT can be determined. As hypomagnesia is a common cause of VT, stat dose magnesium sulphate can be given for torsades or if hypomagnesemia is found/suspected. Long term anti-arrhythmic therapy may be indicated to prevent recurrence of VT. Beta-blockers and a number of class III anti-arrhythmics are commonly used. Lidocaine is now being replaced by amiodarone as the first line anti-arrhythmic treatment of VT. The implantation of an ICD is more effective than drug therapy for prevention of sudden cardiac death due to VT and VF, but may be constrained by cost issues,(RDM) and well as patient co-morbidities and patient preference.
Popular culture
VT is frequently referenced in the 1970s television series Emergency! In the 2006 film Casino Royale, the protagonist, James Bond, suffers ventricular tachycardia from intoxication of digitalis and goes into cardiac arrest. "V-Tach" is what "The Satin Slayer" from the American soap opera All My Children used to kill his victims.[16]
References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I47. 2 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 1 http:/ / www. diseasesdatabase. com/ ddb13819. htm http:/ / www. emedicine. com/ emerg/ topic634. htm http:/ / www. emedicine. com/ med/ topic2367. htm# http:/ / www. emedicine. com/ ped/ topic2546. htm# http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D017180 Wellens HJ, Bar FW, Lie KI. (1978). "The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex". Am J Med 64 (1): 2733. doi:10.1016/0002-9343(78)90176-6. PMID623134. [9] Brugada P, Brugada J, Mont L, Smeets J, Andries EW. (1991). "A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex". Circulation 83 (5): 164959. PMID2022022. [10] Baerman JM, Morady F, DiCarlo LA Jr, de Buitleir M. (1987). "Differentiation of ventricular tachycardia from supraventricular tachycardia with aberration: value of the clinical history". Ann Emerg Med 16 (1): 403. doi:10.1016/S0196-0644(87)80283-4. PMID3800075. [11] Stewart RB, Bardy GH, Greene HL. (1986). "Wide complex tachycardia: misdiagnosis and outcome after emergent therapy". Ann Intern Med 104 (6): 76671. PMID3706928. [12] Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Bella PD, Hindricks G, Jas P, Josephson ME, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D; European Heart Rhythm Association; European Society of Cardiology; Heart Rhythm Society. EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Europace. 2009 Jun;11(6):771-817. Epub 2009 May 14. PMID 19443434 [13] Di Biase, L; Santangeli, P; Astudillo, V; Conti, S; Mohanty, P; Mohanty, S; Sanchez, JE; Horton, R et al. (2010). "Endo-epicardial ablation of ventricular arrhythmias in the left ventricle with the Remote Magnetic Navigation System and the 3.5-mm open irrigated magnetic catheter: results from a large single-center case-control series.". Heart rhythm : the official journal of the Heart Rhythm Society 7 (8): 102935. doi:10.1016/j.hrthm.2010.04.036. PMID20434589. [14] Haghjoo, M; Hindricks, G; Bode, K; Piorkowski, C; Bollmann, A; Arya, A (2009). "Initial clinical experience with the new irrigated tip magnetic catheter for ablation of scar-related sustained ventricular tachycardia: a small case series.". Journal of cardiovascular electrophysiology 20 (8): 9359. doi:10.1111/j.1540-8167.2008.01416.x. PMID19175449. [15] Schwagten, BK; Szili-Torok, T; Rivero-Ayerza, M; Jessurun, E; Valk, S; Jordaens, LJ (2009). "Usefulness of remote magnetic navigation for ablation of ventricular arrhythmias originating from outflow regions.". Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 17 (6): 2459. PMC2711250. PMID19789687. [16] Watkins, Karen. "All My Children Daily Recaps (Continued from Page 2): Monday, February 12, 2007 -- I THOUGHT IT WAS A TRICK...." (http:/ / allmychildren. about. com/ od/ dailyrecaps/ a/ bl20070212r_3. htm). About.com. . Retrieved 2007-10-31.
Torsades de pointes
149
Torsades de pointes
Torsades de pointes
Classification and external resources DiseasesDB 29252 [1] eMedicine MeSH med/2286 D016171 [2] emerg/596 [3]
[4]
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966[5] and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG).
Presentation
The ECG tracing in torsades demonstrates a polymorphic ventricular tachycardia with a characteristic illusion of a twisting of the QRS complex around the isoelectric baseline. It is also associated with a fall in arterial blood pressure, which can produce syncope. Torsades de pointes can degenerate into ventricular fibrillation, which will lead to sudden death in the absence of medical intervention. Torsades de pointes is associated with long QT syndrome, a condition whereby prolonged QT intervals are visible on the ECG. Long QT intervals predispose the patient to an R-on-T phenomenon, where the R wave representing ventricular depolarization occurs during the relative refractory period at the end of repolarization (represented by the latter half of the T-wave). An R-on-T can initiate torsades. Sometimes pathologic T-U waves may be seen in the ECG before the initiation of torsades.[6]
Characteristics
Rotation of the heart's electrical axis by at least 180 Prolonged QT interval (LQTS) Preceded by long and short RR-intervals Triggered by an early premature ventricular contraction (R-on-T PVC)
Causes
Long QT syndrome can either be inherited as congenital mutations of ion channels carrying the cardiac impulse/action potential or acquired as a result of drugs that block these cardiac ion currents. Common causes for torsades de pointes include diarrhea, hypomagnesemia and hypokalemia. It is commonly seen in malnourished individuals and chronic alcoholics. Certain combinations of drugs resulting in drug interactions may contribute: decreasing the metabolism of a medication causing QT elongation such as clarithromycin (Biaxin) or haloperidol (Haldol), taken concomitantly with a specific cytochrome P450 inhibitor like fluoxetine (Prozac) or cimetidine (Tagamet), some dietary supplements like St John's wort, foods like grapefruit will result in higher than normal doses of the medication responsible for the QT elongation. Since these specific drugs worsen the elongation of the QT wave in a dose-dependant manner, inhibition of a drug metabolism raises the risks of developing a malignant torsades de pointed arrythmia. Various medications are known to cause QT elongation. Examples include amiodarone, methadone, lithium, chloroquine, erythromycin, and phenothiazines. It can also be the side effect of some antiarrhythmic medications such as sotalol, procainamide and quinidine. The gastrokinetic drug cisapride (Propulsid) was withdrawn from the US market in 2000 after such interactions lead to deaths caused by long QT syndrome-induced torsades-de-pointes.
Torsades de pointes An FDA warning was issued in September 2011 concerning high doses of the antidepressant Celexa (citalopram). Specifically, ekg analyses revealed an increased frequency of prolongation of the QT interval in patients receiving doses above 40 mg. per day (thereby increasing the risk of Torsades). Physicians were advised that 40 mg. per day is considered the maximum allowable dosage. An FDA warning was issued in September 2011 concerning use of ondansetron (Zofran) in patients with low magnesium or potassium levels, or certain heart conditions, as they may lead to torsades de pointes. http:/ / www. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm272041.htm Factors that are associated with an increased tendency toward torsades de pointes include: Familial long QT syndrome Class IA antiarrhythmics Class III antiarrhythmics Hypomagnesemia Hypokalemia Hypocalcemia Hypoxia Acidosis Heart failure Left ventricular hypertrophy Slow heart rate Female gender Hypothermia Subarachnoid hemorrhage
150
Lead II ECG showing torsades being shocked by an implantable cardioverter-defibrillator back to the patients baseline cardiac rhythm.
Treatment
Treatment is directed at withdrawal of the offending agent, infusion of magnesium sulfate,[7] drugs, and electrical therapy as needed.
[8]
antiarrhythmic
Because of the polymorphic nature of torsades de pointes, synchronized cardioversion may not be possible, and the patient may require an unsynchronized shock (or defibrillation).
History and terminology

The phenomenon was originally described in a French medical journal by Dessertenne in 1966, when he observed this cardiac rhythm disorder in an 80-year-old female patient with complete intermittent atrioventricular block.
References
[1] [2] [3] [4] [5] http:/ / www. diseasesdatabase. com/ ddb29252. htm http:/ / www. emedicine. com/ med/ topic2286. htm http:/ / www. emedicine. com/ emerg/ topic596. htm# http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D016171 Dessertenne, F. (1966). "La tachycardie ventriculaire a deux foyers opposes variables" (in French). Archives des maladies du coeur et des vaisseaux 59 (2): 263272. ISSN0003-9683. PMID4956181. [6] http:/ / www. sage-hindawi. com/ journals/ crp/ aip. 524764. html [7] Hoshino K, Ogawa K, Hishitani T, Isobe T, Eto Y (October 2004). "Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome" (http:/ / www. jacn. org/ cgi/ pmidlookup?view=long& pmid=15466950). J Am Coll Nutr 23 (5): 497S500S. PMID15466950. . [8] Hoshino K, Ogawa K, Hishitani T, Isobe T, Etoh Y (April 2006). "Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome" (http:/ / www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed& issn=1328-8067& date=2006& volume=48& issue=2& spage=112). Pediatr Int 48 (2): 1127. doi:10.1111/j.1442-200X.2006.02177.x. PMID16635167. .
Ventricular fibrillation
151
ECG lead showing VF ICD-10 ICD-9 DiseasesDB MeSH I49.0 [1] [2] [3] [4]
427.41 13798
D014693
Ventricular fibrillation (V-fib or VF) is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest patients. [5] While there is activity, it is undetectable by palpation (feeling) at major pulse points of the carotid and femoral arteries especially by the lay person. Such an arrhythmia is only confirmed by electrocardiography. Ventricular fibrillation is a medical emergency that requires prompt Basic Life Support interventions because should the arrhythmia continue for more than a few seconds, it will likely degenerate further into asystole ("flatline"). The condition results in cardiogenic shock, cessation of effective blood circulation, and sudden cardiac death (SCD) will result in a matter of minutes. If however the patient is revived after a sufficient period (at room temperature, roughly 5 minutes) of cerebral hypoxia, the patient could sustain irreversible brain damage and possibly be left brain dead (death often occurs if normal sinus rhythm is not restored within 90 seconds of the onset of VF, especially if it has degenerated further into asystole).
Signs and symptoms

Ventricular fibrillation is a cause of cardiac arrest and sudden cardiac death. The ventricular muscle twitches randomly, rather than contracting in a coordinated fashion (from the apex of the heart to the outflow of the ventricles), and so the ventricles fail to pump blood into the arteries and into systemic circulation. Ventricular fibrillation is a sudden lethal arrhythmia responsible for many deaths in the Western world, mostly brought on by ischemic heart disease. Despite much work, the underlying nature of fibrillation is not completely understood. Most episodes of fibrillation occur in diseased hearts, but others occur in so-called normal hearts. Much work still has to be done to elucidate the mechanisms of ventricular fibrillation.
152
Cause
Abnormal automaticity
Automaticity is a measure of the propensity of a fiber to initiate an impulse spontaneously. The product of a hypoxic myocardium can be hyperirritable myocardial cells. These may then act as pacemakers. The ventricles are then being stimulated by more than one pacemaker. Scar and dying tissue is inexcitable, but around these areas usually lies a penumbra of hypoxic tissue that is excitable. Ventricular excitability may generate re-entry arrhythmias. It is interesting to note that most cardiac myocardial cells with an associated increased propensity to arrhythmia development have an associated loss of membrane potential. That is, the maximum diastolic potential is less negative and therefore exists closer to the threshold potential. Cellular depolarisation can be due to a raised external concentration of potassium ions K+, a decreased intracellular concentration of sodium ions Na+, increased permeability to Na+, or a decreased permeability to K+. The ionic basic automaticity is the net gain of an intracellular positive charge during diastole in the presence of a voltage-dependent channel activated by potentials negative to 50 to 60mV. Myocardial cells are exposed to different environments. Normal cells may be exposed to hyperkalaemia; abnormal cells may be perfused by normal environment. For example, with a healed myocardial infarction, abnormal cells can be exposed to an abnormal environment such as with a myocardial infarction with myocardial ischaemia. In conditions such as myocardial ischaemia, possible mechanism of arrhythmia generation include the resulting decreased internal K+ concentration, the increased external K+ concentration, norepinephrine release and acidosis.[6] When myocardial cell are exposed to hyperkaliemia, the maximum diastolic potential is depolarized as a result of the alteration of Ik1 potassium current, whose intensity and direction is strictly dependant on intracellular and extracellular potassium concentrations. With Ik1 suppressed, an hyperpolarizing effect is lost and therefore there can be activation of funny current even in myocardial cells (which is normally suppressed by the hyperpolarizing effect of coexisting potassium currents). This can lead to the instauration of automaticity in ischemic tissue.
Re-entry
The role of re-entry or circus motion was demonstrated separately by Mines and Garrey.[7] Mines created a ring of excitable tissue by cutting the atria out of the ray fish. Garrey cut out a similar ring from the turtle ventricle. They were both able to show that, if a ring of excitable tissue was stimulated at a single point, the subsequent waves of depolarisation would pass around the ring. The waves eventually meet and cancel each other out, but, if an area of transient block occurred with a refractory period that blocked one wavefront and subsequently allowed the other to proceed retrogradely over the other path, then a self-sustaining circus movement phenomenon would result. For this to happen, however, it is necessary that there be some form of non-uniformity. In practice, this may be an area of ischaemic or infarcted myocardium, or underlying scar tissue. It is possible to think of the advancing wave of depolarisation as a dipole with a head and a tail. The length of the refractory period and the time taken for the dipole to travel a certain distancethe propagation velocitywill determine whether such a circumstance will arise for re-entry to occur. Factors that promote re-entry would include a slow-propagation velocity, a short refractory period with a sufficient size of ring of conduction tissue. These would enable a dipole to reach an area that had been refractory and is now able to be depolarised with continuation of the wavefront. In clinical practice, therefore, factors that would lead to the right conditions to favour such re-entry mechanisms include increased heart size through hypertrophy or dilatation, drugs which alter the length of the refractory period and areas of cardiac disease. Therefore, the substrate of ventricular fibrillation is transient or permanent conduction block. Block due either to areas of damaged or refractory tissue leads to areas of myocardium for initiation and perpetuation of fibrillation through the phenomenon of re-entry.
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Pathophysiology
Ventricular fibrillation has been described as "chaotic asynchronous fractionated activity of the heart" (Moe et al. 1964). A more complete definition is that ventricular fibrillation is a "turbulent, disorganized electrical activity of the heart in such a way that the recorded electrocardiographic deflections continuously change in shape, magnitude and direction".[8] Ventricular fibrillation most commonly occurs within diseased hearts, and, in the vast majority of cases, is a manifestation of underlying ischemic heart disease. Ventricular fibrillation is also seen in those with cardiomyopathy, myocarditis, and other heart pathologies. In addition, it is seen with electrolyte disturbances and overdoses of cardiotoxic drugs. It is also notable that ventricular fibrillation occurs where there is no discernible heart pathology or other evident cause, the so-called idiopathic ventricular fibrillation. Idiopathic ventricular fibrillation occurs with a reputed incidence of approximately 1% of all cases of out-of-hospital arrest, as well as 3%-9% of the cases of ventricular fibrillation unrelated to myocardial infarction, and 14% of all ventricular fibrillation resuscitations in patients under the age of 40.[9] It follows then that, on the basis of the fact that ventricular fibrillation itself is common, idiopathic ventricular fibrillation accounts for an appreciable mortality. Recently-described syndromes such as the Brugada Syndrome may give clues to the underlying mechanism of ventricular arrhythmias. In the Brugada syndrome, changes may be found in the resting ECG with evidence of right bundle branch block (RBBB) and ST elevation in the chest leads V1-V3, with an underlying propensity to sudden cardiac death.[10] The relevance of this is that theories of the underlying pathophysiology and electrophysiology must account for the occurrence of fibrillation in the apparent "healthy" heart. It is evident that there are mechanisms at work that we do not fully appreciate and understand. Investigators are exploring new techniques of detecting and understanding the underlying mechanisms of sudden cardiac death in these patients without pathological evidence of underlying heart disease.[11] Familial conditions that predispose individuals to developing ventricular fibrillation and sudden cardiac death are often the result of gene mutations that affect cellular transmembrane ion channels. For example, in Brugada Syndrome, sodium channels are affected. In certain forms of long QT syndrome, the potassium inward rectifier channel is affected.
Triggered activity
Triggered activity can occur due to the presence of afterdepolarisations. These are depolarising oscillations in the membrane voltage induced by preceding action potentials. These can occur before or after full repolarisation of the fiber and as such are termed either early (EADs) or delayed afterdepolarisations (DADs). All afterdepolarisations may not reach threshold potential, but, if they do, they can trigger another afterdepolarisation, and thus self-perpetuate.
Characteristics of the ventricular fibrillation waveform

Ventricular fibrillation can be described in terms of its electrocardiographic waveform appearance. All waveforms can be described in terms of certain features, such as amplitude and frequency. Researchers have looked at the frequency of the ventricular fibrillation waveform to see if it helps to elucidate the underlying mechanism of the arrhythmia or holds any clinically useful information. More recently, Gray has suggested an underlying mechanism for the frequency of the waveform that has puzzled investigators as possibly being a manifestation of the Doppler effect of rotors of fibrillation.[12] Analysis of the fibrillation waveform is performed using a mathematical technique known as Fourier analysis.
Ventricular fibrillation Power spectrum The distribution of frequency and power of a waveform can be expressed as a power spectrum in which the contribution of different waveform frequencies to the waveform under analysis is measured. This can be expressed as either the dominant or peak frequency, i.e., the frequency with the greatest power or the median frequency, which divides the spectrum in two halves.
154
Ventricular fibrillation as seen in lead II
Frequency analysis has many other uses in medicine and in cardiology, including analysis of heart rate variability and assessment of cardiac function, as well as in imaging and acoustics.[13] [14]
Treatment
Defibrillation
Electric defibrillator The condition can often be reversed by the electric discharge of direct current from a defibrillator. Although a defibrillator is designed to correct the problem, and its effects can be dramatic, it is not always successful. Implantable electric defibrillator In patients at high risk of ventricular fibrillation, the use of an implantable cardioverter defibrillator has been shown to be beneficial. Precordial thump If no defibrillator is available, a precordial thump can be delivered at the onset of VF for a small chance to regain cardiac function. However, research has shown that the precordial thump releases no more than 30 joules of energy. This is far less than the 200360 J typically used to bring about normal sinus rhythm. Consequently, in the hospital setting, this treatment is not used.
Antiarrhythmic agents
Antiarrhythmic agents like amiodarone or lidocaine can help, but, unlike atrial fibrillation, ventricular fibrillation rarely reverses spontaneously in large adult mammals. Drug therapy with antiarrhythmic agents in ventricular fibrillation does not replace defibrillation and is not the first priority, but is sometimes needed in cases where initial defibrillation attempts are not successful.
Epidemiology
Sudden cardiac arrest is the leading cause of death in the industrialised world. It exacts a significant mortality with approximately 70,000 to 90,000 sudden cardiac deaths each year in the United Kingdom, and survival rates are only 2%.[15] The majority of these deaths are due to ventricular fibrillation secondary to myocardial infarction, or "heart attack".[16] During ventricular fibrillation, cardiac output drops to zero, and, unless remedied promptly, death usually ensues within minutes.
155
History of knowledge of ventricular fibrillation

Lyman Brewer suggests that the first recorded account of ventricular fibrillation dates as far back as 1500 BC, and can be found in the Ebers papyrus of ancient Egypt. The extract recorded 3500 years ago may even date from as far back as 3500 BC. It states: "When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them if the heart trembles, has little power and sinks, the disease is advanced and death is near." A book authored by Jo Miles suggests that it may even go back farther. Tests done on frozen remains found in the Himalayas seemed fairly conclusive that the first known case of ventricular fibrillation dates back to at least 2500 BC.[17] Whether this is a description of ventricular fibrillation is debatable.[18] The next recorded description occurs 3000 years later and is recorded by Vesalius, who described the appearance of "worm-like" movements of the heart in animals prior to death. The significance and clinical importance of these observations and descriptions possibly of ventricular fibrillation were not recognised until John Erichsen in 1842 described ventricular fibrillation following the ligation of a coronary artery (Erichsen JE 1842). Subsequent to this in 1850, fibrillation was described by Ludwig and Hoffa when they demonstrated the provocation of ventricular fibrillation in an animal by applying a "Faradic" (electrical) current to the heart.[19] In 1874, Edm Flix Alfred Vulpian coined the term mouvement fibrillaire, a term that he seems to have used to describe both atrial and ventricular fibrillation.[20] John A. MacWilliam, a physiologist who had trained under Ludwig and who subsequently became Professor of Physiology at the University of Aberdeen, gave an accurate description of the arrhythmia in 1887. This definition still holds today, and is interesting in the fact that his studies and description predate the use of electrocardiography. His description is as follows: "The ventricular muscle is thrown into a state of irregular arrhythmic contraction, whilst there is a great fall in the arterial blood pressure, the ventricles become dilated with blood as the rapid quivering movement of their walls is insufficient to expel their contents; the muscular action partakes of the nature of a rapid incoordinate twitching of the muscular tissue The cardiac pump is thrown out of gear, and the last of its vital energy is dissipated in the violent and the prolonged turmoil of fruitless activity in the ventricular walls." MacWilliam spent many years working on ventricular fibrillation and was one of the first to show that ventricular fibrillation could be terminated by a series of induction shocks through the heart.[21] The first electrocardiogram recording of ventricular fibrillation was by August Hoffman in a paper published in 1912.[22] At this time, two other researchers, Mines and Garrey, working separately, produced work demonstrating the phenomenon of circus movement and re-entry as possible substrates for the generation of arrhythmias. This work was also accompanied by Lewis, who performed further outstanding work into the concept of "circus movement." Later milestones include the work by Kerr and Bender in 1922, who produced an electrocardiogram showing ventricular tachycardia evolving into ventricular fibrillation.[23] The re-entry mechanism was also advocated by DeBoer, who showed that ventricular fibrillation could be induced in late systole with a single shock to a frog heart.[24] The concept of "R on T ectopics" was further brought out by Katz in 1928.[25] This was called the vulnerable period by Wiggers and Wegria in 1940, who brought to attention the concept of the danger of premature ventricular beats occurring on a T wave. Another definition of VF was produced by Wiggers in 1940. He described ventricular fibrillation as "an incoordinate type of contraction which, despite a high metabolic rate of the myocardium, produces no useful beats. As a result, the arterial pressure falls abruptly to very low levels, and death results within six to eight minutes from anemia of the brain and spinal cord".[26] Spontaneous conversion of ventricular fibrillation to a more benign rhythm is rare in all but small animals. Defibrillation is the process that converts ventricular fibrillation to a more benign rhythm. This is usually by application of an electric shock to the myocardium and is discussed in detail in the relevant article.
156
References
[1] [2] [3] [4] [5] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I49. 0 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=427. 41 http:/ / www. diseasesdatabase. com/ ddb13798. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D014693 Michael E Zevitz, MD. "Ventricular Fibrillation" (http:/ / emedicine. medscape. com/ article/ 158712-overview). Medscape. . Retrieved 2011-08-17. [6] Ho K 1993 [7] Mines GR 1913, Garrey WE 1914 [8] Robles de Medina EO, Bernard R, Coumel P, et al. (1978). "Definition of terms related to cardiac rhythm. WHO/ISFC Task Force". Eur J Cardiol 8 (2): 12744. PMID699945. [9] Viskin S, Belhassen B (1990). "Idiopathic ventricular fibrillation" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ 0002-8703(90)90025-S). Am. Heart J. 120 (3): 66171. doi:10.1016/0002-8703(90)90025-S. PMID2202193. . [10] Brugada P, Brugada J (1992). "Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report". J. Am. Coll. Cardiol. 20 (6): 13916. doi:10.1016/0735-1097(92)90253-J. PMID1309182. [11] Saumarez RC, Heald S, Gill J, et al. (1995). "Primary ventricular fibrillation is associated with increased paced right ventricular electrogram fractionation" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=7586358). Circulation 92 (9): 256571. PMID7586358. . [12] Jalife J, Gray RA, Morley GE, Davidenko JM (1998). "Self-organization and the dynamical nature of ventricular fibrillation". Chaos 8 (1): 7993. doi:10.1063/1.166289. PMID12779712. [13] Shusterman V, Beigel A, Shah SI, et al. (1999). "Changes in autonomic activity and ventricular repolarization". J Electrocardiol. 32 Suppl: 18592. doi:10.1016/S0022-0736(99)90078-X. PMID10688324. [14] Kaplan SR, Bashein G, Sheehan FH, et al. (2000). "Three-dimensional echocardiographic assessment of annular shape changes in the normal and regurgitant mitral valve" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0002-8703(00)90077-2). Am. Heart J. 139 (3): 37887. doi:10.1016/S0002-8703(00)90077-2. PMID10689248. . [15] National Institute for Health and Clinical Excellence Guidelines 2000 [16] Myerburg RJ et al. 1995 [17] Brewer LA (1983). "Sphygmology through the centuries. Historical notes". Am. J. Surg. 145 (6): 695701. doi:10.1016/0002-9610(83)90124-1. PMID6344674. [18] Brewer LA (1983). "Sphygmology through the centuries. Historical notes". Am. J. Surg. 145 (6): 696702. doi:10.1016/0002-9610(83)90124-1. PMID6344674. [19] Hoffa M et al. 1850 [20] Vulpian A 1874 [21] MacWilliam JA 1887 [22] Hoffman A 1912 [23] Kerr, WJ et al. 1922 [24] De Boer S 1923 [25] Katz LN 1928 [26] Wiggers, CJ et al. 1940
External links
Interactive models and information (http://thevirtualheart.org/VFindex.html) on ventricular fibrillation and other arrhythmias Research on Primary Ventricular Fibrillation during Acute Myocardial Infarction (http://www. primaryventricularfibrillation.com) When a child's heart stops, onset time of abnormal rhythms is crucial (http://www.brightsurf.com/news/ headlines/24686/When_a_childs_heart_stops_onset_time_of_abnormal_rhythms_is_crucial.html)
Accelerated idioventricular rhythm
157

Classification and external resources ICD-10 MeSH I45.6 [1] [1]
D016170
In accelerated idioventricular rhythm (AIVR), the rate of cardiac contraction is determined by the intrinsic rate of depolarisation of the cardiac cells. It can be present at birth.[2]
Pathophysiology
In normal hearts the sinoatrial node in the atria depolarises at a rate of 70 beats per minute as an effect of the parasympathetic autonomic nervous system (otherwise the SA node would depolarise at a rate of 120 beats per minute). This suppresses the intrinsic depolarisation of the other parts of the heart. The accelerated idioventricular rhythm occurs when depolarization rate of a normally suppressed focus increases to above that of the "higher order" focuses (the sinoatrial node and the atrioventricular node). This most commonly occurs in the setting of a sinus bradycardia.[3] Accelerated idioventricular rhythm is also the most common reperfusion arrhythmia in humans. However, ventricular tachycardia and ventricular fibrillation remain the most important causes of sudden death following spontaneous restoration of antegrade flow. [4]
Appearance
AIVR appears similar to ventricular tachycardia but is benign and doesn't need any treatment. It can most easily be distinguished from VT in that the rate is less than 120 and usually less than 100 bpm.
References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D016170 [2] Freire G, Dubrow I (March 2008). "Accelerated idioventricular rhythm in newborns: a worrisome but benign entity with or without congenital heart disease". Pediatr Cardiol 29 (2): 45762. doi:10.1007/s00246-007-9024-z. PMID17687587. [3] "Accelerated Idioventricular Rhythm: Overview - eMedicine" (http:/ / www. emedicine. com/ med/ topic12. htm). . Retrieved 2008-12-21. [4] AL Moens, MJ Claeys, JP Timmermans, CJ Vrints. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. International Journal of Cardiology 2005;100:179
First-degree atrioventricular block
158

First-degree AV block
Classification and external resources ICD-10 ICD-9 DiseasesDB eMedicine I44.0 [1] [2] [3] [4]
426.11 10477
emerg/233
First-degree AV block, or PR prolongation, is a disease of the electrical conduction system of the heart in which the PR interval is lengthened beyond 0.20 seconds.[5] In first-degree AV block, the impulse conducting from atria to ventricles through the AV node is delayed and travels slower than normal. It has a prevalence in the normal (young adult) population of 0.65-1.1% and the incidence is 0.13 per 1000 persons.
Causes
The most common causes of first-degree heart block are an AV nodal disease, enhanced vagal tone (for example in athletes), myocarditis, acute myocardial infarction (especially acute inferior MI), electrolyte disturbances and medication. The drugs that most commonly cause first-degree heart block are those that increase the refractory time of the AV node, thereby slowing AV conduction. These include calcium channel blockers, beta-blockers, cardiac glycosides, and anything that increases cholinergic activity such as cholinesterase inhibitors. Drugs that increase calcium concentration, such as Digitalis decrease AVN conduction time.
Diagnosis
In normal individuals, the AV node slows the conduction of electrical impulse through the heart. This is manifest on a surface ECG as the PR interval. The normal PR interval is from 120 ms to 200 ms in length. This is measured from the initial deflection of the P wave to the beginning of the QRS complex. In first-degree heart block, the diseased AV node conducts the electrical activity more slowly. This is seen as a PR interval greater than 200 ms in length on the surface ECG. It is usually an incidental finding on a routine ECG. First-degree heart block does not require any particular investigations except for electrolyte and drug screens, especially if an overdose is suspected.
Treatment
The management includes identifying and correcting electrolyte imbalances and withholding any offending medications. This condition does not require admission unless there is an associated myocardial infarction. Even though it usually does not progress to higher forms of heart block, it may require outpatient follow-up and monitoring of the ECG, especially if there is a comorbid bundle branch block. If there is a need for treatment of an unrelated condition, care should be taken not to introduce any medication that may slow AV conduction. If this is not feasible, clinicians should be very cautious when introducing any drug that may slow conduction; and regular monitoring of the ECG is indicated.
159
Prognosis
Isolated first-degree heart block has no direct clinical consequences. There are no symptoms or signs associated with it. It was originally thought of as having a benign prognosis. In the Framingham Heart Study, however, the presence of a prolonged PR interval or first degree AV block doubled the risk of developing atrial fibrillation (irregular heart beat), tripled the risk of requiring an artificial pacemaker, and was associated with a small increase in mortality. This risk was proportional to the degree of PR prolongation.[6] A subset of individuals with the triad of first-degree heart block, right bundle branch block, and either left anterior fascicular block or left posterior fascicular block (known as trifascicular block) may be at an increased risk of progression to complete heart block.
References
[1] [2] [3] [4] [5] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I44. 0 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 11 http:/ / www. diseasesdatabase. com/ ddb10477. htm http:/ / www. emedicine. com/ emerg/ topic233. htm "Lesson VI - ECG Conduction Abnormalities" (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson6/ index. html#First). . Retrieved 2009-01-07.
[6] Cheng S, Keyes MJ, Larson MG, McCabe EL, Newton-Cheh C, Levy D, Benjamin EJ, Vasan RS, Wang TJ (2009). "Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block". JAMA 301 (24): 25712577. doi:10.1001/jama.2009.888.
Second-degree atrioventricular block

[1] [2]

Classification and external resources ICD-10 ICD-9 DiseasesDB eMedicine I44.1 [3] [4] [3] [6] , 426.13 [5]
426.12 10477
emerg/234
Second-degree AV block is a disease of the electrical conduction system of the heart. It refers to a conduction block between the atria and ventricles. The presence of second-degree AV block is diagnosed when one or more (but not all) of the atrial impulses fail to conduct to the ventricles due to impaired conduction.
160
Types
There are two distinct types of second-degree AV block, called Type 1 and Type 2. In both types, a P wave is blocked from initiating a QRS complex; but, in Type 1, there are increasing delays in each cycle before the omission, whereas, in Type 2, there is no such pattern.[2] Type 1 second-degree heart block is considered a more benign entity than type 2 second-degree heart block.http:/ / health.medicscientist.com/wp-content/uploads/2011/04/SeconddegreeAVblock2_thumb.jpg Both types are named after Woldemar Mobitz, even though they were first described by Dusty Andressen. There is still much controversy on how Mobitz got the information from Andressen.[7] [8] Type I is also named for Karel Frederik Wenckebach,[9] and type II is also named for John Hay.[10] [11]
Type 1 (Mobitz I/Wenckebach)

Type 1 Second-degree AV block, also known as Mobitz I or Wenckebach periodicity, is almost always a disease of the AV node. Mobitz I heart block is characterized by progressive prolongation of the PR interval on the electrocardiogram (ECG) on consecutive beats followed by a blocked P wave (i.e., a 'dropped' QRS complex). After the dropped QRS complex, the PR interval resets and the cycle repeats. One of the baseline assumptions when determining if an individual has Mobitz I heart block is that the atrial rhythm has to be regular. If the atrial rhythm is not regular, there could be alternative explanations as to why certain P waves do not conduct to the ventricles. This is almost always a benign condition for which no specific treatment is needed. In symptomatic cases, intravenous atropine or isoproterenol may transiently improve conduction.[12] In horses Mobitz I AV block is considered a normal variant finding, frequently encountered in relaxed, athletically fit animals.[13]
Type 2 (Mobitz II/Hay)

Type 2 Second-degree AV block, also known as Mobitz II is almost always a disease of the distal conduction system (His-Purkinje System). Mobitz II heart block is characterized on a surface ECG by intermittently nonconducted P waves not preceded by PR prolongation and not followed by PR shortening. The medical significance of this type of AV block is that it may progress rapidly to complete heart block, in which no escape rhythm may emerge. In this case, the person may experience a Stokes-Adams attack, cardiac arrest, or Sudden Cardiac Death. The definitive treatment for this form of AV Block is an implanted pacemaker. The impairment is usually below the AV node.[14] Although the terms infranodal block or infrahisian block are often applied to this disorder, they refer to the anatomic location of the block, whereas Mobitz II refers to an electrocardiographic pattern.
161
Symptoms
Most people with Wenckebach (Type I Mobitz) do not show symptoms. However, those that do usually display one or more of the following: Light-headedness Dizziness Syncope (Fainting)
References
[1] "Error: no |title= specified when using {{[[Template:Cite web|Cite web (http:/ / 2. bp. blogspot. com/ -P_dF2bRTOGc/ TqKKeNGhpXI/ AAAAAAAAALo/ vqqZ_e3kXNY/ s1600/ wenckebach. jpg)]}}"]. . [2] "Lesson VI - ECG Conduction Abnormalities" (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson6/ index. html#Wenckebach). . Retrieved 2009-01-07. [3] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I44. 1 [4] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 12 [5] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 13 [6] http:/ / www. emedicine. com/ emerg/ topic234. htm [7] synd/2824 (http:/ / www. whonamedit. com/ synd. cfm/ 2824. html) at Who Named It? [8] W. Mobitz. ber die unvollstndige Strung der Erregungsberleitung zwischen Vorhof und Kammer des menschlichen Herzens. Zeitschrift fr die Gesamte Experimentelle Medizin, Berlin 1924, 41: 180237. [9] K. F. Wenckebach. De Analyse van den onregelmatigen Pols. III. Over eenige Vormen van Allorythmie en Bradykardie. Nederlandsch Tijdschrift voor Geneeskunde, Amsterdam, 1898, 2: 1132. [10] Silverman ME, Upshaw CB, Lange HW (August 2004). "Woldemar Mobitz and His 1924 classification of second-degree atrioventricular block" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=15339865). Circulation 110 (9): 11627. doi:10.1161/01.CIR.0000140669.35049.34. PMID15339865. . [11] J. Hay. Bradycardia and cardiac arrhythmia produced by depression of certain of the functions of the heart. The Lancet 1906, 1: 139143. [12] Lilly, L. S., Pathophysiology of Heart Disease. Baltimore: Lippincott Williams & Wilkins; 2007 [13] Marr, Celia M (1999-07-12). Cardiology of the horse (http:/ / books. google. com/ ?id=2t9BlUut8UwC& pg=PA276& lpg=PA276& dq=mobitz+ horses). ISBN9780702022401. . [14] Wogan JM, Lowenstein SR, Gordon GS (1993). "Second-degree atrioventricular block: Mobitz type II" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ 0736-4679(93)90009-V). J Emerg Med 11 (1): 4754. doi:10.1016/0736-4679(93)90009-V. PMID8445186. .
Third-degree atrioventricular block
162

ICD-10 ICD-9 DiseasesDB eMedicine
I44.2 426.0
[1] [2] [3] [3]
10477
emerg/235
Presentation
Third-degree AV block, also known as complete heart block, is a medical condition in which the impulse generated in the SA node in the atrium does not propagate to the ventricles.[4] Because the impulse is blocked, an accessory pacemaker in the lower chambers will typically activate the ventricles. This is known as an escape rhythm. Since this accessory pacemaker also activates independently of the impulse generated at the SA node, two independent rhythms can be noted on the electrocardiogram (ECG).
Lead I and II in the same patient, demonstrating complete AV block. Note that the P waves are not related to the QRS complexes (PP interval and QRS interval both constant), demonstrating that the atria are electrically disconnected from the ventricles. The QRS complexes represent an escape rhythm arising from the ventricle.
The P waves with a regular P to P interval represents the first rhythm. The QRS complexes with a regular R to R interval represent the second rhythm. The PR interval will be variable, as the hallmark of complete heart block is no apparent relationship between P waves and QRS complexes. One of the pathognomonic characteristic of this block is the absolute absence of the opportunity for atrial impulses to enter and capture the ventricles(unlike AV dissociation,with functional block)due to organic nature of block(eg, fibrosis, calcification, or infiltration of the node) . It means that, in the presence of complete heart block, fusion or capture beats will never be seen.[5] Patients with third-degree AV block typically experience bradycardia (an abnormally low measured heart rate), hypotension, and at times, hemodynamic instability. In some cases, exercising may be difficult, as the heart cannot react quickly enough to sudden changes in demand or sustain the higher heart rates required for prolonged activity.
163
Etiology
Many conditions can cause third-degree heart block, but the most common cause is coronary ischemia. Progressive degeneration of the electrical conduction system of the heart can lead to third-degree heart block. This may be preceded by first-degree AV block, second-degree AV block, bundle branch block, or bifascicular block. In addition, acute myocardial infarction may present with third-degree AV block. An inferior wall myocardial infarction may cause damage to the AV node, causing third-degree heart block. In this case, the damage is usually transitory, and the AV node may recover. Studies have shown that third-degree heart block in the setting of an inferior wall myocardial infarction typically resolves within 2 weeks[citation is needed]. The escape rhythm typically originates in the AV junction, producing a narrow complex escape rhythm. An anterior wall myocardial infarction may damage the distal conduction system of the heart, causing third-degree heart block. This is typically extensive, permanent damage to the conduction system, necessitating a permanent pacemaker to be placed. The escape rhythm typically originates in the ventricles, producing a wide complex escape rhythm. Third-degree heart block may also be congenital and has been linked to the presence of lupus in the mother. It is thought that maternal antibodies may cross the placenta and attack the heart tissue during gestation. The cause of congenital third-degree heart block in many patients is unknown. Studies suggest that the prevalence of congenital third-degree heart block is between 1 in 15,000 and 1 in 22,000 live births. Lastly, Lyme disease can also result in 3rd-degree heart block.
Treatment
Third-degree AV block can be treated by use of a dual-chamber artificial pacemaker. This type of device typically listens for a pulse from the SA node and sends a pulse to the AV node at an appropriate interval, essentially completing the connection between the two nodes. Pacemakers in this role are usually programmed to enforce a minimum heart rate and to record instances of atrial flutter and atrial fibrillation, two common secondary conditions that can accompany third-degree AV block. Treatment may also include medicines to control blood pressure and atrial fibrillation, as well as lifestyle and dietary changes to reduce risk factors associated with heart attack and stroke. Treatment in emergency situations ultimately involves electrical pacing. However the American Heart Association states that giving a trial of atropine while waiting for the pacer to be set up is acceptable. Atropine is effective for treating early Heart Blocks (1st Degree and 2nd Degree type 1) but generally thought to have no effect on 3rd Degree Blocks. The 2005 Joint European Resuscitation and Resuscitation Council (UK) guidelines state that Atropine is the first line treatment especially if there were any adverse signs, namely: 1) heart rate <40 bpm, 2) systolic blood pressure < 100mm Hg, 3) signs of heart failure, and 4) ventricular arrhythmias requiring suppression. If these fail to respond to atropine or there is a potential risk of asystole, transvenous pacing is indicated. The risk factors for asystole include 1) previous asystole, 2) complete heart block with wide complexes and 3) ventricular pause for > 3 seconds. Mobitz Type 2 AV block is another indication for pacing.
164
References
[1] [2] [3] [4] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I44. 2 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 0 http:/ / www. emedicine. com/ emerg/ topic235. htm "Lesson VI - ECG Conduction Abnormalities" (http:/ / library. med. utah. edu/ kw/ ecg/ ecg_outline/ Lesson6/ index. html#Complete). . Retrieved 2009-01-07. [5] Exeer,Nader.Ahmad.MD, Cardiovascular diseases, Conduction disturbances 2010 ,Aliabad university Hospital, kabul Medical university,Kabul,Afghanistan.
External links
Complete heart block ECG (http://www.ecglibrary.com/chb4.html) RN.ORG Nursing Resource (http://www.rn.org/courses/coursematerial-187.pdf)
Long QT syndrome
165
Long QT syndrome
Long QT syndrome
Schematic representation of normal ECG trace (sinus rhythm) with waves, segments, and intervals labeled. ICD-10 ICD-9 DiseasesDB eMedicine MeSH I45.8 [1] [2] [3] [4]
426.82 11104
med/1983 D008133
[5]
The long QT syndrome (LQTS) is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes (TDP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition.[6] The condition is so named because of the appearances of the electrocardiogram (ECG/EKG), on which there is prolongation of the QT interval. In some individuals the QT prolongation occurs only after the administration of certain medications.[6]
Genetics
Genes and mutations
LQTS can arise from mutation of one of several genes.[7] These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly (LQT8) or congenital neural deafness (LQT1). A number of specific gene loci have been identified that are associated with LQTS. Genetic testing for LQTS is clinically available and may help to direct appropriate therapies (Overview of LQTS Genetic Testing [8]). The most common causes of LQTS are mutations in the genes KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3); the following is a list of all known genes associated with LQTS:
Long QT syndrome
166
Type LQT1
OMIM 192500 [9]
Mutation alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1) alpha subunit of the rapid delayed rectifier potassium channel (hERG + MiRP1)
Notes The current through the heteromeric channel (KvLQT1 + minK) is known as IKs. These mutations often cause LQT by reducing the amount of repolarizing current. This repolarizing current is required to terminate the action potential, leading to an increase in the action potential duration (APD). These mutations tend to be the most common yet least severe. Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.
LQT2
152427 [10]
LQT3
603830 [11]
alpha subunit of the sodium Current through this channel is commonly referred to as INa. Depolarizing current through the channel (SCN5A) channel late in the action potential is thought to prolong APD. The late current is due to the failure of the channel to remain inactivated. As a consequence, it can enter a bursting mode, during which significant current enters abruptly when it should not. These mutations are more lethal but less common. anchor protein Ankyrin B LQT4 is very rare. Ankyrin B anchors the ion channels in the cell.
LQT4
600919 [12] 176261 [13]
LQT5
beta subunit MinK (or KCNE1), which coassembles with KvLQT1 beta subunit MiRP1 (or KCNE2), which coassembles with hERG potassium channel KCNJ2 (or Kir2.1) alpha subunit of the calcium channel Cav1.2 encoded by the gene CACNA1c. Caveolin 3
LQT6
603796 [14]
LQT7
170390 [15] 601005 [16]
The current through this channel and KCNJ12 (Kir2.2) is called IK1. LQT7 leads to Andersen-Tawil syndrome. Leads to Timothy's syndrome.
LQT8
LQT9
611818 [17]
LQT10 611819 [18] LQT11 611820 [19] LQT12 601017 [20] LQT13 600734 [21]
SCN4B
AKAP9
SNTA1
GIRK4
Drug induced LQT is usually a result of treatment by anti-arrhythmic drugs such as amiodarone and sotalol or a number of other drugs that have been reported to cause this problem (e.g. cisapride). Some anti-psychotic drugs, such as haloperidol and ziprasidone, have a prolonged QT interval as a rare side-effect. Genetic mutations may make one more susceptible to drug-induced LQT. LQT1 LQT1 is the most common type of long QT syndrome, making up about 30 to 35 percent of all cases. The LQT1 gene is KCNQ1 [22], which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (in particular, the minK beta subunit) to create the IKs ion
Long QT syndrome channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential. Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene, homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome. Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene. Many missense mutations of the LQT1 gene have been identified. These are often associated with a high frequency of syncopes but less sudden death than LQT2. LQT2 The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 25 to 30 percent of all cases. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (hERG) on chromosome 7. The hERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning hERG gene allows protection against early after depolarizations (EADs). Most drugs that cause long QT syndrome do so by blocking the IKr current via the hERG gene. These include erythromycin, terfenadine, and ketoconazole. The hERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and the phenylalanine at position 656. These amino acid residues are poised so that a drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are, therefore, not as prone to blockage. LQT3 The LQT3 type of long QT syndrome involves mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. However, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential. A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease and dilated cardiomyopathy. In rare situations, some affected individuals can have combinations of these diseases. LQT5 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1, which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms, it can lead to Jervell and Lange-Nielsen syndrome LQT6 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2, which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current. LQT7 Andersen-Tawil syndrome is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2, which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis, and skeletal developmental
167
Long QT syndrome abnormalities as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.[23] LQT8 Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly, and immune deficiency. LQT9 This newly discovered variant is caused by mutations in the membrane structural protein, caveolin-3. Caveolins form specific membrane domains called caveolae in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current, which impairs cellular repolarization. LQT10 This novel susceptibility gene for LQT is SCN4B encoding the protein NaV4, an auxiliary subunit to the pore-forming NaV1.5 (gene: SCN5A) subunit of the voltage-gated sodium channel of the heart. The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current. Only one mutation in one patient has so far been found.
168
Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.
Romano-Ward syndrome
Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness. The diagnosis is clinical and is now less commonly used in centres where genetic testing is available, in favour of the LQT1 to 10 scheme given above.
Pathophysiology
All forms of the long QT syndrome involve an abnormal repolarization of the heart. The abnormal repolarization causes differences in the refractory period of the myocytes. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias. It is believed that the so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium channels during the plateau phase of the cardiac action potential. Since adrenergic stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (i.e., exercise, excitement) -- especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise. The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca2+ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca2+ release during repolarization, causing the released Ca2+ to exit the cell through the 3Na+/Ca2+-exchanger, which results in a net depolarizing current.
Long QT syndrome
169
Diagnosis
The diagnosis of LQTS is not easy since 2.5% of the healthy population have prolonged QT interval, and 1015% of LQTS patients have a normal QT interval.[24] A commonly used criterion to diagnose LQTS is the LQTS "diagnostic score".[25] The score is calculated by assigning different points to various criteria (listed below). With four or more points, the probability is high for LQTS; with one point or less, the probability is low. A score of two or three points indicates intermediate probability. QTc (Defined as QT interval / square root of RR interval) >= 480 msec - 3 points 460-470 msec - 2 points 450 msec and male gender - 1 point Torsades de pointes ventricular tachycardia - 2 points T wave alternans - 1 point Notched T wave in at least 3 leads - 1 point Low heart rate for age (children) - 0.5 points Syncope (one cannot receive points both for syncope and torsades de pointes) With stress - 2 points Without stress - 1 point Congenital deafness - 0.5 points Family history (the same family member cannot be counted for LQTS and sudden death) Other family members with definite LQTS - 1 point Sudden death in immediate family (members before the age 30) - 0.5 points
Treatment options
Those diagnosed with long QT syndrome are usually advised to avoid drugs that would prolong the QT interval further or lower the threshold for TDP.[26] In addition to this, there are two intervention options for individuals with LQTS: arrhythmia prevention and arrhythmia termination.
Arrhythmia prevention
Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is after depolarizations, and these after depolarizations are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include: Administration of beta receptor blocking agents, which decreases the risk of stress-induced arrhythmias. Beta blockers are the first choice in treating Long QT syndrome. In 2004, it was shown that genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blockers therapy. To be specific, the presence of QTc >500ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients, primary prevention with ICD (Implantable cardioverter-defibrillator) implantation can be considered.[27] Potassium supplementation: If the potassium content in the blood rises, the action potential shortens, and due to this reason it is believed that increasing potassium concentration could minimize the occurrence of arrhythmias. It should work best in LQT2, since the HERG channel is especially sensitive to potassium concentration, but the use is experimental and not evidence-based. Mexiletine, a sodium channel blocker: In LQT3, the problem is that the sodium channel does not close properly. Mexiletine closes these channels and is believed to be usable when other therapies fail. It should be especially effective in LQT3, but there is no evidence based documentation.
Long QT syndrome Amputation of the cervical sympathetic chain (left stellectomy). This may be used as an add-on therapy to beta blockers, but modern therapy favors mostly ICD implantation if beta blocker therapy fails.
170
Arrhythmia termination
Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. One effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillator (ICD). Also, external defibrillation can be used to restore sinus rhythm. ICDs are commonly used in patients with syncopes despite beta blocker therapy, and in patients having experienced a cardiac arrest. It is hoped that, with better knowledge of the genetics underlying the long QT syndrome, more precise treatments will become available.[28]
Prognosis
The risk for untreated LQTS patients having events (syncopes or cardiac arrest) can be predicted from their genotype (LQT1-8), gender, and corrected QT interval.[29] High risk (>50%) QTc>500 msec LQT1 & LQT2 & LQT3 (males) Intermediate risk (30-50%) QTc>500 msec LQT3 (females) QTc<500 msec LQT2 (females) & LQT3 Low risk (<30%) QTc<500 msec LQT1 & LQT2 (males)
History
The first documented case of Long QT syndrome was described in Leipzig by Meissner in 1856, where a deaf girl died after her teacher yelled at her. When the parents were told about her death, they told that her older brother who also was deaf died after a terrible fright.[30] This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tnsberg, Norway.[31] Italian pediatrician Cesarino Romano, in 1963,[32] and Irish pediatrician Owen Conor Ward, in 1964,[33] separately described the more common variant of Long QT syndrome with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved.[34]
References
[1] [2] [3] [4] [5] [6] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ I45. 8 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=426. 82 http:/ / www. diseasesdatabase. com/ ddb11104. htm http:/ / www. emedicine. com/ med/ topic1983. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D008133 Morita H, Wu J, Zipes DP (August 2008). "The QT syndromes: long and short". Lancet 372 (9640): 75063. doi:10.1016/S0140-6736(08)61307-0. PMID18761222. [7] Hedley PL; Jorgensen P; Schlamowitz S; Wangari, Romilda et al. (2009). "The genetic basis of long QT and short QT syndromes: a mutation update". Human Mutation 30 (11): 1486511. doi:10.1002/humu.21106. PMID19862833. [8] http:/ / www. ncbi. nlm. nih. gov/ bookshelf/ br. fcgi?book=gene& partid=1129#rws [9] http:/ / omim. org/ entry/ 192500 [10] http:/ / omim. org/ entry/ 152427
Long QT syndrome
[11] http:/ / omim. org/ entry/ 603830 [12] http:/ / omim. org/ entry/ 600919 [13] http:/ / omim. org/ entry/ 176261 [14] http:/ / omim. org/ entry/ 603796 [15] http:/ / omim. org/ entry/ 170390 [16] http:/ / omim. org/ entry/ 601005 [17] http:/ / omim. org/ entry/ 611818 [18] http:/ / omim. org/ entry/ 611819 [19] http:/ / omim. org/ entry/ 611820 [20] http:/ / omim. org/ entry/ 601017 [21] http:/ / omim. org/ entry/ 600734 [22] http:/ / www. genenames. org/ data/ hgnc_data. php?match=KCNQ1 [23] Tristani-Firouzi M, Jensen JL, Donaldson MR et al. (2002). "Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)". J. Clin. Invest. 110 (3): 3818. doi:10.1172/JCI15183. PMC151085. PMID12163457. [24] Moric-Janiszewska E, Markiewicz-oskot G, Loskot M, Weglarz L, Hollek A, Szydlowski L (2007). "Challenges of diagnosis of long-QT syndrome in children". Pacing Clin Electrophysiol 30 (9): 11681170. doi:10.1111/j.1540-8159.2007.00832.x. PMID17725765. [25] Schwartz PJ, Moss AJ, Vincent GM, Crampton RS (1993). "Diagnostic criteria for the long QT syndrome. An update". Circulation 88 (2): 7824. PMID8339437. [26] "QT Drug List by Risk Groups" (http:/ / www. azcert. org/ medical-pros/ drug-lists/ drug-lists. cfm). Arizona Center for Education and Research on Therapeutics. . Retrieved 2010-07-04. [27] Priori SG, Napolitano C, Schwartz PJ et al. (2004). "Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers". JAMA 292 (11): 13414. doi:10.1001/jama.292.11.1341. PMID15367556. [28] Compton SJ, Lux RL, Ramsey MR et al. (1996). "Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=8790040). Circulation 94 (5): 101822. PMID8790040. . [29] Ellinor PT, Milan DJ, MacRae CA (2003). "Risk stratification in the long-QT syndrome". N. Engl. J. Med. 349 (9): 9089. doi:10.1056/NEJM200308283490916. PMID12944579. [30] Tranebjaerg L, Bathen J, Tyson J et al. (1999). "Jervell and Lange-Nielsen syndrome: a Norwegian perspective". Am J Med Genet 89 (3): 13746. doi:10.1002/(SICI)1096-8628(19990924)89:3<137::AID-AJMG4>3.0.CO;2-C. PMID10704188. [31] Jervell A, Lange-Nielsen F (July 1957). "Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death". Am. Heart J. 54 (1): 5968. doi:10.1016/0002-8703(57)90079-0. PMID13435203. [32] Romano C, Gemme G, Pongiglione R (September 1963). "Rare cardiac arrythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation" (in Italian). Clin Pediatr (Bologna) 45: 65683. PMID14158288. [33] Ward OC (April 1964). "A new familial cardiac syndrome in children". J Ir Med Assoc 54: 1036. PMID14136838. [34] Moss AJ; Schwartz PJ (2005). "25th Anniversary of the International Long-QT Syndrome Registry" (http:/ / circ. ahajournals. org/ cgi/ content/ full/ 111/ 9/ 1199). Circulation 111 (9): 11991201. doi:10.1161/01.CIR.0000157069.91834.DA. PMID15753228. .
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External links
Long QT syndrome (http://www.dmoz.org/Health/Conditions_and_Diseases/Cardiovascular_Disorders/ Heart_Disease/Arrhythmia/Long_QT_Syndrome//) at the Open Directory Project
172
Antiarrythmic Agents
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.
The cardiac action potential
Singh Vaughan Williams classification

The Singh Vaughan Williams classification, introduced in 1970 based on the seminal work of Bramah N. Singh in his doctoral thesis at Oxford where Vaughan Williams was his advisor and on subsequent work by Singh and his colleagues in the United States, is one of the most widely used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect. However, its dependence on primary mechanism is one of the limitations of the Singh-VW classification, since many antiarrhythmic agents have multiple action mechanisms. Amiodarone, for example, has effects consistent with all of the first four classes. Another limitation is the lack of consideration within the Singh-VW classification system for the effects of drug metabolites. Procainamidea class Ia agent whose metabolite N-acetyl procainamide (NAPA) has a class III actionis one such example. A historical limitation was that drugs such as digoxin and adenosine important antiarrhythmic agents had no place at all in the VW classification system. This has since been rectified by the inclusion of class V. There are five main classes in the Singh Vaughan Williams classification of antiarrhythmic agents: Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux. Class IV agents affect calcium channels and the AV node. Class V agents work by other or unknown mechanisms.
173
Overview table
Class Ia Known as fast-channel blockers-Affect QRS complex Examples Quinidine Procainamide Disopyramide Mechanism (Na+) channel block (intermediate association/dissociation) Clinical uses [1]
Ventricular arrhythmias prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity) procainamide in Wolff-Parkinson-White syndrome treatment and prevention during and immediately after myocardial infarction, though this practice is now discouraged given the increased risk of asystole ventricular tachycardia atrial fibrillation prevents paroxysmal atrial fibrillation treats recurrent tachyarrhythmias of abnormal conduction system. contraindicated immediately post-myocardial infarction. decrease myocardial infarction mortality prevent recurrence of tachyarrhythmias
Ib- Do not affect QRS complex
Lidocaine Phenytoin Mexiletine Tocainide
(Na+) channel block (fast association/dissociation)
Ic Flecainide Propafenone Moricizine (Na+) channel block (slow association/dissociation)
II
Beta-blockers
Propranolol Esmolol Timolol Metoprolol Atenolol Bisoprolol Amiodarone Sotalol Ibutilide Dofetilide Dronedarone E-4031 Verapamil Diltiazem
beta blocking Propranolol also shows some class I action
III
K+ channel blocker Sotalol is also [2] a beta blocker Amiodarone has Class I, II, and III activity
In Wolff-Parkinson-White syndrome (sotalol:) ventricular tachycardias and atrial fibrillation (Ibutilide:) atrial flutter and atrial fibrillation
IV
slow-channel blockers
Ca2+ channel blocker
prevent recurrence of paroxysmal supraventricular tachycardia reduce ventricular rate in patients with atrial fibrillation
Adenosine Digoxin Magnesium Sulfate
Work by other or unknown mechanisms (Direct nodal inhibition).
Used in supraventricular arrhythmias, especially in Heart Failure with Atrial Fibrillation, contraindicated in ventricular arrhythmias. Or in the case of Magnesium Sulfate, used in Torsade de Pointe.
Class I agents
The class I antiarrhythmic agents interfere with the sodium channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials. Class I agents are called Membrane Stabilizing agents. The 'stabilizing' is the word used to describe the decrease of excitogenicity of the plasma membrane which is brought about by these agents. (Also noteworthy is that a few class II agents like propranolol also have a membrane stabilizing effect.) Class I agents are divided into three groups (Ia, Ib and Ic) based upon their effect on the length of the action potential.[3] [4] Ia lengthens the action potential (right shift) Ib shortens the action potential (left shift)
Antiarrhythmic agent Ic does not significantly affect the action potential (no shift)
174
Class Ia
Class Ib
Class Ic
Class II agents
Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the 1-adrenergic receptors, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node. Class II agents include atenolol, esmolol, propranolol, and metoprolol.
Class III agents

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.[5] Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). Drugs include: amiodarone, ibutilide, sotalol, dofetilide, and dronedarone.
Class III
Class IV agents
Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility. Class IV agents include verapamil and diltiazem.
Other agents ("Class V")

Since the development of the original Vaughan-Williams classification system, additional agents have been used that don't fit cleanly into categories I through IV. Some sources use the term "Class V".[6] However, they are more frequently identified by their precise mechanism. Agents include: Digoxin, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system. Adenosine[7] Magnesium sulfate,[8] which has been used for torsades de pointes.[9] [10]
175
Sicilian Gambit classification

Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.[11] [12]
[13]
It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in approximately the Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is therefore not a true classification in that it does not aggregate drugs into categories.[14]
References
[1] Unless else specified in boxes, then ref is: Rang, H. P.. Pharmacology. Edinburgh: Churchill Livingstone. ISBN0-443-07145-4. [2] Kulmatycki KM, Abouchehade K, Sattari S, Jamali F (May 2001). "Drug-disease interactions: reduced beta-adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat". Br. J. Pharmacol. 133 (2): 28694. doi:10.1038/sj.bjp.0704067. PMC1572777. PMID11350865. [3] Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (February 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=6723689). Eur. Heart J. 5 (2): 99107. PMID6723689. . [4] Trevor, Anthony J.; Katzung, Bertram G. (2003). Pharmacology. New York: Lange Medical Books/McGraw-Hill, Medical Publishing Division. pp.43. ISBN0-07-139930-5. [5] Lenz TL, Hilleman DE, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. ( Medline abstract (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=pubmed& dopt=Abstract& list_uids=10907968)) [6] Fogoros, Richard N. (1999). Electrophysiologic testing. Oxford: Blackwell Science. pp.27. ISBN0-632-04325-3. [7] Conti JB, Belardinelli L, Utterback DB, Curtis AB (March 1995). "Endogenous adenosine is an antiarrhythmic agent" (http:/ / circ. ahajournals. org/ cgi/ pmidlookup?view=long& pmid=7882485). Circulation 91 (6): 17617. PMID7882485. . [8] Brugada P (July 2000). "Magnesium: an antiarrhythmic drug, but only against very specific arrhythmias" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=10924290). Eur. Heart J. 21 (14): 1116. doi:10.1053/euhj.2000.2142. PMID10924290. . [9] Hoshino K, Ogawa K, Hishitani T, Isobe T, Eto Y (October 2004). "Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome" (http:/ / www. jacn. org/ cgi/ pmidlookup?view=long& pmid=15466950). J Am Coll Nutr 23 (5): 497S500S. PMID15466950. . [10] Hoshino K, Ogawa K, Hishitani T, Isobe T, Etoh Y (April 2006). "Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome" (http:/ / www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed& issn=1328-8067& date=2006& volume=48& issue=2& spage=112). Pediatr Int 48 (2): 1127. doi:10.1111/j.1442-200X.2006.02177.x. PMID16635167. . [11] "The 'Sicilian Gambit'. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. The Task Force of the Working Group on Arrhythmias of the European Society of Cardiology" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=1723682). Eur. Heart J. 12 (10): 111231. October 1991. PMID1723682. . [12] Vaughan Williams EM (November 1992). "Classifying antiarrhythmic actions: by facts or speculation" (http:/ / jcp. sagepub. com/ cgi/ pmidlookup?view=long& pmid=1474169). J Clin Pharmacol 32 (11): 96477. PMID1474169. . [13] "Milestones in the Evolution of the Study of Arrhythmias" (http:/ / www. medscape. com/ viewarticle/ 412798_3). . Retrieved 2008-07-31. [14] Fogoros, Richard N. (1997). Antiarrhythmic drugs: a practical guide. Oxford: Blackwell Science. pp.49. ISBN0-86542-532-9.
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Sodium channel blockers are agents that impair conduction of sodium ions (Na+) through sodium channels.[1]
Extracellular
The following naturally produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel: Alkaloid based toxins tetrodotoxin (TTX) saxitoxin (STX)
Intracellular
Drugs which block sodium channels by blocking from the intracellular side of the channel include: Local anesthetics Class I antiarrhythmic agents Some anticonvulsants
Unknown mechanism
A-803467: specific blockade of Nav1.8 channels (SCN10A), developed by Icagen and Abbott Laboratories[2] Caffeine has been shown to inhibit Na+ current in ventricular cells of guinea pigs.[3]
Antiarrhythmic
Sodium channel blockers are used in the treatment of cardiac arrhythmia. They are classified as "Type I" in the Vaughan Williams classification. Class I antiarrhythmic agents interfere with the (Na+) channel. Class I agents are grouped by their effect on the Na+ channel, and by their effect on cardiac action potentials. Class I agents are called Membrane Stabilizing Agents. 'Stabilizing' refers to the decrease of excitogenicity of the plasma membrane effected by these agents. A few class II agents, propranolol for example, also have a membrane stabilizing effect.
Class Ia agents
Class Ia agents block the fast sodium channel, which depresses the phase 0 depolarization (i.e. reduces Vmax), which prolongs the action potential duration by slowing conduction. Agents in this class also cause decreased conductivity and increased refractoriness. Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation.
Class Ia agent decreasing Vmax, thereby increasing action potential duration.
Procainamide can be used to treat atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and to treat wide complex hemodynamically stable tachycardias. Oral procainamide is no longer being manufactured in the US,
Sodium channel blocker but intravenous formulations are still available. While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent such as digoxin or verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate. Class Ia agents include quinidine, procainamide and disopyramide.
177
Class Ib agents
Class Ib antiarrhythmic agents are sodium channel blockers. They have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease Vmax in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the Effect of class Ib antiarrhythmic agents on the cardiac action potential. action potential duration. Class Ib drugs tend to be more specific for voltage gated Na channels than Ia. Lidocaine in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This is because lidocaine selectively blocks Na channels in their open and inactive states and has little binding capability in the resting state. Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation. Class Ib agents include lidocaine, mexiletine, tocainide, and phenytoin.
Class Ic agents
Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing Vmax). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have qqthe most potent sodium channel blocking effects. Class Ic agents are indicated for life-threatening Effect of class Ic antiarrhythmic agent on cardiac action potential. ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation). These agents are potentially pro-arrhythmic, especially in settings of structural heart disease (e.g. post-myocardial infarction), and are contraindicated in such settings. Class Ic agents include encainide, flecainide, moricizine, and propafenone. Encainide is not available in the US.
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Other uses
Sodium channel blockers are also used as local anesthetics and epilepsy treatments.[4] Sodium channel blockers have been proposed for use in the treatment of cystic fibrosis,[5] but current evidence is mixed.[6] It has been suggested that the analgesic effect of some antidepressants is due to sodium channel blockade.[7]
References
[1] MeSH Sodium+Channel+Blockers (http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Sodium+ Channel+ Blockers) [2] Jarvis, Michael F.; Prisca Honore and 35 additional coauthors (2007-05-27). "A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat" (http:/ / www. pnas. org/ cgi/ content/ full/ 104/ 20/ 8520). PNAS (National Academy of Sciences of the United States) 104 (20): 85205. doi:10.1073/pnas.0611364104. PMC1895982. PMID17483457. . Retrieved 2007-12-16. [3] Habuchi Y, Tanaka H, Furukawa T, Tsujimura Y (Dec 1991). "Caffeine-induced block of Na+ current in guinea pig single ventricular cells" (http:/ / ajpheart. physiology. org/ cgi/ pmidlookup?view=long& pmid=1661092). Am J Physiol. 261 (6 Pt 2): H185563. PMID1661092. . [4] Wood JN, Boorman J (2005). "Voltage-gated sodium channel blockers; target validation and therapeutic potential". Curr Top Med Chem 5 (6): 52937. doi:10.2174/1568026054367584. PMID16022675. [5] Hirsh AJ, Zhang J, Zamurs A, et al. (April 2008). "Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl (http:/ / jpet. aspetjournals. org/ cgi/ pmidlookup?view=long& pmid=18218832)butyl-guanidine methanesulfonate (552-02), a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease"]. J. Pharmacol. Exp. Ther. 325 (1): 7788. doi:10.1124/jpet.107.130443. PMID18218832. . [6] "Sodium channel blockers for cystic fibrosis" (http:/ / www. cochrane. org/ reviews/ en/ ab005087. html). . [7] Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT (April 2007). "Sodium channel blockade may contribute to the analgesic efficacy of antidepressants" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S1526-5900(06)01120-5). J Pain 8 (4): 31524. doi:10.1016/j.jpain.2006.10.001. PMID17175203. .
Beta blocker
179
Beta blocker
Beta blockers
Drug class
Skeletal formula of propranolol, the first clinically successful beta blocker ATC code MeSH AHFS/Drugs.com Consumer Reports WebMD Biological target C07 D000319 [1] [2] [3] rxlist [5]
list of generics best-buy-drugs medicinenet
[4]
beta receptors
Beta blockers (sometimes written as -blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction[6] (heart attack), and hypertension.[7] As beta adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. In 1958 the first beta blocker, dichloroisoproterenol, was synthesised by Eli Lilly Laboratories,[8] but it was Sir James W. Black in 1962,[9] who found the first clinically significant use of beta blockers with propranolol and pronethalol; it revolutionized the medical management of angina pectoris[10] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.[11] Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular, on -adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response.[12] [13] There are three known types of beta receptor, designated 1, 2 and 3 receptors.[14] 1-adrenergic receptors are located mainly in the heart and in the kidneys.[13] 2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.[13] 3-adrenergic receptors are located in fat cells.[15]
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Medical uses
Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below. Indications for beta blockers include: Angina pectoris Atrial fibrillation Cardiac arrhythmia Congestive heart failure Essential tremor Glaucoma Hypertension Migraine prophylaxis Mitral valve prolapse Myocardial infarction Phaeochromocytoma, in conjunction with -blocker Postural orthostatic tachycardia syndrome
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism Beta blockers have also been used in the following conditions: Acute aortic dissection Hypertrophic obstructive cardiomyopathy Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications) Prevention of variceal bleeding in portal hypertension Possible mitigation of hyperhidrosis Social anxiety disorder and other anxiety disorders
Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their efficacy at reducing morbidity and mortality in congestive heart failure.[16] [17] [18] Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure. Beta blockers are primarily known for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure . Beta blockers, in addition to their sympatholytic B1 activity in the heart, influence the renin/angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduce the heart oxygen demand by lowering extracellular volume and increasing the oxygen carrying capacity of blood. Beta blockers sympatholytic activity reduce heart rate, thereby increasing the ejection fraction of the heart despite an initial reduction in ejection fraction. Trials have shown that beta blockers reduce the absolute risk of death by 4.5% over a 13 month period. As well as reducing the risk of mortality, the number of hospital visits and hospitalizations were also reduced in the trials.[19]
Anxiety and performance enhancement

There is clear evidence from many controlled trials in the past 25 years that beta blockers are effective in anxiety disorders, though the mechanism of action is not known.[20] Some people have used beta blockers for performance enhancement, and especially to combat performance anxiety. In particular, musicians, public speakers, actors, and professional dancers, have been known to use beta blockers to avoid stage fright and tremor during public performance and especially auditions.
Beta blocker The application to stage fright was first recognized in The Lancet in 1976 and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed that 27 percent of its musicians had used beta blockers and that 70 percent obtained them from friends, not physicians.[21] Beta blockers are inexpensive, said to be relatively safe and, on one hand, seem to improve musicians performances on a technical level while some say the performance may be perceived as "soulless and inauthentic".[21] The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. Stutterers also use beta blockers to avoid fight/flight responses, hence reducing the tendency to stutter. Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.[22] Since they promote a lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC).[23] Although they have no recognisable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting. A recent, high-profile transgression took place in the 2008 Summer Olympics, where 50 metre pistol silver medallist and 10 metre air pistol bronze medallist Kim Jong-su tested positive for propranolol and was stripped of his medal.
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Preventing PTSD
Posttraumatic stress disorder (PTSD) is theorized to be the result of neurological patterns caused by adrenaline and fear in the brain. By administering beta blockers immediately following a traumatic event, as well as over the next couple weeks, the formation of PTSD has been reduced in clinical studies.
Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhoea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed 1/-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.[24] Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility (listed below). Adverse effects associated with 2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with 1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia. Hypoglycemia can occur with beta-blockade because 2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking 2-adrenoceptors lowers plasma glucose. 1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta-blockers are to be used cautiously in diabetics. [25] A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes while ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[26] Clinical guidelines in Great Britain, but not in the United States, call for avoiding
Beta blocker diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.[27] Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha adrenergic system stimulation unopposed.[28] The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like furosemide and alpha blockers like phentolamine.[28]
182
Contraindications
They are contraindicative to patients with asthma as stated in the BNF 2011. Beta blockers should also be avoided in patients with history of cocaine use or in cocaine-induced tachycardia or MI.
Toxicity
Glucagon has been used in the treatment of overdose.[29] [30] Glucagon has a positive inotropic action on the heart and decreases renal vascular resistance. It is therefore useful in patients with beta-blocker cardiotoxicity. Glucagon is the specific antidote for beta-blocker poisoning, because it increases intracellular cAMP and cardiac contractility. [31] [32] Cardiac pacing should be reserved for patients unresponsive to pharmacological therapy. Patients who experience bronchospasm due to the B2 blocking effects of non-selective beta-blockers may be treated with anticholinergic drugs such as Ipratropium, which are safer than beta agonists in patients with cardiovascular disease.
-Receptor antagonism
Stimulation of 1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity.[33] Stimulation of 1 receptors on the kidney causes renin release.[34] Stimulation of 2 receptors induces smooth muscle relaxation,[35] induces tremor in skeletal muscle,[36] and increases glycogenolysis in the liver and skeletal muscle.[37] Stimulation of 3 receptors induces lipolysis.[38]
Beta blockers inhibit these normal epinephrine-mediated sympathetic actions,[12] but have minimal effect on resting subjects. That is, they reduce excitement/physical exertion on heart rate and force of contraction,[39] and also tremor[40] and breakdown of glycogen, but increase dilation of blood vessels[41] and constriction of bronchi.[42] It is therefore expected that non-selective beta blockers have an antihypertensive effect.[43] The primary antihypertensive mechanism of betablockers is unclear but it may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[44] It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those -blockers that do cross the blood-brain barrier, e.g. Propranolol). Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states. The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade. Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention.
Beta blocker
183
Intrinsic sympathomimetic activity

Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound such as norepinephrine). See partial agonist for a more general description. Some beta blockers (e.g. oxprenolol, pindolol, penbutolol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the -adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy. Agents with ISA are not used in post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.[24]
1-Receptor antagonism
Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both - and 1-adrenergic receptors, which provides additional arteriolar vasodilating action.
Other effects
Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents.[45] They can also be used to treat glaucoma because they decrease intraocular pressure by lowering aqueous humor secretion.[46]
Examples of beta blockers

Non-selective agents
Alprenolol Bucindolol Carteolol Carvedilol (has additional -blocking activity)
Labetalol (has additional -blocking activity) Nadolol

Dichloroisoprenaline, the first beta blocker.
Oxprenolol Penbutolol (has intrinsic sympathomimetic activity) Pindolol (has intrinsic sympathomimetic activity) Propranolol Sotalol Timolol Eucommia bark (herb)
Beta blocker
184
1-Selective agents
Acebutolol (has intrinsic sympathomimetic activity) Atenolol Betaxolol Bisoprolol Celiprolol Esmolol[47] Metoprolol Nebivolol
2-Selective agents
Butaxamine (weak -adrenergic agonist activity) - No common clinical applications, but used in experiments. ICI-118,551 Highly selective 2-adrenergic receptor antagonist - No known clinical applications, but used in experiments due to its strong receptor specificity.
3-Selective agents
SR 59230A (has additional -blocking activity) - Used in experiments.
Comparative information
Pharmacological differences
Agents with intrinsic sympathomimetic action (ISA) Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol, labetalol. Agents with greater aqueous solubility (hydrophilic beta blockers) Atenolol, celiprolol, nadolol, sotalol Agents with membrane stabilizing effect Acebutolol, betaxolol, pindolol, propranolol Agents with antioxidant effect Carvedilol, nebivolol
Indication differences
Agents specifically indicated for cardiac arrhythmia Esmolol, sotalol, landiolol Agents specifically indicated for congestive heart failure Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol Agents specifically indicated for glaucoma Betaxolol, carteolol, levobunolol, metipranolol, timolol Agents specifically indicated for myocardial infarction Atenolol, metoprolol, propranolol Agents specifically indicated for migraine prophylaxis Timolol, propranolol Propranolol is the only agent indicated for control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with -blocker therapy in phaeochromocytoma.[24]
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185
References
[1] [2] [3] [4] [5] [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D000319 http:/ / www. drugs. com/ drug-class/ cardioselective-beta-blockers. html http:/ / www. consumerreports. org/ health/ best-buy-drugs/ beta_blockers. htm http:/ / www. medicinenet. com/ beta_blockers/ article. htm http:/ / www. rxlist. com/ script/ main/ art. asp?articlekey=90349 Freemantle N, Cleland J, Young P, Mason J, Harrison J (June 1999). "beta Blockade after myocardial infarction: systematic review and meta regression analysis" (http:/ / bmj. com/ cgi/ pmidlookup?view=long& pmid=10381708). BMJ 318 (7200): 17307. PMC31101. PMID10381708. . Retrieved 2010-09-06. [7] Cruickshank JM (August 2010). "Beta blockers in hypertension" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0140-6736(10)61217-2). Lancet 376 (9739): 415; author reply 4156. doi:10.1016/S0140-6736(10)61217-2. PMID20692524. . Retrieved 2010-09-06. [8] [ |William H. Frishman (http:/ / www. nymc. edu/ People/ William. H. Frishman/ index. html)] (2008-12). "Fifty years of beta-blockers: a revolution in CV pharmacotherapy" (http:/ / www. cardiologytoday. com/ view. aspx?rid=33841). Cardiology Today. . Retrieved 2010-09-06. [9] "Sir James Black inventor of beta-blockers passes away" (http:/ / www. news-medical. net/ news/ 20100323/ Sir-James-Black-inventor-of-beta-blockers-passes-away. aspx). . Retrieved 2010-09-06. [10] van der Vring JA (June 1999). "Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN)" (http:/ / ang. sagepub. com/ cgi/ pmidlookup?view=long& pmid=10378820). Angiology 50 (6): 447454. doi:10.1177/000331979905000602. PMID10378820. . Retrieved 2010-09-06. [11] Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 24 (4): 33642. PMC325477. PMID9456487. [12] Frishman W.H.; Cheng-Lai A, Nawarskas J (2005). Current Cardiovascular Drugs (http:/ / books. google. com/ ?id=y3R1Vd3NHqcC& pg=PA152& dq=mode+ of+ action+ of+ beta+ blockers#v=onepage& q=mode of action of beta blockers& f=false). Current Science Group. pp.152. ISBN9781573402217. . Retrieved 2010-09-07. [13] Arcangelo V.P.; Peterson A.M. (2006). Pharmacotherapeutics for advanced practice: a practical approach (http:/ / books. google. com/ ?id=EaP1yJz4fkEC& pg=PA205& dq=beta+ receptors+ heart+ kidneys#v=onepage& q=beta receptors heart kidneys& f=false). Lippincott Williams & Wilkins. pp.205. ISBN9780781757843. . Retrieved 2010-09-07. [14] Frishman W.H.; Cheng-Lai A, Nawarskas J (2005). Current Cardiovascular Drugs (http:/ / books. google. com/ ?id=y3R1Vd3NHqcC& pg=PA152& dq=mode+ of+ action+ of+ beta+ blockers#v=onepage& q=mode of action of beta blockers& f=false). Current Science Group. pp.153. ISBN9781573402217. . Retrieved 2010-09-07. [15] Clment K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J, Silver KD, Shuldiner AR, Froguel P, Strosberg AD (August 1995). "Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity" (http:/ / www. nejm. org/ doi/ abs/ 10. 1056/ NEJM199508103330605). The New England Journal of Medicine 333 (6): 352354. doi:10.1056/NEJM199508103330605. PMID7609752. . Retrieved 2010-09-07. [16] Hjalmarson A, Goldstein S, Fagerberg B et al. (2000). "Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group". JAMA 283 (10): 12951302. doi:10.1001/jama.283.10.1295. PMID10714728. [17] Leizorovicz A, Lechat P, Cucherat M, Bugnard F (2002). "Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies--CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study". Am. Heart J. 143 (2): 301307. doi:10.1067/mhj.2002.120768. PMID11835035. [18] Packer M, Fowler MB, Roecker EB et al. (2002). "Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study". Circulation 106 (17): 21942199. doi:10.1161/01.CIR.0000035653.72855.BF. PMID12390947. [19] Pritchett AM, Redfield MM (2002). "Beta-blockers: new standard therapy for heart failure" (http:/ / www. mayoclinicproceedings. com/ pdf/ 7708/ 7708crc. pdf) (PDF). Mayo Clin. Proc. 77 (8): 839846. doi:10.4065/77.8.839. PMID12173717. . [20] Tryer, Peter. " Anxiolytics not acting at the benzodiazepine receptor: Beta blockers (http:/ / www. sciencedirect. com/ science?_ob=ArticleURL& _udi=B6TBR-475CCDF-5X& _user=10& _coverDate=01/ 31/ 1992& _rdoc=1& _fmt=high& _orig=search& _sort=d& _docanchor=& view=c& _searchStrId=1382141997& _rerunOrigin=scholar. google& _acct=C000050221& _version=1& _urlVersion=0& _userid=10& md5=682ddf55de00bfe80c38a06df8dccdb3)." Progress in Neuro-Psychopharmacology and Biological Psychiatry. Volume 16, Issue 1, January 1992, Pages 17-26. [21] Blair Tindall. " Better Playing Through Chemistry (http:/ / www. nytimes. com/ 2004/ 10/ 17/ arts/ music/ 17tind. html?_r=1)", The New York Times, 17 October 2004. Retrieved 3 July 2011. [22] Schneier FR (2006). "Clinical practice. Social anxiety disorder". N. Engl. J. Med. 355 (10): 10291036. doi:10.1056/NEJMcp060145. PMID16957148. [23] World Anti-Doping Agency (2005-09-19). "The Worl Anti-Doping Code: The 2006 Prohibited List International Standard" (http:/ / multimedia. olympic. org/ pdf/ en_report_1037. pdf). World Anti-Doping Agency. . Retrieved 2006-12-13. [24] Editor Rossi S, ed (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook.
Beta blocker
[25] Beta-Adrenoceptor Antagonists (Beta-Blockers); http:/ / www. cvpharmacology. com/ cardioinhibitory/ beta-blockers. htm [26] Elliott WJ, Meyer PM (2007). "Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis". Lancet 369 (9557): 201207. doi:10.1016/S0140-6736(07)60108-1. PMID17240286. [27] Mayor S (2006). "NICE removes beta blockers as first line treatment for hypertension" (http:/ / www. bmj. com/ cgi/ content/ full/ 333/ 7557/ 8-a). BMJ 333 (7557): 88. doi:10.1136/bmj.333.7557.8-a. PMC1488775. PMID16809680. . [28] eMedicine - Toxicity, Cocaine : Article by Carlos J Roldan (http:/ / www. emedicine. com/ med/ topic400. htm) [29] Weinstein RS, Cole S, Knaster HB, Dahlbert T (February 1985). "Beta blocker overdose with propranolol and with atenolol" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0196-0644(85)81081-7). Ann Emerg Med 14 (2): 161163. doi:10.1016/S0196-0644(85)81081-7. PMID2857542. . [30] "Toxicity, Beta-blocker: Treatment & Medication - eMedicine Emergency Medicine" (http:/ / emedicine. medscape. com/ article/ 813342-treatment). . Retrieved 2009-03-06. [31] Beta-Adrenergic Blocker Poisoning; http:/ / www. courses. ahc. umn. edu/ pharmacy/ 6124/ handouts/ Beta%20blockers. pdf [32] USMLE WORLD 2009 Step1, Pharmacology, Q85 [33] [ |Perez, Dianne M. (http:/ / www. lerner. ccf. org/ moleccard/ perez/ )] (2006). The Adrenergic Receptors In the 21st Century (http:/ / books. google. com/ ?id=QNpIsKwp8PUC& pg=PA135& dq=1+ receptors+ positive+ chronotropic+ inotropic+ effect#v=onepage& q=1 receptors positive chronotropic inotropic effect& f=false). Humana Press Inc.. p.135. ISBN1588294234. . Retrieved 2010-09-08. [34] [ |Jameson, J. Larry (http:/ / www. jamesonlab. northwestern. edu/ )]; [ |Loscalzo, Joseph (http:/ / www. hms. harvard. edu/ dms/ bbs/ fac/ loscalzo. html)] (2010). Harrison's Nephrology and Acid-Base Disorders (http:/ / books. google. com/ ?id=zVQZpJnQM_AC& pg=PA215& dq=1+ receptors+ kidneys+ renin#v=onepage& q& f=false). McGraw-Hill Companies, Inc.. p.215. ISBN0071663398. . Retrieved 2010-09-08. [35] [ |O'Donnell, John M. (http:/ / www. lahey. org/ physdir/ Detail. asp?ID=592)]; Ncul, Flvio E. (2009). Surgical Intensive Care Medicine (http:/ / books. google. com/ ?id=Bih5AXq_0uMC& pg=PA47& dq=b2+ receptors+ smooth+ muscle+ relaxation#v=onepage& q=b2 receptors smooth muscle relaxation& f=false). Springer. p.47. ISBN0387778926. . Retrieved 2010-09-08. [36] Ahrens RC (1990). "Skeletal muscle tremor and the influence of adrenergic drugs". The Journal of Asthma : Official Journal of the Association for the Care of Asthma 27 (1): 1120. PMID1968452. [37] Reents, Stan (2000). Sport and exercise pharmacology (http:/ / books. google. com/ ?id=8ysOZlGnkC0C& pg=PA19& dq=beta+ blocker+ stimulation+ glycogenolysis#v=onepage& q=beta blocker stimulation glycogenolysis& f=false). Human Kinetics. p.19. ISBN0873229371. . Retrieved 2010-09-10. [38] Martini, Frederic H. (2005). Anatomy and Physiology (http:/ / books. google. com/ ?id=0e08PrEMQJoC& pg=PA394& dq=beta+ 3+ stimulating+ lipolysis#v=onepage& q=beta 3 stimulating lipolysis& f=false). Pearson Education. p.394. ISBN0805359478. . Retrieved 2010-09-10. [39] Khan, M. I. Gabriel (2006). Encyclopedia of Heart Diseases (http:/ / books. google. com/ ?id=xco9aJ_Y9XIC& pg=PA160& dq=beta+ blockers+ effects+ on+ heart+ rate#v=onepage& q=beta blockers effects on heart rate& f=false). Elsevier. p.160. ISBN0124060616. . Retrieved 2010-09-10. [40] Lamster, Ira B.; [ |Northridge, Mary E. (http:/ / www. minority. unc. edu/ sph/ minconf/ 2004/ keynote. htm)], eds (2008). Improving Oral Health for the Elderly: An Interdisciplinary Approach (http:/ / books. google. com/ ?id=qs2v9Sm-dVoC& pg=PA87& dq=beta+ blockers+ reduce+ tremor#v=onepage& q=beta blockers reduce tremor& f=false). New York: Springer. p.87. ISBN9780387743370. . Retrieved 2010-10-23. [41] Manger, William Muir; Gifford, Ray Wallace (2001). 100 Questions and Answers about Hypertension (http:/ / books. google. com/ ?id=DYFlmMeIVrIC& pg=PA106& dq=beta+ blockers+ dilation+ of+ blood+ vessels#v=onepage& q=beta blockers dilation of blood vessels& f=false). Blackwell Science. p.106. ISBN0632044810. . Retrieved 2010-09-10. [42] Rothfeld, Glenn S.; Romaine, Deborah S. (2005). The Encyclopedia of Men's Health (http:/ / books. google. com/ ?id=AyPacn1o4nIC& pg=PA48& dq=beta+ blockers+ opening+ of+ bronchi#v=onepage& q& f=false). Amaranth. p.48. ISBN0816051771. . Retrieved 2010-10-23. [43] [ |Hurst, J.W. (http:/ / www. emoryhealthcare. org/ heart-center-atlanta/ history/ j-willis-hurst. html)] (1997). Schlant, Robert C.. ed. Hurst's the Heart (http:/ / books. google. com/ ?id=eWQAJDrVV7gC& pg=PA1564& dq=beta+ blockers+ antihypertensive#v=onepage& q=beta blockers antihypertensive& f=false). 2. Blackwell Science.. p.1564. ISBN007912951X. . Retrieved 2010-10-07. [44] Reid, J.L. (2001). Lecture notes on clinical pharmacology (http:/ / books. google. com/ ?id=dsEmlotDt2wC& pg=PA76& dq=beta+ blockers+ antihypertensive+ effect+ reduction+ of+ cardiac+ output#v=onepage& q=beta blockers antihypertensive effect reduction of cardiac output& f=false). 6. Blackwell Science.. p.76. ISBN0632050772. . Retrieved 2011-03-11. [45] Stoschitzky K, Sakotnik A, Lercher P et al. (1999). "Influence of beta-blockers on melatonin release". Eur. J. Clin. Pharmacol. 55 (2): 111115. doi:10.1007/s002280050604. PMID10335905. [46] Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. pp.15. ISBN1-59541-101-1. [47] Umehara S, Goyagi T, Nishikawa T, Tobe Y, Masaki Y (2010). "Esmolol and landiolol, selective beta1-adrenoreceptor antagonists, provide neuroprotection against spinal cord ischemia and reperfusion in rats" (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 20103544). Anesthesia and Analgesia 21 (3): 11337. doi:10.1213/ANE.0b013e3181cdb06b. PMID20103544. .
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External links
Musicians and beta-blockers (http://musiciansway.com/blog/?p=1656) by Gerald Klickstein, March 11, 2010 (A blog post that considers "whether beta-blockers are safe, effective, and appropriate for performers to use.") Better Playing Through Chemistry (http://www.nytimes.com/2004/10/17/arts/music/17tind.html) by Blair Tindall, New York Times, October 17, 2004. (Discusses the use of beta blockers among professional musicians) Musicians using beta blockers (http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2004/10/17/ MNGB599PJC1.DTL) by Blair Tindall. Condensed version of above article. In Defense of the Beta Blocker (http://www.theatlantic.com/doc/200808u/beta-blockers) by Carl Elliott, The Atlantic, August 20, 2008. (Discusses the use of propranolol by a North Korean pistol shooter in the 2008 Olympics) MeSH beta-Adrenergic+Blockers (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=& term=beta-Adrenergic+Blockers)
Potassium channel blocker

Potassium channel blockers are agents which interfere with conduction through potassium channels.
Arrhythmia
Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents.
Mechanism
Class III agents predominantly block the potassium channels, thereby prolonging [1] repolarization. More specifically, their primary effect is on IKr.[2]
Effect of class III antiarrhythmic agent on cardiac action potential.
Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). Class III antiarrhythmic agents exhibit reverse use dependent prolongation of the action potential duration (Reverse use-dependence). This means that the refractoriness of the ventricular myocyte increases at lower heart rates. This increases the susceptibility of the myocardium to early after-depolarizations (EADs) at low heart rates. Antiarrhythmic agents that exhibit reverse use-dependence are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm. Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.
Potassium channel blocker
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Examples and uses

Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. Amiodarone prolongation of the action potential is uniform over a wide range of heart rates so this drug does not have reverse use-dependent action. Amiodarone was the first agent described in this class.[3] Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated. FDA MedWatch http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ ucm084108.htm Dofetilide blocks only the rapid K channels; this means that at higher heart rates, when there is increased involvement of the slow K channels, dofetilide has less of an action potential-prolonging effect. Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias. Ibutilide is the only antiarrhythmic agent currently approved by the Food and Drug Administration for acute conversion of atrial fibrillation to sinus rhythm. Azimilide Bretylium Clofilium E-4031 Nifekalant[4] Tedisamil Sematilide Ampyra (recently approved for MS)
Side effects
These agents include a risk of torsades de pointes.[5]
Other uses
Potassium channel blockers have also been approved for use in the treatment of multiple sclerosis.[6]
References
[1] Lenz TL, Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy 20 (7): 77686. doi:10.1592/phco.20.9.776.35208. PMID10907968. [2] Riera AR, Uchida AH, Ferreira C, et al. (2008). "Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome". Cardiol J 15 (3): 20919. PMID18651412. [3] "Milestones in the Evolution of the Study of Arrhythmias" (http:/ / www. medscape. com/ viewarticle/ 412798_3). . [4] Sahara M, Sagara K, Yamashita T, Iinuma H, Fu LT, Watanabe H (August 2003). "Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach" (http:/ / www. jstage. jst. go. jp/ article/ circj/ 67/ 8/ 67_712/ _article/ -char/ en). Circ. J. 67 (8): 7124. doi:10.1253/circj.67.712. PMID12890916. . [5] "Introduction: Arrhythmias and Conduction Disorders: Merck Manual Professional" (http:/ / www. merck. com/ mmpe/ sec07/ ch075/ ch075a. html). . [6] Judge SI, Bever CT (July 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0163-7258(05)00228-7). Pharmacol. Ther. 111 (1): 22459. doi:10.1016/j.pharmthera.2005.10.006. PMID16472864. .
189

A calcium channel blocker (CCB) is a chemical that disrupts the movement of calcium (Ca2+) through calcium channels.[1] CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with hypertension. CCBs are particularly efficacious in treating elderly patients.[2] Calcium channel blockers are also frequently used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris. Despite their effectiveness, CCB's often have a high mortality rate over an extended dosage peroid, and have been known to have a high amount of side effects.
Mechanism of action
Calcium channel blockers work by blocking voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels. This decreases intracellular calcium leading to a reduction in muscle contraction. In the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in arterial diameter (CCBs do not work on venous smooth muscle), a phenomenon called vasodilation. Vasodilation decreases total peripheral resistance, while a decrease in cardiac contractility decreases cardiac output. Since blood pressure is determined by cardiac output and peripheral resistance, blood pressure drops. Calcium channel blockers are especially effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.[2] With a relatively low blood pressure, the afterload on the heart decreases; this decreases how hard the heart must work to eject blood into the aorta, and so the amount of oxygen required by the heart decreases accordingly. This can help ameliorate symptoms of ischemic heart disease such as angina pectoris. Unlike beta blockers, calcium channel blockers do not decrease the responsiveness of the heart to input from the sympathetic nervous system. Since moment-to-moment blood pressure regulation is carried out by the sympathetic nervous system (via the baroreceptor reflex), calcium channel blockers allow blood pressure to be maintained more effectively than do beta blockers. However, because calcium channel blockers result in a decrease in blood pressure, the baroreceptor reflex often initiates a reflexive increase in sympathetic activity leading to increased heart rate and contractility. A beta blocker may be combined with a dihydropyridine calcium channel blocker to minimize these effects. Ionic calcium is antagonized by magnesium ions in the nervous system. Because of this, bioavailable supplements of magnesium, possibly including magnesium chloride, magnesium lactate and magnesium aspartate, may increase or enhance the effects of calcium channel blockade.[3]
Cardiovascular action
The calcium channel blockers known as non-dihydropyridines decrease the force of contraction of the myocardium (muscle of the heart). This is known as the negative inotropic effect of calcium channel blockers. It is because of these negative inotropic effects that the nondihydropyridine calcium channel blockers, such as verapamil or diltiazem, may be avoided (or used with caution) in individuals with cardiomyopathy.[4] Many calcium channel blockers also slow down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart (see: cardiac action potential). This results in a negative chronotropic effect, or a lowering of heart rate. This can increase the potential for heart block. The negative chronotropic effects of calcium channel blockers make them a commonly used class of agents in individuals with atrial fibrillation or flutter in whom control of the heart rate is generally a goal. Negative chronotropy can be beneficial when treating a variety of disease processes because lower heart rates represent lower
Calcium channel blocker cardiac oxygen requirements. Elevated heart rate can result in significantly higher 'cardiac work', which can result in symptoms of angina.
190
Classes
Dihydropyridine
Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina (with the exception of amlodipine, nicardipine, and nifedipine, which carry an indication to treat chronic stable angina as well as vasospastic angina) because the vasodilation and hypotension can lead to reflex tachycardia. Dihydropiridine calcium channel blockers can worsen proteinuria in patients with nephropathy.[5] This CCB class is easily identified by the suffix "-dipine". Amlodipine (Norvasc) Aranidipine (Sapresta) Azelnidipine (Calblock) Barnidipine (HypoCa) Benidipine (Coniel) Cilnidipine (Atelec, Cinalong, Siscard) Clevidipine (Cleviprex) Isradipine (DynaCirc, Prescal) Efonidipine (Landel) Felodipine (Plendil) Lacidipine (Motens, Lacipil) Lercanidipine (Zanidip) Manidipine (Calslot, Madipine) Nicardipine (Cardene, Carden SR) Nifedipine (Procardia, Adalat) Nilvadipine (Nivadil) Nimodipine (Nimotop) Nisoldipine (Baymycard, Sular, Syscor) Nitrendipine (Cardif, Nitrepin, Baylotensin) Pranidipine (Acalas)
Side effects of these drugs may include but are not limited to: Dizziness, headache, redness in the face Fluid buildup in the legs Rapid heart rate. Slow heart rate. Constipation Gingival overgrowth Ankle edema
191
Non-dihydropyridine
Phenylalkylamine Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Therefore, as vasodilation is Skeletal formula of verapamil minimal with the phenylalkylamines, the major mechanism of action is causing negative inotropy. Phenylalkylamines are thought to access calcium channels from the intracellular side, although the evidence is somewhat mixed.[6] Verapamil (Calan, Isoptin) Benzothiazepine Benzothiazepine calcium channel blockers are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. Diltiazem (Cardizem) Nonselective While most of the agents listed above are relatively selective, there are additional agents that are considered nonselective. These include mibefradil, bepridil, fluspirilene[7] , and fendiline.[8]
Toxicity
Structural formula of diltiazem
Mild CCB toxicity is treated with supportive care. Non-dihydropyridine CCB may produce profound toxicity and early decontamination, especially for slow release agents, is essential. Treatment involves intravenous calcium, atropine, fluids, insulin and inotropes. Insulin is required because at high doses CCB block the effect of insulin. If unsuccessful ventricular pacing should be used.[9]
192
References
[1] " calcium channel blocker (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ nine/ 20112461. htm)" at Dorland's Medical Dictionary [2] Nelson, Mark. "Drug treatment of elevated blood pressure" (http:/ / www. australianprescriber. com/ magazine/ 33/ 4/ 108/ 12). Australian Prescriber (33): 108112. . Retrieved August 11, 2010. [3] 1. Iseri LT & French JH. Magnesium: natures physiologic calcium blocker. Am Heart J, 108, 188-193, 1984. [4] Lehne, Richard (2010). Pharmacology for Nursing Care, Seventh Edition. St. Louis, Missouri: Saunders Elsevier. pp.505. ISBN978-1-4160-6249-3. [5] Remuzzi G, Scheppati A, Ruggenenti P: Nephropathy in patients with type 2 diabetes. N Engl J Med 2002;346:1145. [6] Hockerman et al, Annu Rev Pharmacol Toxicol. 1997;37:361-96 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 9131258) [7] Bezprozvanny I, Tsien RW (September 1995). "Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967)" (http:/ / molpharm. aspetjournals. org/ cgi/ pmidlookup?view=long& pmid=7565636). Mol. Pharmacol. 48 (3): 5409. PMID7565636. . [8] Scultty S, Tamskovits E (1991). "Effect of Ca2+ antagonists on isolated rabbit detrusor muscle". Acta Physiol Hung 77 (34): 26978. PMID1755331. [9] Calcium Channel Blockers. Medicine 2007;35:599-602
External links
MeSH Calcium+Channel+Blockers (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=& term=Calcium+Channel+Blockers) Official Adalat (Nifedipine) site, Bayer (http://www.adalat.com) Video - Calcium Channel Blockers (http://video.google.ca/videoplay?docid=-903705890888345607)
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Type Ia Antiarrythmics
Procainamide
Procainamide
Systematic (IUPAC) name
4-amino-N-(2-diethylaminoethyl) benzamide
Clinical data AHFS/Drugs.com monograph [1] Pregnancy cat. Legal status Routes C(US) POM (UK) IV, IM, oral Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion 85% (oral) 15 to 20% Hepatic (CYP2D6-mediated) ~2.5 to 4.5 hours Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 51-06-9
[2] [3]
C01 BA02 CID 4913
[4] [5]
APRD00509 4744
[6]
L39WTC366D D08421
[8]
[7]
CHEBI:8428
[9]
CHEMBL640 Chemical data
[10]
Formula Mol. mass
C H NO
13 21 3
235.325 g/mol
Procainamide
[11] [12]
194
SMILES
eMolecules
& PubChem
[13]
(what is this?) (verify)
Procainamide INN ( /prokenmad/; trade names Pronestyl, Procan, Procanbid) is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.
History
Procainamide was approved by the US FDA on June 2, 1950, under the brand-name Pronestyl[14] . It was launched by Squibb in 1951.[15]
Mechanism
It blocks open sodium (Na+) channels and prolongs the cardiac action potential (outward potassium (K+) currents may be blocked). This results in slowed conduction, and ultimately the decreased rate of rise of the action potential, which may result in widening of QRS on electrocardiogram (ECG).
Uses
This drug is used for both supraventricular and ventricular arrhythmias. For example, it can be used to convert new-onset atrial fibrillation, though it is suboptimal for this purpose. It can also be used to treat Wolf-Parkinson-White syndrome by prolonging the refractory period of the accessory pathway. Typically use is secondary to lidocaine in patients who are allergic to lidocaine or dysrhythmias that are refractory to lidocaine.
Administration
Procainamide is administered intravenously or orally. When administered intravenously, a loading dose should first be given, though care should be taken not to cause hypotension. Procainamide's major active metabolite is N-acetyl procainamide (NAPA), which is approximately equipotent with the parent drug as an antiarrhythmic agent.[16] NAPA has an elimination half-life about twice that of procainamide, and it can reach somewhat higher plasma levels during chronic procainamide administration.[17] Loading dose is 100mg IV bolus given slowly over 5 minutes. Max dose is 17mg/kg. Use is discontinued when dysrhythmia is suppressed, or if hypotension ensues, QRS complex widens by 50% or more, or maximum dose is achieved.
Side effects
Adverse effects include rash, myalgia, hypersensitivity reactions (fever, agranulocytosis), Drug-Induced Lupus Erythematosus[18] (particularly in slow-acetylators), and proarrhythmic effects (e.g., torsades de pointes). Treatment with procainamide can cause antibody production against cellular components, accounting for the systemic lupus erythematosus-like adverse reactions.
External links
PubPK - Procainamide [19]
Procainamide
195
References
[1] http:/ / www. drugs. com/ monograph/ procainamide-hydrochloride. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=51-06-9& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BA02 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4913 [5] http:/ / www. drugbank. ca/ drugs/ APRD00509 [6] http:/ / www. chemspider. com/ Chemical-Structure. 4744 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=L39WTC366D [8] http:/ / www. kegg. jp/ entry/ D08421 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:8428 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL640 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28c1ccc%28N%29cc1%29NCCN%28CC%29CC [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28c1ccc%28N%29cc1%29NCCN%28CC%29CC [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=464214863& page2=%3AProcainamide [14] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm [15] Hollman A (February 1992). "Procaine and procainamide". Br Heart J 67 (2): 143. doi:10.1136/hrt.67.2.143. PMC1024743. PMID18610401. [16] Dutcher JS, Strong JM, Lucas SV, Lee WK, Atkinson AJ Jr. Procainamide and N-acetylprocainamide kinetics investigated simultaneously with stable isotope methodology. Clin Pharmacol Ther. 1977 Oct;22(4):447-57. [17] Drayer DE, Reidenberg MM, Sevy RW. N-acetylprocainamide: an active metabolite of procainamide. Proc Soc Exp Biol Med. 1974 Jun;146(2):358-63. [18] Kameda H, Mimori T, Kaburaki J, et al. (November 1998). "Systemic sclerosis complicated by procainamide-induced lupus and antiphospholipid syndrome" (http:/ / rheumatology. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=9851277). Br. J. Rheumatol. 37 (11): 12369. doi:10.1093/rheumatology/37.11.1236. PMID9851277. . [19] http:/ / www. pubpk. org/ index. php?title=Procainamide
Quinidine
196
Quinidine
Quinidine
(9S)-6'-methoxycinchonan- 9-ol
Clinical data AHFS/Drugs.com monograph [1] Pregnancy cat. Legal status Routes ? ? Oral Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 70-80% 50-90% Hepatic 6-8h Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII ChEBI ChEMBL Synonyms 56-54-2
[2] [3] [4] [5]
C01 BA01
CID 441074 APRD00136 389880

[6]
ITX08688JL
[7]
CHEBI:28593 CHEMBL97
[8]
[9]
(2-ethenyl- 4-azabicyclo [2.2.2] oct- 5-yl)- (6-methoxyquinolin- 4-yl)- methanol,
Quinidine
197
Chemical data Formula Mol. mass SMILES C20H24N2O2 324.417 g/mol eMolecules
[10]
& PubChem
[11]
[12]
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent (Ia) in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.
Mechanism
Like all other class I antiarrhythmic agents, quinidine primarily works by blocking the fast inward sodium current (INa). Quinidine's effect on INa is known as a use dependent block. This means that at higher heart rates, the block increases, while at lower heart rates the block decreases. The effect of blocking the fast inward sodium current causes the phase 0 depolarization of the cardiac action potential to decrease (decreased Vmax). Quinidine also blocks the slowly inactivating tetrodotoxin-sensitive Na current, the slow inward calcium current (ICa), the rapid (IKr) and slow (IKs) components of the delayed potassium rectifier current, the inward potassium rectifier current (IKI), the ATP-sensitive potassium channel (IKATP) and Ito. At micromolar concentrations, quinidine inhibits Na/K-ATPase by binding to the same receptor sites as the digitalis glycosides such as ouabain. The effect of quinidine on the ion channels is to prolong the cardiac action potential, thereby prolonging the QT interval on the surface ECG. Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. These are the results of both slowed depolarization and repolarization.
History
The effects of cinchona bark (the botanical source from which quinidine is extracted) had been commented on long before our understanding of cardiac physiology arose. Jean-Baptiste de Snac, in his 1749 work on the anatomy, function, and diseases of the heart, had this to say, "Long and rebellious palpitations have ceded to this febrifuge". [13] "Of all the stomachic remedies, the one whose effects have appeared to me the most constant and the most prompt in many cases is quinquina [Peruvian bark] mixed with a little rhubarb."[14] Snac subsequently became physician to Louis XV of France, a counselor of the state, and superintendent of the mineral waters and medicinals in France. As a result of his influence, throughout the nineteenth century quinine was used to augment digitalis therapy. It was described as "das opium des herzens" (the opium of the heart). But the use of quinidine to treat arrhythmias really only came into its own because a physician listen to the astute observation of one of his patients. In 1912, Karel Frederik Wenckebach saw a man with atrial fibrillation. He was a Dutch merchant, used to good order in his affairs. He would like to have good order in his heart business also and asked "why there were heart specialists if they could not abolish this very disagreeable phenomenon ... he knew himself how to get rid of his attacks. As I did not believe him he promised to come back next morning with a regular pulse, and he did." The man had found by chance that when he took one gram of quinine during an attack it reliably halted it in 25 minutes: otherwise it would last for 2-14 days. Wenckebach often tried quinine again but he succeeded in only one other patient. [15]
Quinidine He made passing mention of it in his book on cardiac arrhythmias published in 1914. Four years later, Walter von Frey of Berlin reported in a leading Viennese medical journal that quinidine was the most effective of the four principle cinchona alkaloids in controlling atrial arrhythmias. [16]
198
Elimination
The half life of oral quinidine is 6 to 8 hours, and it is eliminated by the cytochrome P450 system in the liver. About 20% is excreted unchanged via the kidneys.
Side effects
Quinidine is also an inhibitor of the cytochrome P450 enzyme 2D6, and can lead to increased blood levels of lidocaine, Beta blockers, opioids, and some anti-depressants. Quinidine also inhibits the transport protein P-glycoprotein and so can cause some peripherally acting drugs such as loperamide to have CNS side effects such as respiratory depression if the two drugs are co-administered.[17] Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes and for that reason is not used much today. Torsades can occur after the first dose. Quinidine-induced thrombocytopenia (low platelet count) is mediated by the immune system, and may lead to thrombocytic purpura. Quinidine intoxication can lead to a collection of symptoms collectively known as cinchonism with tinnitus (ringing in the ears) being among the most characteristic and common symptoms of this toxicity syndrome.
Other uses
Intravenous quinidine is also indicated for treatment of Plasmodium falciparum malaria.[18] However, quinidine is not considered the first line therapy for P. falciparum. The recommended treatments for plasmodium falciparum according to the Toronto Notes 2008 are quinine (not to be confused with "quinidine") + doxycycline combination or atovaquone/proguanil (Malarone TM). Quinidine sulfate is used in the treatment of atrial fibrillation in horses. Quinidine-based ligands are used in AD-mix- for Sharpless asymmetric dihydroxylation.
References
[1] http:/ / www. drugs. com/ monograph/ quinidine-sulfate. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=56-54-2& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BA01 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=441074 [5] http:/ / www. drugbank. ca/ drugs/ APRD00136 [6] http:/ / www. chemspider. com/ Chemical-Structure. 389880 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=ITX08688JL [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:28593 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL97 [10] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%28c4cc1c%28nccc1%5BC%40H%5D%28O%29%5BC%40%40H%5D2N3CC%5BC%40%40H%5D%28C2%29%5BC%40%40H%5D%28%2FC%3DC% [11] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%28c4cc1c%28nccc1%5BC%40H%5D%28O%29%5BC%40%40H%5D2N3CC%5BC%40%40H%5D%28C2%29%5BC%40%40H%5D%28%2FC% [12] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=408381751& page2=%3AQuinidine [13] "Plants in Cardiology: Quinine and Quinidine" (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC1024726/ pdf/ brheartj00046-0041. pdf). . [14] "Jean-Baptiste Senac and His Treatise on the Heart" (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC324686/ pdf/ thij00063-0010. pdf). . [15] "Plants in Cardiology: Quinine and Quinidine" (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC1024726/ pdf/ brheartj00046-0041. pdf). .
Quinidine
[16] Sneader, Walter (Jun 20, 2005). Drug Discovery: A History (http:/ / books. google. com/ books?id=mYQxRY9umjcC& pg=PA95& lpg=PA95& dq=Frey+ Berlin+ quinidine& source=bl& ots=uOG-tmWYga& sig=WiTyEuQ1nwbxKAWGWJCQmCRmCW8& hl=en& ei=TqvdTrujH5T6ggflm5T5BQ& sa=X& oi=book_result& ct=result& resnum=2& ved=0CCMQ6AEwAQ#v=onepage& q=Frey Berlin quinidine& f=false). John Wiley and Sons. p.95. . [17] Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (2000). "Increased drug delivery to the brain by P-glycoprotein inhibition". Clin. Pharmacol. Ther. 68 (3): 2317. doi:10.1067/mcp.2000.109156. PMID11014404. [18] "From the Centers for Disease Control and Prevention. Availability and use of parenteral quinidine gluconate for severe or complicated malaria" (http:/ / jama. ama-assn. org/ cgi/ pmidlookup?view=long& pmid=11236771). JAMA 285 (6): 730. February 2001. doi:10.1001/jama.285.6.730. PMID11236771. .
199
External links
MedlinePlus (http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682396.html) Poisons Information Monograph (http://www.inchem.org/documents/pims/pharm/quinidin.htm)
Disopyramide
200
Disopyramide
Disopyramide
4-(diisopropylamino)-2-phenyl-2-(pyridin-2-yl)butanamide
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Norpace monograph a682408
[2] [1]
B2(AU) C(US) POM (UK) -only (US) Oral, intravenous Pharmacokinetic data
Bioavailability Protein binding Metabolism Half-life Excretion
High 50% to 65% (concentration-dependent) Hepatic (CYP3A4-mediated) 6.7 hours (range 4 to 10 hours) Renal (80%) Identifiers
CAS number ATC code PubChem
3737-09-5 C01 BA03 CID 3114
[3]
[4]
[5]
Disopyramide
[6]
201
DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
APRD00507 3002
[7]
GFO928U8MQ D00303
[9]
[8]
CHEBI:4657
[10]
[11]
Formula Mol. mass SMILES
C21H29N3O 339.475 g/mol eMolecules

[12]
& PubChem
[13]
[14]
Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication. It is a Class Ia antiarrhythmic (sodium channel blocker) used in the treatment of ventricular tachycardias. It has no effect on alpha or beta adrenergic receptors. It resembles quinidine but it has a marked anti-muscarinic effect on the heart, for this reason, it is not considered as a drug of 1st choice. It is also used in ventricular arrhythmia and supraventricular arrhythmia that might follow myocardial infarctions.
Cardiac adverse effects

Acute heart failure[15] Severe hypotension
Extracardiac effects
Dry mouth Constipation Urinary retention Blurred vision Glaucoma Rash Agranulocytosis
Additionally, disopyramide may enhance the hypoglycaemic effect of gliclazide, insulin, and metformin.
Chemistry
U.S. Patent 3225054 [16]
Disopyramide
202
External links
Disopyramide on RxList [17]
References
[1] http:/ / www. drugs. com/ monograph/ disopyramide-phosphate. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682408. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=3737-09-5& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BA03 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3114 [6] http:/ / www. drugbank. ca/ drugs/ APRD00507 [7] http:/ / www. chemspider. com/ Chemical-Structure. 3002 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=GFO928U8MQ [9] http:/ / www. kegg. jp/ entry/ D00303 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:4657 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL517 [12] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28N%29C%28c1ncccc1%29%28c2ccccc2%29CCN%28C%28C%29C%29C%28C%29C [13] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28N%29C%28c1ncccc1%29%28c2ccccc2%29CCN%28C%28C%29C%29C%28C%29C [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=460794639& page2=%3ADisopyramide [15] http:/ / www. zealandpharma. com/ diseases/ Acute-Heart-Failure#top [16] http:/ / www. google. com/ patents?vid=3225054 [17] http:/ / www. rxlist. com/ cgi/ generic2/ disopyr_cp. htm
203
Type Ib Antiarrythmics
Lidocaine
Lidocaine
2-(diethylamino)N-(2,6-dimethylphenyl)acetamide
Clinical data Trade names Xylocaine
AHFS/Drugs.com Micromedex Detailed Consumer Information [1] Pregnancy cat. Legal status Routes A(AU) B(US) Prescription Only (S4) (AU) ? (US) IV, subcutaneous, topical Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 35% (oral) 3% (topical) Hepatic, 90% CYP1A2-mediated 1.52 hours renal Identifiers CAS number 137-58-6 [3] 73-78-9 (hydrochloride) N01 BB02 CID 3676
[4] [2]
ATC code PubChem
C01 BB01
[5]
D04 AB01
[6]
S02 DA01
[7]
C05 AD01
[8]
[9]
Lidocaine
[10]
204
DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Synonyms
DB00281 3548
[11]
98PI200987 D00358
[13]
[12]
CHEBI:6456 CHEMBL79
[14] [15]
N-(2,6-dimethylphenyl)-N2,N2-diethylglycinamide Chemical data
C14H22N2O 234.34 g/mol eMolecules

[16]
& PubChem
[17]
Physical data Melt. point 68C (154F) (what is this?) (verify)

[18]
Lidocaine (INN) ( /ladken/), Xylocaine, or lignocaine (former BAN) ( /lnken/) is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.
History
Lidocaine, the first amino amide-type local anesthetic, was first synthesized under the name Xylocaine by Swedish chemist Nils Lfgren in 1943.[19] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[19] It was first marketed in 1949. Etymology: from one of its many chemical names [alpha-Diethylamino-2,6-dimethylacetani- ] - lide + ~ocaine.
Indications
The efficacy profile of lidocaine as a local anesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block and surface anesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and peridural anesthesias; lidocaine, on the other hand, has the advantage of a rapid onset of action. Epinephrine vasoconstricts arteries and hence delays the resorption of Lidocaine, almost doubling the duration of anaesthesia. For surface anesthesia several formulations are available that can be used e.g. for endoscopies, before intubations etc. Buffering the pH of lidocaine makes local freezing less painful.[20] Topical lidocaine has been shown to relieve postherpetic neuralgia (arising, for example, from shingles) in some patients, though there is not enough study evidence to recommend it as a first-line treatment.[21] It also has uses as a temporary fix for tinnitus. Although not completely curing the illness, it has been shown to reduce the effects by around two thirds.[22] Lidocaine is also the most important class 1B antiarrhythmic drug: it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digitalis poisoning, cardioversion or cardiac catheterization). However, a routine prophylactic administration is no longer recommended for acute cardiac infarction; the overall benefit of this measure is not convincing.
Lidocaine Lidocaine has also been efficient in refractory cases of status epilepticus. Inhaled lidocaine can be used as an antitussive (cough suppressor) acting peripherally below the larynx.[23] [24] Lidocaine has also proved effective in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge [25]
205
Contraindications
Contraindications for the use of lidocaine include: Heart block, second or third degree (without pacemaker) Severe sinoatrial block (without pacemaker) Serious adverse drug reaction to lidocaine or amide local anaesthetics Concurrent treatment with quinidine, flecainide, disopyramide, procainamide (Class I antiarrhythmic agents) Prior use of Amiodarone hydrochloride Hypotension not due to Arrhythmia Bradycardia Accelerated idioventricular rhythm Pacemaker
Porphyria, especially acute porphyria (AIP); lidocaine is known to be porphyrogenic although similar drugs (e.g. bupivacaine, tetracaine) are known to be safe.[26] [27]
Adverse effects
Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and allergic reactions only rarely occur.[28] Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth (also known as circumoral paraesthesia), tinnitus, tremor, dizziness, blurred vision, seizures) followed by depression, and with increasingly heavier exposure: drowsiness, loss of consciousness, respiratory depression and apnoea). Cardiovascular effects include hypotension, bradycardia, arrhythmias, and/or cardiac arrest some of which may be due to hypoxemia secondary to respiratory depression.[29] ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (3mg/minute). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia, arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.[29]
Overdosage
Overdosage with lidocaine can be a result of excessive administration via topical or parenteral routes, accidental oral ingestion of topical preparations by children, accidental intravenous (rather than subcutaneous, intrathecal or paracervical) injection or prolonged use of subcutaneous infiltration anesthesia during cosmetic surgical procedures. These occurrences have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma or serum to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. It is important in the interpretation of analytical results to recognize that lidocaine is often routinely administered intravenously as an antiarrhthymic agent in critical
Lidocaine cardiac care situations.[30] Treatment with intravenous lipid emulsions (used for parental feeding) to reverse the effects of local anaesthetic toxicity is becoming more common place. [31]
206
Insensitivity to lidocaine
Relative insensitivity to lidocaine is genetic. In hypokalemic sensory overstimulation, relative insensitivity to lidocaine has been described in people who also have attention deficit hyperactivity disorder. In dental anesthesia, a relative insensitivity to lidocaine can occur for anatomical reasons due to unexpected positions of nerves. Some people with Ehlers-Danlos syndrome are insensitive to lidocaine.[32]
Dosage forms
Lidocaine, usually in the form of lidocaine hydrochloride, is available in various forms including: Injected local anesthetic (sometimes combined with epinephrine to reduce bleeding) Dermal patch (sometimes combined with prilocaine) Intravenous injection (sometimes combined with epinephrine to reduce bleeding) Intravenous infusion Nasal instillation/spray (combined with phenylephrine)
Oral gel (often referred to as "viscous lidocaine" or abbreviated "lidocaine visc" or "lidocaine hcl visc" in pharmacology; used as teething gel) Oral liquid Topical gel (as with Aloe vera gels that include lidocaine)[33] Topical liquid Topical patch (lidocaine 5% patch is marketed as "Lidoderm" in the US (since 1999) and "Versatis" in the UK (since 2007 by Grnenthal)) Topical aerosol spray Inhaled via a nebulizer
Adulterant in cocaine
Lidocaine is often added to cocaine as a diluent.[34] Cocaine numbs the gums when applied, and since lidocaine causes stronger numbness,[35] a user gets the impression of high-quality cocaine when in actuality, the user is receiving a diluted product.[36]
Preparation
Lidocaine may be prepared in two steps by the reaction of 2,6-xylidine with chloroacetyl chloride, followed by the reaction with diethylamine:[37] [38]
Lidocaine
207
Pharmacokinetics
Lidocaine is approximately 95% metabolized (dealkylated) in the liver by CYP3A4 to the pharmacologically-active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half life than lidocaine but also is a less potent sodium channel blocker.[39] The elimination half-life of lidocaine is approximately 90120 minutes in most patients. This may be prolonged in patients with hepatic impairment (average 343 minutes) or congestive heart failure (average 136 minutes).[40]
Pharmacodynamics
Anesthesia
Lidocaine alters signal conduction in neurons by blocking the fast voltage gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation.[41] With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential. This creates the anaesthetic effect by not merely preventing pain signals from propagating to the brain but by stopping them before they begin. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations will also affect other modalities of neuron signaling.
Illegal uses
Lidocaine is not currently listed by the World Anti-Doping Agency as an illegal substance.[42] Lidocaine is used as an adjuvant, adulterant, mimic and diluent to illegal street drugs (e.g. cocaine). (See U.S. DEA web site). Use as a gag reflex reducer. http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC459418/ pdf/ thorax00202-0029. pdf
Compendial status
Japanese Pharmacopoeia 15 United States Pharmacopeia 31[43]
Notes and references

[1] http:/ / www. drugs. com/ cons/ lidocaine. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=137-58-6& rn=1 [3] http:/ / toolserver. org/ ~magnus/ cas. php?language=en& cas=73-78-9& title= [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N01BB02 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BB01 [6] http:/ / www. whocc. no/ atc_ddd_index/ ?code=D04AB01 [7] http:/ / www. whocc. no/ atc_ddd_index/ ?code=S02DA01 [8] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C05AD01 [9] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3676 [10] http:/ / www. drugbank. ca/ drugs/ DB00281 [11] http:/ / www. chemspider. com/ Chemical-Structure. 3548 [12] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=98PI200987 [13] http:/ / www. kegg. jp/ entry/ D00358 [14] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:6456 [15] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL79 [16] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28Nc1c%28cccc1C%29C%29CN%28CC%29CC [17] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28Nc1c%28cccc1C%29C%29CN%28CC%29CC [18] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=464370713& page2=%3ALidocaine [19] Nils Lfgren (1948). Xylocaine: a new synthetic drug. [20] Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R (2010). Tzortzopoulou, Aikaterini. ed. "Adjusting the pH of lidocaine for reducing pain on injection". Cochrane Database Syst Rev 12 (12): CD006581. doi:10.1002/14651858.CD006581.pub2.
Lidocaine
PMID21154371. [21] Khaliq W, Alam S, Puri N (2007). Khaliq, Waqas. ed. "Topical lidocaine for the treatment of postherpetic neuralgia". Cochrane Database Syst Rev (2): CD004846. doi:10.1002/14651858.CD004846.pub2. PMID17443559. [22] http:/ / newsvote. bbc. co. uk/ 1/ hi/ health/ 7175306. stm [23] RSD931, a novel antitussive agent acting on airway sensory nerves (http:/ / onlinelibrary. wiley. com/ doi/ 10. 1038/ sj. bjp. 0705056/ pdf) [24] Inhaled lidocaine is used to suppress cough during bronchoscopy. Animal studies and a few human studies suggest that lidocaine has an antitussive effect... (http:/ / books. google. jo/ books?id=LngD6RFXY_AC& pg=PA305& lpg=PA305& dq=lidocaine+ cough+ antitussive+ below+ larynx& source=bl& ots=TK5FF3Ut7Y& sig=BUrpcqNdr8TqKjs6oxYxy4_AoS0& hl=en& ei=kZW2TdzDF9DFswbq65nJDQ& sa=X& oi=book_result& ct=result& resnum=1& ved=0CBYQ6AEwAA#v=onepage& q& f=false) [25] 17. Birsa LM, Verity PG, Lee RF, (2010). "Evaluation of the effects of various chemicals on discharge of and pain caused by jellyfish nematocysts". Comparative Biochemistry and Physiology, Part C 151 (4): 426430. doi:10.1016/j.cbpc.2010.01.007. PMID20116454. [26] http:/ / db. porphyriafoundation. com/ forms/ drug-list. lasso [27] www.merck.com/media/mmpe/pdf/Table_155-4.pdf [28] D Jackson, AH Chen, and CR Bennett (1994). "Identifying true lidocaine allergy" (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7844301). J Am Dent Assoc 125 (10): 13621366. PMID7844301. . [29] Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3 [30] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 840-844. [31] Pickard J Guidelines and the adoption of 'lipid rescue' therapy for local anaesthetic toxicity. Anaesthesia 2009;64:122-5 [32] Grahame, Rodney; Grahame, R; Norris, P; Hopper, C (2005). "Local anaesthetic failure in joint hypermobility syndrome". Journal of the Royal Society of Medicine 98 (2): 8485. doi:10.1258/jrsm.98.2.84. PMC1079398. PMID15684369. [33] Solarcaine topical gel (http:/ / www. solarcaine. com), July 27, 2009 [34] Naissa Prvide Bernardo, Maria Elisa Pereira Bastos Siqueira, Maria Jos Nunes de Paiva, Patrcia Penido Maia (2003). "Caffeine and other adulterants in seizures of street cocaine in Brazil" (http:/ / www. sciencedirect. com/ science/ article/ B6VJX-497HGRX-5/ 2/ 3b5f81654f1e907ceb3095b4b5207362). International Journal of Drug Policy 14 (4): 331334. doi:10.1016/S0955-3959(03)00083-5. . [35] Howell, Kimberly. "Take a big-picture approach when dealing with corneal sensation" (http:/ / www. eyeplastics. org/ topics/ thyroid/ thyroid_news/ corneal_sensation. htm). . Retrieved 2009-04-23. "Lidocaine is more potent, with rapid diffusion and penetration." [36] 599 F.2d 635 (http:/ / bulk. resource. org/ courts. gov/ c/ F2/ 599/ 599. F2d. 635. 78-5314. html) [37] T. J. Reilly (1999). "The Preparation of Lidocaine" (http:/ / jchemed. chem. wisc. edu/ Journal/ Issues/ 1999/ Nov/ abs1557. html). J. Chem. Ed. 76 (11): 1557. doi:10.1021/ed076p1557. . [38] J.L. Bengt, M.L. Niles, U.S. Patent 2441498 (http:/ / www. google. com/ patents?vid=2441498) (1948). [39] Flomenbaum NE, Howland MA, Goldfrank, LR, et al., ed (2006). Goldfrank's Toxicologic Emergencies, 8th ed.. McGraw-Hill. [40] Thomson PD, Melmon KL, Richardson JA, et al. (1973). "Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans". Ann. Intern. Med. 78 (4): 499508. PMID4694036. [41] Catterall WA (2002). "Molecular mechanisms of gating and drug block of sodium channels". Novartis Found Symp. Novartis Foundation Symposia 241: 20632. doi:10.1002/0470846682.ch14. ISBN9780470846681. PMID11771647. [42] http:/ / www. wada-ama. org/ Documents/ World_Anti-Doping_Program/ WADP-Prohibited-list/ WADA_Prohibited_List_2010_EN. pdf [43] Revision Bulletin: Lidocaine and Prilocaine CreamRevision to Related Compounds Test (http:/ / www. usp. org/ USPNF/ notices/ lidocaineAndPrilocaine. html)
208
External links
U.S. National Library of Medicine: Drug Information Portal - Lidocaine (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Lidocaine)
Phenytoin
209
Phenytoin
Phenytoin
5,5-diphenylimidazolidine-2,4-dione
Clinical data Trade names Dilantin
AHFS/Drugs.com monograph [1] MedlinePlus Pregnancy cat. Legal status Routes a682022 D Prescription only Oral, parenteral Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion 70-100% oral, 24.4% for rectal and intravenous administration 90% hepatic 624 hours Primarily through the bile, urinary Identifiers CAS number ATC code PubChem DrugBank ChemSpider 57-41-0
[3] [4] [2]
N03 AB02 CID 1775 DB00252 1710

[9]
N03 AB04
[5]
, N03 AB05
[6]
[7] [8]
Phenytoin
[10]
210
UNII KEGG ChEBI ChEMBL
6158TKW0C5 D00512
[11]
CHEBI:8107 CHEMBL16
[12] [13]
[14]
& PubChem
[15]
[16]
Phenytoin sodium is a commonly used antiepileptic. Phenytoin (fnit'oin, IPA) acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels. Aside from seizures, it is an option in the treatment of trigeminal neuralgia in the event that carbamazepine or other first-line treatment seems inappropriate. It is sometimes considered a class 1b antiarrhythmic.[17]
Trade names
Phenytoin sodium has been marketed as Phenytek by Mylan Laboratories, previously Bertek Pharmaceuticals, and Dilantin; Australia also Dilantin Kapseals and Dilantin Infatabs in the USA, Eptoin by Abbott Group in India and as Epanutin in the UK and Israel, by Parke-Davis, now part of Pfizer. In the USSR and post-USSR countries, it was/is marketed as (Diphenin, Dipheninum),.
History
Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908.[18] Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, outside scientists including H. Houston Merritt and Tracy Putnam discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with phenobarbital. According to Goodman and Gilman's Pharmacological Basis of Therapeutics, In contrast to the earlier accidental discovery of the antiseizure properties of bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals.[19] There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. Jack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. He is believed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s. Dreyfus' experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked,.[20] Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially because Parke-Davis was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies. It was approved by the USA Food and Drug Administration in 1953 for use in seizures. Dilantin made an appearance in the 1962 novel One Flew Over the Cuckoo's Nest by Ken Kesey, both as an anticonvulsant and as a mechanism to control inmate behavior.
Phenytoin In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list means that the FDA has identified a potential safety issue, but does not mean that FDA has identified a causal relationship between the drug and the listed risk. According to the FDA's New Safety Information Identified by the Adverse Event Reporting System (AERS) Phenytoin Injection (Dilantin) has been associated with the risk of Purple Glove Syndrome.
211
Side-effects
Neurologic
At therapeutic doses, phenytoin produces horizontal gaze nystagmus. At toxic doses, patients experience sedation, cerebellar ataxia, and ophthalmoparesis, as well as seizures. Idiosyncratic side-effects of phenytoin, as with other anticonvulsants, include rash and severe allergic reactions. Phenytoin may accumulate in the cerebral cortex over long periods of time, as well as causing atrophy of the cerebellum when administered at chronically high levels. Despite this, the drug has a long history of safe use, making it one of the more popular anti-convulsants prescribed by doctors, and a common "first line of defense" in seizure cases.
Hematologic
It has been suggested that phenytoin causes a reduction in folic acid levels, predisposing patients to megaloblastic anemia. Folic acid is presented in foods as polyglutamate, which is then converted into monoglutamates by intestinal conjugase. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency.[21] Other side effects may include: agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia.
Teratogenicity
Phenytoin is a known teratogen. The syndrome consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, microcephaly) and a mild form of mental retardation (average IQ=71).[22] This syndrome resembles the well-described Fetal Alcohol Syndrome[23] and has also been called the "fetal hydantoin syndrome". Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry question definitively.
[24]
may one day answer this
Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data do not provide clear answers.[25]
Carcinogenicity
There is no good evidence that phenytoin is a human carcinogen.[26] [27]
Gingival
Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a randomized controlled trial suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin.[28] Plasma concentrations needed to induce gingival lesions has not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.
Phenytoin
212
Suicide risk
Following almost 200 studies of 11 anti-seizure drugs, the FDA has also warned of an increased suicide risk for any patients treated with certain anti-seizure drugs. The study of 44,000 patients found that patients whose epilepsy is treated with drugs face about twice the risk of suicidal thoughts compared to placebo-takers. Although phenytoin was not named in the study, the FDA announced that it expected the risk applied to every epilepsy drug.[29]
Dermatologic
Hypertrichosis, rash, exfoliative dermatitis, pruritis.
In autoimmune disease
Phenytoin has been known to cause drug-induced lupus.[30] Phenytoin therapy has been linked to the life-threatening skin reactions StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502.[31] This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.
In immunodeficiency disease
Phenytoin is also associated with induction of reversible IgA deficiency.[31]
Interactions
Phenytoin is an inducer of the CYP3A4 and CYP2C19 families of the P450 enzyme responsible for the hepatic degradation of various drugs. Warfarin (Coumadin) increases serum phenytoin levels and prolongs the serum half-life of phenytoin by inhibiting its metabolism. hydantoins fosphenytoin mephenytoin ethotoin
Pharmacokinetic
Phenytoin kinetics are nonlinear and saturable, resulting in highly variable concentrations even with minor dosage changes. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated.
Chemistry
Phenytoin, 5,5-diphenylimidazolidinedione is synthesized in two different ways. The first involves a base catalyzed addition of Urea to benzil followed by a benzilic acid rearrangement (1,2 phenyl migration) to form the desired product. This is known as the Biltz Synthesis of phenytoin.[18]
Phenytoin
213
The second method involves the reaction of benzophenone with sodium cyanide in the presence of ammonium carbonate, followed by the simultaneous cyclization of the resulting product (carboxyaminonitrile) and its rearrangement under the reaction conditions to form phenytoin. US patent 2409754 [32], Hense, H. R., "Method for obtaining hydantoins", issued 1946-10-22, assigned to Parke Davis
References
[1] http:/ / www. drugs. com/ monograph/ phenytoin. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682022. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=57-41-0& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N03AB02 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N03AB04 [6] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N03AB05 [7] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1775 [8] http:/ / www. drugbank. ca/ drugs/ DB00252 [9] http:/ / www. chemspider. com/ Chemical-Structure. 1710 [10] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=6158TKW0C5 [11] http:/ / www. kegg. jp/ entry/ D00512 [12] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:8107 [13] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL16 [14] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC2NC%28%3DO%29NC2%28c1ccccc1%29c3ccccc3 [15] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC2NC%28%3DO%29NC2%28c1ccccc1%29c3ccccc3 [16] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=457457901& page2=%3APhenytoin [17] Balaji S (October 2004). "Medical therapy for sudden death" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0031395504000513). Pediatr. Clin. North Am. 51 (5): 137987. doi:10.1016/j.pcl.2004.04.002. PMID15331289. . [18] Biltz, H. (1908). "Constitution of the Products of the Interaction of Substituted Carbamides on Benzil and Certain New Methods for the Preparation of 5,5-Diphenylhydantoin". Chemische Berichte 41: 137993. [19] Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th ed. (New York: McGraw-Hill, 2001). [20] Dreyfus, Jack (1998). A Remarkable Medicine Has Been Overlooked: Including an Autobiography and the Clinical Section of the Broad Range of Use of Phenytoin. Continuum International Publishing Group. ISBN0-8264-1069-3. [21] Carl GF, Smith ML (1992). "Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin". Epilepsia 33 (2): 3725. doi:10.1111/j.1528-1157.1992.tb02330.x. PMID1547769. [22] Beckmann, Charles R., et al. (2002). Obstetrics and Gynecology (4th ed.). Baltimore: Lippincott Williams & Wilkins. [23] CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http:/ / www. cdc. gov/ fas/ faspub. htm.
Phenytoin
[24] http:/ / www. epilepsy. com/ info/ women_pregnancy_registry. html?thebanner=women_pregnancy_registry [25] Adab N, Tudur SC, Vinten J, Williamson P, Winterbottom J (2004). Adab, Naghme. ed. "Common antiepileptic drugs in pregnancy in women with epilepsy". Cochrane Database Syst Rev (3): CD004848. doi:10.1002/14651858.CD004848. PMID15266543. [26] Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216. [27] Maeda T, Sano N, Togei K, Shibata M, Izumi K, Otsuka H (1988). "Lack of carcinogenicity of phenytoin in (C57BL/6 x C3H)F1 mice". J Toxicol Environ Health 24 (1): 1119. doi:10.1080/15287398809531144. PMID3373561. [28] Arya R, Gulati S, Kabra M, Sahu JK, Kalra V (Apr 2011). "Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children". Neurology 76 (15): 133843. doi:10.1212/WNL.0b013e3182152844. PMC3090066. PMID21482950. [29] FDA warns of risks from epilepsy drugs (http:/ / web. archive. org/ web/ 20080204155102/ http:/ / news. yahoo. com/ s/ ap/ 20080201/ ap_on_he_me/ epilepsy_drugs). [30] Scheinfeld N (August 2003). "Phenytoin in cutaneous medicine: its uses, mechanisms and side effects" (http:/ / dermatology. cdlib. org/ 93/ reviews/ dilantin/ scheinfeld. html). Dermatol. Online J. 9 (3): 6. PMID12952753. . [31] Man CB, Kwan P, Baum L, et al. (May 2007). "Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese". Epilepsia 48 (5): 10158. doi:10.1111/j.1528-1167.2007.01022.x. PMID17509004. [32] http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=US2409754
214
External links
Medicines for Epilepsy: Dilantin (http://www.epilepsyfoundation.org/answerplace/Medical/treatment/ medications/typesmedicine/dilantin.cfm) Epilepsy Foundation (broken link). Remarkable Medicine, a website about the Dreyfus Foundation's work to expand the indications for phenytoin (http://www.remarkablemedicine.com) Phenytoin Pharmacokinetics (http://www.pubpk.org/index.php?title=Phenytoin) (not a public link)
Mexiletine
215
Mexiletine
Mexiletine
(RS)-1-(2,6-dimethylphenoxy)propan-2-amine OR 2-(2-aminopropoxy)-1,3-dimethylbenzene
Clinical data AHFS/Drugs.com monograph [1] MedlinePlus Pregnancy cat. Legal status Routes a607064
[2]
B1(AU) C(US) POM (UK) Oral, IV Pharmacokinetic data
90% 50-60% Hepatic (CYP2D6 and 1A2- mediated) 10-12 hours Renal (10%) Identifiers
CAS number ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
31828-71-4 C01 BB02 CID 4178 2629

[6]
[3]
[4]
[5]
APRD00242 4034
[8]
[7]
1U511HHV4Z D08215
[10]
[9]
CHEBI:6916
[11]
CHEMBL558
[12]
Chemical data Formula C H NO

11 17
Mexiletine
216
Mol. mass SMILES 179.259 g/mol eMolecules
[13]
& PubChem
[15]
[14]
Mexiletine (INN, sold under the trade name Mexitil) belongs to the Class IB anti-arrhythmic group of medicines. It is used to treat arrhythmias within the heart, or seriously irregular heartbeats. It slows conduction in the heart and makes the heart tissue less sensitive. Dizziness, heartburn, nausea, nervousness, trembling, unsteadiness are common side effects. It is available in injection and capsule form. Class IB antiarrhythmics decrease action potential duration by shortening the repolarization phase. This is achieved by blocking sodium channels.[16] Mexiletine may also be of use in patients experiencing refractory pain[17] and is also effective for treating muscle stiffness resulting from myotonia congenita (Thomsen disease) or myotonic dystrophy (Steinert's disease).
References
[1] http:/ / www. drugs. com/ monograph/ mexiletine-hydrochloride. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a607064. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=31828-71-4& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BB02 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4178 [6] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2629 [7] http:/ / www. drugbank. ca/ drugs/ APRD00242 [8] http:/ / www. chemspider. com/ Chemical-Structure. 4034 [9] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=1U511HHV4Z [10] http:/ / www. kegg. jp/ entry/ D08215 [11] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:6916 [12] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL558 [13] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%28c1c%28cccc1C%29C%29CC%28N%29C [14] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%28c1c%28cccc1C%29C%29CC%28N%29C [15] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=462252080& page2=%3AMexiletine [16] Mexiletine (http:/ / www. rxlist. com/ cgi/ generic/ mexiletine_cp. htm), RxList.com [17] Sweetman S (ed.) (2002). Martindale: The complete drug reference (33rd ed. ed.). London: Pharmaceutical Press. ISBN0-85369-499-0.
Further reading
Peck T; Hill S, Williams M (eds.) (2004). Pharmacology for Anaesthesia and Intensive Care (2nd ed. ed.). Cambridge University Press. ISBN0-521-68794-2.
External links
MedlinePlus Drug Information: Mexiletine (http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/ a607064.html)
217
Type Ic Antiarrythmics
Flecainide
Flecainide
(RS)-N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Tambocor monograph a608040 C ? Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion 95% 40% CYP2D6 (limited) 20 hours (range 12-27 hours) Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 54143-55-4 C01 BC04 CID 3356
[3] [2] [1]
[4]
[5] [6]
APRD00129 3239
[7]
K94FTS1806 D07962
[9]
[8]
[10]
Flecainide
218
Formula Mol. mass SMILES C17H20F6N2O3 414.343 g/mol eMolecules (what is this?) (verify)
[11]
& PubChem
[12]
[13]
Flecainide acetate ( /flkenad/ USdict:fleknd) is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias (abnormal fast rhythms of the heart). It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation (episodic irregular heartbeat originating in the upper chamber of the heart), paroxysmal supraventricular tachycardia (episodic rapid but regular heartbeat originating in the atrium), and ventricular tachycardia (rapid rhythms of the lower chambers of the heart). Flecainide works by regulating the flow of sodium in the heart, causing prolongation of the cardiac action potential. Flecainide was originally sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February 10, 2004, and is now available in generic version and under the trade names Almarytm, Apocard, Ecrinal, and Flcaine.
Uses
Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal re-entrant tachycardia (AVNRT) and Wolff-Parkinson-White syndrome (WPW). This is because of the action of flecainide on the His-Purkinje system. It also has limited use in the treatment of certain forms of ventricular tachycardia (VT). In particular, flecainide has been useful in the treatment of ventricular tachycardias that are not in the setting of an acute ischemic event. It has use in the treatment of right ventricular outflow tract (RVOT) tachycardia[14] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).[15] However, studies have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.[16] [17] In individuals suspected of having the Brugada syndrome, the administration of flecainide may help reveal the ECG findings that are characteristic of the disease process. This may help make the diagnosis of the disease in equivocal cases.[18] Flecainide has been introduced into the treatment of arrhythmias in the pediatric population. According to recent research published in Nature Medicine, flecainide inhibits the release of the cardiac ryanodine receptormediated Ca2+, and is therefore believed to medicate the underlying molecular cause of catecholaminergic polymorphic ventricular tachycardia in both mice and humans.[19]
Dosing
The dosing of flecainide is varied, with consideration made to the individual's other medications and comorbid conditions and how they may affect the metabolism of flecainide. Individuals with significant renal impairment may require measurement of the plasma level of flecainide to ensure that the drug level remains within the therapeutic range (i.e.: that toxic levels do not occur). In addition, lower drug levels may be sought for the treatment of benign arrhythmias, to lower the chance of inducing a toxic effect of the drug. When used in the pediatric population, the dose of flecainide may be adjusted to the individual's body surface area. Since food digestion can alter the absorption of the drug, Flecainide should be taken one hour before meals. Given the variable half-life of flecainide and the characteristic QRS prolongation on ECG elicited in flecainide toxicity, especially at rapid heart rates,[20] starting flecainide or changing the level of the drug is done under telemetry monitoring (preferably in a hospital telemetry unit) until a steady state plasma level has been achieved, typically three to five days after the dose has been increased.
Flecainide For the treatment of supraventricular tachycardias and paroxysmal atrial fibrillation or flutter in individuals without significant structural heart disease, a starting dose of 50mg twice a day may be appropriate. The dose may be increased (once a steady state level has been reached) if breakthrough dysrhythmias occur. For the treatment of life-threatening ventricular arrhythmias (i.e.: ventricular tachycardia), a starting dose of 100mg twice a day may be appropriate. As with the treatment of benign arrhythmias, the dose of flecainide given for the treatment of life-threatening ventricular dysrhythmias should not be increased until a steady state has been achieved.
219
Mechanism of action
Flecainide works by blocking the Nav1.5 sodium channel in the heart, causing prolongation of the cardiac action potential.[21] This thereby slows conduction of the electrical impulse within the heart. The greatest effect is on the His-Purkinje system and ventricular myocardium. The effect of flecainide on the ventricular myocardium causes decreased contractility of the muscle, which leads to a decrease in the ejection fraction. The effect of flecainide on the sodium channels of the heart increases as the heart rate increases.[22] This is known as use-dependence. This means that flecainide is potentially more useful to break a tachyarrhythmia (because it has increased effect during the fast heart rate) than to prevent a bradyarrhythmia from occurring (because of its lowered effectiveness during slower heart rates).
Metabolism and drug interactions

Flecainide has high bioavailability after an oral dose,[23] meaning that most of the drug that is ingested will enter the systemic blood stream. Peak serum concentrations can be seen 1 to 6 hours after ingestion of an oral dose. While the plasma half-life is about 20 hours, it is quite variable, and can range from 12 to 27 hours.[24] During oral loading with flecainide, a steady state equilibrium is typically achieved in 3 to 5 days. The majority of flecainide is eliminated by the kidneys, with the remainder metabolized by the cytochrome P450 2D6 isoenzyme in the liver.[25] Therefore, alterations in renal function or urine pH will greatly affect the elimination of flecainide, as more is eliminated by the hepatic route. Because of the dual elimination routes of flecainide and its tendency to decrease myocardial contractility,[26] flecainide interacts with numerous pharmaceuticals and can potentiate the effects of other myocardial depressants and AV node blocking agents. In addition, flecainide can decrease the metabolism or elimination of many (but not all) agents that use the cytochrome P450 enzyme system. A full list of drug interactions with flecainide can be obtained from the manufacturer. Some important drug interactions with flecainide include: Alcohol - may further depress normal heart function. Amiodarone - inhibits cytochrome P450 2D6 and may increase flecainide levels Cimetidine - increases flecainide levels by 30% and half-life by 10% Digoxin - may increase digoxin levels Paroxetine - increased effect of both drugs. Propafenone - increased effect of both drugs and increased risk of toxicity. Quinidine - inhibits cytochrome P450 2D6 and may increase flecainide levels
Flecainide
220
Serious adverse reactions

Results of a medical study known as the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients with structural heart disease (such as a history of MI (heart attack), or left ventricular dysfunction) and also patients with ventricular arrhythmias, should not take this drug. The results were so significant that the preliminary results were published. [27] In patients with these kinds of heart diseases, flecainide actually increases the chance of suffering a fatal arrhythmia. The dose may need to be adjusted in certain clinical scenarios. As with all other antiarrhythmic agents, there is a risk of proarrhythmia associated with the use of flecainide. This risk is probably increased when flecainide is co-administered with other class Ic antiarrhythmics, such as encainide. The risk of proarrhythmia may also be increased by hypokalemia.[28] The risk of proarrhythmia is not necessarily associated with the length of time an individual is taking flecainide, and cases of late proarrhythmia have been reported.[29] Because of the role of both the liver and the kidneys in the elimination of flecainide, the dosing of flecainide may need to be adjusted in individuals who develop either liver failure or renal failure. Because of the negative inotropic effects of flecainide,[26] it should be used with caution in individuals with depressed ejection fraction, and may worsen congestive heart failure in these individuals. It should be avoided in people with ischaemic heart disease and the elderly. As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers.[30] Therefore, capture thresholds should be remeasured in individuals with pacemakers after the steady-state flecainide dose is changed.
Toxicity
Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsade de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug,[31] it is infeasible to check the plasma concentration in an individual on a regular basis. Signs of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility. Treatment Treatment of flecainide toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent,[31] and administration of a sodium load[31] (often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily obviate the need for a beating heart and to increase blood flow to the liver.[32] [33]
Flecainide
221
Long term effects

In the long term, flecainide seems to be safe in patients with a healthy heart with no signs of left ventricular hypertrophy, ischemic heart disease or heart failure.
References
[1] http:/ / www. drugs. com/ monograph/ tambocor. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a608040. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=54143-55-4& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BC04 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3356 [6] http:/ / www. drugbank. ca/ drugs/ APRD00129 [7] http:/ / www. chemspider. com/ Chemical-Structure. 3239 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=K94FTS1806 [9] http:/ / www. kegg. jp/ entry/ D07962 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL652 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=FC%28F%29%28F%29COc2cc%28C%28%3DO%29NCC1NCCCC1%29c%28OCC%28F%29%28F%29F%29cc2 [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=FC%28F%29%28F%29COc2cc%28C%28%3DO%29NCC1NCCCC1%29c%28OCC%28F%29%28F%29F%29cc2 [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=418535280& page2=%3AFlecainide [14] Gill J, Mehta D, Ward D, Camm A (1992). "Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality". Br Heart J 68 (4): 3927. doi:10.1136/hrt.68.10.392. PMC1025139. PMID1449923. [15] Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, Motomiya T, Sugiura M, Hiraoka M (1990). "[Effects of oral flecainide treatment of refractory tachyarrhythmias]". Kokyu to Junkan 38 (5): 4716. PMID2115193. [16] Echt D, Liebson P, Mitchell L, Peters R, Obias-Manno D, Barker A, Arensberg D, Baker A, Friedman L, Greene H (1991). "Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial". N Engl J Med 324 (12): 7818. doi:10.1056/NEJM199103213241201. PMID1900101. [17] Greenberg H, Dwyer E, Hochman J, Steinberg J, Echt D, Peters R (1995). "Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I". Br Heart J 74 (6): 6315. doi:10.1136/hrt.74.6.631. PMC484119. PMID8541168. [18] Gasparini M, Priori S, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S (2003). "Flecainide test in Brugada syndrome: a reproducible but risky tool". Pacing Clin Electrophysiol 26 (1 Pt 2): 33841. doi:10.1046/j.1460-9592.2003.00045.x. PMID12687841. [19] Watanabe, Hiroshi; Nagesh Chopra, Derek Laver, Hyun Seok Hwang, Sean S. Davies, Daniel E. Roach, Henry J. Duff, Dan M. Roden, Arthur A. M. Wilde, Bjrn C. Knollmann (2009-04-01). "Flecainide prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans." (http:/ / www. nature. com/ nm/ journal/ v15/ n4/ abs/ nm. 1942. html). Nature Medicine 15 (4): 380383. doi:10.1038/nm.1942. PMC2904954. PMID19330009. . Retrieved 2009-05-04. [20] Katristis D, Rowland E, O'Nunain S, Shakespeare C, Poloniecki J, Camm A (1995). "Effect of flecainide on atrial and ventricular refractoriness and conduction in patients with normal left ventricle Implications for possible antiarrhythmic and proarrhythmic mechanisms". Eu Heart J 16 (1): 19301935. PMID8682029. [21] Ramos E, O'leary M (2004). "State-dependent trapping of flecainide in the cardiac sodium channel". J Physiol 560 (Pt 1): 3749. doi:10.1113/jphysiol.2004.065003. PMC1665201. PMID15272045. [22] Wang Z, Fermini B, Nattel S (1993). "Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue". J Pharmacol Exp Ther 267 (2): 57581. PMID8246130. [23] Smith G (1985). "Flecainide: a new class Ic antidysrhythmic". Drug Intell Clin Pharm 19 (10): 7037. PMID3902429. [24] Padrini R, Piovan D, Busa M, al-Bunni M, Maiolino P, Ferrari M (1993). "Pharmacodynamic variability of flecainide assessed by QRS changes". Clin Pharmacol Ther 53 (1): 5964. doi:10.1038/clpt.1993.9. PMID8422742. [25] Haefeli W, Bargetzi M, Follath F, Meyer U (1990). "Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo". J Cardiovasc Pharmacol 15 (5): 7769. doi:10.1097/00005344-199005000-00013. PMID1692938. [26] Santinelli V, Arnese M, Oppo I, Matarazzi C, Maione S, Palma M, Giunta A (1993). "Effects of flecainide and propafenone on systolic performance in subjects with normal cardiac function". Chest 103 (4): 106873. doi:10.1378/chest.103.4.1068. PMID8131440. [27] Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989). "Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.". N Engl J Med. 321 (6): 406412. doi:10.1056/NEJM198908103210629. PMID2473403. [28] Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, Ikeda U, Shimada K (2001). "Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia". Pacing Clin Electrophysiol 24 (1): 11921. doi:10.1046/j.1460-9592.2001.00119.x. PMID11227957.
Flecainide
[29] Morganroth J (1992). "Early and late proarrhythmia from antiarrhythmic drug therapy". Cardiovasc Drugs Ther 6 (1): 114. doi:10.1007/BF00050910. PMID1533532. [30] Fornieles-Prez H, Montoya-Garca M, Levine P, Sanz O (2002). "Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate". Pacing Clin Electrophysiol 25 (5): 8712. doi:10.1046/j.1460-9592.2002.00871.x. PMID12049386. [31] Winkelmann B, Leinberger H (1987). "Life-threatening flecainide toxicity. A pharmacodynamic approach". Ann Intern Med 106 (6): 80714. PMID3107447. [32] Corkeron M, van Heerden P, Newman S, Dusci L (1999). "Extracorporeal circulatory support in near-fatal flecainide overdose". Anaesth Intensive Care 27 (4): 4058. PMID10470398. [33] Yasui R, Culclasure T, Kaufman D, Freed C (1997). "Flecainide overdose: is cardiopulmonary support the treatment?". Ann Emerg Med 29 (5): 6802. doi:10.1016/S0196-0644(97)70257-9. PMID9140253.
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External links
Family Practice Notebook (http://www.fpnotebook.com/CV190.htm) Medline Plus (http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202240.html) Atrial Fibrillation Foundation (http://www.affacts.org/Medications/flecainide.html) RxList (http://www.rxlist.com/cgi/generic2/flecainide.htm) Cleveland Clinic (http://www.clevelandclinic.org/health/health-info/docs/0600/0686.asp?index=4834& src=news) Drugs.com (http://www.drugs.com/MTM/flecainide.html) WholeHealthMD.com (http://www.wholehealthmd.com/refshelf/drugs_view/1,1524,254,00.html) HealthSquare.com (http://www.healthsquare.com/newrx/tam1424.htm)
Propafenone
223
Propafenone
Propafenone
1-{2-[2-hydroxy-3-(propylamino)propoxy]phenyl}-3-phenylpropan-1-one
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Rythmol monograph a698002 C Prescription only Oral Pharmacokinetic data Bioavailability Protein binding Half-life ? 97% 2-10 hours Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 54063-53-5 C01 BC03 CID 4932 DB01182 4763
[7] [8] [3] [2] [1]
[4]
[5] [6]
68IQX3T69U D08435
[9]
[10]
C H NO
21 27
341.444 g/mol eMolecules (what is this?) (verify)

[11]
& PubChem
[12]
[13]
Propafenone Propafenone ( /propfnon/ proh-paf-i-nohn; brand name Rythmol SR or Rytmonorm) is a class Ic anti-arrhythmic medication, which treats illnesses associated with rapid heart beats such as atrial and ventricular arrhythmias.
224
Mechanism of action
Propafenone works by slowing the influx of sodium ions into the cardiac muscle cells, causing a decrease in excitability of the cells.
Metabolism
Propafenone is metabolized primarily in the liver. Because of its short half-life, it requires dosing two or three times daily to maintain steady blood levels. The long-term safety of propafenone is unknown. Because it is structurally similar to another anti-arrhythmic medicine, flecainide, similar cautions should be exercised in its use. Flecainide and propafenone, like other antiarrhythmic drugs have been shown to increase the occurrence of arrhythmias (5.3% for propafenone, Teva physician prescribing information), primarily in patients with underlying heart disease. However, their use in structurally normal hearts is considered safe.
Side effects
Side effects attributed to propafenone include hypersensitivity reactions, lupus-like syndrome, agranulocytosis, CNS disturbances such as dizziness, lightheadedness, gastrointestinal upset, a metallic taste and bronchospasm. About 20% of patients discontinued the drug due to side effects.
Initiation of therapy
Propafenone generally needs to be started in a hospital setting to assure ECG monitoring of the patient. There are many different dosages of propafenone, depending on clinical presentation of the arrhythmia. The treatment is generally begun with relatively high dosages (450-900mg/d) decreasing to near 300 mg/d. In most western countries the accepted maximal dosage is 900mg/d. For economic and patient convenience reasons, some clinicians are starting certain antiarrhythmic agents in an outpatient setting for some patients. No consensus exists regarding the safety of this practice, and information is needed to determine which agents and which patients are appropriate for outpatient initiation of antiarrhythmic therapy. From a clinical point of view, this drug is used primarily in patients with relatively preserved myocardial function. http://www.ahrq.gov/clinic/epcsums/atrialsum.htm
Contraindications and cautions

Caution should be used in administrating propafenone in individuals with hepatic dysfunction, asthma, CHF, or bradycardia.
Patent issues
The patents for the Rythmol family of products are owned by Reliant Pharmaceuticals, Inc., in Liberty Corner, N.J. Reliant acquired the patents from developer Abbott Laboratories, Inc., in 2003. Rythomol was originally developed in Europe and marketed by Knoll Pharma both in Europe and North America. The product was taken over by Abbott in 2001 when Abbott purchased Knoll. Reliant Pharmaceuticals filed a federal patent infringement lawsuit against generic drug maker Par Pharmaceuticals, Inc., on December 19, 2006. The lawsuit, filed in the federal district court for Delaware, seeks to prevent Par from manufacturing a generic version of Rythmol. Par is seeking approval to do so from the U.S. Food and Drug
Propafenone Administration. Reliant's patent for the drug was issued in October, 1997, and it expires in 2014. Par believes the patent is invalid, according to its filing with the FDA.
225
External links
Rythmol [14] (manufacturer's website) Propafenone [15] (patient information)
References
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] http:/ / www. drugs. com/ monograph/ propafenone-hydrochloride. html http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a698002. html http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=54063-53-5& rn=1 http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BC03 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4932 http:/ / www. drugbank. ca/ drugs/ DB01182 http:/ / www. chemspider. com/ Chemical-Structure. 4763 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=68IQX3T69U http:/ / www. kegg. jp/ entry/ D08435 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL631 http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28c1ccccc1OCC%28O%29CNCCC%29CCc2ccccc2 http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28c1ccccc1OCC%28O%29CNCCC%29CCc2ccccc2 http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=416712608& page2=%3APropafenone http:/ / www. reliantrx. com/ health/ rythmol. html http:/ / www. meds-help. com/ propafenone/
Moricizine
226
Moricizine
Moricizine
ethyl [10-(3-morpholin-4-ylpropanoyl)-10H-phenothiazin-2-yl]carbamate
Clinical data Trade names Ethmozine
AHFS/Drugs.com Consumer Drug Information [1] MedlinePlus Pregnancy cat. Legal status a601214 B (U.S.) ? Pharmacokinetic data Bioavailability Protein binding Half-life 38% 95% 3-4 hours (healthy volunteers), 6-13 hours (cardiac disease) Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 31883-05-3 None CID 34633
[4] [5] [3] [2]
APRD01124 31872
[6]
2GT1D0TMX1 D05077
[8]
[7]
CHEBI:6997
[9]
CHEMBL1075
[10]
Chemical data Formula Mol. mass SMILES C H NOS

22 25 3 4
427.518 g/mol eMolecules

[11]
& PubChem
[12]
[13]
Moricizine Moricizine (Ethmozine) is a phenothiazine derivative with Vaughan Williams class Ic antiarrhythmic properties. It undergoes extensive first-pass metabolism, has a bioavailability of 34-38 percent, and is 95 percent bound to plasma proteins. Moricizine is extensively metabolized and may have pharmacologically active metabolites. A recent clinical study has shown that moricizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations . Compared with disopyramide and quinidine, moricizine was equally or more effective in suppressing ventricular premature depolarizations, couplets, and nonsustained ventricular tachycardia. Further studies are needed comparing moricizine with other class 1 agents in the treatment of life-threatening arrhythmias; available data suggest that moricizine is comparable with these agents in the treatment of ventricular tachycardias and fibrillation. Moricizine appears to have a low incidence of serious adverse effects compared with other antiarrhythmics. This combination of apparently similar efficacy with a decreased incidence of adverse effects makes moricizine a worthwhile addition to currently available antiarrhythmic agents.
227
External links
Moricizine [14] MedlinePlus DrugInfo medmaster-a601080 [15]
References
[1] http:/ / www. drugs. com/ cdi/ moricizine. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a601214. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=31883-05-3& rn=1 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=34633 [5] http:/ / www. drugbank. ca/ drugs/ APRD01124 [6] http:/ / www. chemspider. com/ Chemical-Structure. 31872 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=2GT1D0TMX1 [8] http:/ / www. kegg. jp/ entry/ D05077 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:6997 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1075 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28OCC%29Nc2cc1N%28c3c%28Sc1cc2%29cccc3%29C%28%3DO%29CCN4CCOCC4 [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28OCC%29Nc2cc1N%28c3c%28Sc1cc2%29cccc3%29C%28%3DO%29CCN4CCOCC4 [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=462253689& page2=%3AMoricizine [14] http:/ / www. meds-help. com/ moricizine [15] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ medmaster/ a601080. html
228
Type II Antiarrythmics
Propranolol
Propranolol
(RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
Clinical data AHFS/Drugs.com monograph [1] Licence data Pregnancy cat. Legal status Routes USFDA: link C(AU) C(US) Prescription Only (S4) (AU) POM (UK) -only (US) oral, IV Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 26% hepatic (extensive) 4-5 hours renal <1% Identifiers CAS number 525-66-6
[3] [2]
Propranolol
[4]
229
ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
C07 AA05 CID 4946 564

[6]
[5]
DB00571 4777
[8]
[7]
9Y8NXQ24VQ D08443
[10]
[9]
CHEBI:8499 CHEMBL27
[11] [12]
Chemical data Formula Mol. mass SMILES C16H21NO2 259.34 g/mol eMolecules
[13]
& PubChem
[14]
[15]
Propranolol (INN) is a sympatholytic non-selective beta blocker. Sympatholytics are used to treat hypertension, anxiety and panic. It was the first successful beta blocker developed. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca and Wyeth product under the brand names Inderal, Inderal LA, Avlocardyl (also available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum (depending on marketplace and release rate), Bedranol SR (Sandoz).
An 80mg capsule of Propranolol.
Propranolol is one of the banned substances in the Olympics, presumably for its use in controlling social anxiety (stage fright) and tremors.
History and development

Scottish scientist James W. Black successfully developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early -adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of a aryloxy bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models. Newer, more selective beta-blockers (such as nebivolol, carvedilol, or metoprolol) are now used in the treatment of hypertension.
Propranolol
230
Indications
Propranolol is indicated for the management of various conditions including: Hypertension Angina pectoris Tachyarrhythmias Myocardial infarction Control of tachycardia/tremor associated with anxiety, hyperthyroidism or lithium therapy. Essential tremor Migraine prophylaxis [16] [17] Cluster headaches prophylaxis Tension headache (Off the label use) Shaky hands Treating the excessive drinking of fluids in psychogenic polydipsia,[19] [20] Antipsychotic-induced akathisia,[21] Aggressive behavior of patients with brain injuries[22] Post-traumatic stress disorder Glaucoma Primary exertional headache[23] While once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.[24] Propranolol is also used to lower portal vein pressure in portal hypertension and prevent esophageal variceal bleeding.
There has been some experimentation in psychiatric areas:[18]
Off-label and investigational use

Propranolol is often used by musicians and other performers to prevent stage fright. It has been taken by surgeons to reduce their own innate hand tremors during surgery.[25] Propranolol 80mg daily should be used post discharge in STEMI patients. Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder.[26] [27] [28] [29] Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Studies have shown that individuals given propranolol immediately after a traumatic experience show less severe symptoms of PTSD compared to their respective control groups that did not receive the drug (Vaiva et al., 2003). Propranolol reduces the effects of nightmare-related cardiac activity by keeping sinus rhythm low during nightmares, as a higher pulse and increased adrenaline are associated with severe nightmares. However, results remain inconclusive as to the success of propranolol in treatment of PTSD, including nightmares experienced by those with PTSD. There are also many ethical and legal questions surrounding the use of Propranolol-based medications for use as a "memory dampener," including: altering (memory-recalled) evidence during an investigation, modifying behavioral response to past (albeit traumatic) experiences, the regulation of these drugs, and others.[30] Propranolol in combination with etodolac is currently being investigated in a Phase 3 trial of 400 colorectal cancer patients as a potential treatment for prevention of colorectal cancer recurrence.[31] The aim of this study is to assess the use of perioperative medical intervention using a combination of a propranolol and etodolac in order to attenuate the surgically induced immunosuppression and other physiological perturbations, aiming to reduce the rate of tumor recurrence and distant metastatic disease.
Propranolol Evidence from June 2008 suggests that propranolol can be used to treat severe infantile hemangiomas (IHs).[32] This treatment has proven superior to corticosteroids, as propranolol has fewer side effects and is more effective when treating IHs. Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in patients with severe burns.[33] In children with burns, treatment with propranolol during hospitalization attenuated hypermetabolism and reversed muscle wasting. Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on Plasmodium falciparum and so the treatment of malaria. In vitro positive effects until recently had not been matched by useful in vivo anti-parasite activity against P. vinckei,[34] or P. yoelii nigeriensis.[35] However, a single study from 2006 has suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role for combination therapies.[36]
231
Precautions and contraindications

Propranolol should be used with caution in patients with:[37] Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked. Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated Phaeochromocytoma, as hypertension may be aggravated without prior alpha blocker therapy Myasthenia gravis, may be worsened Other drugs with bradycardic effects Propranolol is contraindicated in patients with:[37] Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD) Bradycardia (<60 beats/minute) Sick sinus syndrome Atrioventricular block (second or third degree) Shock Severe hypotension Cocaine toxicity [per American Heart Association guidelines, 2005]
Adverse effects
Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).
Pregnancy and lactation

Propranolol, like other beta blockers, is classified as Pregnancy category C in the United States and ADEC Category C in Australia. Beta-blocking agents in general reduce perfusion of the placenta which may lead to adverse outcomes for the neonate, including pulmonary or cardiac complications, or premature birth. The newborn may experience additional adverse effects such as hypoglycemia and bradycardia. Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.
Propranolol
232
Pharmacokinetics
Propranolol is rapidly and completely absorbed, with peak plasma levels achieved approximately 13 hours after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.27.5 hours) than the parent compound (34 hours), is also pharmacologically active. Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life and may be up to 12 hours, if the single dose is high enough (e.g., 80mg). Effective plasma concentrations are between 10100ng/mL. Toxic levels are associated with plasma concentrations above 2000ng/ml.
Mechanism of action
Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine and norepinephrine on both 1and 2-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdosage). Research has also shown that propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine release (present experiments have shown that the concentration of norepinephrine is increased in the synapse but do not have the ability to discern which effect is taking place).[38] Since propranolol blocks -adrenoceptors, the increase in synaptic norepinephrine only results in -adrenergic activation, with the 1-adrenoceptor being particularly important for effects observed in animal models. Therefore, some have suggested that it be looked upon as an indirect 1 agonist as well as a antagonist. Probably owing to the effect at the 1-adrenoceptor, the racemate and the individual enantiomers of propranolol have been shown to substitute for cocaine in rats, with the most potent enantiomer being S-()-propranolol. In addition, some evidence suggests that propranolol may function as a partial agonist at one or more serotonin receptors (possibly 5-HT1B). Both enantiomers of the drug have a local anesthetic (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. Few studies have demonstrated propranolol's ability to block cardiac, neuronal, and skeletal voltage-gated sodium channels, accounting for its known membrane stabilizing effect and anti-arrhythmic and other central nervous system effects.[39] [40] [41]
Interactions
Beta blockers, including propranolol, have an additive effect with other drugs which decrease blood pressure, or which decrease cardiac contractility or conductivity. Clinically-significant interactions particularly occur with:[37] verapamil epinephrine 2-adrenergic receptor agonists clonidine ergot alkaloids isoprenaline non-steroidal anti-inflammatory drugs quinidine cimetidine lidocaine
phenobarbital rifampicin
Propranolol Fluvoxamine slows down the metabolism of propranolol significantly leading to increased blood levels of propranolol.[42]
233
Dosage
The usual maintenance dose ranges for oral propranolol therapy vary by indication: Hypertension, angina, essential tremor 120-320mg daily in divided doses Sustained-release formulations are available in some markets. Migraine Prophylaxis The initial dose is 80mg Inderal daily in divided doses. The usual effective dose range is 160mg to 240mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, Inderal therapy should be discontinued. Tachyarrhythmia, anxiety (GAD), hyperthyroidism 10-40mg 3-4 times daily Performance anxiety 5-10mg 30min or 1.5hrs before and after performance, optionally 5-10mg night before. Up to 40mg if necessary, but side-effects may present.[43] Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis.[44]
Chemistry
Propranolol, 1-(iso-propylamino)-3-(1-naphthyloxy)-2-propanol, is synthesized in two ways from the same initial substance. The first way consists of reacting 1-naphthol with epichlorohydrin. Opening of the epoxide ring gives 1-chloro-3-(1-naphthyloxy)-2-propanol, which is reacted further with iso-propylamine, giving propranolol. The second method uses the same reagents in the presence of a base and consists of initially making 3-(1-naphthyloxy)propylenoxide, the subsequent reaction with isopropylamine which results in epoxide ring opening leading to the formation of propranolol.
A.F. Crowther, L.H. Smith, U.S. Patent 3337628 [45] (1967). A.F. Crowther, L.H. Smith, U.S. Patent 3520919 [46] (1970). A.F. Crowther, L.H. Smith, GB 994918 [47] (1963). A.F. Crowther, L.H. Smith, DE 1493897 [48] (1963).
Propranolol A.F. Crowther, L.H. Smith, BE 640312 [49] (1964). A.F. Crowther, L.H. Smith, BE 640313 [50] (1964).
234
References
[1] http:/ / www. drugs. com/ monograph/ propranolol-hydrochloride. html [2] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Propranolol& SearchType=BasicSearch [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=525-66-6& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AA05 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4946 [6] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=564 [7] http:/ / www. drugbank. ca/ drugs/ DB00571 [8] http:/ / www. chemspider. com/ Chemical-Structure. 4777 [9] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=9Y8NXQ24VQ [10] http:/ / www. kegg. jp/ entry/ D08443 [11] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:8499 [12] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL27 [13] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=CC%28C%29NCC%28COc1cccc2c1cccc2%29O [14] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=CC%28C%29NCC%28COc1cccc2c1cccc2%29O [15] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=464216937& page2=%3APropranolol [16] Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus:a role in migraine, Kevin G. Shields and Peter J. Goadsby, http:/ / brain. oxfordjournals. org/ content/ 128/ 1/ 86. full. pdf+ html [17] The biochemistry of migraine By Mervyn J. Eadie, http:/ / books. google. com/ books?id=JYeyCc9M6acC& pg=PA148& lpg=PA148& dq=Propranolol+ migraine+ mechanism,& source=bl& ots=Ep2oSjxpAo& sig=7H_KHF3xoIP0nBKJJaqsDl_IhAs& hl=en& ei=TXVPTuu6DKHE4gT6gLnXBw& sa=X& oi=book_result& ct=result& resnum=4& ved=0CCoQ6AEwAzgK#v=onepage& q=Propranolol%20migraine%20mechanism%2C& f=false [18] Kornischka J, Cordes J, Agelink MW (April 2007). "[40 years beta-adrenoceptor blockers in psychiatry]" (in German). Fortschritte Der Neurologie-Psychiatrie 75 (4): 199210. doi:10.1055/s-2006-944295. PMID17200914. [19] Vieweg V, Pandurangi A, Levenson J, Silverman J (1994). "The consulting psychiatrist and the polydipsia-hyponatremia syndrome in schizophrenia". International Journal of Psychiatry in Medicine 24 (4): 275303. doi:10.2190/5WG5-VV1V-BXAD-805K. PMID7737786. [20] Kishi Y, Kurosawa H, Endo S (1998). "Is propranolol effective in primary polydipsia?". International Journal of Psychiatry in Medicine 28 (3): 31525. doi:10.2190/QPWL-14H7-HPGG-A29D. PMID9844835. [21] Kramer MS, Gorkin R, DiJohnson C (1989). "Treatment of neuroleptic-induced akathisia with propranolol: a controlled replication study". The Hillside Journal of Clinical Psychiatry 11 (2): 10719. PMID2577308. [22] Thibaut F, Colonna L (1993). "[Anti-aggressive effect of beta-blockers]" (in French). L'Encphale 19 (3): 2637. PMID7903928. [23] Clinical summary (http:/ / www. medlink. com/ medlinkcontent. asp) [24] Sheetal Ladva (2006-06-28). "NICE and BHS launch updated hypertension guideline" (http:/ / www. nice. org. uk/ download. aspx?o=335988). National Institute for Health and Clinical Excellence. . Retrieved 2009-10-11. [25] Elman MJ, Sugar J, Fiscella R, et al. (1998). "The effect of propranolol versus placebo on resident surgical performance". Transactions of the American Ophthalmological Society 96: 28391; discussion 2914. PMC1298399. PMID10360293. [26] "Doctors test a drug to ease traumatic memories - Mental Health - MSNBC.com" (http:/ / www. msnbc. msn. com/ id/ 10806799/ ). . Retrieved 2007-06-30. [27] Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (2007). "Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder". Journal of Psychiatric Research 42 (6): 5036. doi:10.1016/j.jpsychires.2007.05.006. PMID17588604. [28] Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (May 2008). "Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder". Journal of Psychiatric Research 42 (6): 5036. doi:10.1016/j.jpsychires.2007.05.006. PMID17588604. [29] http:/ / www. cbsnews. com/ stories/ 2006/ 11/ 22/ 60minutes/ main2205629. shtml?tag=contentMain;contentBody A pill to forget [30] Kolber, Adam J. (2006). "Therapeutic Forgetting: The Legal and Ethical Implications of Memory Dampening". Vanderbilt Law Review, San Diego Legal Studies Paper No. 07-37. 59: 1561. [31] "-adrenergic Blocker and a COX2 Inhibitor for Prevention of Colorectal Cancer Recurrence" (http:/ / clinicaltrials. gov/ ct2/ show/ NCT00888797). . Retrieved 2010-07-19. [32] Laut-Labrze C et al. (June 2008). "Propranolol for Severe Hemangiomas of Infancy". New England Journal of Medicine 358 (24): 26492651. doi:10.1056/NEJMc0708819. PMID18550886. [33] Herndon DN et al. (October 2001). "Reversal of Catabolism by Beta-Blockade after Severe Burns". New England Journal of Medicine 345 (17): 12231229. doi:10.1056/NEJMoa010342. PMID11680441.
Propranolol
[34] Ohnishi S, Sadanaga K, Katsuoka M, Weidanz W (1990). "Effects of membrane acting-drugs on plasmodium species and sickle cell erythrocytes". Mol Cell Biochem 91 (12): 15965. doi:10.1007/BF00228091. PMID2695829. [35] Singh N, Puri S (2000). "Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant Plasmodium yoelii nigeriensis". Acta Trop 77 (2): 18593. doi:10.1016/S0001-706X(00)00133-9. PMID11080509. [36] Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K (December 2006). "Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy". PLoS Med 3 (12): e528. doi:10.1371/journal.pmed.0030528. PMC1716186. PMID17194200. [37] Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. [38] Young R, Glennon RA (April 2009). "S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats". Psychopharmacology (Berl.) 203 (2): 36982. doi:10.1007/s00213-008-1317-2. PMID18795268. [39] Wang, D. W., Mistry, A. M., Kahlig, K. M., Kearney, J. A., Xiang, J., and George, A. L. Jr. (2010). Propranolol blocks cardiac and neuronal voltage-gated sodium channels. Front. Pharmacol. 1:144. doi: 10.3389/fphar.2010.00144. [40] Bankston, J. R., and Kass, R. S. (2010). Molecular determinants of local anesthetic action of beta-blocking drugs: implications for therapeutic management of long QT syndrome variant 3. J. Mol. Cell. Cardiol. 48, 246253. [41] Desaphy, J. F., Pierno, S., De Luca, A., Didonna, P., and Camerino, D. C. (2003). Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders. Mol. Pharmacol. 63, 659670. [42] van Harten J (1995). "Overview of the pharmacokinetics of fluvoxamine". Clinical Pharmacokinetics 29 (Suppl 1): 19. doi:10.2165/00003088-199500291-00003. PMID8846617. [43] Laverdure B, Boulenger JP (1991). "[Beta-blocking drugs and anxiety. A proven therapeutic value]" (in French). L'Encphale 17 (5): 48192. PMID1686251. [44] *Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. [45] http:/ / www. google. com/ patents?vid=3337628 [46] [47] [48] [49] [50] http:/ / www. google. com/ patents?vid=3520919 http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=GB994918 http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE1493897 http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=BE640312 http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=BE640313
235
External links
Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart Institute Journal 24 (4): 33642. PMC325477. PMID9456487. Scientific American Interview with James McGaugh (http://www.sciam.com/article.cfm?chanID=sa004& articleID=0006783F-2CFE-1FE2-ACFE83414B7FFE9F&pageNumber=1&catID=4) CBS NEWS 60 Minutes: A Pill To Forget (http://www.cbsnews.com/stories/2006/11/22/60minutes/ main2205629.shtml) U.S. National Library of Medicine: Drug Information Portal - Propranolol (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=propranolol)
Esmolol
236
Esmolol
Esmolol
methyl (RS)-3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}propanoate
Clinical data AHFS/Drugs.com Pregnancy cat. Legal status Routes monograph
[1]
C(AU) C(US) ? iv Pharmacokinetic data
60% Erythrocytic 9 minutes Renal Identifiers
CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
103598-03-4 C07 AB09 CID 59768 DB00187 53916

[6]
[2]
[3] [4]
[5]
MDY902UXSR D07916
[8] [9]
[7]
CHEBI:4856
[10]
Formula Mol. mass
C H NO
16 25
295.374 g/mol
Esmolol
[11] [12]
237
SMILES
eMolecules (what is this?) (verify)
& PubChem
[13]
Esmolol (trade name Brevibloc) is a cardioselective beta1 receptor blocker with rapid onset,[14] a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages. It is a class II antiarrhythmic.[15] Esmolol decreases the force and rate of heart contractions by blocking beta-adrenergic receptors of the sympathetic nervous system, which are found in the heart and other organs of the body. Esmolol prevents the action of two naturally occurring substances: epinephrine and norepinephrine.
Dosing
Esmolol is given by slow intravenous injection. It is commonly used in patients during surgery to prevent or treat tachycardia, and is also used in treatment of acute supraventricular tachycardia. Esmolol is also the drug of choice when aortic dissection is suspected.
Metabolism
Esmolol is rapidly hydrolyzed by plasma esterases and not by plasma cholinesterases. Esmolol's short duration of action is based on the ester-methyl side chain which allows for quick hydrolysis. Esmolol's structure is reflected in its name, Es-molol as in ester-methyl. Plasma cholinesterases and red cell membrane acetylcholinesterase do not have any action. This metabolism results in the formation of a free acid and methanol. The amount of methanol produced is similar to endogenous methanol production. Its elimination half-life is about 9 minutes.
References
[1] [2] [3] [4] http:/ / www. drugs. com/ monograph/ esmolol-hydrochloride. html http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=103598-03-4& rn=1 http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AB09 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=59768
[5] http:/ / www. drugbank. ca/ drugs/ DB00187 [6] http:/ / www. chemspider. com/ Chemical-Structure. 53916 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=MDY902UXSR [8] http:/ / www. kegg. jp/ entry/ D07916 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:4856 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL768 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28OC%29CCc1ccc%28OCC%28O%29CNC%28C%29C%29cc1 [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28OC%29CCc1ccc%28OCC%28O%29CNC%28C%29C%29cc1 [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=412885041& page2=%3AEsmolol [14] Deng CY, Lin SG, Zhang WC et al. (December 2006). "Esmolol inhibits Na+ current in rat ventricular myocytes" (http:/ / journals. prous. com/ journals/ servlet/ xmlxsl/ pk_journals. xml_summaryn_pr?p_JournalId=6& p_RefId=1037498). Methods Find Exp Clin Pharmacol 28 (10): 697702. doi:10.1358/mf.2006.28.10.1037498. PMID17235414. . [15] Jaillon P, Drici M (December 1989). "Recent antiarrhythmic drugs". Am. J. Cardiol. 64 (20): 65J69J. doi:10.1016/0002-9149(89)91203-4. PMID2688391.
Timolol
238
Timolol
Timolol
(S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Timoptic monograph a602022
[2] [1]
C(AU) C(US) Prescription only oral, Ophthalmic Pharmacokinetic data
Bioavailability Metabolism Half-life Excretion
60% Hepatic: 80% 2.5-5 hours Renal Identifiers
26839-75-8 C07 AA06 CID 33624 565

[6]
[3]
[4] [5]
APRD00229 31013
[8]
[7]
5JKY92S7BR D08600
[10]
[9]
CHEBI:9599
[11]
[12]
Formula Mol. mass
C H NOS
13 24 4 3
316.421 g/mol
Timolol
[13] [14]
239
SMILES
eMolecules (what is this?) (verify)
& PubChem
[15]
Timolol maleate is a non-selective beta-adrenergic receptor blocker.
Uses
In its oral form (Blocadren), it is used: to treat high blood pressure to prevent heart attacks to prevent migraine headaches[16] In its ophthalmic form (brand names Timoptol in Italy; Timoptic), it is used to treat open-angle and occasionally secondary glaucoma by reducing aqueous humour production through blockage of the beta receptors on the ciliary epithelium. The pharmacological mechanism by which it actually does this is still unknown. First beta-blocker approved for topical use in treatment of glaucoma in the USA (1978). With monotherapy, depresses IOP 18-34% below baseline within first few treatments. However, there are short-term escape and long-term drift effects in some patients. That is, tolerance develops. May reduce extent of diurnal IOP curve up to 50%. IOP higher during sleep. 5-10x more potent beta-blocker than propranolol. Light sensitive; preserved with 0.01% benzalkonium Cl (and also comes BAC free). Can also be used in adjunctive therapy with pilocarpine or CAIs.
Side effects
The most serious possible side effects include cardiac arrhythmias and severe bronchospasms. Timolol can also lead to fainting, congestive heart failure, depression, confusion, worsening of Raynaud's syndrome and impotence.
Usual dosage
Children and Adults: Ophthalmic: Initial: 0.25% solution, instill 1 drop twice daily; increase to 0.5% solution if response not adequate; decrease to 1 drop/day if *controlled; do not exceed 2 drops twice daily of 0.5% solution Adults: Oral: Hypertension: Initial: 10mg twice daily, increase gradually every 14 days, usual dosage: 2040mg/day in 2 divided doses; maximum: 60mg/day Prevention of myocardial infarction: 10mg twice daily initiated within 16 weeks after infarction Migraine headache: Initial: 10mg twice daily, increase to maximum of 30mg/day
Formulations
Gel-forming solution, ophthalmic, as maleate (Timoptic-XE): 0.25% (2.5 mL, 5 mL); 0.5% (2.5 mL, 5 mL) Solution, ophthalmic, as hemihydrate (Betimol): 0.25% (5 mL, 10 mL, 15 mL); 0.5% (5 mL, 10 mL, 15 mL) [contains benzalkonium chloride] Solution, ophthalmic, as maleate: 0.25% (5 mL, 10 mL, 15 mL); 0.5% (5 mL, 10 mL, 15 mL) [contains benzalkonium chloride] Timoptic: 0.25% (5 mL, 10 mL); 0.5% (5 mL, 10 mL) [contains benzalkonium chloride] Solution, ophthalmic, as maleate [preservative free] (Timoptic OcuDose): 0.25% (0.2 mL);0.5% (0.2 mL) [single use] Tablet, as maleate (Blocadren): 5mg, 10mg, 20mg For ophthalmic use, timolol is also available combined with other medications:
Timolol Combigan - timolol and brimonidine Cosopt - timolol maleate and dorzolamide hydrochloride DuoTrav - timolol and travoprost Xalacom (Pfizer) - timolol and latanoprost
240
Brand names
In Canada: Apo-Timol, Apo-Timop, Gen-Timolol, Nu-Timolol, Phoxal-timolol, PMS-Timolol, Tim-AK, Timoptic, Timoptic-XE. In the United States: Betimol, Blocadren, Istalol, Timoptic, Timoptic-XE, Timoptic OcuDose.
Chemical synthesis
References
[1] http:/ / www. drugs. com/ monograph/ timolol-eent. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a602022. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=26839-75-8& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AA06 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=33624 [6] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=565 [7] http:/ / www. drugbank. ca/ drugs/ APRD00229 [8] http:/ / www. chemspider. com/ Chemical-Structure. 31013 [9] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=5JKY92S7BR [10] http:/ / www. kegg. jp/ entry/ D08600 [11] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:9599 [12] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL499 [13] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%5BC%40H%5D%28COc1nsnc1N2CCOCC2%29CNC%28C%29%28C%29C [14] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%5BC%40H%5D%28COc1nsnc1N2CCOCC2%29CNC%28C%29%28C%29C [15] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=457286138& page2=%3ATimolol
Timolol
[16] Dawn A. Marcus; Philip A. Bain (27 February 2009). Effective Migraine Treatment in Pregnant and Lactating Women: A Practical Guide (http:/ / books. google. com/ books?id=Z5YWpjj89NEC& pg=PA141). . pp.141. ISBN9781603274388. . Retrieved 14 November 2010.
241
External links
http://dx.doi.org/10.1021/jo00881a011
Metoprolol
242
Metoprolol
Metoprolol
(RS)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
Clinical data Trade names AHFS/Drugs.com MedlinePlus Licence data Pregnancy cat. Legal status Routes Lopressor, Toprol-xl monograph a682864
[2] [3] [1]
USFDA: link C(AU) C(US)
Prescription only Oral, IV Pharmacokinetic data
12% Hepatic via CYP2D6, CYP3A4 3-7 hours Renal Identifiers
51384-51-1 C07 AB02 CID 4171 553

[7]
[4]
[5]
[6]
APRD00208 4027
[9]
[8]
GEB06NHM23 D02358
[11]
[10]
CHEBI:6904 CHEMBL13 Chemical data
[12] [13]
Formula Mol. mass
C H NO
15 25
267.364g/mol
Metoprolol
[14] [15]
243
SMILES
eMolecules Physical data
& PubChem
Melt. point
120C (248F) (what is this?) (verify)

[16]
Metoprolol ( /mtoproll/) is a selective 1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate (where 100mg metoprolol tartrate corresponds to 95mg metoprolol succinate). The tartrate is an immediate-release and the succinate is an extended-release formulation[17] .
Medical uses
Metoprolol is used for a number of conditions including: hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches.[18] Treatment of heart failure.[19] Vasovagal syncope[20] Adjunct in treatment of hyperthyroidism Long QT syndrome, especially for patients with asthma, as metoprolol's 1 selectivity tends to interfere less with asthma drugs which are often 2-adrenergic receptor-agonist drugs
Due to its selectivity in blocking the beta1 receptors in the heart, metoprolol is also prescribed for off-label use in performance anxiety, social anxiety disorder, and other anxiety disorders.
Metabolism
Metoprolol undergoes a-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6 [21] and a small percentage by CYP3A4.
Adverse effects
Side effects, especially with higher dosages, include the following: dizziness, drowsiness, fatigue, diarrhea, unusual dreams, ataxia, trouble sleeping, depression, and vision problems. It may also reduce blood flow to the hands and feet, causing them to feel numb and cold; smoking may worsen this effect.[22] Serious side effects which are advised to be reported immediately include, but are not limited to, symptoms of bradycardia (a very slow heartbeat (less than 50bpm)), persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of the fingers and toes, numbness/tingling/swelling of the hands or feet, sexual dysfunction, erectile dysfunction (impotence), hair loss, mental/mood changes, depression, trouble breathing, cough, dyslipidemia, and increased thirst. Other highly unlikely symptoms include easy bruising or bleeding, persistent sore throat or fever, yellowing skin or eyes, stomach pain, dark urine, and persistent nausea. Symptoms of an allergic reaction include: rash, itching, swelling, and severe dizziness. Taking it with alcohol might cause mild body rashes and therefore is not recommended.[22]
Metoprolol
244
Precautions
Metoprolol may worsen the symptoms of heart failure in some patients, who may experience chest pain or discomfort; dilated neck veins; extreme fatigue; irregular breathing; an irregular heartbeat; shortness of breath; swelling of the face, fingers, feet, or lower legs; weight gain; or wheezing.[23] This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.[23] This medicine may cause some people to become less alert than they are normally, making it dangerous for them to drive, use machines, or do other things.[23]
Overdosage
Excessive doses of metoprolol can cause severe hypotension, bradycardia, metabolic acidosis, seizures and cardiorespiratory arrest. Blood or plasma concentrations may be measured to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 200 g/L during therapeutic administration, but can range from 1-20 mg/L in overdose victims.[24] [25] [26]
Physical properties
Metoprolol has a very low melting point, around 138 C. Because of this metoprolol is always manufactured in a salt-based solution, as drugs with melting points below 100 C are difficult to work with in a manufacturing environment. The free base exists as a waxy white solid, and the tartrate salt is finer crystalline material.(Metox-Wockhardt)
Pharmacology
Selective Moderately lipophilic Without intrinsic sympathomimetic activity (ISA) With weak membrane stabilizing activity Short half-life, therefore must be taken at least twice daily or as a slow-release preparation Decreases heart rate, contractility and cardiac output, therefore decreasing blood pressure Metabolized in the liver to inactive metabolite
Metoprolol
245
Chemistry
Metoprolol, 1-(iso-propylamino)-3-[4(2-methoxyethyl)phenoxy]-2-propanol, is synthesized by reacting 4-(2-methoxyethyl)phenol with epichlorohydrin in the presence of a base, isolating 1,2-epoxy-3-[4(2-methoxyethyl)phenoxy]propane, the subsequent reaction with isopropylamine, gives an opening of the epoxide ring and leads to the formation of metoprolol.
P.A.E. Carlsson, S.A.I. Carlsson, H.R. Corrodi, L.Ek, B.A.H. Ablad, A.E. Brandstrom, U.S. Patent 3873600 [27] (1975). A.E. Brandstrom, P.A.E. Carlsson, S.A.I. Carlsson, H.R. Corrodi, L.Ek, DE 2106209 [28] (1971).
Brand names
It is marketed under the brand name Lopressor by Novartis, and Toprol-XL (in the USA); Selokeen (in the Netherlands); as Minax by Alphapharm (in Australia), Metrol by Arrow Pharmaceuticals (in Australia), as Betaloc by AstraZeneca, as Bloxan by Krka (company) (in Slovenia), as Neobloc by Unipharm (in Israel), Presolol by Hemofarm (in Serbia) and as Corvitol by Berlin-Chemie AG (in Germany). In India, this drug is available under the brand names of Metxl, Metolar and Starpress. A number of generic products are available as well.
Toprol XL 50 mg
References
[1] http:/ / www. drugs. com/ monograph/ metoprolol-succinate. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682864. html [3] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Metoprolol& SearchType=BasicSearch [4] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=51384-51-1& rn=1 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AB02 [6] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4171 [7] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=553 [8] http:/ / www. drugbank. ca/ drugs/ APRD00208 [9] http:/ / www. chemspider. com/ Chemical-Structure. 4027 [10] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=GEB06NHM23 [11] http:/ / www. kegg. jp/ entry/ D02358 [12] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:6904 [13] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL13 [14] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%28c1ccc%28cc1%29CCOC%29CC%28O%29CNC%28C%29C
Metoprolol
[15] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%28c1ccc%28cc1%29CCOC%29CC%28O%29CNC%28C%29C [16] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=459444186& page2=%3AMetoprolol [17] Pharmacist's Letter/Prescriber's Letter 25 (250302). 2009. http:/ / www. ncbop. org/ PDF/ MetoprololShortageMarch2009. pdf. Retrieved 3 June 2011. [18] "Metoprolol" (http:/ / www. drugs. com/ monograph/ metoprolol-succinate. html). The American Society of Health-System Pharmacists. . Retrieved 3 April 2011. [19] "Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)". Lancet 353 (9169): 20017. June 12 1999. doi:10.1016/S0140-6736(99)04440-2. PMID10376614. [20] Zhang Q, Jin H, Wang L, Chen J, Tang C, Du J (April 2008). "Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents" (http:/ / www. medscimonit. com/ fulltxt. php?ICID=850297). Medical science monitor : international medical journal of experimental and clinical research 14 (4): CR199203. PMID18376348. . [21] Clin Pharmacokinet. 2005;44(10):1067-81. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild MJ. [22] Metoprolol (http:/ / www. drugs. com/ metoprolol. html), drugs.com [23] MayoClinic.com Drug Information Metoprolol Precautions (http:/ / www. mayoclinic. com/ health/ drug-information/ DR602483/ DSECTION=precautions-) [24] Page C, Hacket LP, Isbister GK. The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report. J. Med. Tox. 5: 139-143, 2009. [25] Albers S, Elshoff JP, Vlker C, Richter A, Ler S. HPLC quantification of metoprolol with solid-phase extraction for the drug monitoring of pediatric patients. Biomed. Chromatogr. 19: 202-207, 2005. [26] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1023-1025. [27] http:/ / www. google. com/ patents?vid=3873600 [28] http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE2106209
246
External links
AstraZeneca's page for Toprol-XL (http://www.toprol-xl.com/index.aspx) Novartis's page for Lopressor (http://www.pharma.us.novartis.com/product/pi/pdf/lopressor.pdf) (PDF) U.S. National Library of Medicine: Drug Information Portal - Metoprolol (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Metoprolol)
Atenolol
247
Atenolol
Atenolol
(RS)-2-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}acetamide
Clinical data Trade names AHFS/Drugs.com MedlinePlus Licence data Pregnancy cat. Legal status Routes Tenormin monograph a684031
[2] [3] [1]
USFDA: link C(AU) D(US)
Prescription only Oral or IV Pharmacokinetic data
40-50% 6-16% Hepatic <10% 6-7hours Renal Lactic (In lactiferous females) Identifiers
CAS number ATC code PubChem
29122-68-7 C07 AB03 CID 2249
[4]
[5]
[6]
Atenolol
[7] [8]
248
IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
548
APRD00172 2162
[9]
50VV3VW0TI D00235
[11]
[10]
CHEBI:2904 CHEMBL24 Chemical data
[12] [13]
C14H22N2O3 266.336 g/mol eMolecules (what is this?) (verify)

[14]
& PubChem
[15]
[16]
Atenolol is a selective 1 receptor antagonist, a drug belonging to the group of beta blockers (sometimes written -blockers), a class of drugs used primarily in cardiovascular diseases. Introduced in 1976, atenolol was developed as a replacement for propranolol in the treatment of hypertension. The chemical works by slowing down the heart and reducing its workload. Unlike propranolol, atenolol does not pass through the blood-brain barrier thus avoiding various central nervous system side effects.[17] Atenolol is one of the most widely used -blockers in the United Kingdom and was once the first-line treatment for hypertension. The role for -blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line, as they perform less appropriately or effectively than newer drugs, particularly in the elderly. Some evidence suggests that even in normal doses the most frequently used -blockers carry an unacceptable risk of provoking type 2 diabetes.[18]
Medical uses
Atenolol is used for a number of conditions including: hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, prevention of migraine headaches, and the symptoms of alcohol withdrawal.[19] It is also used to treat the symptoms of Graves Disease, until antithyroid medication can take effect. Due to its hydrophilic properties, the drug is less suitable in migraine prophylaxis compared to propranolol, because, for this indication, atenolol would have to reach the brain in high concentrations, which is not the case.
Hypertension
If atenolol alone fails to control arterial hypertension, the drug can be combined with a diuretic (e.g. with chlortalidone in co-tenidone) and/or a vasodilator (hydralazine, or in severe cases minoxidil). Central alpha-agonists (e.g. clonidine), ACE Inhibitors or Angiotensin II receptor antagonists such as losartan can also be given additionally. Exert caution with calcium-antagonists of the verapamil-type (non-Dihydropyridine, see also Diltiazem) as adjunct therapy because of additional negative impact on the muscular strength of the heart. Use of calcium-antagonists of the nifedipine-type is controversial.
Atenolol
249
Contraindications
bradycardia (pulse less than 50 bpm) cardiogenic shock asthma (may cause broncho-constriction), although unlikely as atenolol is cardioselective symptomatic hypotension (blood pressure of less than 90/60mm Hg with dizziness, vertigo etc.) angina of the Prinzmetal type (vasospastic angina) metabolic acidosis (a severe condition with a more acidic blood than normal) severe disorders in peripheral arterial circulation AV-Blockage of second and third degree (a particular form of arrhythmia) acutely decompensated congestive heart failure (symptoms may be fluid retention with peripheral edema and/or abdominal fluid retention (ascites), and/or lung edema) sick sinus syndrome (a particular form of arrhythmia) hypersensitivity and/or allergy to atenolol pheochromocytoma (a rare type of tumor of the adrenal glands) Caution: patients with preexisting bronchial asthma Caution: only if clearly needed during pregnancy, as atenolol may retard fetal growth and possibly cause other abnormalities.
Side effects
Atenolol causes significantly fewer central nervous system side effects (depression, nightmares) and fewer bronchospastic reactions, both due to its particular pharmacologic profile. It was the main -blocker identified as carrying a higher risk of provoking type 2 diabetes, leading to its downgrading in the United Kingdom in June 2006 to fourth-line agent in the management of hypertension.[18] In addition, -blockers blunt the usual sympathetic nervous system response to hypoglycemia (i.e. sweating, agitation, tachycardia). These drugs therefore have an ability to mask a dangerously low blood sugar, which further decreases their safety and utility in diabetic patients. Side effects include: indigestion, constipation dry mouth dizziness or faintness (especially cases of orthostatic hypotension) cold extremities hair loss impotence rhinitis depression confusion insomnia, nightmares fatigue, weakness or lack of energy
These side effects may or may not be experienced, but if they are, you should notify your doctor. More serious side effects can include: hallucinations low blood pressure (hypotension) skin reactions, e.g. rash, hives, flaking of skin, worsening of psoriasis sensation of 'pins and needles' hands or feet
Atenolol irritated eyes, visual disturbances difficulty hearing difficulty speaking unsteadiness when walking
250
Serious side effects may require urgent medical attention. Some of these side effects are rare and others (not mentioned in the above list) can occur in some people.
Asthma
Atenolol is classified as a 1-selective (or 'cardioselective') drug, one that exerts greater blocking activity on myocardial 1-receptors than on 2 receptors in the lung. The 2 receptors are responsible for keeping the bronchial system open. If these receptors are blocked, bronchospasm with serious lack of oxygen in the body can result. However, due to its cardioselective properties, the risk of bronchospastic reactions if using atenolol is reduced compared to nonselective drugs as propranolol. Nonetheless, this reaction may also be encountered with atenolol at high doses. Although traditionally B-blockers have been contraindicated when a person carries a diagnosis of asthma, recent studies have revealed that at moderate doses selective B blockers such as Atenolol are well tolerated. Provisional data suggests that antihypertensive therapy with atenolol provides weaker protective action against cardiovascular complications (e.g. myocardial infarction and stroke) compared to other antihypertensive drugs. In some cases, diuretics are superior. However, controlled studies are lacking.[20] Unlike most other commonly-used -blockers, atenolol is excreted almost exclusively by the kidneys. This makes it attractive for use in individuals with end-stage liver disease.
Overdose
Symptoms of overdose are due to excessive pharmacodynamic actions on 1 and also 2-receptors. These include bradycardia, severe hypotension with shock, acute heart failure, hypoglycemia and bronchospastic reactions. Treatment is largely symptomatic. Hospitalization and intensive monitoring is indicated. In early cases emesis can be induced. Activated charcoal is useful to absorb the drug. Atropine will counteract bradycardia, glucagon helps with hypoglycemia, dobutamine can be given against hypotension and the inhalation of a 2-mimetic as hexoprenalin or salbutamol will terminate bronchospasms. Blood or plasma atenolol concentrations may be measured to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 3mg/L during therapeutic administration, but can range from 330mg/L in overdose victims.[21]
[22]
Pregnancy
FDA pregnancy category D. This medication can cause harm to an unborn baby. Do not use atenolol if you are pregnant. Tell your doctor if you become pregnant during treatment. Use an effective form of birth control while you are using this medication. Atenolol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.[23]
Pharmacokinetic data
tcmax = 2 to 4 hours after oral dosing (time elapsed before maximal concentration in the blood plasma is reached) The mean elimination halflife is 6 hours. However, the action of the usual oral dose of 25 to 100mg lasts over a period of 24 hours. Atenolol is a hydrophilic drug. The concentration found in brain tissue is approximately 15% of the plasma concentration only. The drug crosses the placenta barrier freely. In the milk of breastfeeding mothers, approximately 3 times the plasma concentrations are measured.
Atenolol Atenolol is almost exclusively eliminated renally and is well removable by dialysis. A compromised liver function does not lead to higher peak-activity and/or a longer halflife with possible accumulation.
251
Popular Culture
Atenolol has been referenced as the gateway drug for treating hypertension. It is the most widely prescribed drug for this use but patients do not often remain on it because of the side effects it carries.
References
[1] http:/ / www. drugs. com/ monograph/ atenolol. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a684031. html [3] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Atenolol& SearchType=BasicSearch [4] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=29122-68-7& rn=1 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AB03 [6] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2249 [7] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=548 [8] http:/ / www. drugbank. ca/ drugs/ APRD00172 [9] http:/ / www. chemspider. com/ Chemical-Structure. 2162 [10] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=50VV3VW0TI [11] http:/ / www. kegg. jp/ entry/ D00235 [12] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:2904 [13] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL24 [14] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%28N%29Cc1ccc%28OCC%28O%29CNC%28C%29C%29cc1 [15] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%28N%29Cc1ccc%28OCC%28O%29CNC%28C%29C%29cc1 [16] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=458476745& page2=%3AAtenolol [17] Agon P, Goethals P, Van Haver D, Kaufman JM (August 1991). "Permeability of the blood-brain barrier for atenolol studied by positron emission tomography". J. Pharm. Pharmacol. 43 (8): 597600. PMID1681079. [18] Sheetal Ladva (2006-06-30). "Updated NICE guideline on the management of hypertension in adults in primary care" (http:/ / www. nelm. nhs. uk/ en/ NeLM-Area/ Evidence/ Guidelines/ Updated-NICE-guideline-on-the-management-of-hypertension-in-adults-in-primary-care/ ). National Institute for Health and Clinical Excellence. . Retrieved 2009-02-03. [19] "Atenolol" (http:/ / www. drugs. com/ monograph/ atenolol. html). The American Society of Health-System Pharmacists. . Retrieved 3 April 2011. [20] Carlberg B, Samuelsson O, Lindholm LH (2004). "Atenolol in hypertension: is it a wise choice?". Lancet 364 (9446): 16849. doi:10.1016/S0140-6736(04)17355-8. PMID15530629. [21] DeLima LG, Kharasch ED, Butler S. Successful pharmacologic treatment of massive atenolol overdose: sequential hemodynamics and plasma atenolol concentrations. Anesthesiology 83:204-207, 1995. [22] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 116-117. [23] "Atenolol, Prescription Marketed Drugs, www.drugsdb.eu" (http:/ / www. drugsdb. eu/ drug. php?d=Atenolol& m=State Of Florida Doh Central Pharmacy& id=b9f26cb9-7155-4c81-9b2e-7f1d72bddc46. xml). .
External links
Atenolol (http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Atenolol) U.S. National Library of Medicine: Drug Information Portal
Bisoprolol
252
Bisoprolol
Bisoprolol
(RS)-1-{4-[(2-isopropoxyethoxy)methyl]phenoxy}3-(isopropylamino)propan-2-ol
Clinical data Trade names Zebeta
AHFS/Drugs.com monograph [1] MedlinePlus Licence data Pregnancy cat. Legal status Routes a693024
[2] [3]
USFDA: link C(AU) C(US)
Prescription only oral Pharmacokinetic data
Bioavailability Protein binding Metabolism Half-life
>90% 30%
[4]
50% Hepatic 1012hours Identifiers

[5]
CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
66722-44-9 C07 AB07 CID 2405
[6]
[7]
[8] [9]
APRD00257 2312
[10]
Y41JS2NL6U D02342
[12]
[11]
CHEBI:3127
[13]
[14]
Formula
C H NO
18 31
Bisoprolol
253
Mol. mass SMILES 325.443 g/mol eMolecules
[15]
& PubChem
[17]
[16]
Bisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type 1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets (Bisoprolol Fumarate) as a new molecular entity on July 31, 1992. It has since been approved by the FDA for manufacture by Teva, Mylan, Sandoz, and Mutual Pharmaceutical Company.[18]
Clinical use
Bisoprolol is beneficial in treatment for: high blood pressure (hypertension), reduced blood flow to the heart (cardiac ischemia); preventative treatment before and primary treatment after heart attacks decreasing the chances of recurrence.[19] During hypertension there is an elevated blood pressure, which is what Bisoprolol targets.[20] [21] While in cardiac ischemia the drug is used to reduce the activity of the heart muscle and therefore reduce oxygen and nutrient demand, so reduced blood supply can still transport sufficient amounts of oxygen and nutrients. [24][27][30] Many beta-blockers are now available and in general they are all equally effective. There are, however, differences between them which may affect choice in treating particular diseases or individual patients. Beta-blockers with a relatively short duration of action have to be given two or three times daily. Many of these are, however, available in modified-release formulations so that administration once daily is adequate for hypertension. For angina twice-daily treatment may sometimes be needed even with a modified-release formulation. Some beta-blockers such as atenolol, bisoprolol, carvedilol, celiprolol, and nadolol have an intrinsically longer duration of action and need to be given only once daily.
Mechanism of Action
Bisoprolol is cardioprotective because it selectively and competitively blocks catecholamine (adrenalin) stimulation of beta-1 adrenergic receptors (1 adrenoreceptor) mainly found in the heart muscle cells and heart conduction tissue (cardio specific) but also found in juxtaglomerular cells in the kidney [24]. Normally adrenalin and noradrenalin stimulation of the 1 adrenoreceptor activates a signalling cascade (Gs protein and cAMP) which ultimately lead to increased contractility and increased heart rate of the heart muscle and heart pacemaker respectively [23]. Bisoprolol competitively blocks the activation of this cascade and therefore decreases the adrenergic tone/stimulation of the heart muscle and pacemaker cells. Decreased adrenergic tone shows less contractility of heart muscle and lowered heart rate of heart pacemaker [25][28][29]. These are the favourable factors that are decreased and treat hypertension, heart attacks and ischemia. The decreases in contractility and heart rate are beneficial for hypertension because they reduce blood pressure[20] [27] but for preventative measures for heart attacks and cardiac ischemia these decreases in heart rate and contraction decrease the hearts demand for oxygen and nutrients; primary treatment post heart attacks is to prevent recurrence of the infarction [27][30][21] .
Bisoprolol
254
Cautions
Beta-blockers can precipitate asthma and this effect can be dangerous. Beta-blockers should be avoided in patients with a history of asthma or bronchospasm; if there is no alternative, a cardioselective beta-blocker can be used with extreme caution under specialist supervision. Atenolol, bisoprolol, metoprolol, nebivolol, and (to a lesser extent) acebutolol, have less effect on the beta2 (bronchial) receptors and are, therefore, relatively cardioselective, but they are not cardiospecific. They have a lesser effect on airways resistance but are not free of this side effect.
Side effects
Overdose of Bisoprolol leads to fatigue, hypotension[27], low blood sugar [29], bronchospasms and bradycardia [27]. Bronchospasms and low blood sugar because at high doses drug can be an antagonist for 2 adrenergic receptors located in lung and in liver. Bronchspasm due to blockage in lungs of 2 receptor and low blood sugar because of decreased stimulation of glycogenolysis and gluconeogenesis in the liver via 2 receptor.[24][26][27]
Indications
Bisoprolol (Concor,[22] Zebeta,[23] Concore,[24] Monocor[25] ) can be used to treat cardiovascular diseases such as hypertension, coronary heart disease, arrhythmias, ischemic heart diseases and treatment of myocardial infarction after the acute event. Patients with compensated congestive heart failure may be treated with Bisoprolol as a comedication (usually together with an ACE inhibitor, a diuretic and a digitalis-glycosid, if indicated). In patients with congestive heart failure, it reduces the need for and the consumption of oxygen of the heart muscle. It is very important to start with low doses, as bisoprolol reduces also the muscular power of the heart, which is an undesired
Zebeta 5 MG Oral Tablet
effect in congestive heart failure. The drug is also used to treat other conditions, including dysautonomia, anxiety and hyperthyroidism (over active thyroid gland). Bisoprolol will give a positive result in doping tests.[26]
Bisoprolol
255
Pharmacology and biochemistry

Bisoprolol has both lipid and water soluble properties making it a prime candidate over other -blockers and even over other 1-blockers, being water soluble it will have decreased incidence of central nervous system side effects (inability to diffuse into brain) compared to purely lipophilic compounds [25][28]. Bisoprolol has an approximate half-life of 10-12 hours and when ingested has nearly complete absorption into the blood stream[28][29]. The high absorption is indicative of high bioavailability (approx. 90%)[28][29]. When being eliminated, the body evenly distributes it (50-50) between kidney excretion Selectivity of various -blockers and liver biotransformation (then excreted) [25][28][29]. These factors make it a convenient once/day dosage when its being administered. [28][29]
1 Selectivity
Bisoprolol beta 1-selectivity is especially important in comparison to other non-selective beta blockers. The effects of the drug are limited to areas containing 1 adrenoreceptors which is mainly the heart and a little bit of the kidney [25][28]. Bisoprolol minimizes the side effects that might occur from administration of a non-specific beta blocker where blockage of the other adrenoreceptors (2, 3, 1, 2) occurs. The other receptors elicit a variety of responses in the body and blockage of them could cause a wide range of reactions; but 1 adrenoreceptors are cardio specific for the most part, making Bisoprolol ideal for treatment of cardiac events [25][29]. Bisoprolol has a higher degree of 1-selectivity compared to other 1-selective -blockers such as atenolol, metoprolol and betaxolol.[27] [28] [29] [30] [31] [32] [33] [34] [35] [36] However Nebivolol is approximately 3.5 times more 1-selective.[37] [38]
Antihypertensive effect
Bisoprolol has a stronger antihypertensive effect than propranolol.[27]
Cardioprotection
Bisoprolol in animal models has been shown to be cardioprotective.[27]
Renin-angiotensin system
Bisoprolol inhibits renin secretion by about 65% and tachycardia by about 35%.[27]
Pharmacology of side effects

In animal testing bisoprolol compared to propranolol has shown less sedative effects and only slightly reduced glucose tolerance.[39]
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References
[1] http:/ / www. drugs. com/ monograph/ zebeta. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a693024. html [3] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Bisoprolol& SearchType=BasicSearch [4] Bhring KU, Sailer H, Faro HP, Leopold G, Pabst J, Garbe A (1986). "Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans". J. Cardiovasc. Pharmacol. 8 Suppl 11: S218. PMID2439794. [5] Leopold G (1986). "Balanced pharmacokinetics and metabolism of bisoprolol". J. Cardiovasc. Pharmacol. 8 Suppl 11: S1620. PMID2439789. [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=66722-44-9& rn=1 [7] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AB07 [8] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2405 [9] http:/ / www. drugbank. ca/ drugs/ APRD00257 [10] http:/ / www. chemspider. com/ Chemical-Structure. 2312 [11] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=Y41JS2NL6U [12] http:/ / www. kegg. jp/ entry/ D02342 [13] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:3127 [14] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL645 [15] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%28c1ccc%28cc1%29COCCOC%28C%29C%29CC%28O%29CNC%28C%29C [16] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%28c1ccc%28cc1%29COCCOC%28C%29C%29CC%28O%29CNC%28C%29C [17] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=443424134& page2=%3ABisoprolol [18] http:/ / www. drugs. com/ pro/ bisoprolol. html [19] Rosenberg, Jens, and Finn Gustafsson. "Bisoprolol for Congestive Heart Failure." Expert Opinion on Pharmacotherapy 9.2 (2008): 293-300. Print [20] Amabile, G. And Serradimigni, A. "Comparison of bisoprolol with nifedipine for treatment of essential hypertension in the elderly: Comparative double-blind trial European Heart Journal 8 (1987): 65-69. Web. 5 Feb. 2011 [21] Thadani, Udho. "Beta Blockers in Hypertension." The American Journal of Cardiology 52.9 (1983): D10-15. Web. 6 Feb. 2011 [22] Bisoprolol at Merck Serono (http:/ / www. bisoprolol. com) [23] "Prescription Drugs: Zebeta" (http:/ / www. pdrhealth. com/ drugs/ rx/ rx-mono. aspx?contentFileName=Zeb1667. html& contentName=Zebeta& contentId=651). Physicians' Desktop Reference. . Retrieved 2007-12-23. [24] "Pharmaceuticals" (http:/ / web. archive. org/ web/ 20071222004138/ http:/ / www. merck. ph/ index. php?option=com_content& task=view& id=23& Itemid=48). Merck Philippines. Archived from the original (http:/ / www. merck. ph/ index. php?option=com_content& task=view& id=23& Itemid=48) on 2007-12-22. . Retrieved 2008-01-01. [25] "Products: Monocor" (http:/ / www. biovail. com/ english/ products/ default. asp?s=1& product=10& viewer=patient& state=displayProduct& country=Canada). Biovail Corporation. . Retrieved 2007-12-23. [26] Ratiopharm packing slip, dated 03.08.2006 [27] Harting J, Becker KH, Bergmann R, et al. (February 1986). "Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol". Arzneimittelforschung 36 (2): 2008. PMID2870720. [28] Haeusler G, Schliep HJ, Schelling P, et al. (1986). "High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol". J. Cardiovasc. Pharmacol. 8 Suppl 11: S215. PMID2439793. [29] Kaumann AJ, Lemoine H (October 1985). "Direct labelling of myocardial beta 1-adrenoceptors. Comparison of binding affinity of 3H-(-)-bisoprolol with its blocking potency". Naunyn Schmiedebergs Arch. Pharmacol. 331 (1): 2739. PMID2866449. [30] Klockow M, Greiner HE, Haase A, Schmitges CJ, Seyfried C (February 1986). "Studies on the receptor profile of bisoprolol". Arzneimittelforschung 36 (2): 197200. PMID2870719. [31] Manalan AS, Besch HR, Watanabe AM (August 1981). "Characterization of [3H](+/-)carazolol binding to beta-adrenergic receptors. Application to study of beta-adrenergic receptor subtypes in canine ventricular myocardium and lung". Circ. Res. 49 (2): 32636. PMID6113900. [32] Schliep HJ, Schulze E, Harting J, Haeusler G (April 1986). "Antagonistic effects of bisoprolol on several beta-adrenoceptor-mediated actions in anaesthetized cats". Eur. J. Pharmacol. 123 (2): 25361. doi:10.1016/0014-2999(86)90666-7. PMID3011461. [33] Schliep HJ, Harting J (1984). "Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs". J. Cardiovasc. Pharmacol. 6 (6): 115660. doi:10.1097/00005344-198406060-00024. PMID6084774. [34] Schnabel P, Maack C, Mies F, Tyroller S, Scheer A, Bhm M (October 2000). "Binding properties of beta-blockers at recombinant beta1-, beta2-, and beta3-adrenoceptors" (http:/ / meta. wkhealth. com/ pt/ pt-core/ template-journal/ lwwgateway/ media/ landingpage. htm?issn=0160-2446& volume=36& issue=4& spage=466). J. Cardiovasc. Pharmacol. 36 (4): 46671. PMID11026647. . [35] Smith C, Teitler M (April 1999). "Beta-blocker selectivity at cloned human beta 1- and beta 2-adrenergic receptors" (http:/ / www. kluweronline. com/ art. pdf?issn=0920-3206& volume=13& page=123). Cardiovasc Drugs Ther 13 (2): 1236. doi:10.1023/A:1007784109255. PMID10372227. .
Bisoprolol
[36] Wellstein A, Palm D, Belz GG (1986). "Affinity and selectivity of beta-adrenoceptor antagonists in vitro". J. Cardiovasc. Pharmacol. 8 Suppl 11: S3640. PMID2439796. [37] Bundkirchen A, Brixius K, Blck B, Nguyen Q, Schwinger RH (January 2003). "Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies". Eur. J. Pharmacol. 460 (1): 1926. doi:10.1016/S0014-2999(02)02875-3. PMID12535855. [38] Nuttall SL, Routledge HC, Kendall MJ (June 2003). "A comparison of the beta1-selectivity of three beta1-selective beta-blockers". J Clin Pharm Ther 28 (3): 17986. doi:10.1046/j.1365-2710.2003.00477.x. PMID12795776. [39] Lettenbaur H. EMD 33 512 (Bisoprolol): Prfung der Wirkung auf die Serumglukosekonzentration an Ratten im Vergleich zu Propranolol. Merck KGaA, Darmstadt, 1979.
257
23. Bristow, MR., Hershberger, RE., Port, JD., Minobe, W., Rasmussen, R. Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium Molecular Pharamcology 35 (1989): 295-203. Web. 5 Feb. 2011. 24. CIBIS Investigators and Committees. "A Randomized Trial of Beta-blockade in Heart Failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS)." Circulation 90 (1994): 1765-773. Web. 4 Feb. 2011. 25. Haeusler, G., HJ Schliep ... Ect. All. "High Beta 1-selectivity and Favourable Pharmacokinetics as the Outstanding Properties of Bisoprolol." Journal of Cardiovascular Pharmacology 2-15 8 (1986). Web. 5 Feb. 2011. 26. Hauck, R. W., Ch Schulz, H. P. Emslander, and *M Bohm. "Pharmacological Actions of the Selective and Non-selective Beta-adrenoceptor Antagonists Celiprolol, Bisoprolol and Propranolol on Human Bronchi." British Journal of Pharmacology (1994): 1043-049. Web. 5 Feb. 2011. 27. Konishi, M., and G. Haraguchi ... Ect. All. "Comparative Effects of Carvedilol vs Bisoprolol for Severe Congestive Heart Failure." Circulation 6 (2010): 1127-134. Web. 6 Feb. 2011. 28. Leopold, G., W. Ungethcm ... Etc. All. "Basic Pharmacokinetics of Bisoprolol, a New Highly Beta 1-selective Adrenoceptor Antagonist." Journal of Clinical Pharmacology 26 (1986): 616-21. Web. 7 Feb. 2011 29. Leopold, G., W. Ungethcm ... Etc. All. "Pharmacodynamic Profile of Bisoprolol, a New Beta1-selective Adrenoceptor Antagonist." British Journal of Clinical Pharmacology 22 (1986): 293-300. Web. 6 Feb. 2011. 30. Poolewilson, P. "The Cardiac Insufficiency Bisoprolol Study II." The Lancet 353.9161 (1999): 1360. Print.
External links
Monocor Prescribing information (http://www.biovail.com/include/asp/filedownload.asp?color=white& disposition=inline&getFile={77045530-E1A8-4636-8750-2C9C4C216F4E}) (PDF)
258
Type III Antiarrythmics

Amiodarone
Amiodarone
(2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Cordarone monograph a687009 D(US) Prescription only oral or intravenous Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 20 - 55% Liver 58 days (range 15-142 days) Primarily Hepatic and Biliary Identifiers CAS number ATC code PubChem DrugBank ChemSpider 1951-25-3 C01 BD01 CID 2157
[3] [2] [1]
[4]
[5] [6]
APRD00288 2072
[7]
Amiodarone
[8]
259
UNII KEGG ChEBI ChEMBL
N3RQ532IUT D02910
[9]
CHEBI:2663
[10]
[11]
C25H29I2NO3 645,31 g/mol eMolecules (what is this?) (verify)

[12]
& PubChem
[13]
[14]
Amiodarone is an antiarrhythmic agent (medication used for irregular heart beat) used for various types of tachyarrhythmias (fast forms of irregular heart beat), both ventricular and supraventricular (atrial) arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985. Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication. Related newer compounds, such as dronedarone, have lower efficacy but a reduced rate of side-effects.
History
Amiodarone was initially developed in 1961 at the Labaz company, Belgium, by chemists Tondeur and Binon. It became popular in Europe as a treatment for angina pectoris.[15] [16] As a doctoral candidate at Oxford University, Dr. Bramah Singh determined that amiodarone and sotalol had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents).[17] Today the mechanisms of action of amiodarone and sotalol remain unknown. It is thought to involve prolonging the action potential duration, prolonging the refractory period, or interacting with K+ channels. Based on Singh's work, the Argentinian physician Dr. Mauricio Rosenbaum began using amiodarone to treat his patients who suffered from supraventricular and ventricular arrhythmias, with impressive results. Based on papers written by Dr. Rosenbaum developing Singh's theories, physicians in the United States began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s.[18] [19] By 1980, amiodarone was commonly prescribed throughout Europe for the treatment of arrhythmias, but in the U.S. amiodarone remained unapproved by the Food and Drug Administration, and physicians were forced to directly obtain amiodarone from pharmaceutical companies in Canada and Europe. The FDA was reluctant to officially approve the use of amiodarone, since initial reports had shown increased incidence of serious pulmonary side-effects of the drug. In the mid 1980s, the European pharmaceutical companies began putting pressure on the FDA to approve amiodarone by threatening to cut the supply to American physicians if it were not approved. In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias.[20] This makes amiodarone one of the few drugs approved by the FDA without rigorous randomized clinical trials.
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Dosing
Amiodarone is available in oral and intravenous formulations. Orally, it is available under the trade names Pacerone (produced by Upsher-Smith Laboratories, Inc.) and Cordarone (produced by Wyeth-Ayerst Laboratories) in 200 mg and 400mg tablets; It is also available under the trade name Aratac (produced by Alphapharm Pty Ltd) in 100mg and 200mg tablets in Australia and New Zealand. Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.) in doses of 100mg and 200mg scored tablets. In South America, it is known as Atlansil and is produced by Roemmers. It is also available in intravenous ampules and vials, typically in 150mg increments. The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated. When administered orally, the bioavailability of amiodarone is quite variable. Absorption ranges from 22 to 95%, with better absorption when it is given with food.[21] Amiodarone is fat-soluble, and tends to concentrate in tissues including fat, muscle, liver, lungs, and skin. This confers a high volume of distribution (5000 liters in a 70kg adult) and a long half-life. Due to the long half-life of amiodarone, oral loading typically takes days to weeks. An oral loading dose is typically a total of 10grams, divided over one to two weeks but there are many other dosing regimens. Once an individual is loaded, a typical maintenance dose of amiodarone is 100 or 200mg either once or twice daily. An intravenous loading dose is typically 300mg in 20-30cc D5W for cardiac arrest. The loading infusion for dysrhythmias is typically 150mg in a 100cc bag of D5W given over 10 minutes. Both can be followed by a 360mg slow infusion over 6 hours then a maintenance infusion of 540mg over 18 hours.
Mechanism of action
Amiodarone is categorized as a class III antiarrhythmic agent, and prolongs phase 3 of the cardiac action potential. It has numerous other effects however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV. Amiodarone shows beta blocker-like and potassium channel blocker-like actions on the SA and AV nodes, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the cardiac action potential, via sodium-channel effects. Amiodarone resembles thyroid hormone, and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions [22]
Indications for use

Because amiodarone has a low incidence of pro-arrhythmic effects, it has been used both in the treatment of acute life-threatening arrhythmias as well as the chronic suppression of arrhythmias. It is useful both in supraventricular arrhythmias and ventricular arrhythmias.
The treatment of choice for ventricular fibrillation (VF) is electrical defibrillation. However, amiodarone can be useful in shock-refractory VF. In the ARREST trial, amiodarone was shown to improve survival to hospital admission (when compared to placebo) in individuals who suffer cardiac arrest with shock-refractory VF.[23] It is on the basis of this study that the guidelines created by the American Heart Association for the treatment of VF include amiodarone as a second line agent (after epinephrine or vasopressin). ARREST was not adequately powered to demonstrate survival to hospital discharge.
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Amiodarone may be used in the treatment of ventricular tachycardia in certain instances. Individuals with hemodynamically unstable ventricular tachycardia should not initially receive amiodarone. These individuals should be cardioverted out of their unstable rhythm. Amiodarone can be used in individuals with hemodynamically stable ventricular tachycardia. In these cases, amiodarone can be used regardless of the individual's underlying heart function and the type of ventricular tachycardia; it can be used in individuals with monomorphic ventricular tachycardia, but is contraindicated in individuals with polymorphic ventricular tachycardia as it is associated with a prolong QT interval which will be made worse with anti-arrhythmic drugs. The dose of amiodarone is 150 mg IV administered over 10 minutes.
Atrial fibrillation
Individuals who have undergone open heart surgery are at an increased risk of developing atrial fibrillation (or AF) in the first few days post-procedure. In the ARCH trial, intravenous amiodarone (2 grams administered over 2 days) has been shown to reduce the incidence of atrial fibrillation after open heart surgery when compared to placebo.[24] However, clinical studies have failed to demonstrate long-term efficacy and have shown potentially fatal side effects such as pulmonary toxicities. While Amiodarone is not approved for AF by the FDA, it is a commonly prescribed off-label treatment due to the lack of efficacious treatment alternatives. So called 'acute onset atrial fibrillation', defined by the North American Society of Pacing and Electrophysiology (NASPE) in 2003, responds well to short duration treatment with amiodarone. This has been demonstrated in seventeen randomised controlled trials, of which five included a placebo arm. The incidence of severe side effects in this group is low. The benefit of amiodarone in the treatment of atrial fibrillation in the critical care population has yet to be determined but it may prove to be the agent of choice where the patient is haemodynamically unstable and unsuitable for DC cardioversion. It is recommended in such a role by the UK government's National Institute for Health and Clinical Excellence (NICE).
Contraindications
Individuals who are pregnant or may become pregnant are strongly advised to not take amiodarone. Since amiodarone can be expressed in breast milk, women taking amiodarone are advised to stop nursing. It is contraindicated in individuals with sinus nodal bradycardia, atrioventricular block, and second or third degree heart block who do not have an artificial pacemaker. Individuals with baseline depressed lung function should be monitored closely if amiodarone therapy is to be initiated. The injection should not be given to neonates, because the benzyl alcohol it contains may cause the fatal "gasping syndrome". Amiodarone can worsen the cardiac arrhythmia brought on by Digitalis toxicity. Not to be given with Lidocaine increases risk of asystole
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Metabolism
Amiodarone is extensively metabolized in the liver by cytochrome P450 3A4, and can affect the metabolism of numerous other drugs. It interacts with digoxin, warfarin, phenytoin and others. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone. On August 8, 2008 FDA issued a warning of the risk of rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20mg. This drug combination especially with higher doses of simvastatin should be avoided.[25]
Interactions with other drugs

The pharmacokinetics of numerous drugs, including many that are commonly administered to individuals with heart disease, are affected by amiodarone. Particularly, doses of digoxin should be halved in individuals taking amiodarone. Amiodarone potentiates the action of warfarin. Individuals taking both of these medications should have their warfarin dose halved and their anticoagulation status (measured as prothrombin time (PT) and international normalized ratio (INR)) measured more frequently. The effect of amiodarone in the warfarin concentration can be as early as a few days after initiation of treatment, or can be delayed a few weeks. Amiodarone inhibits the action of the cytochrome P450 isozyme family. This reduces the clearance of many drugs, including the following: Cyclosporine Digoxin Flecainide Procainamide Quinidine Sildenafil Simvastatin Theophylline Warfarin
Excretion
Excretion is primarily hepatic and biliary with almost no elimination via the renal route and it is not dialyzable [Package Insert- Pacerone(R)]. Elimination half-life average of 58 days (ranging from 25100 days [Remington: The Science and Practice of Pharmacy 21st edition]) for amiodarone and 36 days for the active metabolite, desethylamiodarone (DEA) [Package Insert- Pacerone(R)]. There is 10-50% transfer of amiodarone and DEA in the placenta as well as presence in breast milk [Package Insert- Pacerone(R)]. Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs) [Package Insert- Pacerone(R)], therefore, if an individual was taking amiodarone on a chronic basis, if it is stopped it will remain in the system for weeks to months.
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Side effects
Amiodarone has numerous side effects. Most individuals administered amiodarone on a chronic basis will experience at least one side effect.
Lung
The most serious reaction that is due to amiodarone is interstitial lung disease. Risk factors include high cumulative dose, more than 400 milligrams per day, duration over two months, increased age, and preexisting pulmonary disease. Some individuals were noted to develop pulmonary fibrosis after a week of treatment, while others did not develop it after years of continuous use. Common practice is to avoid the agent if possible in individuals with decreased lung function. The most specific test of pulmonary toxicity due to amiodarone is a dramatically decreased DLCO noted on pulmonary function testing.
A chest X-ray demonstrating pulmonary fibrosis due to amiodarone.
Thyroid
Due to the iodine content of the agent (37.3% by weight), abnormalities in thyroid function are common. Amiodarone is structurally similar to thyroxine (a thyroid hormone), which contributes to the effects of amiodarone on thyroid function. Both under- and overactivity of the thyroid may occur on amiodarone treatment. Measurement of free thyroxine (FT4) alone may be unreliable in detecting these problems and thyroid-stimulating hormone (TSH) should therefore also be checked every 6 months.[26]
Thyroxine and amiodarone have similar structures.
Hypothyroidism (slowing of the thyroid, due to the Wolff-Chaikoff effect) occurs frequently; in the SAFE trial, which compared amiodarone with other medications for the treatment of atrial fibrillation, biochemical hypothyroidism (as defined by a TSH level of 4.5-10 mU/l) occurred in 25.8% of the amiodarone-treated group as opposed to 6.6% of the control group (taking placebo or sotalol). Overt hypothyroidism (defined as TSH >10 mU/l) occurred at 5.0% compared to 0.3%; most of these (>90%) were detected within the first six months of amiodarone treatment.[27] Hyperthyroidism (an overactive thyroid, due to the Jod-Basedow Effect) can also occur. However, in the SAFE trial, the increased rate of hyperthyroidism (5.3% compared to 2.4%) was not statistically significant. Most hyperthyroid patients (defined as TSH <0.35 mU/l) were asymptomatic.[27] Thyroid uptake measurements (I-123 or I-131), which are used to differentiate causes of hyperthyroidism, are generally unreliable in patients who have been taking amiodarone. Because of the high iodine content of amiodarone, the thyroid gland is effectively saturated, thus preventing further uptake of isotopes of iodine. However, the radioactive iodine uptake (nuclear thyroid uptake test) may still be helpful in the diagnosis and management of amiodarone-induced hyperthyroidism.
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Eye
Corneal micro-deposits (Corneal verticillata, also called vortex keratopathy) are almost universally present (over 90%) in individuals taking amiodarone for at least 6 months. These deposits typically do not cause any symptoms. About 1 in 10 individuals may complain of a bluish halo. Optic neuropathy occurs in 1-2% of people and is not dosage dependent. Bilateral optic disk swelling and mild and reversible visual field defects can also occur.
Gastrointestinal system and liver

Abnormal liver enzyme results are common in patients on amiodarone. Much rarer are jaundice, hepatomegaly (liver enlargement), and hepatitis (inflammation of the liver).[28] Low-dose amiodarone has been reported to cause pseudo-alcoholic cirrhosis.[29] [30]
Skin
Long-term administration of amiodarone is associated with a blue-grey discoloration of the skin. This is more commonly seen in individuals with lighter skin tones. The discoloration may revert upon cessation of the drug. However, the skin color may not return completely to normal. Individuals taking amiodarone may become more sensitive to the harmful effects of UV-A light. Using sunblock that also blocks UV-A rays appears to prevent this side effect.
Neurological
Long-term administration of amiodarone has been associated with peripheral neuropathies.[31]
Epididymis
Amiodarone is sometimes responsible for epididymitis, a condition of the scrotum normally associated with bacterial infections but which can also occur as a non-bacterial inflammatory condition. Amiodarone accumulates in the head of the organ and can cause unilateral or bilateral inflammation. It tends to resolve if amiodarone is stopped.[32]
Gynecomastia
Some cases of gynecomastia have been reported with men on amiodarone.[33]
References
[1] http:/ / www. drugs. com/ monograph/ amiodarone-hydrochloride. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a687009. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=1951-25-3& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BD01 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2157 [6] http:/ / www. drugbank. ca/ drugs/ APRD00288 [7] http:/ / www. chemspider. com/ Chemical-Structure. 2072 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=N3RQ532IUT [9] http:/ / www. kegg. jp/ entry/ D02910 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:2663 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL633 [12] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=Ic1cc%28cc%28I%29c1OCCN%28CC%29CC%29C%28%3DO%29c2c3ccccc3oc2CCCC [13] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=Ic1cc%28cc%28I%29c1OCCN%28CC%29CC%29C%28%3DO%29c2c3ccccc3oc2CCCC [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=456688942& page2=%3AAmiodarone [15] Deltour G, Binon F, Tondeur R, et al. (1962). "[Studies in the benzofuran series. VI. Coronary-dilating activity of alkylated and aminoalkylated derivatives of 3-benzoylbenzofuran.]" (in French). Archives internationales de pharmacodynamie et de thrapie 139: 24754.
Amiodarone
PMID14026835. [16] Charlier R, Deltour G, Tondeur R, Binon F (1962). "[Studies in the benzofuran series. VII. Preliminary pharmacological study of 2-butyl-3-(3,5-diiodo-4-beta-N-diethylaminoethoxybenzoyl)-benzofuran.]" (in French). Archives internationales de pharmacodynamie et de thrapie 139: 25564. PMID14020244. [17] Singh BN, Vaughan Williams EM (1970). "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle". Br. J. Pharmacol. 39 (4): 65767. PMC1702721. PMID5485142. [18] Rosenbaum MB, Chiale PA, Halpern MS, et al. (1976). "Clinical efficacy of amiodarone as an antiarrhythmic agent". Am. J. Cardiol. 38 (7): 93444. doi:10.1016/0002-9149(76)90807-9. PMID793369. [19] Rosenbaum MB, Chiale PA, Haedo A, Lzzari JO, Elizari MV (1983). "Ten years of experience with amiodarone". Am. Heart J. 106 (4 Pt 2): 95764. doi:10.1016/0002-8703(83)90022-4. PMID6613843. [20] "Drug Approval Package" (http:/ / www. fda. gov/ cder/ foi/ nda/ pre96/ 18-972_Cardarone. htm). . Retrieved 2007-09-30. [21] Siddoway LA (2003). "Amiodarone: guidelines for use and monitoring" (http:/ / www. aafp. org/ afp/ 20031201/ 2189. html). American Family Physician 68 (11): 218996. PMID14677664. . [22] Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition. [23] Kudenchuk PJ, Cobb LA, Copass MK, et al. (1999). "Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation". N. Engl. J. Med. 341 (12): 8718. doi:10.1056/NEJM199909163411203. PMID10486418. [24] Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR (1999). "Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial". J. Am. Coll. Cardiol. 34 (2): 3437. doi:10.1016/S0735-1097(99)00212-0. PMID10440143. [25] "Information on Simvastatin/Amiodarone" (http:/ / www. fda. gov/ cder/ drug/ infopage/ simvastatin_amiodarone/ default. htm). . Retrieved 2008-09-21. [26] British National Formulary guidance on thyroid function monitoring ( BNF Amiodarone (http:/ / www. bnf. org/ bnf/ bnf/ 49/ openat/ 2417. htm?q="amiodarone")) [27] Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM (October 2007). "Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation" (http:/ / www. amjmed. com/ article/ PIIS0002934307004718/ abstract). Am J Med 120 (10): 88085. doi:10.1016/j.amjmed.2007.04.022. PMID17904459. . [28] Flaharty KK, Chase SL, Yaghsezian HM, Rubin R (1989). "Hepatotoxicity associated with amiodarone therapy". Pharmacotherapy 9 (1): 3944. PMID2646621. [29] Singhal A, Ghosh P, Khan SA (2003). "Low dose amiodarone causing pseudo-alcoholic cirrhosis". Age and ageing 32 (2): 2245. doi:10.1093/ageing/32.2.224. PMID12615569. [30] Puli SR, Fraley MA, Puli V, Kuperman AB, Alpert MA (2005). "Hepatic cirrhosis caused by low-dose oral amiodarone therapy". Am. J. Med. Sci. 330 (5): 25761. doi:10.1097/00000441-200511000-00012. PMID16284489. [31] A G Fraser, I N McQueen, A H Watt, and M R Stephens (June 1985). "Peripheral neuropathy during longterm high-dose amiodarone therapy" (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC1028375/ ). J Neurol Neurosurg Psychiatry 48 (6): 576578. doi:10.1136/jnnp.48.6.576. PMC1028375. PMID2989436. . [32] Thomas A, Woodard C, Rovner ES, Wein AJ (February 2003). "Urologic complications of nonurologic medications". Urol. Clin. North Am. 30 (1): 12331. doi:10.1016/S0094-0143(02)00111-8. PMID12580564. [33] (http:/ / www. ccjm. org/ content/ 71/ 6/ 511. full. pdf) Gynecomastia: Its features, and when and how to treat it
265
External links
Siddoway LA (December 2003). "Amiodarone: guidelines for use and monitoring" (http://www.aafp.org/afp/ 20031201/2189.html). Am Fam Physician 68 (11): 218996. PMID14677664. Amiodarone (MedicineNet.com) (http://www.medicinenet.com/amiodarone/article.htm) Amiodarone (FamilyPracticeNotebook.com) (http://www.fpnotebook.com/CV/Pharm/Amdrn.htm) Amiodarone (The WorldWide Intensivist) (http://www.anaesthetist.com/icu/manage/drugs/heart/ amiodarone.htm) U.S. National Library of Medicine: Drug Information Portal - Amiodarone (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Amiodarone) Amiodarone (FDA MedWatch) (http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ucm118073.htm)
Sotalol
266
Sotalol
Sotalol
(RS)-N-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl}methanesulfonamide
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Betapace monograph a693010 B(US) Prescription only oral Pharmacokinetic data Bioavailability Metabolism Half-life Excretion >95% Not metabolized 12 hours Renal Lactic (In lactating females) Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 3930-20-9 C07 AA07 CID 5253 DB00489 5063
[7] [8] [3] [2] [1]
[4]
[5] [6]
A6D97U294I D08525
[9]
[10]
C H NOS
12 20 2 3

[11]
& PubChem
[12]
[13]
Sotalol Sotalol is a drug used in individuals with rhythm disturbances (cardiac arrhythmias) of the heart, and to treat hypertension in some individuals. It is a non-selective competitive -adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels.[14] [15] Because of this dual action, Sotalol prolongs both the PR interval and the QT interval. Originally discovered around 1960, sotalol became widely used first as a -blocker in the 1980s, and its function as an antiarrhythmic drug was discovered soon after.[16] Due to the dual action of sotalol, it is often used preferentially to other -blockers as treatment for both ventricular fibrillation and ventricular tachycardia.[14] [17] Trade names for Sotalol include Betapace and Betapace AF (Berlex Laboratories), and Sotalex and Sotacor (Bristol-Myers Squibb).
267
Indications
Sotalol is used to treat ventricular tachycardias[18] as well as atrial fibrillation.[19] Betapace AF is specifically labeled for atrial fibrillation. Some evidence suggests that sotalol should be avoided in the setting of decreased ejection fraction due to an increased risk of death.[20] It has also been suggested that it be used in the prevention of atrial fibrillation.[21]
Ventricular Fibrillation and Tachycardia

Ventricular fibrillation is an uncontrolled and asynchronous series of contractions of the ventricles resulting in poor cardiac output. It is often associated with factors that affect the electrical signal for contraction and trigger a premature contraction before complete relaxation.[22] Ventricular tachycardia is closely associated with ventricular fibrillation and is an abnormally high rate of contraction from the ventricles often resulting from increased intracellular calcium levels. This increase in cytosolic calcium leads to an increase in calcium release from the sarcoplasmic reticulum, which increases rate of contraction by providing more calcium for interaction with force-generating filaments in the muscle cell for a prolonged period of time.[23]
Mechanisms of Action
-Blocker Action
Sotalol non-selectively binds to both 1- and 2-adrenergic receptors preventing activation of the receptors by their stimulatory ligand1. Without the binding of this ligand to the receptor, the G-protein complex associated with the receptor cannot activate production of cyclic AMP, which is responsible for turning on calcium inflow channels.[24] A decrease in activation of calcium channels will therefore result in a decrease in intracellular calcium. In cardiac cells, calcium is important in generating electrical signals for contraction, as well as generating force for contraction.[25] In consideration of these important properties of calcium, two conclusions can be drawn. Firstly, with less calcium in the cell, there is a decrease in electrical signals for contraction, thus allowing time for the hearts natural pacemaker to rectify arrhythmic contractions3. Secondly, lower calcium means a decrease in strength and rate of the contractions, which can be helpful in treatment of abnormally high heart rates in patients with tachycardia3.
Type III Antiarrhythmic Action

Sotalol also acts on potassium channels and causes a delay in relaxation of the ventricles2. By blocking these potassium channels, sotalol inhibits efflux of K+ ions, which results in an increase in the time before another electrical signal can be generated in ventricular myocytes8. This increase in the period before a new signal for contraction is generated, helps to correct arrhythmias by reducing the potential for premature or abnormal contraction of the ventricles but also prolongs the frequency of ventricular contraction to help treat tachycardia.
Sotalol
268
References
[1] http:/ / www. drugs. com/ monograph/ sotalol-hydrochloride. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a693010. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=3930-20-9& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C07AA07 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5253 [6] http:/ / www. drugbank. ca/ drugs/ DB00489 [7] http:/ / www. chemspider. com/ Chemical-Structure. 5063 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=A6D97U294I [9] http:/ / www. kegg. jp/ entry/ D08525 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL471 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29C%28O%29CNC%28C%29C%29C [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29C%28O%29CNC%28C%29C%29C [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=420038718& page2=%3ASotalol [14] Bertrix, Lucien et al. Protection against ventricular and atrial fibrillation by sotalol. Cardiovascular Research 1986; 20, 358-363. [15] Edvardsson, N et al. Sotalol-induced delayed ventricular repolarization in man. European Heart Journal 1980; 1, 335-343 [16] Antonaccio M, Gomoll A. Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol. Am J Cardiol 1993; 72, 27A-37A [17] Dorian P, Newman D. Effect of sotalol on ventricular fibrillation and defibrillation in humans. Am J Cardiol 1993; 72, 72A-79A [18] Boriani G, Lubinski A, Capucci A, et al. (December 2001). "A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=11913480). Eur. Heart J. 22 (23): 218091. doi:10.1053/euhj.2001.2679. PMID11913480. . [19] Singh BN, Singh SN, Reda DJ, et al. (May 2005). "Amiodarone versus sotalol for atrial fibrillation" (http:/ / content. nejm. org/ cgi/ pmidlookup?view=short& pmid=15872201& promo=ONFLNS19). N. Engl. J. Med. 352 (18): 186172. doi:10.1056/NEJMoa041705. PMID15872201. . [20] Waldo A, Camm A, deRuyter H, Friedman P, MacNeil D, Pauls J, Pitt B, Pratt C, Schwartz P, Veltri E (1996). "Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol". Lancet 348 (9019): 712. doi:10.1016/S0140-6736(96)02149-6. PMID8691967. [21] Patel A, Dunning J (April 2005). "Is Sotalol more effective than standard beta-blockers for the prophylaxis of atrial fibrillation during cardiac surgery" (http:/ / icvts. ctsnetjournals. org/ cgi/ pmidlookup?view=long& pmid=17670378). Interact Cardiovasc Thorac Surg 4 (2): 14750. doi:10.1510/icvts.2004.102152. PMID17670378. . [22] Wiggers, C. The mechanism and nature of ventricular fibrillation. The American Heart Journal 1940; 20, 399-412 [23] Priori, S et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001; 103, 196-200 [24] Charnet, P et al. cAMP-dependent phosphorylation of the cardiac L-type Ca channel: A missing link? Biochimie 1995; 77, 957-962 [25] Kassotis, J et al. Beta receptor blockade potentiates the antiarryhthmic actions of d-sotalol on re-entrant ventricular tachycardia in a canine model of myocardial infarction. Journal of Cardiovascular Electrophysiology 2003; 14, 1233-1244
Ibutilide
269
Ibutilide
Ibutilide
N-(4-{4-[ethyl(heptyl)amino]-1-hydroxybutyl}phenyl)methanesulfonamide
Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Corvert monograph a601248 C ? Intravenous Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion N/A 40% Hepatic oxidation 6 hours (2-12 hours) Renal (82%), fecal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 122647-32-9 C01 BD05 CID 60753
[3] [2] [1]
[4] [5] [6]
APRD01025 54755
[7]
9L5X4M5L6I D00648
[9]
[8]
[10]
C H NOS
20 36 2 3
384.578 g/mol eMolecules

[11]
& PubChem
[12]
Ibutilide
270
[13]
Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period (physiology) of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents. Ibutilide is marketed as Corvert by Pfizer. Administration resulted in successful heart rhythm control in 31-44% of patients within 90 minutes, with sustained polymorphic ventricular tachycardia in 0.9-2.5% of patients. It appears to show better results in atrial flutter as compared to atrial fibrillation.[14]
Mechanism of action
Unlike most other Class III antiarrhythmic drugs, ibutilide does not produce its prolongation of action potential via blockade of cardiac delayed rectifier of potassium current, nor does it have a sodium-blocking, antiadrenergic, and calcium blocking activity that other Class III agents possess. Thus it is often referred as a pure Class III antiarrhythmic drug. It does have action on the slow sodium channel and promotes the influx of sodium through these slow channels. Although potassium current seems to play a role, their interactions are complex and not well understood.[15] Ibutilides unique mechanism works by an activation of a specific inward sodium current, thus producing its therapeutic response in which a prolonged action potential increases myocytes cardiac refractoriness in case of atrial fibrillation and flutter.
Pharmacokinetics
Absorption
Ibutilide is intravenously administered. It has a high first-pass metabolism, which results in a poor bioavailability when taken orally. Individual pharmacokinetic properties are highly viable during the clinical trial.[15] [16]
Distribution
Ibutilide has a relatively large volume of distribution among individual subjects, which is about 11L/kg. Approximately 40% of the drug is bound with plasma albumin of healthy volunteers in a trial. This is also approximately close to patients with atrial fibrillation and flutter.[16]
Metabolism
Ibutilide has a high systemic plasma clearance that closes to the hepatic blood flow (29mL/min/kg). Its metabolic pathway is via livers cytochrome P450 system by isoenzymes other than CYP3A4 and CYP2D6 by which the heptyl side chain of ibutilide is oxidized.[15] [16] With eight metabolites are detected in the urine, however, only one is an active metabolite that shares the similar electrophysiologic property of the Class III antiarrhythmic agents.[15] [16] [17] The plasma concentration of this metabolite is only less than 10% of ibutilide.[16]
Ibutilide
271
Excretion
After administration of ibutilide, it is quickly excreted by renal pathway with a half-life of approximately 6 hours. Approximately 82% of a 0.01mg/kg dose is excreted in the urine during the trial. Among those, around 7% is excreted as unchanged drug. The reminder of the drug is excreted in feces (about 19%).[15]
Adverse effects and contraindications

Like other antiarrhythmics, ibutilide can lead to arrhythmia, especially torsades de pointes. Consequently, the drug is contraindicated in patients that are likely to develop arrhythmia; this includes patients that had polymorphic ventricular tachycardia in the past, QT prolongation, sick sinus syndrome, recent myocardial infarction, and others.[18]
Patient Information
This medication will be given intravenously for your heart disease. You will have continuously ECG monitoring during the infusion and 4 hours after your infusion. Some of the minor side effects are headache and irregular heartbeat. If you experience chest pain and respiratory difficulties, you should report to your doctors immediately.[19]
References
[1] http:/ / www. drugs. com/ monograph/ corvert. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a601248. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=122647-32-9& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BD05 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=60753 [6] http:/ / www. drugbank. ca/ drugs/ APRD01025 [7] http:/ / www. chemspider. com/ Chemical-Structure. 54755 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=9L5X4M5L6I [9] http:/ / www. kegg. jp/ entry/ D00648 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL533 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29C%28O%29CCCN%28CC%29CCCCCCC%29C [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29C%28O%29CCCN%28CC%29CCCCCCC%29C [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=407854380& page2=%3AIbutilide [14] Kowey, PR; Stoenescu, ML (2005). "Selection of drugs in pursuit of a rhythm control strategy". Progress in cardiovascular diseases 48 (2): 13945. doi:10.1016/j.pcad.2005.06.009. PMID16253653. [15] Howard, P.A., Ibutilide: An antiarrhythmic agent for the treatment of atrial fibrillation or flutter. Annals of Pharmacotherapy, 1999. 33(1): p. 38-47. PMID9972384 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 9972384) [16] Pharmacia-Upjohn, Corvert (ibutilide fumarate) injection package insert. July 2002: Kalamazoo, MI. [17] Kelly C. Rogers, P., and Douglas A. Wolfe MD, Ibutilide: A class III rapidly acting antidysrhythmic for atrial fibrillation or atrial flutter. Journal of Emergency Medicine January 2001. Volume 20( Issue 1): p. 67-71. [18] Jasek, W, ed (2007) (in German). Austria-Codex. 1 (2007/2008 ed.). Vienna: sterreichischer Apothekerverlag. pp.176871. ISBN3-85200-181-4. [19] Lexi-Comp, Lexi-Drugs Online : Ibutilide.
Dofetilide
272
Dofetilide
Dofetilide
N-[4-(2-{[2-(4-methane sulfonamidophenoxy)ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide

Clinical data AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status monograph a601235 ? ? Pharmacokinetic data Bioavailability Protein binding Half-life 96% (oral) 60% -70% 10 hours Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 115256-11-6 C01 BD04 CID 71329
[3] [2] [1]
[4] [5] [6]
APRD00367 64435
[7]
R4Z9X1N2ND D00647
[9]
[8]
CHEBI:4681
[10]
[11]
C H NOS
19 27 3
5 2

[12]
& PubChem
[13]
[14]
Dofetilide is a class III antiarrhythmic agent.[15] It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 g of dofetilide.
Dofetilide Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription by physicians who have undergone specific training in the risks of treatment with dofetilide. In addition, it is only available by mail order or through specially trained local pharmacies to individuals who are prescribed dofetilide by a physician who is registered as being able to prescribe the pharmaceutical.
273
Uses
It is used for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.[16] [17]
Pharmacokinetics
The elimination half-life of dofetilide is roughly 10 hours, however this is variable based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours.
Mechanism of action
Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).[18] This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter. Dofetilide does not affect Vmax (The slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential. There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
Metabolism
A steady-state plasma level of dofetilide is achieved in 23 days. 80% of dofetilide is excreted by the kidneys, so the dose of dofetilide should be adjusted in individuals with renal insufficiency, based on creatinine clearance. In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil, cimetidine, hydrochlorothiazide, itraconazole, ketoconazole, prochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide. About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system.
Dofetilide
274
Side effects
Torsade de pointes is the most serious side effect of dofetilide therapy. The incidence of torsade de pointes is dose-related, and is 0.3-10.5%. The risk appears to be dose-dependent, with an increased incidence of torsades de pointes associated with higher doses of dofetilide administered. The risk of inducing torsade de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation .
Clinical use
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (DIAMOND) study, dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction.[19] Because of the results of the DIAMOND study, many physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction.
References
[1] http:/ / www. drugs. com/ monograph/ dofetilide. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a601235. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=115256-11-6& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01BD04 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=71329 [6] http:/ / www. drugbank. ca/ drugs/ APRD00367 [7] http:/ / www. chemspider. com/ Chemical-Structure. 64435 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=R4Z9X1N2ND [9] http:/ / www. kegg. jp/ entry/ D00647 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:4681 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL473 [12] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29CCN%28CCOc2ccc%28cc2%29NS%28%3DO%29%28%3DO%29C%29C%29C [13] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DS%28%3DO%29%28Nc1ccc%28cc1%29CCN%28CCOc2ccc%28cc2%29NS%28%3DO%29%28%3DO%29C%29C%29C [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=457790505& page2=%3ADofetilide [15] Lenz TL, Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy 20 (7): 77686. doi:10.1592/phco.20.9.776.35208. PMID10907968. [16] Banchs JE, Wolbrette DL, Samii SM et al. (November 2008). "Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter". J Interv Card Electrophysiol 23 (2): 1115. doi:10.1007/s10840-008-9290-6. PMID18688699. [17] Lenz TL, Hilleman DE (November 2000). "Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter" (http:/ / journals. prous. com/ journals/ servlet/ xmlxsl/ pk_journals. xml_summaryn_pr?p_JournalId=4& p_RefId=601530). Drugs Today 36 (11): 75971. doi:10.1358/dot.2000.36.11.601530. PMID12845335. . [18] Roukoz H, Saliba W (January 2007). "Dofetilide: a new class III antiarrhythmic agent" (http:/ / www. future-drugs. com/ doi/ abs/ 10. 1586/ 14779072. 5. 1. 9?url_ver=Z39. 88-2003& rfr_id=ori:rid:crossref. org& rfr_dat=cr_pub=ncbi. nlm. nih. gov). Expert Rev Cardiovasc Ther 5 (1): 919. doi:10.1586/14779072.5.1.9. PMID17187453. . [19] Torp-Pedersen C, ller M, M Bloch-Thomsen PE et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group" (http:/ / content. nejm. org/ cgi/ pmidlookup?view=short& pmid=10486417& promo=ONFLNS19). N. Engl. J. Med. 341 (12): 85765. doi:10.1056/NEJM199909163411201. PMID10486417. .
E-4031
275
E-4031
E-4031
N-[4-[1-[2-(6-Methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]
Clinical data Pregnancy cat. ? Legal status ? Identifiers CAS number 113558-89-7 113559-13-0 (dihydrochloride) ? CID 3185
[2] [1]
ATC code PubChem Synonyms
(1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl-aminobenzoyl)piperidine) Chemical data
Formula Mol. mass
C21H27N3O3S 401.52 g/mol (what is this?) (verify)

[3]
E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.[4]
Chemistry
E-4031 is a synthetized toxin that is a methanesulfonanilide class III antiarrhythmic drug.[5]
Target
E-4031 acts on a specific class of voltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the IKr current, which repolarizes the myocardial cells.[6] [7] The hERG channel is encoded by ether-a-go-go related gene (hERG).[8]
Mode of action
E-4031 blocks hERG-type potassium channels [8] [9] by binding to the open channels.[10] Its structural target within the hERG-channel is unclear, but some other methanesulfonanilide class III antiarrhythmic drugs are known to bind to the S6 domain or C-terminal of the hERG-channel.[11] [12] [13] [14] [15] [16] Reducing IKr in myocardial cells prolongs the cardiac action potential and thus prolongs the QT-interval.[10] non-cardiac cells, blocking Ikr has a different effect: it increases the frequency of action potentials.[8]
[17]
In
E-4031
276
Toxicity
As E-4031 can prolong the QT-interval, it can cause lethal arrhythmias.[16]
Therapeutic use
As of yet, E-4031 is solely used for research purposes. So far, one clinical trial has been conducted to test the effect of E-4031 on prolongation of the QT-interval.[18]
References
[1] [2] [3] [4] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=113558-89-7& rn=1 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3185 http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=366892602& page2=%3AE-4031 Kim I, Boyle KM, Carrol JL (2005) Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells. J Appl Physiol 98(4):1469-1477. [5] Miyake K, Yamanaka M, Katoh H, Shino M, Hamano S, Nomoto K-I, Oinuma H, Sawada K (1990) 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem 33, 3, 903 [6] Gerlach AC, Stoehr SJ, Castle NA (2009 Oct 5. [Epub ahead of print]) Pharmacological Removal of hERG Potassium Channel Inactivation by ICA-105574. [7] Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP (2008) Human ether--go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98:137-148 [8] Weinsberg F, Bauer CK, Schwarz JR (1997) The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumour cells (GH3/B6 cells). Pflgers Arch Eur J Physiol 434:110 [9] Sanguinetti MC, Jurkiewicz NK (1990) Two Components of Cardiac Delayed Rectifier K + Current. J Gen Physiol 96:195-215 [10] Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996) Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K+ Channel. Circ Res 78:499-503. [11] Lees-Miller JP, Duan Y, Teng GQ, and Duff HJ (2000) Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 57:367374 [12] Mitcheson JS, Chen J, Lin M, Culberson C, and Sanguinetti MC (2000a) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 97:1232912333 [13] Kamiya K, Mitcheson JS, Yasui K, Kodama I, and Sanguinetti MC (2001) Open channel block of HERG K_ channels by vesnarinone. Mol Pharmacol 60:244253 [14] Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, and Sanguinetti MC (2002) Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+- channel block. J Biol Chem 277:2358723595 [15] Sanchez-Chapula JA, Ferrer T, Navarro-Polanco RA, and Sanguinetti MC (2003) Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol 63:10511058 [16] Perry M, De Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, and Mitcheson J (2004) Structural Determinants of HERG Channel Block by Clofilium and Ibutilide. Mol Pharmacol 66:240249 [17] Wettwer E, Grundke M, Ravins U (1992) Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes. Cardiovasc Res 26(11): 1145-52 [18] Okada Y, Ogawa S, Sadanaga T, Mitamura H (1996) Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography. J Am Coll Cardiol 27(1): 84-9
277
Type IV Antiarrythmics
Verapamil
Verapamil
(RS)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-prop-2-ylpentanenitrile
Clinical data Licence data Pregnancy cat. Legal status Routes USFDA: link C(US) Prescription only Oral, Intravenous Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 35.1% Hepatic 2.8-7.4 hours Renal: 11% Identifiers CAS number ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 52-53-9
[2] [3] [1]
C08 DA01 CID 2520 2406

[5]
[4]
APRD00335 2425
[7]
[6]
CJ0O37KU29 D02356
[9]
[8]
CHEBI:9948
[10]
CHEMBL6966
[11]
Verapamil
278
Chemical data Formula Mol. mass SMILES C27H38N2O4 454.602 g/mol eMolecules (what is this?) (verify)
[12]
& PubChem
[13]
[14]
Verapamil (brand names: Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS) is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches.[15] It is also an effective preventive medication for migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class IV antiarrhythmic, more effective than digoxin in controlling ventricular rate, and was approved by the U.S. Food and Drug Administration (FDA) in March 1982.[16]
Mechanism and uses

Verapamil's mechanism in all cases is to block voltage-dependent calcium channels. In cardiac pharmacology, calcium channel blockers are considered class IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrio-ventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias. Calcium channels are also present in the smooth muscle that lines blood vessels. By relaxing the tone of this smooth muscle, calcium-channel blockers dilate the blood vessels. This has led to their use in treating hypertension and angina pectoris. The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts. Verapamil is also used intra-arterially to treat cerebral vasospasm.[17] Verapamil has been used to treat cluster headaches,[18] but it can also cause headaches as a side effect.
Pharmacokinetic details
Given orally, 90100% of Verapamil is absorbed, but due to high first-pass metabolism, bioavailability is much lower (1035%). It is 90% bound to plasma proteins and has a volume of distribution of 35 L/kg. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 34% is excreted unchanged in urine. This is a non-linear dependence between plasma concentration and dosage. Onset of action is 12 hours after oral dosage. Half-life is 512 hours (with chronic dosages). It is not cleared by hemodialysis. Verapamil has been reported to be effective in both short-term[19] and long-term treatment of mania and hypomania.[20] Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.[21] It has on occasion been used to control mania in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium (which has a small but significant incidence of causing cardiac malformation), Verapamil is usable as an alternative, albeit presumably a less effective one.
Verapamil
279
Side effects
Some possible side effects of the drug are headaches, facial flushing, dizziness, swelling, increased urination, fatigue, nausea, ecchymosis, lightheadedness, and constipation. Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia.
Overdose
Acute overdose is often manifested by nausea, asthenia, bradycardia, dizziness, hypotension and cardiac arrhythmia. Plasma, serum or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in Verelan 300mg Extended Release Capsule hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50-500 g/L in persons on therapy with the drug, but may rise to 14mg/L in acute overdose patients and are often at levels of 510mg/L in fatal poisonings.[22] [23]
Uses in cell biology

Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein.[24] This is useful as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It is also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342. Radioactively-labelled verapamil and positron emission tomography can be used with to measure P-glycoprotein function.[25]
Veterinary use
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given post-operatively in rabbits who have suffered trauma to abdominal organs to prevent formation of these intra-abdominal adhesions.
Potential use in the treatment of malaria

Recent resistance to the anti-malarial drug chloroquine has hindered the treatment of malaria in Southeast Asia, South America and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. It has been shown that verapamil, when used in combination with chloroquine, enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.[26] [27]
Verapamil
280
References
[1] http:/ / www. accessdata. fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Verapamil& SearchType=BasicSearch [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=52-53-9& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C08DA01 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2520 [5] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2406 [6] http:/ / www. drugbank. ca/ drugs/ APRD00335 [7] http:/ / www. chemspider. com/ Chemical-Structure. 2425 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=CJ0O37KU29 [9] http:/ / www. kegg. jp/ entry/ D02356 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:9948 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL6966 [12] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=N%23CC%28c1cc%28OC%29c%28OC%29cc1%29%28CCCN%28CCc2ccc%28OC%29c%28OC%29c2%29C%29C%28C%29C [13] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=N%23CC%28c1cc%28OC%29c%28OC%29cc1%29%28CCCN%28CCc2ccc%28OC%29c%28OC%29c2%29C%29C%28C%29C [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=461939027& page2=%3AVerapamil [15] Ellen Beck; William J. Sieber; Raul Trejo (2005). "Management of Cluster Headaches" (http:/ / www. aafp. org/ afp/ 20050215/ 717. html). American Family Physician 71 (4): 717724. . [16] "verapamil, Calan, Verelan, Verelan PM, Isoptin, Covera-HS" (http:/ / www. medicinenet. com/ verapamil/ article. htm). MedicineNet.com. . Retrieved 6 October 2011. [17] Peter Jun; Nerissa Ko; Joey English; Christopher Dowd; Van Halbach; Randall Higashida; Michael Lawton; Steven Hetts. "Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage". PMID20616179. [18] Frank Drislane; Michael Benatar; Bernard S. Chang; Juan Acosta, Andrew Tarulli (1 January 2009). Blueprints Neurology (http:/ / books. google. com/ books?id=vj3td6GY0gcC& pg=PA71). Lippincott Williams & Wilkins. pp.71. ISBN9780781796859. . Retrieved 14 November 2010. [19] AJ Giannini, J Houser, MC Giannini, RH Loiselle (1 December 1984). "Antimanic effects of verapamil" (http:/ / ajp. psychiatryonline. org/ cgi/ content/ abstract/ 141/ 12/ 1602). American Journal of Psychiatry 141 (12): 16021605. PMID6439057. . [20] AJ Giannini, RS Taraszewski, RH Loiselle (1 December 1987). "Verapamil and lithium in maintenance therapy of manic patients" (http:/ / jcp. sagepub. com/ cgi/ content/ abstract/ 27/ 12/ 980). Journal of Clinical Pharmacology 27 (12): 980986. PMID3325531. . [21] AJ Giannini, AM Nakoneczie, SM Melemis, J Ventresco, M Condon (2000). "Magnesium oxide augmentation of verapamil maintenance therapy in mania". Psychiatry Research 93: 8387. doi:10.1016/S0165-1781(99)00116-X. PMID10699232. [22] Wilimowska J, Piekoszewski W, Krzyanowska-Kierepka E, Florek E. Monitoring of verapamil enantiomers concentration in overdose. Clin. Toxicol. 44: 169-171, 2006. [23] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, California, 2008, pp. 1637-1639. [24] Bellamy WT. (1996). "P-glycoproteins and multidrug resistance". Annu Rev Pharmacol Toxicol 36: 16183. doi:10.1146/annurev.pa.36.040196.001113. PMID8725386. [25] Luurtsema, Gert; Windhorst, Albert D.; Mooijer, Martien P.J.; Herscheid, Jacobus D.M.; Lammertsma, Adriaan A.; Franssen, Eric J.F. (December 2002). "Fully automated high yield synthesis of (R)- and (S)-[11C]verapamil for measuring P-glycoprotein function with positron emission tomography". Journal of Labelled Compounds and Radiopharmaceuticals 45 (14): 11991207. doi:10.1002/jlcr.632. ISSN1099-1344. [26] Martin, S. K., A. M. Oduola, and W. K. Milhous (1987). "Reversal of chloroquine resistance in Plasmodium falciparum by verapamil". Science 235 (4791): 899901. doi:10.1126/science.3544220. PMID3544220. [27] Krogstad, D.J., et al (1987). "Efflux of Chloroquine from Plasmodium falciparum: Mechanism of Chloroquine Resistance" (http:/ / sciencemag. org/ cgi/ search?volume=238& firstpage=1283& search_citation-search. x=44& search_citation-search. y=2& search_citation-search=search). Science 238: 1283. doi:10.1126/science.3317830. PMID3317830. .
Verapamil
281
External links
MedlinePlus DrugInfo medmaster-a684030 (http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/ a684030.html) Securon Summary of Product Characteristics (http://emc.medicines.org.uk/emc/industry/default. asp?page=displaydoc.asp&documentid=972)
Diltiazem
282
Diltiazem
Diltiazem
cis-(+)-[2-(2-dimethylaminoethyl)-5-(4-methoxyphenyl) -3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9, 11-trien-4-yl]ethanoate

Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Cardizem, Dilacorxr monograph a684027
[2] [1]
D: (USA) ? Oral Pharmacokinetic data
40% Hepatic 3-4.5 hours Renal Biliary Lactic (in lactating females) Identifiers
CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI
42399-41-7 C08 DB01 CID 39186
[3]
[4] [5] [6]
APRD00473 35850
[7]
EE92BBP03H D07845
[9]
[8]
CHEBI:101278
[10]
Diltiazem
[11]
283
ChEMBL
C22H26N2O4S 414.519 g/mol eMolecules

[12]
& PubChem
[13]
[14]
Diltiazem is a non-dihydropyridine (non-DHP) member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia. It is also an effective preventive medication for migraine. It is a class 3 anti-anginal drug, and a class IV antiarrhythmic. It is a common adulterant of cocaine seized in the UK,[15] and has been found to reduce cocaine cravings in rats, indicating that it may prolong the "high" (see below). It incites very minimal reflex sympathetic changes. It is based upon a 1,4-thiazepine ring. Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.
Brand names
Progor Herben Altiazem Cardizem Cartia XT Tiazac Tiazac XC Tiamate Taztia XT Tildiem in particular in Europe Adizem Viazem Dilatam Dilzem Angiozem Dilatem Dilcardia Diltelan Diltime Dyalec Filazem Tildiem Vasmulax Vasocardol & Vasocardol CD, in Australia Zandil Zemtrial Angizem CD Angizem
Diltiazem Dilcontin SR in India (Sustained Release) Dilt-CD Dilt-XR Corzem in Jordan
284
Mechanism
Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. Its pharmacological activity is somewhat similar to verapamil.[16] Potent vasodilator of coronary vessels. Vasodilator of peripheral vessels. This reduces peripheral resistance and afterload.
180mg Cardizem capsule
Negative inotropic effect. Diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption.
Negative chronotropic effect. Diltiazem causes a modest lowering of heart rate. This effect is due to slowing of the SA (sinoatrial) node. It results in reduced myocardium oxygen consumption. Negative dromotropic effect. By slowing conduction through the AV (atrioventricular) node, diltiazem increases the time needed for each beat. This results in reduced myocardium oxygen consumption by the body.
Nontherapeutic effects and toxicities

Reflex sympathetic response. Caused by the peripheral dilation of vessels and the resulting drop in BP; the response works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Undesirable effects of Diltiazem include hypotension, bradycardia, dizziness, flushing.[17]
Indications
Angina: Stable angina (exercise-induced) . Diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.[18] [19] Variant angina. Diltiazem is effective due to its direct effects on coronary dilation. Unstable angina (preinfarction, crescendo). Diltiazem may be particularly effective if the underlying mechanism is vasospasm. Supraventricular tachycardias. Diltiazem appears to be as effective as verapamil in treating reentrant supraventricular tachycardia.[20] Atrial fibrillation[21] or atrial flutter. Hypertension. Because of its vasodilatory effects, diltiazem is useful for treating hypertension. Calcium channel blockers are well-tolerated, and especially effective in treating low-renin hypertension.[22]
Diltiazem
285
Contraindications and precautions

CHF. Patients with reduced ventricular function may not be able to counteract the inotropic and chronotropic effects of diltiazem, the result being an even higher compromise of function. SA node or AV conduction disturbances. Use of diltiazem should be avoided in patients with SA or AV nodal abnormalities, because of its negative chronotropic and dromotropic effects Low blood pressure. Patients with systolic blood pressures below 90mm Hg should not be treated with diltiazem. Wolff-Parkinson-White syndrome. Diltiazem may paradoxically increase ventricular rate in patients with WPW syndrome because of accessory conduction pathways. Diltiazem is relatively contraindicated in the presence of sick sinus syndrome, atrioventricular node conduction disturbances, bradycardia, impaired left ventricle function, peripheral artery occlusive disease, and chronic obstructive pulmonary disease.
Drug interactions
Beta-blockers
Intravenous diltiazem should be used with caution with beta-blockers because, while the combination is most therapeutically beneficial, there are rare instances of dysrhythmia and AV node block.[23]
Quinidine
Quinidine should not be used concurrently with calcium channel blockers because of reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes.
Miscellaneous
Inhibition of hepatic enzymes. Diltiazem and verapamil inhibit hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, possibly resulting in drug interactions.
Potential future indications

Diltiazem is prescribed off-label by doctors in the US for prophylaxis of cluster migraine. It works amazingly well in some patients. There is some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine.[24] [25] [26] [27] [28] [29] [30] Recent research has shown that diltiazem is able to reduce cocaine cravings in drug-addicted rats.[31] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signalling in the brain.[32] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[33] and reduces the development of tolerance.[34] Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.[35] When applied topically, it is made into a cream form using either vaseline or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates.[36] [37] Like all non-surgical treatments of anal fissure it does not address the long term problem of increased basal anal tone and does not decrease the subsequent recurrence rate that can vary between 40 to 60%.
Diltiazem
286
References
[1] http:/ / www. drugs. com/ monograph/ diltiazem-hydrochloride. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a684027. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=42399-41-7& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C08DB01 [5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=39186 [6] http:/ / www. drugbank. ca/ drugs/ APRD00473 [7] http:/ / www. chemspider. com/ Chemical-Structure. 35850 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=EE92BBP03H [9] http:/ / www. kegg. jp/ entry/ D07845 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:101278 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL23 [12] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC2N%28c3c%28S%5BC%40%40H%5D%28c1ccc%28OC%29cc1%29%5BC%40H%5D2OC%28%3DO%29C%29cccc3%29CCN%28C%29C [13] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC2N%28c3c%28S%5BC%40%40H%5D%28c1ccc%28OC%29cc1%29%5BC%40H%5D2OC%28%3DO%29C%29cccc3%29CCN%28C%29C [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=457794717& page2=%3ADiltiazem [15] "Full list of impurities found in cocaine" (http:/ / news. bbc. co. uk/ 1/ hi/ uk/ 8040690. stm). BBC. May 12, 2009. . [16] O'Connor, Stephen E.; Grosset, Alain; Janiak, Philip (1999). "The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem". Fundamental & Clinical Pharmacology 13 (2): 14553. doi:10.1111/j.1472-8206.1999.tb00333.x. PMID10226758. [17] Ramoska, E; Spiller, H; Winter, M; Borys, D (1993). "A one-year evaluation of calcium channel blocker overdoses: Toxicity and treatment". Annals of Emergency Medicine 22 (2): 196200. doi:10.1016/S0196-0644(05)80202-1. PMID8427431. [18] Grossman, Ehud; Messerli, Franz H. (2004). "Calcium antagonists". Progress in Cardiovascular Diseases 47 (1): 3457. doi:10.1016/j.pcad.2004.04.006. PMID15517514. [19] Claas, Steven A; Glasser, Stephen P (2005). "Long-acting diltiazem HCL for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris". Expert Opinion on Pharmacotherapy 6 (5): 76576. doi:10.1517/14656566.6.5.765. PMID15934903. [20] Gabrielli, Andrea; Gallagher, T. James; Caruso, Lawrence J.; Bennett, Neil T.; Layon, A. Joseph (2001). "Diltiazem to treat sinus tachycardia in critically ill patients: A four-year experience". Critical Care Medicine 29 (10): 18749. doi:10.1097/00003246-200110000-00004. PMID11588443. [21] Wattanasuwan, N.; Khan, IA; Mehta, NJ; Arora, P; Singh, N; Vasavada, BC; Sacchi, TJ (2001). "Acute Ventricular Rate Control in Atrial Fibrillation : IV Combination of Diltiazem and Digoxin vs IV Diltiazem Alone". Chest 119 (2): 5026. doi:10.1378/chest.119.2.502. PMID11171729. [22] Basile, Jan (2004). "The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension". The Journal of Clinical Hypertension 6 (11): 62129; quiz 6301. doi:10.1111/j.1524-6175.2004.03683.x. [23] Edoute, Yeouda; Nagachandran, Pradeep; Svirski, Boris; Ben-Ami, Haim (2000). "Cardiovascular Adverse Drug Reaction Associated with Combined -Adrenergic and Calcium Entry-Blocking Agents". Journal of Cardiovascular Pharmacology 35 (4): 5569. doi:10.1097/00005344-200004000-00007. PMID10774785. [24] Grossman, Ehud; Messerli, Franz H. (2004). "Calcium antagonists". Progress in Cardiovascular Diseases 47 (1): 3457. doi:10.1016/j.pcad.2004.04.006. PMID15517514. [25] Montastruc, JL; Senard, JM (1992). "Mdicaments anticalciques et prophylaxie de la migraine [Calcium channel blockers and prevention of migraine]" (in French). Pathologie et Biologie 40 (4): 3818. PMID1353873. [26] Kim, KE (1991). "Comparative clinical pharmacology of calcium channel blockers". American family physician 43 (2): 5838. PMID1990741. [27] Andersson, KE; Vinge, E (1990). "Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine". Drugs 39 (3): 35573. doi:10.2165/00003495-199039030-00003. PMID1970289. [28] Paterna, S; Martino, SG; Campisi, D; Cascio Ingurgio, N; Marsala, BA (1990). "Evaluation of the effects of verapamil, flunarizine, diltiazem, nimodipine and placebo in the prevention of hemicrania. A double-blind randomized cross-over study". La Clinica terapeutica 134 (2): 11925. PMID2147612. [29] Smith, R; Schwartz, A (1984). "Diltiazem Prophylaxis in Refractory Migraine". New England Journal of Medicine 310 (20): 13278. doi:10.1056/NEJM198405173102015. PMID6144044. [30] Peroutka, Stephen J. (1983). "The Pharmacology of Calcium Channel Antagonists: a Novel Class of Anti-migraine Agents?". Headache: the Journal of Head and Face Pain 23 (6): 27883. doi:10.1111/j.1526-4610.1983.hed2306278.x. [31] http:/ / www. sciencedaily. com/ releases/ 2008/ 02/ 080227155016. htm [32] Mills, K; Ansah, T; Ali, S; Mukherjee, S; Shockley, D (2007). "Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers". Life Sciences 81 (7): 6008. doi:10.1016/j.lfs.2007.06.028. PMC2765982. PMID17689567.
Diltiazem
[33] Kishioka, S; Ko, MC; Woods, JH (2000). "Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys". European Journal of Pharmacology 397 (1): 8592. doi:10.1016/S0014-2999(00)00248-X. PMID10844102. [34] Verma, V; Mediratta, PK; Sharma, KK (2001). "Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers". Indian journal of experimental biology 39 (7): 63642. PMID12019755. [35] Jonas, Marion; Neal, Keith R.; Abercrombie, John F.; Scholefield, John H. (2001). "A randomized trial of oral vs. topical diltiazem for chronic anal fissures". Diseases of the Colon & Rectum 44 (8): 10748. doi:10.1007/BF02234624. [36] Nash, G. F.; Kapoor, K.; Saeb-Parsy, K.; Kunanadam, T.; Dawson, P. M. (2006). "The long-term results of diltiazem treatment for anal fissure". International Journal of Clinical Practice 60 (11): 14113. doi:10.1111/j.1742-1241.2006.00895.x. PMID16911570. [37] Sajid, M. S.; Rimple, J.; Cheek, E.; Baig, M. K. (2007). "The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis". International Journal of Colorectal Disease 23 (1): 16. doi:10.1007/s00384-007-0384-x. PMID17846781.
287
External links
U.S. National Library of Medicine: Drug Information Portal - Diltiazem (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Diltiazem)
288
Type V Antiarrythmics
Adenosine
Adenosine
(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
Clinical data Trade names Adenocard
AHFS/Drugs.com monograph [1] Pregnancy cat. Legal status Routes C Australia - Legal; UK - Legal; US - Rx only Intravenous Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion Rapidly cleared from circulation via cellular uptake No Rapidly converted to inosine and adenosine monophosphate cleared plasma <30 seconds - half life <10 seconds can leave cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid Identifiers CAS number ATC code PubChem 58-61-7
[2]
C01 EB10
[3] [4]
CID 60961
Adenosine
[5]
289
DrugBank ChemSpider UNII KEGG ChEBI ChEMBL
DB00640 54923
[6]
K72T3FS567 C00212
[8]
[7]
CHEBI:16335
[9]
[10]
CHEMBL606298
[11]
& PubChem
[12]
[13]
Adenosine is a purine nucleoside comprising a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a -N9-glycosidic bond. Adenosine plays an important role in biochemical processes, such as energy transferas adenosine triphosphate (ATP) and adenosine diphosphate (ADP)as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing with each hour an organism is awake. Adenosine is often abbreviated Ado.
Pharmacological effects
Adenosine is an endogenous purine nucleotide that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A1, A2A, A2B, and A3).[14] Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (6001,200 nM). Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.
Adenosine receptors
The different adenosine receptor subtypes (A1, A2A, A2B, and A3) are all seven transmembrane spanning G-protein coupled receptors. These four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors couple to Gs and mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine receptors couple to Gi which inhibits adenylate cyclase activity. Additionally, A1 receptors couple to Go, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gq and stimulate phospholipase activity.
Adenosine
290
Anti-inflammatory properties
Adenosine is believed to be an anti-inflammatory agent at the A(2A) receptor.[15] [16] Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound healing deficiencies and diabetes mellitus in humans is currently under clinical investigation. Methotrexate's anti-inflammatory effect may be due to its stimulation of adenosine release.
Action on the heart

When administered intravenously, adenosine causes transient heart block in the Atrioventricular (AV) node. This is mediated via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing outward K+ flux. It also causes endothelial dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilation of the "normal" segments of arteries; i.e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments. In individuals suspected of suffering from a supraventricular tachycardia (SVT), adenosine is used to help identify the rhythm. Certain SVTs can be successfully terminated with adenosine.[17] This includes any re-entrant arrhythmias that require the AV node for the re-entry, e.g., AV reentrant tachycardia (AVRT), AV nodal reentrant tachycardia (AVNRT). In addition, atrial tachycardia can sometimes be terminated with adenosine. Adenosine has an indirect effect on atrial tissue causing a shortening of the refractory period. When administered via a central lumen catheter, adenosine has been shown to initiate atrial fibrillation because of its effect on atrial tissue. In individuals with accessory pathways, the onset of atrial fibrillation can lead to a life-threatening ventricular fibrillation. Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation, atrial flutter) or ventricles (e.g., monomorphic ventricular tachycardia) and do not involve the AV node as part of the re-entrant circuit are not typically converted by adenosine. However, the ventricular response rate is temporarily slowed with adenosine in such cases. Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class IV antiarrhythmic agent. When adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest.[18] By nature of caffeine's purine structure[19] it binds to some of the same receptors as adenosine.[19] The pharmacological effects of adenosine may therefore be blunted in individuals who are taking large quantities of methylxanthines (e.g., caffeine, found in coffee and tea, or theobromine, as found in chocolate). [20]
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.
Action in the central nervous system
Adenosine Generalized, adenosine has an inhibitory effect in the central nervous system (CNS). Caffeine's stimulatory effects, on the other hand, are primarily (although not entirely) credited to its inhibition of adenosine by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate.
291
Dosage
When given for the evaluation or treatment of a supraventricular tachycardia (SVT), the initial dose is 6mg, given as a rapid parenteral infusion. Due to adenosine's extremely short half-life, the IV line is started as proximal (near) to the heart as possible, such as the cubital fossa. The IV push is often followed with an immediate flush of 10-20ccs of saline. If this has no effect (i.e. no evidence of transient AV block), a 12mg dose can be given 12 minutes after the first dose. AHA 2010 IS NO LONGER RECOMMENDING A SECOND DOSE OF 12MG. PLEASE VIEW ALGORITHM AS CONFIRMATION. Some clinicians may prefer to administer a higher dose (typically 18mg), rather than repeat a dose that apparently had no effect. When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14mg/kg/min, administered for 4 or 6 minutes, depending on the protocol. The recommended dose may be increased in patients on theophylline since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole (Persantine) and diazepam (Valium) because adenosine potentiates the effects of these drugs. The recommended dose is also reduced by half in patients who are presenting congestive heart failure, myocardial infarction, shock, hypoxia, and/or hepatic or renal insufficiency, and in elderly patients.
Drug interactions
Dopamine may precipitate toxicity in the patient. Carbamazepine may increase heart block. Theophylline and caffeine (methylxanthines) competitively antagonize adenosine's effects; an increased dose of adenosine may be required. Dipyridamole potentiates the action of adenosine, requiring the use of lower doses.
Contraindications
Common Contraindications for adenosine are: 2nd or 3rd degree heart block (without a pacemaker) Sick sinus syndrome (without a pacemaker) Long QT syndrome Severe hypotension Decompensated heart failure Asthma, traditionally an absolute CI this is being contended and it is now considered relative (however, selective adenosine agonists are being investigated for use in treatment of asthma)[21] Poison/drug-induced tachycardia In Wolff-Parkinson-White syndrome, adenosine may be administered if equipment for cardioversion is immediately available as a backup.
Side effects
Many individuals experience facial flushing, a temporary rash on the chest, lightheadedness, diaphoresis, or nausea after administration of adenosine due to its vasodilatory effects. Metallic taste is a hallmark side effect of adenosine administration. These symptoms are transitory, usually lasting less than one minute. It is classically associated with a sense of "impending doom", more prosaically described as apprehension. This lasts a few seconds after administration of a bolus dose, during transient asystole induced by intravenous administration. In some cases adenosine can make patients' limbs feel numb for about 25 minutes after administration intravenously depending on the dosage (usually above 12mg).
Adenosine
292
Metabolism
Adenosine used as a second messenger can be the result of de novo purine biosynthesis via adenosine monophosphate (AMP), though it is possible other pathways exist.[22] When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red cells and the vessel wall. Dipyridamole, an inhibitor of adenosine deaminase, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation. Adenosine deaminase deficiency is a known cause of immunodeficiency.
Analogs and viruses

The adenosine analog, NITD008 has been reported to directly inhibit the recombinant an RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This suppresses peak viremia, rise in cytokines and prevented infected animal from death raising the possibility of a new treatment for this flavivirus.[23] The 7-deaza-adenosine analog has been shown to inhibit the replication of the hepatitis C virus.[24] Such adenosine analogs are potentially clinically useful since they can be taken orally.
References
[1] http:/ / www. drugs. com/ monograph/ adenosine. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=58-61-7& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01EB10 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=60961 [5] http:/ / www. drugbank. ca/ drugs/ DB00640 [6] http:/ / www. chemspider. com/ Chemical-Structure. 54923 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=K72T3FS567 [8] http:/ / www. kegg. jp/ entry/ C00212 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:16335 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL606298 [11] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=n2c1c%28ncnc1n%28c2%29%5BC%40%40H%5D3O%5BC%40%40H%5D%28%5BC%40%40H%5D%28O%29%5BC%40H%5D3O%29CO%29N [12] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=n2c1c%28ncnc1n%28c2%29%5BC%40%40H%5D3O%5BC%40%40H%5D%28%5BC%40%40H%5D%28O%29%5BC%40H%5D3O%29CO%29N [13] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=456665987& page2=%3AAdenosine [14] Hask G, Linden J, Cronstein B, Pacher P (September 2008). "Adenosine receptors: therapeutic aspects for inflammatory and immune diseases". Nat Rev Drug Discov 7 (9): 75970. doi:10.1038/nrd2638. PMC2568887. PMID18758473. [15] Nakav S, Chaimovitz C, Sufaro Y (2008). Bozza, Patricia. ed. "Anti-Inflammatory Preconditioning by Agonists of Adenosine A1 Receptor" (http:/ / www. plosone. org/ article/ info:doi/ 10. 1371/ journal. pone. 0002107). PLoS ONE 3 (5): e2107. doi:10.1371/journal.pone.0002107. PMC2329854. PMID18461129. . [16] Trevethick MA, Mantell SJ, Stuart EF, Barnard A, Wright KN, Yeadon M (October 2008). "Treating lung inflammation with agonists of the adenosine A2A receptor: promises, problems and potential solutions". Br. J. Pharmacol. 155 (4): 46374. doi:10.1038/bjp.2008.329. PMC2579671. PMID18846036. [17] Mitchell J, Lazarenko G (November 2008). "Wide QRS complex tachycardia. Diagnosis: Supraventricular tachycardia with aberrant conduction; intravenous (IV) adenosine" (http:/ / caep. ca/ template. asp?id=563f5c92af544619b2ac53fbba2ce6c5). CJEM 10 (6): 5723, 581. PMID19000353. . [18] Pijls, Nico H. J.; Bernard De Bruyne (2000). Coronary Pressure. Springer. ISBN0-7923-6170-9. [19] "Caffeine" (http:/ / www. chemistryexplained. com/ Bo-Ce/ Caffeine. html). Chemistry Explained. . [20] "Vitamin B4" (http:/ / www. rspharmchem. com/ vitamin-b4. htm). R&S Pharmchem. April 2011. . [21] Brown RA, Spina D, Page CP (March 2008). "Adenosine receptors and asthma". Br. J. Pharmacol. 153 Suppl 1 (S1): S44656. doi:10.1038/bjp.2008.22. PMC2268070. PMID18311158. [22] PMID 8020339 [23] Yin Z, Chen YL, Schul W, Wang QY, Gu F, Duraiswamy J, Reddy Kondreddi R, Niyomrattanakit P, Lakshminarayana SB, Goh A, Xu HY, Liu W, Liu B, Lim JY, Ng CY, Qing M, Lim CC, Yip A, Wang G, Chan WL, Tan HP, Lin K, Zhang B, Zou G, Bernard KA, Garrett C, Beltz K, Dong M, Weaver M, He H, Pichota A, Dartois V, Keller TH, Shi PY. (2009). Proc Natl Acad Sci U S A. 106: 2043520439
Adenosine
doi:10.1073/pnas.0907010106 PMID 19918064 [24] Olsen, DB; Eldrup, AB; Bartholomew, L; Bhat, B; Bosserman, MR; Ceccacci, A; Colwell, LF; Fay, JF et al. (2004). "A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties". Antimicrobial agents and chemotherapy 48 (10): 394453. doi:10.1128/AAC.48.10.3944-3953.2004. PMC521892. PMID15388457.
293
External links
Sleep chemical central to effectiveness of deep brain stimulation (http://www.brightsurf.com/news/headlines/ 34975/Sleep_chemical_central_to_effectiveness_of_deep_brain_stimulation.html)
Digoxin
294
Digoxin
Digoxin
4-[(3S,5R,8R,9S,10S,12R,13S,14S)-3[(2S,4S,5R,6R)-5-[(2S,4S,5R,6R)-5[(2S,4S,5R,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyl-oxan2-yl]oxy-4-hydroxy-6-methyl-oxan-2-yl] oxy-12,14-dihydroxy-10,13-dimethyl-1, 2,3,4,5,6,7,8,9,11,12,15,16,17-tetra decahydrocyclopenta[a]phenanthren17-yl]-5H-furan-2-one

Clinical data Trade names Lanoxin
AHFS/Drugs.com monograph [1] MedlinePlus Pregnancy cat. Legal status Routes a682301
[2]
A (Au), C (U.S.) S4 (Au), POM (UK), -only (U.S.) Oral, Intravenous Pharmacokinetic data
Bioavailability Protein binding Metabolism Half-life
60 to 80% (Oral) 25% Hepatic (16%) 36 to 48 hours (patients with normal renal function) 3.5 to 5 days (patients with impaired renal function) Renal Identifiers
Excretion
CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG
20830-75-5 C01 AA02
[3]
[5]
[4]
C01 AA05
[7]
C01 AA08
[6]
CID 2724385 DB00390 2006532

[8]
[9]
73K4184T59 D00298
[11]
[10]
Digoxin
[12]
295
ChEBI ChEMBL
CHEBI:4551
CHEMBL1751
[13]
Chemical data Formula Mol. mass SMILES C41H64O14 780.938 g/mol eMolecules
[14]
& PubChem
[15]
Physical data Melt. point 249.3C (481F)
Solubility in water 0.0648mg/mL (20C) (what is this?) (verify)

[16]
Digoxin INN ( /ddksn/),[17] also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata.[18] Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Digoxin preparations are commonly marketed under the trade names Lanoxin, Digitek, and Lanoxicaps. It is also available as a 0.05mg/mL oral solution and 0.25mg/mL or 0.5mg/mL injectable solution. It is marketed by GlaxoSmithKline and many other pharmaceutic manufacturers.
Medical use
Today, the most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response, but beta-blockers or calcium channel-blockers should be the first choice.[19] [20] High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling. The use of digoxin in heart problems during sinus rhythm was once standard, but is now controversial. In theory the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable and other effective treatments are now available. Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment. It has fallen out of favor because did not demonstrate a mortality benefit in patients with congestive heart failure; however, it did demonstrate a reduction in hospitalizations for congestive heart failure.[21] Because other therapies have shown a mortality benefit in congestive heart failure, it is recommended to maximize other therapies (eg, beta-blockers) first before using digoxin.
Digoxin
296
Pharmacokinetic properties
Digoxin is usually given by mouth, but can also be given by IV injection in urgent situations (the IV injection should be slow, heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea), digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours, digoxin is given once daily, usually in 125 g or 250 g dosing. In patients with decreased kidney function the half-life is considerably longer, calling for a reduction in dosing or a switch to a different glycoside such as digitoxin (not available in the United States), which has a much longer elimination half-life of around 7 days but is mainly eliminated from the body via the liver, and thus not affected by changes in kidney function. Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 to 1.0 ng/mL are recommended. [22] This recommendation is based on post-hoc analysis of prospective trials, suggesting that higher levels may be associated with increased mortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generally titrated to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 1.0 and 2.0 ng/mL. In suspected toxicity or ineffectiveness, digoxin levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects below). Quinidine, verapamil, and amiodarone increases plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance) so plasma digoxin must be monitored carefully. Researchers at Yale University looked at data from an earlier study to see if digoxin affected men and women differently. That study determined that digoxin, which has been used for centuries and makes the heart contract more forcefully, did not reduce deaths overall but did result in less hospitalization. Researcher Dr. Harlan Krumholz said they were surprised to find that women in the study who took digoxin died more frequently (33%) than women who took a placebo pill (29%). They calculated that digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study. Digoxin is also used as a standard control substance to test for p-glycoprotein inhibition.
Adverse effects
The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 g/L.[23] They are also more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with K+ ions for the same binding site on the Na+/K+ ATPase pump. Common adverse effects (1% of patients) include: loss of appetite, nausea, vomiting and diarrhea as the gastrointestinal motility increase. Other common effects are blurred vision, visual disturbances (yellow-green halos and problems with color perception), confusion, drowsiness, dizziness, insomnia, nightmares, agitation, and depression, as well as a higher acute sense of sensual activities.[24] Less frequent adverse effects (0.1%1%) include: acute psychosis, delirium, amnesia, convulsions, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or fibrillation, and heart block[23] Rarely, digoxin has been shown to cause thrombocytopenia. Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side-effect thought to be due to the estrogen-like steroid moiety of the digoxin molecule[25] but when systematically sought, the evidence for this is equivocal.[26] The pharmacological actions of digoxin usually results in electrocardiogram (ECG) changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular conduction (for example paroxysmal atrial tachycardia with A-V block - so-called "PAT with block") is said to be pathognomonic
Digoxin (i.e. diagnostic) of digoxin toxicity.[27] An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called xanthopsia. It has been proposed that the painter Vincent van Gogh's "Yellow Period" may have somehow been influenced by concurrent digitalis therapy. Other oculotoxic effects of digoxin include generalized blurry vision as well as seeing a "halo" around each point of light.[28] The latter effect can also be seen in van Gogh's Starry Night. Evidence of van Gogh's digoxin use is supported by multiple self portraits that include the foxglove plant, from which digoxin is obtained. (E.g. Portrait of Dr. Gachet) Digoxin plasma concentrations may increase while on antimalarial medication hydroxychloroquine (based on two case reports from 1982).[29] In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalaemia occurs (inexorably rising potassium level due to paralysis of the cell membrane bound ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names of Digibind and Digifab).[30] Toxicity can also be treated with higher than normal doses of potassium. Digoxin is not removed by hemo or peritoneal dialysis with enough effectiveness to treat toxicity. Digoxin has potentially dangerous interactions with verapamil,[31] amiodarone, erythromycin, and epinephrine (as would be injected with a local anesthetic).
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Actions
The main pharmacological effects of digoxin are on the heart. Extracardiac effects are responsible for some of the therapeutic and many of the adverse effects (see below). It has mechanical effects as it increases myocardial contractility, however, the duration of the contractile response is just slightly increased. Overall, the heart rate is decreased, while blood pressure increases as the stroke volume is increased, leading to increased tissue perfusion. Myocardial efficiency improves due to improved hemodynamics, and the ventricular function curve is improved. Other, electrical effects are an initial brief increase in action potential, followed by a decrease as the K+ conductance increases due to an increased intracellular amounts of Ca2+ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased excitability. Other, more indirect effects are cholinomimetic because of vagal stimulation, giving rise to AV nodal delay. The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased, in the atria, AV node, Purkinje fibers and ventricles. ECG changes are increased PR interval, due to decreased AV conduction, and a decreased QT interval because of the altered duration of decreased action potential. Also, the T wave is inverted, accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigeminy) resulting in ventricular tachycardia and fibrillation. Slight vasodilation is seen in heart failure. This effect is contrary to effects that should be seen as a result of increased intracellular calcium levels, but this occurs since digoxin improves hemodynamics, which leads to restored angiotensin levels and decreased sympathetic discharge, causing indirect vasodilation. Digoxin also affects the kidney by increased renal blood flow and increased GFR. A mild diuretic effect is seen only in heart failure.
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Mechanism of action
The mechanism of action is not completely understood; however the current hypothesis is outlined below. Digoxin binds to a site on the extracellular aspect of the -subunit of the Na+/K+ ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes, which leads to a rise in the level of intracellular calcium ions. This occurs because the sodium/calcium exchanger on the plasma membrane depends on a constant inward sodium gradient to pump out calcium. Digoxin decreases sodium concentration gradient and the subsequent calcium outflow, thus raising the calcium concentration in myocardiocytes and pacemaker cells. Increased intracellular calcium lengthens Phase 4 and Phase 0 of the cardiac action potential, which leads to a decrease in heart rate.[32] Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility, the force of contraction, of the heart. There is also evidence that digoxin increases vagal activity, thereby decreasing heart rate by slowing depolarization of pacemaker cells in the AV node.[33] This negative chronotropic effect would therefore be synergistic with the direct effect on cardiac pacemaker cells. Digoxin is used widely in the treatment of various arrhythmias.
Society and culture

Charles Cullen admitted in 2003 to killing as many as 40 hospital patients with overdoses of heart medicationusually digoxinat hospitals in New Jersey and Pennsylvania over his 16-year career as a nurse. On March 10, 2006 he was sentenced to 18 consecutive life sentences and is not eligible for parole.[34] On April 25, 2008 the FDA issued a press release[35] alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan.[36] It was found that some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. A class-action lawsuit against the Icelandic generic drug maker Actavis was announced two weeks later.[37] On March 31, 2009 the FDA announced another generic digoxin pill recall by posting this company press release on the agency's web site: "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability". This March 31 press release from Caraco, a generic pharmaceutical company, states that: [All] tablets of Caraco brand Digoxin, USP, 0.125mg, and Digoxin, USP, 0.25mg, distributed prior to March 31, 2009, which are not expired and are within the expiration date of September, 2011, are being voluntarily recalled to the consumer level. The tablets are being recalled because they may differ in size and therefore could have more or less of the active ingredient, digoxin. On May 6, the Public Radio program Health in a Heartbeat, produced by the University of Florida, discussed a recent study of the National Academy of Sciences, which suggests that digoxin has beneficial effects not only for the heart but also in reducing the risk of certain kinds of cancer..[38] However, an article published in the Proceedings of the National Academy of Sciences soon after indicated that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug.[39]
Digoxin
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References
[1] http:/ / www. drugs. com/ monograph/ digoxin. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682301. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=20830-75-5& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01AA02 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01AA05 [6] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01AA08 [7] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2724385 [8] http:/ / www. drugbank. ca/ drugs/ DB00390 [9] http:/ / www. chemspider. com/ Chemical-Structure. 2006532 [10] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=73K4184T59 [11] http:/ / www. kegg. jp/ entry/ D00298 [12] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:4551 [13] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1751 [14] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=O%3DC%5C1OC%2FC%28%3DC%2F1%29%5BC%40H%5D2CC%5BC%40%40%5D8%28O%29%5BC%40%5D2%28C%29%5BC%40H%5D%28O%29 [15] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=O%3DC%5C1OC%2FC%28%3DC%2F1%29%5BC%40H%5D2CC%5BC%40%40%5D8%28O%29%5BC%40%5D2%28C%29%5BC%40H%5D%28 [16] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=459476549& page2=%3ADigoxin [17] OED [18] A. Hollman (1996). "Digoxin comes from Digitalis lanata" (http:/ / www. bmj. com/ cgi/ content/ full/ 312/ 7035/ 912) (letter). British Medical Journal 312 (7035): 912. . [19] Sticherling C, Oral H, Horrocks J, et al. (November 2000). "Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness" (http:/ / circ. ahajournals. org/ cgi/ content/ full/ 102/ 20/ 2503). Circulation 102 (20): 25038. PMID11076824. . [20] Hallberg P, Lindbck J, Lindahl B, Stenestrand U, Melhus H (October 2007). "Digoxin and mortality in atrial fibrillation: a prospective cohort study" (http:/ / www. springerlink. com/ content/ 62g4v62272167l75/ ?p=7c71dc6f1f0e463ab54515c25f735dd9& pi=3). Eur. J. Clin. Pharmacol. 63 (10): 95971. doi:10.1007/s00228-007-0346-9. PMID17684738. . [21] "The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group". The New England journal of medicine 336 (8): 525533. February 1997. doi:10.1056/NEJM199702203360801. PMID9036306. [22] Sharon Ann Hunt, William T. Abraham, Marshall H. Chin, et al. (September 2005). "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society". Circulation 112 (12): e154e235. doi:10.1161/CIRCULATIONAHA.105.167586. PMID16160202. [23] Rossi S, ed (2006). Australian Medicines Handbook 2006. Adelaide. ISBN0-9757919-2-3. [24] K.D Tripathi, ed (2007). Essentials of Medical Pharmacology. New Delhi. ISBN81-8448-085-7. [25] Moscovitz T, Aldrighi JM, Abrahanshon PA, et al. (April 2005). "Repercussions of digoxin, digitoxin and estradiol on the endometrial histomorphometry of oophorectomized mice" (http:/ / informahealthcare. com/ doi/ abs/ 10. 1080/ 09513590400021219). Gynecol. Endocrinol. 20 (4): 21320. doi:10.1080/09513590400021219. PMID16019364. . [26] Thompson, D.F.; Carter, J.R. (1993). "Drug-induced gynecomastia". Pharmacotherapy 13 (1): 3745. PMID8094898. [27] Doering, W.; Konig, E.; Sturm, W. (1977). "Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl)". Z Kardiol 66 (3): 1218. PMID857452. [28] Goldfrank, LW. Goldfrank's Toxicologic Emergencies, 8th Edition. New York: McGraw-Hill, 2006. [29] Leden I (1982). "Digoxin-hydroxychloroquine interaction?". Acta Med Scand 211 (5): 4112. doi:10.1111/j.0954-6820.1982.tb01971.x. PMID7113754. [30] Flanagan, R.J.; Jones, A.L. (2004). "Fab Antibody Fragments: Some Applications in Clinical Toxicology" (http:/ / drugsafety. adisonline. com/ pt/ re/ drs/ fulltext. 00002018-200427140-00004. htm). Drug Safety 27 (14): 111533. doi:10.2165/00002018-200427140-00004. PMID15554746. . [31] Kaplanski, J.; Weinhouse, E.; Topaz, M.; Genchik, G. (1983). "Verapamil and digoxin: interactions in the rat". Res Commun Chem Pathol Pharmacol 42 (3): 37788. PMID6665298. [32] K.D Tripathi, Essentials of Medical Pharmacology, 6th Edition Pages 498, Jaypee Publications [33] DJ Goodman et al. (1975). "Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation" (http:/ / www. circ. ahajournals. org/ cgi/ reprint/ 51/ 2/ 251). Circulation 51 (2): 251256. . [34] "Victims' families set to confront killer" (http:/ / usatoday. com/ news/ nation/ 2006-01-01-patient-deaths_x. htm). USA Today. 2006-01-01. . [35] "Recalls, Market Withdrawals, & Safety Alerts" (http:/ / www. fda. gov/ oc/ po/ firmrecalls/ actavis04_08. html). Fda.gov. 2008-10-15. . Retrieved 2011-11-08.
Digoxin
[36] "Urgent Digitek Digoxin Recall" (http:/ / www. usrecallnews. com/ 2008/ 04/ urgent-digitek-digoxin-recall. html). U.S. Recall News. 28 April 2008. . Retrieved 25 July 2009. [37] "Patients Sue Icelandic Drugmaker Over Recalled Heart Drug" (http:/ / blogs. wsj. com/ health/ 2008/ 05/ 09/ patients-sue-icelandic-drugmaker-over-recalled-heart-drug/ ). Wall Street Journal. 9 May 2008. . Retrieved 25 July 2009. [38] "Heart medication may fights cancer Health Science Center News & Communications - University of Florida" (http:/ / www. news. health. ufl. edu/ heartbeat/ heartbeat. aspx?ID=8724). News.health.ufl.edu. 2009-05-06. . Retrieved 2011-11-08. [39] Miguel Lopez-Lazaro,1. "Digoxin, HIF-1, and cancer" (http:/ / www. pnas. org/ content/ 106/ 9/ E26. full). Pnas.org. . Retrieved 2011-11-08.
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Further reading
Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN0-443-07145-4. Summary of Product Characteristics, Digoxin 0,125mg, Zentiva a.s. Lllmann (2003). Pharmakologie und Toxikologie (15th ed.). Georg Thieme Verlag. ISBN3-13-368515-5.
External links
U.S. National Library of Medicine: Drug Information Portal Digoxin (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Digoxin) Commonly used website to calculate empiric digoxin doses for medical purposes (http://clincalc.com/Digoxin)
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Artificial Pacemakers
Artificial pacemaker
A pacemaker (or artificial pacemaker, so as not to be confused with the heart's natural pacemaker) is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart. The primary purpose of a pacemaker is to maintain an adequate heart rate, either because of the heart's native pacemaker is not fast enough, or there is a block in the heart's electrical conduction system. Modern pacemakers are externally programmable and allow the cardiologist to select the optimum pacing modes for individual patients. Some combine a pacemaker and defibrillator in a single implantable device. Others have multiple electrodes stimulating differing positions within the heart to improve synchronisation of the lower chambers of the heart.
A pacemaker, scale in centimeters
An artificial pacemaker with electrode for transvenous insertion. The body of the device is about 4 centimeters long, the electrode measures between 50 and 60 centimeters (20 to 24 inches).
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History
In 1899, J A McWilliam reported in the British Medical Journal of his experiments in which application of an electrical impulse to the human heart in asystole caused a ventricular contraction and that a heart rhythm of 60-70 beats per minute could be evoked by impulses applied at spacings equal to 60-70/minute.[1] In 1926, Dr Mark C Lidwell of the Royal Prince Alfred Hospital of Sydney, supported by physicist Edgar H Booth of the University of Sydney, devised a portable apparatus which "plugged into a lighting point" and in which "One pole was applied to a skin pad soaked in strong salt solution" while the other pole "consisted of a needle insulated except at its point, and was plunged into the appropriate cardiac chamber". "The pacemaker rate was variable from about 80 to 120 pulses per minute, and likewise the voltage variable from 1.5 to 120 volts" In 1928, the apparatus was used to revive a stillborn infant at Crown Street Women's Hospital, Sydney whose heart continued "to beat on its own accord", "at the end of 10 minutes" of stimulation.[2] [3] In 1932, American physiologist Albert Hyman, working independently, described an electro-mechanical instrument of his own, powered by a spring-wound hand-cranked motor. Hyman himself referred to his invention as an "artificial pacemaker", the term continuing in use to this day.[4] [5] An apparent hiatus in publication of research conducted between the early 1930s and World War II may be attributed to the public perception of interfering with nature by 'reviving the dead'. For example, "Hyman did not publish data on the use of his pacemaker in humans because of adverse publicity, both among his fellow physicians, and due to newspaper reporting at the time. Lidwell may have been aware of this and did not proceed with his experiments in humans".[3]
The first implantable pacemaker
In 1958, Arne Larsson (1915-2001) became the first to receive an implantable pacemaker. He had a total of 26 devices during his life and campaigned for other patients needing pacemakers.
An external pacemaker was designed and built by the Canadian electrical engineer John Hopps in 1950 based upon observations by cardio-thoracic surgeon Wilfred Gordon Bigelow at Toronto General Hospital . A substantial external device using vacuum tube technology to provide transcutaneous pacing, it was somewhat crude and painful to the patient in use and, being powered from an AC wall socket, carried a potential hazard of electrocution of the patient by inducing ventricular fibrillation. A number of innovators, including Paul Zoll, made smaller but still bulky transcutaneous pacing devices in the following years using a large rechargeable battery as the power supply.[6] In 1957, Dr. William L. Weirich published the results of research performed at the University of Minnesota. These studies demonstrated the restoration of heart rate, cardiac output and mean aortic pressures in animal subjects with complete heart block through the use of a myocardial electrode. This effective control of postsurgical heart block proved to be a significant contribution to decreasing mortality of open heart surgery in this time period.[7] In 1958 Colombian electrical engineer Jorge Reynolds Pombo constructed an external pacemaker, similar to those of Hopps and Zoll, weighing 45 kg and powered by a 12 volt auto battery, but connected to electrodes attached to the heart. This apparatus was successfully used to sustain a 70 year old priest, Gerardo Florez.
Artificial pacemaker The development of the silicon transistor and its first commercial availability in 1956 was the pivotal event which led to rapid development of practical cardiac pacemaking. In 1958, engineer Earl Bakken of Minneapolis, Minnesota, produced the first wearable external pacemaker for a patient of Dr. C. Walton Lillehei. This transistorised pacemaker, housed in a small plastic box, had controls to permit adjustment of pacing heart rate and output voltage and was connected to electrode leads which passed through the skin of the patient to terminate in electrodes attached to the surface of the myocardium of the heart. The first clinical implantation into a human of a fully implantable pacemaker was in 1958 at the Karolinska Institute in Solna, Sweden, using a pacemaker designed by Rune Elmqvist and surgeon ke Senning, connected to electrodes attached to the myocardium of the heart by thoracotomy. The device failed after three hours. A second device was then implanted which lasted for two days. The world's first implantable pacemaker patient, Arne Larsson, went on to receive 26 different pacemakers during his lifetime. He died in 2001, at the age of 86, outliving the inventor as well as the surgeon.[8] In 1959, temporary transvenous pacing was first demonstrated by Furman et al. in which the catheter electrode was inserted via the patient's basilic vein.[9] In February 1960, an improved version of the Swedish Elmqvist design was implanted in Montevideo, Uruguay in the Casmu Hospital by Doctors Fiandra and Rubio. That device lasted until the patient died of other ailments, 9 months later. The early Swedish-designed devices used rechargeable batteries, which were charged by an induction coil from the outside. Implantable pacemakers constructed by engineer Wilson Greatbatch entered use in humans from April 1960 following extensive animal testing. The Greatbatch innovation varied from the earlier Swedish devices in using primary cells (mercury battery) as the energy source. The first patient lived for a further 18 months. The first use of transvenous pacing in conjunction with an implanted pacemaker was by Parsonnet in the USA,[10] [11] [12] Lagergren in Sweden[13] [14] and Jean-Jaques Welti in France[15] in 1962-63. The transvenous, or pervenous, procedure involved incision of a vein into which was inserted the catheter electrode lead under fluoroscopic guidance, until it was lodged within the trabeculae of the right ventricle. This method was to become the method of choice by the mid-1960s. The preceding implantable devices all suffered from the unreliability and short lifetime of the available primary cell technology which was mainly that of the mercury battery. In the late 1960s, several companies, including ARCO in the USA, developed isotope powered pacemakers, but this development was overtaken by the development in 1971 of the lithium-iodide cell by Wilson Greatbatch. Lithium-iodide or lithium anode cells became the standard for future pacemaker designs. A further impediment to reliability of the early devices was the diffusion of water vapour from the body fluids through the epoxy resin World's first Lithium-iodide cell powered encapsulation affecting the electronic circuitry. This phenomenon was pacemaker. Cardiac Pacemakers Inc. 1972 overcome by encasing the pacemaker generator in an hermetically sealed metal case, initially by Telectronics of Australia in 1969 followed by Cardiac Pacemakers Inc of Minneapolis in 1972. This technology, using titanium as the encasing metal, became the standard by the mid-1970s. Others who contributed significantly to the technological development of the pacemaker in the pioneering years were Bob Anderson of Medtronic Minneapolis, J.G (Geoffrey) Davies of St George's Hospital London, Barouh Berkovits and Sheldon Thaler of American Optical, Geoffrey Wickham of Telectronics Australia, Walter Keller of Cordis Corp. of Miami, Hans Thornander who joined previously mentioned Rune Elmquist of Elema-Schonander in Sweden, Janwillem van den Berg of Holland and Anthony Adducci of Cardiac Pacemakers Inc.Guidant.
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Methods of pacing
Percussive pacing
Percussive pacing, also known as transthoracic mechanical pacing, is the use of the closed fist, usually on the left lower edge of the sternum over the right ventricle in the vena cava, striking from a distance of 20 30cm to induce a ventricular beat (the British Journal of Anesthesia suggests this must be done to raise the ventricular pressure to 10 15mmHg to induce electrical activity). This is an old procedure used only as a life saving means until an electrical pacemaker is brought to the patient.[16]
An ECG in a person with an atrial pacemaker. Note the circle around one of the sharp electrical spike in the position were one would expect the P wave.
Transcutaneous pacing
Transcutaneous pacing (TCP), also called external pacing, is recommended for the initial stabilization of hemodynamically significant bradycardias of all types. The procedure is performed by placing two pacing pads on the patient's chest, either in the anterior/lateral position or the anterior/posterior position. The rescuer selects the pacing rate, and gradually increases the pacing current (measured in mA) until electrical capture (characterized by a wide QRS complex with a tall, broad T wave on the ECG) is achieved, with a corresponding pulse. Pacing artifact on the ECG and severe muscle twitching may make this determination difficult. External pacing should not be relied upon for an extended period of time. It is an emergency procedure that acts as a bridge until transvenous pacing or other therapies can be applied.
Epicardial pacing (temporary)

Temporary epicardial pacing is used during open heart surgery should the surgical procedure create atrio ventricular block. The electrodes are placed in contact with the outer wall of the ventricle (epicardium) to maintain satisfactory cardiac output until a temporary transvenous electrode has been inserted.
Transvenous pacing (temporary)

Transvenous pacing, when used for temporary pacing, is an alternative to transcutaneous pacing. A pacemaker wire is placed into a vein, under sterile conditions, and then passed into either the right atrium or right ventricle. The pacing wire is then connected to an external pacemaker outside the body. Transvenous pacing is often used as a bridge to permanent pacemaker placement. It can be kept in place until a permanent pacemaker is implanted or until there is no longer a need for a pacemaker and then it is removed.
ECG rhythm strip of a threshold determination in a patient with a temporary (epicardial) ventricular pacemaker. The epicardial pacemaker leads were placed after the patient collapsed during aortic valve surgery. In the first half of the tracing, pacemaker stimuli at 60 beats per minute result in a wide QRS complex with a right bundle branch block pattern. Progressively weaker pacing stimuli are administered, which results in asystole in the second half of the tracing. At the end of the tracing, distortion results from muscle contractions due to a (short) hypoxic seizure. Because decreased pacemaker stimuli do not result in a ventricular escape rhythm, the patient can be said to be pacemaker-dependent and needs a definitive pacemaker.
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Permanent pacing
Permanent pacing with an implantable pacemaker involves transvenous placement of one or more pacing electrodes within a chamber, or chambers, of the heart. The procedure is performed by incision of a suitable vein into which the electrode lead is inserted and passed along the vein, through the valve of the heart, until positioned in the chamber. The procedure is facilitated by fluoroscopy which enables the physician or cardiologist to view the passage of the electrode lead. After satisfactory lodgement of the electrode is confirmed, the opposite end of the electrode lead is connected to the pacemaker generator. There are three basic types of permanent pacemakers, classified according to the number of chambers involved and their basic operating mechanism:[17] Single-chamber pacemaker. In this type, only one pacing lead is placed into a chamber of the heart, either the atrium or the ventricle.[17]
Right atrial and right ventricular leads as visualized under x-ray during a pacemaker implant procedure. The atrial lead is the curved one making a U shape in the upper left part of the figure.
Dual-chamber pacemaker. Here, wires are placed in two chambers of the heart. One lead paces the atrium and one paces the ventricle. This type more closely resembles the natural pacing of the heart by assisting the heart in coordinating the function between the atria and ventricles.[17] Rate-responsive pacemaker. This pacemaker has sensors that detect changes in the patient's physical activity and automatically adjust the pacing rate to fulfill the body's metabolic needs.[17] The pacemaker generator is a hermetically sealed device containing a power source, usually a lithium battery, a sensing amplifier which processes the electrical manifestation of naturally occurring heart beats as sensed by the heart electrodes, the computer logic for the pacemaker and the output circuitry which delivers the pacing impulse to the electrodes. Most commonly, the generator is placed below the subcutaneous fat of the chest wall, above the muscles and bones of the chest. However, the placement may vary on a case by case basis. The outer casing of pacemakers is so designed that it will rarely be rejected by the body's immune system. It is usually made of titanium, which is inert in the body.
Basic function
Modern pacemakers usually have multiple functions. The most basic form monitors the heart's native electrical rhythm. When the pacemaker fails to sense a heartbeat within a normal beat-to-beat time period, it will stimulate the ventricle of the heart with a short low voltage pulse. This sensing and stimulating activity continues on a beat by beat basis. The more complex forms include the ability to sense and/or stimulate both the atrial and ventricular chambers.
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The revised NASPE/BPEG generic code for antibradycardia pacing[18]

I II III IV V Multisite pacing O = None
Chamber(s) paced Chamber(s) sensed Response to sensing Rate modulation O = None A = Atrium V = Ventricle D = Dual (A+V) O = None A = Atrium V = Ventricle D = Dual (A+V) O = None T = Triggered I = Inhibited D = Dual (T+I) O = None
R = Rate modulation A = Atrium V = Ventricle D = Dual (A+V)
From this the basic ventricular "on demand" pacing mode is VVI or with automatic rate adjustment for exercise VVIR - this mode is suitable when no synchronization with the atrial beat is required, as in atrial fibrillation. The equivalent atrial pacing mode is AAI or AAIR which is the mode of choice when atrioventricular conduction is intact but the natural pacemaker the sinoatrial node is unreliable - sinus node disease (SND) or sick sinus syndrome. Where the problem is atrioventricular block (AVB) the pacemaker is required to detect (sense) the atrial beat and after a normal delay (0.1-0.2 seconds) trigger a ventricular beat, unless it has already happened - this is VDD mode and can be achieved with a single pacing lead with electrodes in the right atrium (to sense) and ventricle (to sense and pace). These modes AAIR and VDD are unusual in the US but widely used in Latin America and Europe.[19] [20] The DDDR mode is most commonly used as it covers all the options though the pacemakers require separate atrial and ventricular leads and are more complex, requiring careful programming of their functions for optimal results.
Biventricular pacing (BVP)

A biventricular pacemaker, also known as CRT (cardiac resynchronization therapy) is a type of pacemaker that can pace both the septal and lateral walls of the left ventricle. By pacing both sides of the left ventricle, the pacemaker can resynchronize a heart whose opposing walls do not contract in synchrony, which occurs in approximately 25-50 % of heart failure patients. CRT devices have at least two leads, one in the right ventricle to stimulate the septum, and another inserted through the coronary sinus to pace the lateral wall of the left ventricle. Often, for patients in normal sinus rhythm, there is also a lead in the right atrium to facilitate synchrony with the atrial contraction. Thus, timing between the atrial and ventricular contractions, as well as between the septal and lateral walls of the left ventricle can be adjusted to achieve optimal cardiac function. CRT devices have been shown to reduce mortality and improve quality of life in patients with heart failure symptoms; a LV ejection fraction less than or equal to 35% and QRS duration on EKG of 120 msec or greater.[21] [22] [23] CRT can be combined with an implantable cardioverter-defibrillator (ICD).[24]
Three leads can be seen cardiac resynchronization lead (solid black arrow), a (dashed black arrow), and (red arrow). The corona around the outside of the l pacing of the left ventricl ventricular lead in this c aspects that represent con the generator is larger tha generators, demonstrating a pacemaker and a cardi capable of delivering e dangerously fast abnorma
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Advancements in function
A major step forward in pacemaker function has been to attempt to mimic nature by utilizing various inputs to produce a rate-responsive pacemaker using parameters such as the QT interval, pO2 - pCO2 (dissolved oxygen or carbon dioxide levels) in the arterial-venous system, physical activity as determined by an accelerometer, body temperature, ATP levels, adrenaline, etc. Instead of producing a static, predetermined heart rate, or intermittent control, such a pacemaker, a 'Dynamic Pacemaker', could compensate for both actual respiratory loading and potentially anticipated respiratory loading. The first dynamic pacemaker was invented by Dr. Anthony Rickards of the National Health Hospital, London, UK, in 1982.
X-ray image of installed pacemaker showing wire routing
Dynamic pacemaking technology could also be applied to future artificial hearts. Advances in transitional tissue welding would support this and other artificial organ/joint/tissue replacement efforts. Stem cells may or may not be of interest to transitional tissue welding. Many advancements have been made to improve the control of the pacemaker once implanted. Many of these have been made possible by the transition to microprocessor controlled pacemakers. Pacemakers that control not only the ventricles but the atria as well have become common. Pacemakers that control both the atria and ventricles are called dual-chamber pacemakers. Although these dual-chamber models are usually more expensive, timing the contractions of the atria to precede that of the ventricles improves the pumping efficiency of the heart and can be useful in congestive heart failure. Rate responsive pacing allows the device to sense the physical activity of the patient and respond appropriately by increasing or decreasing the base pacing rate via rate response algorithms. The DAVID trials[25] have shown that unnecessary pacing of the right ventricle can exacerbate heart failure and increases the incidence of atrial fibrillation. The newer dual chamber devices can keep the amount of right ventricle pacing to a minimum and thus prevent worsening of the heart disease.
Considerations
Insertion
A pacemaker is typically inserted into the patient through a simple surgery using either local anesthetic or a general anesthetic. The patient may be given a drug for relaxation before the surgery as well. An antibiotic is typically administered to prevent infection.[26] In most cases the pacemaker is inserted in the left shoulder area where an incision is made below the collar bone creating a small pocket where the pacemaker is actually housed in the patient's body. The lead or leads (the number of leads varies depending on the type of pacemaker) are fed into the heart through a large vein using a fluoroscope to monitor the progress of lead insertion. The Right Ventricular lead would be positioned away from the apex (tip) of the right ventricle and up on the inter ventricular septum, below the outflow tract, to prevent deterioration of the strength of the heart. The actual surgery may take about 30 to 90 minutes. Following surgery the patient should exercise reasonable care about the wound as it heals. There is a followup session during which the pacemaker is checked using a "programmer" that can communicate with the device and allows a health care professional to evaluate the system's integrity and determine the settings such as pacing voltage output. The patient should have the strength of their heart analyzed frequently with echocardiography, every 1 or 2 years, to make sure the that placement of the right ventricular lead has not lead to weakening of the left ventricle.
Artificial pacemaker The patient may want to consider some basic preparation before the surgery. The most basic preparation is that people who have body hair on the chest may want to remove the hair by clipping just prior to surgery or using a depilatory agent (preoperative shaving has been on the decline as it can cause skin breakage and increase infection risk of any surgical procedure) as the surgery will involve bandages and monitoring equipment to be afixed to the body. Since a pacemaker uses batteries, the device itself will need replacement as the batteries lose power. Device replacement is usually a simpler procedure than the original insertion as it does not normally require leads to be implanted. The typical replacement requires a surgery in which an incision is made to remove the existing device, the leads are removed from the existing device, the leads are attached to the new device, and the new device is inserted into the patient's body replacing the previous device. Pacemaker patient identification card International pacemaker patient identification cards carry information such as patient data (among others, symptom primary, ECG, aetiology), pacemaker center (doctor, hospital), IPG (rate, mode, date of implantation, manufacturer, type) and lead.[27] [28]
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Living with a pacemaker

Periodic pacemaker checkups Once the pacemaker is implanted, it is periodically checked to ensure the device is operational and performing appropriately. Depending on the frequency set by the following physician, the device can be checked as often as is necessary. Routine pacemaker checks are typically done in-office every six (6) months, though will vary depending upon patient/device status and remote monitoring availability. At the time of in-office follow-up, the device will be interrogated to perform diagnostic testing. These tests include:
Two types of remote monitoring devices used by pacemaker patients
Sensing: the ability of the device to "see" intrinsic cardiac activity (Atrial and ventricular depolarization). Impedance: A test to measure lead integrity. Large and/or sudden increases in impedance can be indicative of a lead fracture while large and/or sudden decreases in impedance can signify a breach in lead insulation. Threshold: this test confirms the minimum amount of energy (Both volts and pulse width) required to reliably depolarize (capture) the chamber being tested. Determining the threshold allows the Allied Professional, Representative, or Physician to program an output that recognizes an appropriate safety margin while optimizing device longevity. As modern pacemakers are "on-demand", meaning that they only pace when necessary, device longevity is affected by how much it is utilized. Other factors affecting device longevity include programmed output and algorithms (features) causing a higher level of current drain from the battery. An additional aspect of the in-office check is to examine any events that were stored since the last follow-up. These are typically stored based on specific criteria set by the physician and specific to the patient. Some devices have the availability to display intracardiac electrograms of the onset of the event as well as the event itself. This is especially helpful in diagnosing the cause or origin of the event and making any necessary programming changes.
Artificial pacemaker Lifestyle considerations A patient's lifestyle is usually not modified to any great degree after insertion of a pacemaker. There are a few activities that are unwise such as full contact sports and activities that involve intense magnetic fields. The pacemaker patient may find that some types of everyday actions need to be modified. For instance, the shoulder harness of a vehicle seatbelt may be uncomfortable if the harness should fall across the pacemaker insertion site. Any kind of an activity that involves intense magnetic fields should be avoided. This includes activities such as arc welding possibly, with certain types of equipment,[29] or maintaining heavy equipment that may generate intense magnetic fields (such as an MRI (Magnetic Resonance Imaging Machine)). However, in February 2011 the FDA approved a new pacemaker device called the Revo MRI SureScan which is the first to be proven safe for MRI use. There are several limitations to its use including certain patients qualifications, body parts, and scan settings. A 2008 U.S. study has found[30] that the magnets in some portable music players, when placed within an inch of pacemakers, may cause interference. Some medical procedures may require the use of antibiotics to be administered before the procedure. The patient should inform all medical personnel that they have a pacemaker. Some standard medical procedures such as the use of Magnetic resonance imaging (MRI) may be ruled out by the patient having a pacemaker. In addition, according to the American Heart Association, some home devices have a remote potential to cause interference by occasionally inhibiting a single beat. Cellphones available in the United States (less than 3 watts) do not seem to damage pulse generators or affect how the pacemaker works.[31] Turning off the pacemaker According to a consensus statement by the Heart Rhythm Society, it is legal and ethical to honor requests by patients, or by those with legal authority to make decisions for patients, to deactivate implanted cardiac devices. Lawyers say that the legal situation is similar to removing a feeding tube. A patient has a right to refuse or discontinue treatment, including a pacemaker that keeps him or her alive. Physicians have a right to refuse to turn it off, but they should refer the patient to a physician who will.[32] Some patients believe that hopeless, debilitating conditions like strokes, in combination with dementia, can cause so much suffering to themselves and their families that they would prefer not to prolong their lives with supportive measures, such as cardiac devices.[33]
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Privacy and security

Security and privacy concerns have been raised with pacemakers that allow wireless communication. Unauthorized third parties may be able to read patient records contained in the pacemaker, or reprogram the devices, as has been demonstrated by a team of researchers.[34] The demonstration worked at short range; they did not attempt to develop a long range antenna. The proof of concept exploit helps demonstrate the need for better security and patient alerting measures in remotely accessible medical implants.[34]
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Complications
A possible complication of dual-chamber artificial pacemakers is pacemaker-mediated tachycardia (PMT), a form of reentrant tachycardia. In PMT, the artificial pacemaker forms the anterograde (atrium to ventricle) limb of the circuit and the atrioventricular (AV) node forms the retrograde limb (ventricle to atrium) of the circuit.[35] Treatment of PMT typically involves reprogramming the pacemaker.[35]
Other devices with pacemaker function

Sometimes devices resembling pacemakers, called implantable cardioverter-defibrillators (ICDs) are implanted. These devices are often used in the treatment of patients at risk from sudden cardiac death. An ICD has the ability to treat many types of heart rhythm disturbances by means of pacing, cardioversion, or defibrillation. Some ICD devices can distinguish between ventricular fibrillation and ventricular tachycardia (VT), and may try to pace the heart faster than its intrinsic rate in the case of VT, to try to break the tachycardia before it progresses to ventricular fibrillation. This is known as fast-pacing, overdrive pacing, or anti-tachycardia pacing (ATP). ATP is only effective if the underlying rhythm is ventricular tachycardia, and is never effective if the rhythm is ventricular fibrillation.
NASPE / BPEG Defibrillator (NBD) code - 1993[36]

I Shock chamber O = None A = Atrium V = Ventricle II III IV
Antitachycardia pacing chamber Tachycardia detection Antibradycardia pacing chamber O = None A = Atrium V = Ventricle E = Electrogram H = Hemodynamic O = None A = Atrium V = Ventricle D = Dual (A+V)
D = Dual (A+V) D = Dual (A+V)
Short form of the NASPE/BPEG Defibrillator (NBD) code[36]

ICD-S ICD with shock capability only ICD-B ICD with bradycardia pacing as well as shock ICD-T ICD with tachycardia (and bradycardia) pacing as well as shock
References
[1] McWilliam JA (1899). "Electrical stimulation of the heart in man". Br Med J 1 (1468): 34850. doi:10.1136/bmj.1.1468.348.. Partial quote in "Electrical Stimulation of the Heart in Man - 1899" (http:/ / www. hrsonline. org/ News/ ep-history/ timeline/ 1800s. cfm#elec), Heart Rhythm Society, Accessed May 11, 2007. [2] Lidwell M C, "Cardiac Disease in Relation to Anaesthesia" in Transactions of the Third Session, Australasian Medical Congress, Sydney, Australia, Sept. 2-7 1929, p 160. [3] Mond H, Sloman J, Edwards R (1982). "The first pacemaker". Pacing and clinical electrophysiology : PACE 5 (2): 27882. doi:10.1111/j.1540-8159.1982.tb02226.x. PMID6176970. [4] Aquilina O, " A brief history of cardiac pacing (http:/ / www. impaedcard. com/ issue/ issue27/ aquilinao2/ AquilinaO. htm)", Images Paediatr Cardiol 27 (2006), pp.17-81. [5] Furman S, Szarka G, Layvand D (2005). "Reconstruction of Hyman's second pacemaker" (http:/ / www. blackwell-synergy. com/ openurl?genre=article& sid=nlm:pubmed& issn=0147-8389& date=2005& volume=28& issue=5& spage=446). Pacing Clin Electrophysiol 28 (5): 44653. doi:10.1111/j.1540-8159.2005.09542.x. PMID15869680. . [6] Harvard Gazette: Paul Maurice Zoll (http:/ / news. harvard. edu/ gazette/ 2001/ 04. 19/ 12-zoll. html) [7] Weirich W, Gott V, Lillehei C (1957). "The treatment of complete heart block by the combined use of a myocardial electrode and an artificial pacemaker". Surg Forum 8: 3603. PMID13529629. [8] Success Stories : Larsson, Arne : St. Jude Medical (http:/ / www. sjm. com/ successstories/ successstory. aspx?name=Larsson,+ Arne)
[9] Furman S, Schwedel JB (1959). "An intracardiac pacemaker for Stokes-Adams seizures" (http:/ / www. blackwell-synergy. com/ openurl?genre=article& sid=nlm:pubmed& issn=0147-8389& date=2006& volume=29& issue=5& spage=453). N. Engl. J. Med. 261 (5): 9438. doi:10.1111/j.1540-8159.2006.00399.x. PMID16689837. . [10] "Permanent Transvenous Pacing in 1962", Parsonnet V, PACE,1:285, 1978 [11] "Preliminary Investigation of the Development of a Permanent Implantable Pacemaker Using an Intracardiac Dipolar Electrode", Parsonnet V, Zucker I R, Asa M M, Clin. Res., 10:391, 1962 [12] Parsonnet V, Zucker IR, Maxim Asa M (1962). "An intracardiac bipolar electrode for interim treatment of complete heart block". Am. J. Cardiol. 10 (2): 2615. doi:10.1016/0002-9149(62)90305-3. PMID14484083. [13] Lagergren H (1978). "How it happened: my recollection of early pacing". Pacing Clin Electrophysiol 1 (1): 1403. doi:10.1111/j.1540-8159.1978.tb03451.x. PMID83610. [14] Lagergren H, Johansson L (1963). "Intracardiac stimulation for complete heart block". Acta Chir Scand 125: 5626. PMID13928055. [15] Jean Jaques Welti:Biography, Heart Rhythm Foundation [16] Eich C, Bleckmann A, Paul T (October 2005). "Percussion pacing in a three-year-old girl with complete heart block during cardiac catheterization" (http:/ / bja. oxfordjournals. org/ cgi/ content/ full/ 95/ 4/ 465). Br J Anaesth 95 (4): 4657. doi:10.1093/bja/aei209. PMID16051649. . [17] "Pacemakers, Patient and Public Information Center : Heart Rhythm Society" (http:/ / www. hrspatients. org/ patients/ treatments/ pacemakers. asp). . [18] Bernstein A, Daubert J, Fletcher R, Hayes D, Lderitz B, Reynolds D, Schoenfeld M, Sutton R (2002). "The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group". Pacing Clin Electrophysiol 25 (2): 2604. PMID11916002. [19] Bohm A, Pinter A, Szekely A, Preda I (1998). "Clinical Observations with Long-term Atrial Pacing" (http:/ / www3. interscience. wiley. com/ journal/ 119941339/ abstract). Pacing Clin Electrophysiol 21 (1): 2469. doi:10.1111/j.1540-8159.1998.tb01097.x. PMID9474681. . [20] Pitts Crick JC for the European Multicenter Study Group (1991). "European Multicenter Prospective Follow-Up Study of 1,002 Implants of a Single Lead VDD Pacing System" (http:/ / www3. interscience. wiley. com/ journal/ 119992153/ abstract). Pacing Clin Electrophysiol 14 (11): 17424. doi:10.1111/j.1540-8159.1991.tb02757.x. PMID1749727. . [21] Cleland JG, Daubert JC, Erdmann E, et al. (2005). "The effect of cardiac resynchronization on morbidity and mortality in heart failure" (http:/ / content. nejm. org/ cgi/ content/ full/ 352/ 15/ 1539). N. Engl. J. Med. 352 (15): 153949. doi:10.1056/NEJMoa050496. PMID15753115. . [22] Bardy GH, Lee KL, Mark DB, et al. (2005). "Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure" (http:/ / content. nejm. org/ cgi/ pmidlookup?view=short& pmid=15659722& promo=ONFLNS19). N. Engl. J. Med. 352 (3): 22537. doi:10.1056/NEJMoa043399. PMID15659722. . [23] Cleland J, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L (2005). "The effect of cardiac resynchronization on morbidity and mortality in heart failure". N Engl J Med 352 (15): 153949. doi:10.1056/NEJMoa050496. PMID15753115. [24] Bristow M, Saxon L, Boehmer J, Krueger S, Kass D, De Marco T, Carson P, DiCarlo L, DeMets D, White B, DeVries D, Feldman A (2004). "Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure". N Engl J Med 350 (21): 214050. doi:10.1056/NEJMoa032423. PMID15152059. [25] Wilkoff BL, Cook JR, Epstein AE, et al. (December 2002). "Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial" (http:/ / jama. ama-assn. org/ cgi/ content/ full/ 288/ 24/ 3115). JAMA 288 (24): 311523. doi:10.1001/jama.288.24.3115. PMID12495391. . [26] de Oliveira JC, Martinelli M, D'Orio Nishioka SA, et al. (2009). "Efficacy of antibiotic prophylaxis prior to the implantation of pacemakers and cardioverter-defibrillators: Results of a large, prospective, randomized, double-blinded, placebo-controlled trial". Circ Arrhythmia Electrophysiol 2 (1): 2934. doi:10.1161/CIRCEP.108.795906. PMID19808441. [27] European Pacemaker Patient Identification card (http:/ / www. xs4all. nl/ ~fbaart/ aktueel/ pm. htm) [28] Eucomed (http:/ / www. eucomed. com/ ) [29] Testing of work environments for electromagnetic interference (Pacing Clin Electrophysiol. 1992) - PubMed Result. PMID1279591. [30] "MP3 Headphones Interfere With Implantable Defibrillators, Pacemakers - Beth Israel Deaconess Medical Center" (http:/ / www. bidmc. org/ News/ InResearch/ 2008/ November/ MP3PlayerStudy. aspx). www.bidmc.org. . Retrieved 2008-11-10. [31] http:/ / www. americanheart. org/ presenter. jhtml?identifier=4676 [32] Heart devices can be turned off near end of life; (http:/ / www. ama-assn. org/ amednews/ 2010/ 05/ 31/ prsa0531. htm) Physicians can deactivate implanted defibrillators and pacemakers when terminally ill patients request it, according to new guidelines from the Heart Rhythm Society. Kevin B. O'Reilly, amednews, May 31, 2010. [33] What Broke My Fathers Heart (http:/ / www. nytimes. com/ 2010/ 06/ 20/ magazine/ 20pacemaker-t. html) By KATY BUTLER, New York Times, June 14, 2010 [34] Halperin, Daniel; Thomas S. Heydt-Benjamin, Benjamin Ransford, Shane S. Clark, Benessa Defend, Will Morgan, Kevin Fu, Tadayoshi Kohno, and William H. Maisel (May 2008). "Pacemakers and Implantable Cardiac Defibrillators: Software Radio Attacks and Zero-Power Defenses" (http:/ / www. secure-medicine. org/ icd-study/ icd-study. pdf) (PDF). IEEE Symposium on Security and Privacy. . Retrieved 2008-08-10. [35] eMedicine > Pacemaker-Mediated Tachycardia (http:/ / emedicine. medscape. com/ article/ 159645-overview) Author: Brian Olshansky, MD. Coauthor(s): Chirag M Sandesara, MD; Noel G Boyle, MB, BCh, MD, PhD. Updated: Jun 17, 2008
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[36] Bernstein A, Camm A, Fisher J, Fletcher R, Mead R, Nathan A, Parsonnet V, Rickards A, Smyth N, Sutton R (1993). "North American Society of Pacing and Electrophysiology policy statement. NASPE/BPEG defibrillator code". Pacing Clin Electrophysiol 16 (9): 177680. PMID7692407.
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External links
Implantable Cardioverter Defibrillator from National Heart, Lung and Blood Institute (http://www.nhlbi.nih. gov/health/dci/Diseases/icd/icd_whatis.html) Biventricular Pacemaker: What is Cardiac Resynchronization Therapy? Podcast from the Medical University of South Carolina (http://www.muschealth.com/multimedia/Podcasts/displayPod.aspx?podid=293& autostart=false&groupid=6) Current indications for CRT-P and CRT-D: Webinar from the European Heart Rhythm Association (EHRA) (http://www.escardio.org/communities/EHRA/education/webinars/Pages/welcome.aspx)
Implantable cardioverter-defibrillator
An implantable cardioverter-defibrillator (ICD) is a small battery-powered electrical impulse generator which is implanted in patients who are at risk of sudden cardiac death due to ventricular fibrillation and ventricular tachycardia. The device is programmed to detect cardiac arrhythmia and correct it by delivering a jolt of electricity. In current variants, the ability to revert ventricular fibrillation has been extended to include both atrial and ventricular arrhythmias as well as the ability to perform biventricular pacing in patients with congestive heart failure or bradycardia.
Guidant ICD
Implantation
The process of implantation of an ICD is similar to implantation of a pacemaker. Similar to pacemakers, these devices typically include electrode wire(s) which pass through a vein to the right chambers of the heart, usually being lodged in the apex of the right ventricle. The difference is that pacemakers are more often temporary and generally designed to consistently correct bradycardia, while ICDs are often permanent safeguards against sudden abnormalities. The most recent development is the subcutaneous ICD (S-ICD). Current state-of-the-art electronics and batteries have enabled an implantable device to deliver enough energy to defibrillate the heart Automatic implantable cardioverter defibrillator. without the need for a lead in or on the heart. This prevents lead-related problems and the risk of dangerous infections in or near the heart. This ICD is positioned just under the skin and outside the ribcage. It can be placed during a minor procedure under conscious sedation. A study of 300 patients is in progress for US approvals.[1]
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Working mechanism
ICDs constantly monitor the rate and rhythm of the heart and can deliver therapies, by way of an electrical shock, when the electrical manifestations of the heart activity exceeds the preset number. More modern devices can distinguish between ventricular fibrillation and ventricular tachycardia (VT), and may try to pace the heart faster than its intrinsic rate in the case of VT, to try to break the tachycardia before it progresses to ventricular fibrillation. This is known as fast-pacing, overdrive pacing, or anti-tachycardia pacing (ATP). ATP is only effective if the underlying rhythm is ventricular tachycardia, and is never effective if the rhythm is ventricular fibrillation. Many modern ICDs use a combination of various methods to determine if a fast rhythm is normal, ventricular tachycardia, or ventricular fibrillation. Rate discrimination evaluates the rate of the lower chambers of the heart (the ventricles) and compares it to the rate in the upper chambers of the heart (the atria). If the rate in the atria is faster than or equal to the rate in the ventricles, then the rhythm is most likely not ventricular in origin, and is usually more benign. If this is the case, the ICD does not provide any therapy. Rhythm discrimination will see how regular a ventricular tachycardia is. Generally, ventricular tachycardia is regular. If the rhythm is irregular, it is usually due to conduction of an irregular rhythm that originates in the atria, such as atrial fibrillation. Morphology discrimination checks the morphology of every ventricular beat and compares it to what the ICD believes is a normally conducted ventricular impulse for the patient. This normal ventricular impulse is often an average of a multiple of beats of the patient taken in the recent past.
History
The development of the ICD was pioneered at Sinai Hospital in Baltimore by a team including Michel Lead II electrocardiogram showing Torsades being shocked by an implantable Mirowski, Morton Mower, and [2] cardioverter-defibrillator back to the patient's baseline cardiac rhythm. William Staewen. Mirowski teamed up with Mower and Staewen and together they commenced their research in 1969 but it was 11 years before they treated their first patient. Similar developmental work was carried out almost coincidentally by Schuder and colleagues at the University of Missouri. More than a decade of research went into the development of an implantable defibrillator that would automatically sense the onset of ventricular fibrillation and deliver an electric countershock within 1520 seconds, converting the rhythm to sinus rhythm. Improved versions were programmed to be able to detect ventricular tachycardia, often a forerunner of ventricular fibrillation. These were then called implantable cardioverters. The work was commenced against much skepticism even by leading experts in the field of arrhythmias and sudden death. There was doubt that their ideas would ever become a clinical reality. In 1972 Bernard Lown, the inventor of the external defibrillator, stated in the journal Circulation - "The very rare patient who has frequent bouts of ventricular fibrillation is best treated in a coronary care unit and is better served by an effective antiarrhythmic program or surgical correction of inadequate coronary blood flow or ventricular malfunction. In fact, the implanted defibrillator system represents an imperfect solution in search of a plausible and practical application". The problems to be overcome were the design of a system which would allow detection of ventricular fibrillation or ventricular tachycardia. Despite the lack of financial backing and grants, they persisted and the first device was implanted in February 1980 at Johns Hopkins Hospital by Dr. Levi Watkins, Jr. Modern ICDs do not require a thoracotomy and possess pacing, cardioversion, and defibrillation capabilities.
Implantable cardioverter-defibrillator Internal cardioverter defibrillators have also been used twice in dogs to prevent sudden death from arrhythmia. The first defibrillator was implanted at Washington State University by a team of cardiologists led by Dr Lynne Johnson in 2003. The patient was a Boxer dog with life threatening arrhythmias from arrhythmogenic right ventricular cardiomyopathy, an inherited disease. On July 21, 2008, a second ICD was implanted in a 6-month-old German Shepherd dog with inherited ventricular arrhythmias. The 5-hour long surgery took place at Louisiana State University and was led by Dr Romain Pariaut. So far, these pets are the only two client-owned dogs that have received such a high-tech treatment.
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Living with an ICD

People that have an implanted cardioverter-defibrillator can live full and happy lives. Usually the ICD improves the living conditions of a patient significantly. As with a pacemaker, living with an ICD does impose some restrictions on the person's lifestyle.
Quality of Life
Implantable cardioverter defibrillators have demonstrated clear life-saving benefits but concerns about patient acceptance and psychological adjustment to the ICD have been the focus of much research.[3] Researchers including those from the field of cardiac psychology have concluded that the QoL of ICD patients is at least equal to, or better than those taking anti-arrhythmic medications.[4] The A normal chest X-ray after placement of an ICD, largest study of examined 2,521 patients with stable heart failure in the showing the ICD generator in the upper left chest SCD-HeFT trial.[5] Results indicated that there were no differences and the ICD lead in the right ventricle of the heart. Note the 2 opaque coils along the ICD lead. between ICD treated and medication-treated groups at 30 months in patient reported QoL.[6] Psychological adjustment following ICD implantation has also been well-studied. Anxiety is a common psychological side effect with approximately 13-38% of ICD patients reporting clinically significant anxiety.[7] [8] The primary etiological factors contributing to anxiety in ICD patients has not been determined, however. Depressive symptoms are also common but incidence of these problems have shown to be similar to those observed in other cardiac patient groups with approximately 24-41% of patients with ICDs experiencing depressive symptoms.[8] Problems in psychosocial adjustment to ICDs, including the experience of anxiety, among spouses or other romantic partners are also prevalent.[9] This phenomenon may be related, at least in part, to shared shock anxiety and avoidance of physical and sexual contact.[10]
Physical activities
Almost all forms of physical activities can be performed by patients with an ICD. All forms of sports that do not pose a risk of damaging the ICD can be enjoyed by the patient. Special care should be placed not to put excessive strain on the shoulder, arm and torso area where the ICD is implanted. Doing so may damage the ICD or the leads going from the unit to the patient's heart.
Electronic equipment
As a general rule, all electronic equipment is safe to use for patients with an ICD if kept at relative small distance from the unit. Most electronic equipment such as cellphones, devices that generate radio waves or radio interference should be kept at least 15 centimetres (6in) from the ICD.[11]
Implantable cardioverter-defibrillator Electronic equipment used in a professional environment or equipment using large magnets or generating magnetic fields must be avoided by patients with an ICD. Both the magnetic fields and the EMI (Electromagnetic Interference) in an MRI scanner can interfere with the correct working of the ICD. As with other metallic objects, an ICD is a contraindication to the use of magnetic resonance imaging. Experiments are on the way for solving this kind of problem. For example Medtronic showed interesting results with a pacemaker.[12]
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Clinical trials
A number of clinical trials have demonstrated the superiority of the ICD over AAD (antiarrhythmic drugs) in the prevention of death from malignant arrhythmias. The SCD-HeFT trial (published in 2005) showed a significant all-cause mortality benefit for patients with ICD. Congestive heart failure patients that were implanted with an ICD had an all-cause death risk 23% lower than placebo and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population.1 Reporting in 1999, the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial consisted of 1,016 patients, and deaths in those treated with AAD were more frequent (n=122) compared with deaths in the ICD groups (n=80, p < 0.001)[13]. In 2002 the MADITII trial showed benefit of ICD treatment in patients after myocardial infarction with reduced left ventricular function (EF<30). Initially ICDs were implanted via thoracotomy with defibrillator patches applied to the epicardium or pericardium. The device was attached via subcutaneous and transvenous leads to the device contained in a subcutaneous abdominal wall pocket. The device itself acts as an electrode. Most ICDs nowadays are implanted transvenously with the devices placed in the left pectoral region similar to pacemakers. Intravascular spring or coil electrodes are used to defibrillate. The devices have become smaller and less invasive as the technology advances. Current ICDs weigh only 70grams and are about 12.9mm thick. A recent study by Birnie et al. at the University of Ottawa Heart Institute has demonstrated that ICDs are underused in both the United States and Canada.[14] An accompanying editorial by Dr. Chris Simpson of Queen's University explores some of the economic, geographic, social and political reasons for this.[15]
Notes
[1] Bardy, Gust H.; Smith, Hood, Crozier et. al. (May 2010). An Entirely Subcutaneous Implantable CardioverterDefibrillator (http:/ / content. nejm. org/ cgi/ content/ full/ NEJMoa0909545). New England Journal of Medicine. PMID20463331. . Retrieved 13 May 2010. [2] Mirowski M, Mower MM, Staewen WS, et al: Standby automatic defibrillator: An approach to prevention of sudden coronary death. Arch Intern Med 126:158-161, 1970 [3] Burns JL, Serber ER, Keim S, Sears SF. Measuring patient acceptance of implantable cardiac device therapy: initial psychometric investigation of the Florida Patient Acceptance Survey. J Cardiovasc Electrophysiol 2005;16:384-390. [4] Sears S, Matchett M, Conti J. Effective management of ICD patient psychosocial issues and patient critical events. J Cardiovasc Electrophysiol 2009;20(11):1297-304 [5] Bardy, Lee, Mark et al., 2005 [6] Mark DB, Anstrom KJ, Sun JL, Clapp-Channing NE, Tsiatis AA, Davidson-Ray L, Lee KL, Bardy GH. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med 2008; 359(10):999-1008 [7] Bilge AK, Ozben B, Demircan S, et al. Depression and anxiety status of patients with implantable cardioverter defibrillator and precipitating factors. Pacing Clin Electrophysiol. 2006 Jun;29(6):619-26 [8] Sears SF, Jr., Todaro JF, Lewis TS, Sotile W, Conti JB. Examining the psychosocial impact of implantable cardioverter defibrillators: a literature review. Clin Cardiol 1999;22:481-489 [9] Vasquez-Sowell L, Sears SF, Walker RL, Kuhl EA, Conti JB. Anxiety and marital adjustment in patients with Implantable Cardioverter Defibrillator and their spouses. Journal of Cardiopulmonary Rehabilitation and Prevention 2007;27:46-49 [10] Vasquez LD, Sears SF, Shea JB, Vasquez PM. Sexual health for patients with an Implantable Cardioverter Defibrillator. Circulation 2010;122:465-467 [11] Medtronic Patient Website FAQ: Can magnets affect my device? (http:/ / www. medtronic. com/ your-health/ heart-failure/ living-with-a-device/ questions-answers/ index. htm#question7) [12] http:/ / wwwp. medtronic. com/ Newsroom/ NewsReleaseDetails. do?itemId=1242305667391& format=print& lang=en_US [13] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=pubmed& dopt=Abstract& list_uids=10551706& query_hl=5 [14] Birnie, David H; Sambell, Christie; Johansen, Helen; Williams, Katherine; Lemery, Robert; Green, Martin S; Gollob, Michael H; Lee, Douglas S; Tang, Anthony SL (July 2007). "Use of implantable cardioverter defibrillators in Canadian and US survivors of out-of-hospital
cardiac arrest" (http:/ / www. cmaj. ca/ cgi/ reprint/ 177/ 1/ 41). Canadian Medical Association Journal 177 (1): 416. doi:10.1503/cmaj.060730. PMC1896034. PMID17606938. . Retrieved 2007-07-29. [15] Simpson, Christopher S (July 2007). "Implantable cardioverter defibrillators work so why aren't we using them?" (http:/ / www. cmaj. ca/ cgi/ reprint/ 177/ 1/ 49). Canadian Medical Association Journal 177 (1): 4951. doi:10.1503/cmaj.070470. PMC1896028. PMID17606939. . Retrieved 2007-07-29.
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References
Bardy GH, Lee KL, Mark DB, et al. for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225-237 (http://content.nejm.org/cgi/content/abstract/352/3/225) Stevenson W, Chaitman B, Ellenbogen K, Epstein A, Gross W, Hayes D, Strickberger S, Sweeney M (2004). "Clinical assessment and management of patients with implanted cardioverter-defibrillators presenting to nonelectrophysiologists". Circulation 110 (25): 38669. doi:10.1161/01.CIR.0000149716.03295.7C. PMID15611390. Full text (http://circ.ahajournals.org/cgi/content/full/110/25/3866) Kumar and Clarke. Internal Medicine. 2009. Sears S (http://www.ecu.edu/cs-cas/psyc/searss/), Matchett M, Conti J. Effective management of ICD patient psychosocial issues and patient critical events. J Cardiovasc Electrophysiol 2009;20(11):1297-304. Sears SF, Jr., Todaro JF, Lewis TS, Sotile W, Conti JB. Examining the psychosocial impact of implantable cardioverter defibrillators: a literature review. Clin Cardiol 1999;22:481-489. Burns JL, Serber ER, Keim S, Sears SF. Measuring patient acceptance of implantable cardiac device therapy: initial psychometric investigation of the Florida Patient Acceptance Survey. J Cardiovasc Electrophysiol 2005;16:384-390. Mark DB, Anstrom KJ, Sun JL, Clapp-Channing NE, Tsiatis AA, Davidson-Ray L, Lee KL, Bardy GH. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med 2008; 359(10):999-1008. Bilge AK, Ozben B, Demircan S, et al. Depression and anxiety status of patients with implantable cardioverter defibrillator and precipitating factors. Pacing Clin Electrophysiol. 2006 Jun;29(6):619-26.
External links
A Defibrillator in Action (http://www.doctorshangout.com/forum/topics/a-defibrillator-in-action) Information on ICDs (http://www.aral.org.uk/html/icds.html) from the charity Arrhythmia Alliance East Carolina Heart Institute at ECU, Cardiac Psychology Lab, Focus on ICD (http://www.ecu.edu/cs-cas/ psyc/cardiacpsychology) Samuel F. Sears, Jr., Ph.D., East Carolina University, Cardiac Psychology, ICD QoL Specialist (http://www. ecu.edu/cs-cas/psyc/searss) Video, Coping with an ICD (http://www.brighamandwomens.org/cvcenter/videos/SuccessfulLivingICD. aspx)
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Transcutaneous pacing (also called external pacing) is a temporary means of pacing a patient's heart during a medical emergency. It is accomplished by delivering pulses of electric current through the patient's chest, which stimulates the heart to contract. The most common indication for transcutaneous pacing is an abnormally slow heart rate. By convention, a heart rate of less than 60 beats per minute in the adult patient is called bradycardia. Not all instances of bradycardia require medical treatment. Normal heart rate varies substantially between individuals, and many athletes in particular have a relatively slow resting heart rate. In addition, the heart rate is known to naturally slow with age. It is only when bradycardia presents with signs and symptoms of shock that it requires emergency treatment with transcutaneous pacing. Some common causes of hemodynamically significant bradycardia include acute myocardial infarction, sinus node dysfunction and complete heart block. Transcutaneous pacing is no longer indicated for the treatment of asystole (cardiac arrest associated with a "flat line" on the ECG), with the possible exception of witnessed asystole (as in the case of bifascicular block that progresses to complete heart block without an escape rhythm). During transcutaneous pacing, pads are placed on the patient's chest, either in the anterior/lateral position or the anterior/posterior position. The anterior/posterior position is preferred as it minimizes transthoracic electrical impedance by "sandwiching" the heart between the two pads. The pads are then attached to a monitor/defibrillator, a heart rate is selected, and current (measured in milliamps) is increased until electrical capture (characterized by a wide QRS complex with tall, broad T wave on the ECG) is obtained, with a corresponding pulse. Pacing artifact on the ECG and severe muscle twitching may make this determination difficult. It is therefore advisable to use another instrument (e.g. SpO2 monitor or bedside doppler) to confirm mechanical capture. Transcutaneous pacing may be uncomfortable for the patient. Sedation should therefore be considered. Before pacing the patient in a prehospital setting sedation is recommended by administering an analgesic or an anxioloytic. Prolonged transcutaneous pacing may cause burns on the skin. According to the Zoll M Series Operator's Guide," Continuous pacing of neonates can cause skin burns. If it is necessary to pace for more than 30 minutes, periodic inspection of the underlying skin is strongly advised." It is meant to stabilize the patient until a more permanent means of pacing is achieved. Other forms of cardiac pacing are transvenous pacing, epicardial pacing, and permanent pacing with an implantable pacemaker. In addition to synchronozied transcutaneous pacing offered by newer cardiac monitor/defibrillators there is also an option for Asynchronous Pacing. Sometimes in the prehospital setting a situation may arise where ECG electrodes are not available or something interferes with their adhesion to the patient's skin. In these rare situations where the patient must be paced and there are no other alternatives Asynchronous Pacing may be used. Again this setting should only be used as a last resort due to possible adverse cardiac effects it could cause.
References
1. Bledsole, B., Porter, R., and Cherry, R. "Paramedic Care: Principles & Practice: Volume 3". Third Edition, Pearson, 2009. ISBN 978-0-13-513702-4 2. Urden, L., Stacy, K., and Lough, M. Thelan's Critical Care Nursing: Diagnosis and Management. Fourth Edition, Mosby, 1998. ISBN 0-323-01461-5 3. Handbook of Emergency Cardiovascular Care for Healthcare Providers. Editors Hazinski, M., Cummins, R., and Field, J. 2004. ISBN 0-87493-448-6
Transvenous pacing
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Transvenous pacing
Transvenous cardiac pacing, also called endocardial pacing, is a potentially life saving intervention used primarily to correct profound bradycardia. It can be used to treat symptomatic bradycardias that do not respond to transcutaneous pacing or to drug therapy. Transvenous pacing is achieved by threading a pacing electrode through a vein into the right atrium, right ventricle, or both. This means of pacing the heart is not as popular as other means of pacing (see transcutaneous pacing, implanted pacemaker, epicardial pacing) because it is a temporary solution to pace the heart and yet involves a similar level of risk of bleeding as a more permanent solution like placing an implanted pacemaker. For patients who present in an emergency setting with symptomatic bradycardias, usually drugs like atropine or sympathomimetic drugs (e.g. epinephrine, dopamine, etc.) can be used to increase the heart rate to an adequate level until the underlying cause of the bradycardia can be isolated and then, possibly, a permanent pacemaker can be placed. For patients for whom transvenous pacing is chosen, the procedure is done at the bedside with a local anesthetic alone or in conjunction with conscious sedation. The pacing electrode is advanced through the vein under flouroscopic and electrocardiographic guidance. An x-ray after the procedure is always obtained to confirm placement of the pacing electrode. The greater use of atropine and epinephrine or external pacing may obviate the need for transvenous pacing by stabilizing patients early in the process of caring for the patient. Some debate exists over the efficacity and reliability of transvenous pacing, especially if the need for permanent pacing is anticipated.
References
1. Urden, L., Stacy, K., and Lough, M. Thelan's Critical Care Nursing: Diagnosis and Management. Fourth Edition, Mosby, 1998. ISBN 0-323-01461-5 2. Handbook of Emergency Cardiovacular Care for Healthcare Providers. Editors Hazinski, M., Cummins, R., and Field, J. 2004. ISBN 0-87493-448-6 3. Murphy, J. J. Problems with temporary cardiac pacing. British Medical Journal. 2001 September 8; 323(7312): 527.
Pacemaker syndrome
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Pacemaker syndrome
Pacemaker syndrome
Pacemaker
Pacemaker syndrome is a disease that represents the clinical consequences of suboptimal atrioventricular (AV) synchrony or AV dyssynchrony, regardless of the pacing mode, after the pacemaker plantation.[1] [2] It is an iatrogenic diseasean adverse effect resulting from medical treatmentthat is often underdiagnosed.[1] [3] In general, the symptoms of the syndrome are a combination of decreased cardiac output, loss of atrial contribution to ventricular filling, loss of total peripheral resistance response, and nonphysiologic pressure waves.[2]
[4] [5]
ECG of Pacemaker syndrome
Individuals with a low heart rate prior to pacemaker implantation are more at risk of developing pacemaker syndrome. Normally the first chamber of the heart (atrium) contracts as the second chamber (ventricle) is relaxed, allowing the ventricle to fill before it contracts and pumps blood out of the heart. When the timing between the two chambers goes out of synchronization, less blood is delivered on each beat. Patients who develop pacemaker syndrome may require adjustment of the pacemaker timing, or another lead fitted to regulate the timing of the chambers separately.
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Signs and symptoms

No specific set of criteria has been developed for diagnosis of pacemaker syndrome. Most of the signs and symptoms of pacemaker syndrome are nonspecific, and many are prevalent in the elderly population at baseline. In the lab, pacemaker interrogation plays a crucial role in determining if the pacemaker mode had any contribution to symptoms.[5] [6] [7] Symptoms commonly documented in patients history, classified according to etiology:[2] [8] [5] [6] [9] Neurological - Dizziness, near syncope, and confusion. Heart failure - Dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema. Hypotension - Seizure, mental status change, diaphoresis, and signs of orthostasis and shock. Low cardiac output - Fatigue, weakness, dyspnea on exertion, lethargy, and lightheadedness. Hemodynamic - Pulsation in the neck and abdomen, choking sensation, jaw pain, right upper quadrant (RUQ) pain, chest colds, and headache. Heart rate related - Palpitations associated with arrhythmias In particular, the examiner should look for the following in the physical examination, as these are frequent findings at the time of admission:[2] [5] [8] [6] Vital signs may reveal hypotension, tachycardia, tachypnea, or low oxygen saturation. Pulse amplitude may vary, and blood pressure may fluctuate. Look for neck vein distension and cannon waves in the neck veins. Lungs may exhibit crackles. Cardiac examination may reveal regurgitant murmurs and variability of heart sounds. Liver may be pulsatile, and the RUQ may be tender to palpation. Ascites may be present in severe cases. The lower extremities may be edematous. Neurologic examination may reveal confusion, dizziness, or altered mental status.
Causes
The etiology is poorly understood. However several risk factors are associated with pacemaker syndrome.[5] [10]
Risk factors
In the preimplantation period, two variables are predicted to predispose to the syndrome. First is low sinus rate, and second is a higher programmed lower rate limit. In postimplantation, an increased percentage of ventricular paced beats is the only variable that significantly predicts development of pacemaker syndrome.[10] Patients with intact VA conduction are at greater risk for developing pacemaker syndrome. Around 90% of patients with preserved AV conduction have intact VA conduction, and about 30-40% of patients with complete AV block have preserved VA conduction. Intact VA conduction may not be apparent at the time of pacemaker implantation or even may develop at any time after implantation.[2] [5] [10] [11] Patients with noncompliant ventricles and diastolic dysfunction are particularly sensitive to loss of atrial contribution to ventricular filling, where that highly increase the chance of developing the syndrome. This includes patients with cardiomyopathy (hypertensive, hypertrophic, restrictive) and elderly individuals.[5] [7] [10]
[12]
Other factors correlated with development of pacemaker syndrome include decreased stroke volume, decreased cardiac output, and decreased left atrial total emptying fraction associated with ventricular pacing.[5] [10]
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Pathophysiology
The loss of physiologic timing of atrial and ventricular contractions, or sometimes called AV dyssynchrony, leads to different mechanisms of symptoms production. This altered ventricular contraction will decrease cardiac output, and in turn will lead to systemic hypotensive reflex response with varying symptoms.[1] [2] [4] [5]
Loss of atrial contraction

Inappropriate pacing in patients with decreased ventricular compliance, which may be caused by diseases such as hypertensive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and aging, can result in loss of atrial contraction and significantly reduces cardiac output. Because in such cases the atrias are required to provide 50% of cardiac output, which normally provides only 15% - 25% of cardiac output.[12] [8]
Cannon A waves
Atrial contraction against a closed tricuspid valve can cause pulsation in the neck and abdomen, headache, cough, and jaw pain.[10] [8]
Increased atrial pressure

Ventricular pacing is associated with elevated right and left atrial pressures, as well as elevated pulmonary venous and pulmonary arterial pressures, which can lead to symptomatic pulmonary and hepatic congestion.[5]
Increased production of natriuretic peptides

Patients with pacemaker syndrome exhibit increased plasma levels of ANP. That's due to increase in left atrial pressure and left ventricular filling pressure, which is due to decreased cardiac output caused by dyssynchrony in atrial and ventricular contraction. ANP and BNP are potent arterial and venous vasodilators that can override carotid and aortic baroreceptor reflexes attempting to compensate for decreased blood pressure. Usually patients with cannon a waves have higher plasma levels of ANP than those without cannon a waves.[1] [13] [14]
VA conduction
A major cause of AV dyssynchrony is VA conduction. VA conduction, sometimes referred to as retrograde conduction, leads to delayed, nonphysiologic timing of atrial contraction in relation to ventricular contraction. Nevertheless, many conditions other than VA conduction promote AV dyssynchrony.[1] [2] [4] [8] [10] This will further decrease blood pressure, and secondary increase in ANP and BNP.[13] [14]
Prevention
At the time of pacemaker implantation, AV synchrony should be optimized to prevent the occurrence of pacemaker syndrome. Where patients with optimized AV synchrony have shown great results of implantation and very low incidence of pacemaker syndrome than those with suboptimal AV synchronization.[1] [4] [5]
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Treatment
Diet
Diet alone cannot treat pacemaker syndrome, but an appropriate diet to the patient, in addition to the other treatment regimens mentioned, can improve the patient's symptoms. Several cases mentioned below: For patients with heart failure, low-salt diet is indicated.[15] For patients with autonomic insufficiency, a high-salt diet may be appropriate.[15] For patients with dehydration, oral fluid rehydration is needed.[15]
Medication
No specific drugs are used to treat pacemaker syndrome directly because treatment consists of upgrading or reprogramming the pacemaker.[15]
Medical Care
For some patients who are ventricularly paced, usually the addition of an atrial lead and optimizing the AV synchrony usually resolves symptoms.[1] [4] [8] [10] In patients with other pacing modes, other than ventricular pacing, symptoms usually resolve after adjusting and reprogramming of pacemaker parameters, such as tuning the AV delay, changing the postventricular atrial refractory period, the sensing level, and pacing threshold voltage. The optimal values of these parameters for each individual differ. So, achieving the optimal values is by experimenting with successive reprogramming and measurement of relevant parameters, such as blood pressure, cardiac output, and total peripheral resistance, as well as observations of symptomatology.[1] [4] [8] [10] In rare instances, using hysteresis to help maintain AV synchrony can help alleviate symptoms in ventricularly inhibited paced (VVI) patients providing they have intact sinus node function. Hysteresis reduces the amount of time spent in pacing mode, which can relieve symptoms, particularly when the pacing mode is generating AV dyssynchrony.[4] [10] If symptoms persist after all these treatment modalities, replacing the pacemaker itself is sometimes beneficial and can alleviate symptoms.[1] [4] [8] Medical care includes supportive treatment, in case any of the following complications happen, medical team should be ready. Possible complications include heart failure, hypotension, tachycardia, tachypnea, and oxygenation deficit.[1] [8] [6]
Surgical Care
Sometimes surgical intervention is needed. After consulting an electrophysiologist, possibly an additional pacemaker lead placement is needed, which eventually relieve some of the symptoms.[1] [4]
Complications
Studies have shown that patients with Pacemaker syndrome and/or with sick sinus syndrome are at higher risk of developing fatal complications that calls for the patients to be carefully monitored in the ICU. Complications include atrial fibrillation, thrombo-embolic events, and heart failure.[7]
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Epidemiology
The reported incidence of pacemaker syndrome has ranged from 2%[16] to 83%[11] . The wide range of reported incidence is likely attributable to two factors which are the criteria used to define pacemaker syndrome and the therapy used to resolve that diagnosis.[17]
History
Pacemaker syndrome was first described in 1969 by Mitsui et al. as a collection of symptoms associated with right ventricular pacing.[18] [19] [17] The name pacemaker syndrome was first coined by Erbel in 1979.[20] [18] Since its first discovery, there have been many definitions of pacemaker syndrome, and the understanding of the cause of pacemaker syndrome is still under investigation. In a general sense, pacemaker syndrome can be defined as the symptoms associated with right ventricular pacing relieved with the return of A-V and V-V synchrony.[17]
References
[1] Ellenbogen KA, Gilligan DM, Wood MA, Morillo C, Barold SS (May 1997). "The pacemaker syndrome -- a matter of definition" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0002914997000854). Am. J. Cardiol. 79 (9): 12269. doi:10.1016/S0002-9149(97)00085-4. PMID9164889. . [2] Chalvidan T, Deharo JC, Djiane P (July 2000). "[Pacemaker syndromes]" (in French). Ann Cardiol Angeiol (Paris) 49 (4): 2249. PMID12555483. [3] Baumgartner, William A.; Yuh, David D.; Luca A. Vricella (2007). The Johns Hopkins manual of cardiothoracic surgery. New York: McGraw-Hill Medical Pub. ISBN0-07-141652-8. [4] Frielingsdorf J, Gerber AE, Hess OM (October 1994). "Importance of maintained atrio-ventricular synchrony in patients with pacemakers" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=7821326). Eur. Heart J. 15 (10): 143140. PMID7821326. . [5] Furman S (January 1994). "Pacemaker syndrome". Pacing Clin Electrophysiol 17 (1): 15. doi:10.1111/j.1540-8159.1994.tb01342.x. PMID7511223. [6] Nishimura RA, Gersh BJ, Vlietstra RE, Osborn MJ, Ilstrup DM, Holmes DR (November 1982). "Hemodynamic and symptomatic consequences of ventricular pacing". Pacing Clin Electrophysiol 5 (6): 90310. PMID6184693. [7] Santini M, Alexidou G, Ansalone G, Cacciatore G, Cini R, Turitto G (March 1990). "Relation of prognosis in sick sinus syndrome to age, conduction defects and modes of permanent cardiac pacing" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ 0002-9149(90)91379-K). Am. J. Cardiol. 65 (11): 72935. doi:10.1016/0002-9149(90)91379-K. PMID2316455. . [8] Petersen HH, Videbaek J (September 1992). "[The pacemaker syndrome]" (in Danish). Ugeskr. Laeg. 154 (38): 254751. PMID1413181. [9] Alicandri C, Fouad FM, Tarazi RC, Castle L, Morant V (July 1978). "Three cases of hypotension and syncope with ventricular pacing: possible role of atrial reflexes". Am. J. Cardiol. 42 (1): 13742. doi:10.1016/0002-9149(78)90998-0. PMID677029. [10] Schller H, Brandt J (April 1991). "The pacemaker syndrome: old and new causes". Clin Cardiol 14 (4): 33640. doi:10.1002/clc.4960140410. PMID2032410. [11] Heldman D, Mulvihill D, Nguyen H, et al. (December 1990). "True incidence of pacemaker syndrome". Pacing Clin Electrophysiol 13 (12 Pt 2): 174250. doi:10.1111/j.1540-8159.1990.tb06883.x. PMID1704534. [12] Gross JN, Keltz TN, Cooper JA, Breitbart S, Furman S (December 1992). "Profound "pacemaker syndrome" in hypertrophic cardiomyopathy" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ 0002-9149(92)90313-N). Am. J. Cardiol. 70 (18): 150711. doi:10.1016/0002-9149(92)90313-N. PMID1442632. . [13] Theodorakis GN, Panou F, Markianos M, Fragakis N, Livanis EG, Kremastinos DT (February 1997). "Left atrial function and atrial natriuretic factor/cyclic guanosine monophosphate changes in DDD and VVI pacing modes" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0002914997892855). Am. J. Cardiol. 79 (3): 36670. doi:10.1016/S0002-9149(97)89285-5. PMID9036762. . [14] Theodorakis GN, Kremastinos DT, Markianos M, Livanis E, Karavolias G, Toutouzas PK (November 1992). "Total sympathetic activity and atrial natriuretic factor levels in VVI and DDD pacing with different atrioventricular delays during daily activity and exercise" (http:/ / eurheartj. oxfordjournals. org/ cgi/ pmidlookup?view=long& pmid=1334465). Eur. Heart J. 13 (11): 147781. PMID1334465. . [15] "Pacemaker Syndrome: Treatment & Medication - eMedicine Cardiology" (http:/ / emedicine. medscape. com/ article/ 159706-treatment). . [16] Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE (December 1994). "Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0140-6736(94)90347-6). Lancet 344 (8936): 15238. doi:10.1016/S0140-6736(94)90347-6. PMID7983951. . Retrieved 2009-06-19. [17] Farmer DM, Estes NA, Link MS (2004). "New concepts in pacemaker syndrome" (http:/ / www. ipej. org/ 4/ 195). Indian Pacing and Electrophysiology Journal 4 (4): 195200. PMC1502063. PMID16943933. . Retrieved 2009-06-19. [18] Travill CM, Sutton R (August 1992). "Pacemaker syndrome: an iatrogenic condition" (http:/ / heart. bmj. com/ cgi/ pmidlookup?view=long& pmid=1389730). British Heart Journal 68 (2): 1636. doi:10.1136/hrt.68.8.163. PMC1025005. PMID1389730. . Retrieved 2009-06-19.
Pacemaker syndrome
[19] Mitsui T, Hori M, Suma K, et al. The "pacemaking syndrome." In: Jacobs JE, ed. Proceedings of the 8th Annual International Conference on Medical and Biological Engineering. Chicago, IL: Association for the Advancement of Medical Instrumentation;. 1969;29-3. [20] 2 Erbel R. Pacemaker syndrome. AmJ Cardiol 1979;44:771-2.
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External links
PreOp Patient Education Permanent Pacemaker Implant Surgery (http://www.youtube.com/ watch?v=UdaTqPSO3Rs)
Pacemaker failure
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Pacemaker failure
Pacemaker failure
Classification and external resources ICD-10 T82.1
Pacemaker failure is the inability of an implanted artificial pacemaker to perform its intended function of regulating the beating of the heart. It is defined by the requirement of repeat surgical pacemaker-related procedure after the initial implantation. A study of pacemaker failure in Oregon in the 1970's indicates that 10% of implanted pacemakers failed within the first month. Causes of pacemaker failure included: lead related failure (lead migration, lead fracture, ventricular perforation), unit malfunction (battery failure or component malfunction), problems at the insertion site (infections, tissue breakdown, battery pack migration), failures related to exposure to high voltage electricity or high intensity microwaves, and a miscellaneous category (one patient had ventricular tachycardia when using his electric razor and another patient suffered from persistent pacing of the diaphragm muscle)[1] .
Causes
Many devices interfere with pacemakers causing failure. Power-generating equipment, arc welding equipment and powerful magnets (as in medical devices, heavy equipment or motors) can inhibit pulse generators. Patients who work with or near such equipment should know that their pacemakers may not work properly in those conditions.[2] With the advances of technology, Federal Communications Commission (FCC) is making new frequencies available. Newer cellphones using these new frequencies might make pacemakers less reliable. A group of cellphone companies is studying that possibility.[2] Equipment used by doctors and dentists can affect your pacemaker.[2] Magnetic resonance imaging (MRI) uses a powerful magnet to produce images of internal organs and functions. Metal objects are attracted to the magnet and are normally not allowed near MRI machines. The magnet can interrupt the pacing and inhibit the output of pacemakers. If MRI must be done, the pacemaker output in some models can be reprogrammed.[2] In February 2011, the FDA approved an MRI-safe pacemaker.[3] Extracorporeal shock-wave lithotripsy (ESWL) procedure is safe for most pacemaker patients, with some reprogramming of the pacing. Careful follow-up after the procedure is required. Patients with certain kinds of pacemakers implanted in the abdomen should avoid ESWL.[2] Diagnostic radiation (such as screening X-ray) appears to have no effect on pacemaker pulse generators. However, therapeutic radiation (such as for treating cancerous tumors) may damage the pacemaker's circuits. The degree of damage is unpredictable and may vary with different systems. But the risk is significant and builds up as the radiation dose increases. The American Heart Association recommends that the pacemaker be shielded as much as possible, and moved if it lies directly in the radiation field.[2] Short-wave or microwave diathermy uses high-frequency, high-intensity signals. These may bypass pacemaker's noise protection and interfere with or permanently damage the pulse generator.[2]
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See Also
Pacemaker crosstalk
References
[1] Reinhart, Steven; McAnulty J, Dobbs J (April 1981). "Type and timing of permanent pacemaker failure" (http:/ / www. chestjournal. org/ content/ 81/ 4/ 433). Chest (Portland, Oregon) 81 (4): 4335. doi:10.1378/chest.81.4.433. PMID7067508. . Retrieved 2009-09-08. [2] "Pacemakers" (http:/ / www. americanheart. org/ presenter. jhtml?identifier=4676). American Heart Association. . Retrieved 6 April 2011. [3] Miller, Reed (9 February 2011). "FDA approves first "MRI-safe" pacemaker" (http:/ / www. theheart. org/ article/ 1182875. do). theheart.org. . Retrieved 4 April 2011.
Pacemaker crosstalk
Pacemaker crosstalk results when pacemaker generated electrical event in one chamber is sensed by the lead in another chamber, resulting in inappropriate inhibition of pacing artifact in the second chamber.[1]
Cause
Crosstalk occurs only in dual chamber or biventricular pacemakers, though it rarely seen more recent models of dual chamber pacemakers due to ventricular blanking period, which coincides with the atrial stimulus to prevent ventricular channel oversensing of atrial output, along with bipolar leads with a smaller pacing spike, and steroid eluting leads with a lower pacing threshold. Crosstalk is more common in unipolar systems due to larger pacing spike. Crosstalk is sometimes referred to as known crosstalk inhibition, far-field sensing, or self-inhibition. In some cases, crosstalk can occur in the pulse generator circuit itself, though more common causes include atrial lead dislodgement into the ventricle, ventricular lead dislodgement into the atrium, high atrial output current, high ventricular sensitivity, and short ventricular blanking period.[1]
Treatment
In general, the treatment of crosstalk includes decreasing atrial pacing output, decreasing atrial pulse width, decreasing ventricular sensitivity, increasing the ventricular blanking period, activating ventricular safety pacing, and new atrial lead implant if insulation failure mandates unipolar programming.[1]
References
[1] Yarlagadda, Chakri. "Pacemaker Malfunction" (http:/ / emedicine. medscape. com/ article/ 156583-overview). eMedicine. . Retrieved 19 September 2010.
327
Cardioversion
Cardioversion
Cardioversion
Intervention ICD-9-CM 99.6 [1] MeSH D004554 [2]
Cardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle. Pharmacologic cardioversion, also called chemical cardioversion, uses antiarrhythmia medication instead of an electrical shock.[3]
Synchronized electrical cardioversion

To perform synchronized electrical cardioversion two electrode pads are used (or, alternatively, the traditional hand-held "paddles"), each comprising a metallic plate which is faced with a saline based conductive gel. The pads are placed on the chest of the patient, or one is placed on the chest and one on the back. These are connected by cables to a machine which has the combined functions of an ECG display screen and the electrical function of a defibrillator. A synchronizing function (either manually operated or automatic) allows the cardioverter to deliver a reversion shock, by way of the pads, of a selected amount of electric current over a predefined number of milliseconds at the optimal moment in the cardiac cycle which corresponds to the R wave of the QRS complex on the ECG. Timing the shock to the R wave prevents the delivery of the shock during the vulnerable period (or relative refractory period) of the cardiac cycle, which could induce ventricular fibrillation. If the patient is conscious, various drugs are often used to help sedate the patient and make the procedure more tolerable. However, if the patient is hemodynamically unstable or unconscious, the shock is given immediately upon confirmation of the arrhythmia. When synchronized electrical cardioversion is performed as an elective procedure, the shocks can be performed in conjunction with drug therapy until sinus rhythm is attained. After the procedure, the patient is monitored to ensure stability of the sinus rhythm. Synchronized electrical cardioversion is used to treat hemodynamically significant supraventricular (or narrow complex) tachycardias, including atrial fibrillation and atrial flutter. It is also used in the emergent treatment of wide complex tachycardias, including ventricular tachycardia, when a pulse is present. Pulseless ventricular tachycardia and ventricular fibrillation are treated with unsynchronized shocks referred to as defibrillation. Electrical therapy is inappropriate for sinus tachycardia, which should always be a part of the differential diagnosis.
Pharmacologic cardioversion
Various antiarrhythmic agents can be used to return the heart to normal sinus rhythm. Pharmacological cardioversion is an especially good option in patients with fibrillation of recent onset. Drugs that are effective at maintaining normal rhythm after electric cardioversion, can also be used for pharmacological cardioversion. Drugs like amiodarone, diltiazem, verapamil and metoprolol are frequently given before cardioversion to decrease the heart rate, stabilize the patient and increase the chance that cardioversion is successful. There are various classes of agents
Cardioversion that are most effective for pharmacological cardioversion. Class I agents are sodium (Na) channel blockers (which slow conduction by blocking the Na+ channel) and are divided into 3 subclasses a, b and c. Class Ia slows phase 0 depolarization in the ventricles and increases the absolute refractory period. Procainamide, quinidine and disopyramide are Class Ia agents. Class 1b drugs shorten phase 3 repolarization. They include Lidocaine, Mexiletine and Phenytoin. Class Ic greatly slow phase 0 depolarization in the ventricles (however unlike 1a have no effect on the refractory period). Flecainide, moricizine and propafenone are Class Ic agents. Class II agents are beta blockers which inhibit SA and AV node depolarization and slow heart rate. They also decrease cardiac oxygen demand and can prevent cardiac remodeling. Not all beta blockers are the same, some are cardio selective (affecting only beta 1 receptors) which others are non-selective (affecting beta 1 and 2 receptors). Beta blockers that target the beta-1 receptor are called cardio selective because beta-1 is responsible for increasing heart rate; hence a beta blocker will slow the heart rate. Class III agents (prolong repolarization by blocking outward K+ current): Amiodarone and sotalol are effective Class III agents. Ibutilide is another Class III agent but has a different mechanism of action (acts to promote influx of sodium through slow-sodium channels). It has been shown to be effective in acute cardioversion of recent-onset atrial fibrillation and atrial flutter. Class IV drugs are calcium (Ca) channel blockers. They work by inhibiting the action potential of the SA and AV nodes. If the patient is stable, adenosine may be administered first, as the medicine performs a sort of "chemical cardioversion" and may stabilize the heart and let it resume normal function on its own without using electricity.
328
References
[1] http:/ / icd9cm. chrisendres. com/ index. php?srchtype=procs& srchtext=99. 6& Submit=Search& action=search [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?field=uid& term=D004554 [3] Shea, Julie B.; William H. Maisel (2002). "Cardioversion" (http:/ / circ. ahajournals. org/ cgi/ content/ full/ 106/ 22/ e176). Circulation 106 (22): e1768. doi:10.1161/01.CIR.0000040586.24302.B9. PMID12451016. .
External links
Cardioversion from the National Institutes of Health (http://www.nlm.nih.gov/medlineplus/ency/article/ 007110.htm) Pharmacological Cardioversion from the American Academy of Family Physicians (http://www.aafp.org/afp/ 980800ap/dello.html) Synchronized Electrical Cardioversion from eMedicine Online (http://www.emedicine.com/med/topic2968. htm) Cardioversion from the Heart Rhythm Society (http://hrspatients.org/patients/treatments/cardioversion.asp)
Article Sources and Contributors
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Xdaedalus, Yerpo, Yhevhe, Youdiil, Z0OMD, Zachlipton, ZamorakO o, 1991, , , 653 anonymous edits Electrophysiology study Source: http://en.wikipedia.org/w/index.php?oldid=441913787 Contributors: Alvin Seville, Arcadian, Facts707, Jiwhit01, John of Reading, LeadSongDog, LilHelpa, Nolank270, TheBearPaw, TonyHagale, Woohookitty, 6 anonymous edits P wave Source: http://en.wikipedia.org/w/index.php?oldid=431869340 Contributors: Amissiri, Arcadian, Bob K31416, Lambiam, Mikael Hggstrm, 3 anonymous edits QRS complex Source: http://en.wikipedia.org/w/index.php?oldid=463113436 Contributors: Alex Sims, Alex.tan, AndrewTJ31, Arcadian, Arfgab, Bruguiea, Eleassar, EoGuy, Epinheiro, Facts707, Garion96, Iohannes Animosus, Izik, Jiwhit01, Jmh649, John of Reading, Joy, Klox, LilHelpa, MaSt, Mcstrother, Mdcollard, Melaen, Mikael Hggstrm, MoodyGroove, Rjwilmsi, 20 anonymous edits QT interval Source: http://en.wikipedia.org/w/index.php?oldid=456372113 Contributors: Anypodetos, Arcadian, Axl, BCable, Badgettrg, Beelaj., Cardiacsafety, Cardiacsafety2000, Cmattoon, Coolhandscot, CopperKettle, Dbialac, Dono, Drphilharmonic, Eastlaw, Fvasconcellos, Gabbe, Gaius Cornelius, Informavoreglutton, Jkanters, Ksheka, Larrykoen, Lbeben, LilHelpa, Magisterkrishna, Maltmomma, Mikael Hggstrm, Oliverkeenan, PDH, Pagrashtak, Pasd, Pt, RTucker, Rjwilmsi, Samw, Sbmehta, Scott182, Shandris, Tatsundo h, Teglsbo, Tmallard, Tolstoy the Cat, Wouterstomp, 41 anonymous edits ST segment Source: http://en.wikipedia.org/w/index.php?oldid=431869524 Contributors: Arcadian, Hopping, Iacomus, Lambiam, MegaSloth, 1 anonymous edits T wave Source: http://en.wikipedia.org/w/index.php?oldid=436486754 Contributors: Arcadian, Bobblewik, Brim, Facts707, Lambiam, Mboverload, Mikael Hggstrm, Srich32977, 32 anonymous edits Tilt table test Source: http://en.wikipedia.org/w/index.php?oldid=437622170 Contributors: Ajrv7i, Arcadian, Arentath8, ArrhythmiaAlliance, Astroview120mm, BillC, Bloodshedder, CharacterZero, Charles Gaudette, ChaseKiwi, Chidicon, Chwats, CliffC, Dave314159, Destynova, Dieter Hammhauser, Eve Teschlemacher, Freedomlinux, Graham87, Hankwang, Herbythyme, Hoverflysmiles, Icairns, Ijustam, Insomniduck, Jacqui M, Jagra, John of Reading, Kevin mcmlxxxiv, Kylelovesyou, Limbo@MX, Looie496, Lozeldafan, Mat8989, Mebden, Naniwako, Peterpeter13, Philo-Zenodotus, RabidDeity, Research247, Rhcastilhos, RoyBoy, Rsabbatini, Swerdnaneb, The Baroness of Morden, Thorwald, WhatamIdoing, WinterSpw, 37 anonymous edits Holter monitor Source: http://en.wikipedia.org/w/index.php?oldid=463563300 Contributors: Acsholter, Afkafka, Arcadian, Carlosguitar, Chwats, CliffC, CommonsDelinker, Cquan, Dean.jenkins, Diberri, Enricoros, Facts707, Graham87, GregorB, HaeB, Hooperbloob, Hornet35, Jacklee, Jason7825, Jfdwolff, Jhaaksma, Jiezell, Jimaginator, Jrozario, Kkmurray, Ldueck, Lusum, Macro987, Martineyre, Mattucket, Mercury, NUMBER4940, Naniwako, Nanodance, Nohat, Omegatron, Parkerjackson, Pgelliott, Phillip.vollman, Pion, Rhcastilhos, SU Linguist, Sardanaphalus, Shchvova, Stevenfruitsmaak, Thatguyflint, Thundragon, Trellemare, Tristaess, Vikom, YUL89YYZ, 55 anonymous edits Cardiac dysrhythmia Source: http://en.wikipedia.org/w/index.php?oldid=464218410 Contributors: Acdx, Aetheling, Akjar13, Andrew73, Anim8cme, AnnaFrance, Arcadian, ArrhythmiaAlliance, Astronautics, Aweird1, AxelBoldt, Axl, Bark, Bemoeial, BennyTec, Blanchardb, Brianpie, CMBJ, Caeculus, Calmer Waters, Captain-n00dle, Cholerashot, Christopher Crossley, Chriswaterguy, Closedmouth, Connelly, Conversion script, DabMachine, Dancter, Danjeffers, Danny, Demiurg, Dodger27, Dreadstar, Dvorsky, Dysprosia, Edward, Eewild, Eras-mus, Explosius, Facts707, Favonian, Findlewindle, Finlay McWalter, FourteenDays, GBuilder, Gaius Cornelius, Garik, GinaDana, Glangmann, Gnusmas, GoldenGoose100, Graham87, Gronky, Gtrmp, Gumlyner, Hadal, HangingCurve, Hankwang, Hehkuviini, Hello32020, Heron, Hob, Hu12, Hugh2414, IceCreamAntisocial, JVinocur, Jean-Cedric Plourde, Jeffschuler, Jfdwolff, Jiwhit01, Jkanters, Jmarchn, Jmh649, Jonas094, Jorunn, Joshuajohnlee, Kaitlinxo, Karen Johnson, Katieh5584, Kd4ttc, Keilana, Kelly Martin, Kitch, Kochipoik, Kpjas, Krzysztof P. Jasiutowicz, Ksheka, Kwvan, LIC Habeeb, Lbyron, LeadSongDog, Lmunicki, LuisArmandoRasteletti, Manuel Anastcio, MariskaScholten, MathiasFox, Mendaliv, Mergneed, Michael Hardy, Mikael Hggstrm, Mike2vil, Mikeking.fd, Mitsuki152, MoodyGroove, Morgan Hauser, Morgan Wick, Mschel, Myanw, Nagy, Naniwako, Nbrysiewicz, Nescio, Nyh, Ohnoitsjamie, Owain.davies, Oxymoron83, PFHLai, Patxi lurra, Ph.eyes, Pharaclipper, Philobiomedic, Pichu0102, Pilarian, Pt, RJASE1, Rasmus Faber, Relaxoguy, Renato Caniatti, Repku, Rich Farmbrough, RodC, Rssnkgp02, S.borchers, Saistmp, Search4Lancer, Sfemc, Shoessss, Skepticus, Snalwibma, Somej, Someone else, Statkit1, Stevenfruitsmaak, Subversive.sound, Supersheep, Supten, Sushi, Suwa, Sw258, Talon Artaine, TamePhysician, Teresag, The Anome, Tide rolls, Trainspotter, Tristanb, Turdfergeson1, Tyrol5, Ummel, Urgos, Ursa Gamma, Vendettax, Versageek, Walkerma, WaltJones1989, West81, Wogan May, World4health, Wouterstomp, WriterHound, Writerite, Xoder, Zariane, Zofchro, 270 anonymous edits Palpitation Source: http://en.wikipedia.org/w/index.php?oldid=461266941 Contributors: A dullard, Aceshire, AppaBalwant, Arcadian, Aureliusweb, Barticus88, Blindman shady, Bobo192, C6541, CameronHarris, Cghiotto, Chemira, Chowbok, Chrisbolt, Christian75, CrookedAsterisk, Dabido3, Dancter, Dariusz Peczek, Disorders, Dunnob, Dycedarg, Ejk81, Eleos, Epingchris, Epinheiro, Facts707, Fred Bauder, FuzionZero, Glory holes, Happy B., Haukurth, HeteroZellous, ImplicitD, Iroony, JNW, JackWasey, JederCoulious, Jfdwolff, Johnthepcson, JonHarder, Jorunn, KaragouniS, Krankman, LOL, Lb.at.wiki, LeadSongDog, Lifeartist, Londonsista, Mandy443, Metasquares, MoodyGroove, Muntfish, Omegatron, OverlordQ, Oxymoron83, Oz1sej, Pai.vishwain, Ph.eyes, PhilKnight, Philobiomedic, PianoSpleen, Prisonnet, RelentlessRecusant, Ronhjones, Snowolf, Spenb, Stevenfruitsmaak, Str4nd, Svadhisthana, TheEgyptian, Toddst1, Tristanb, Trumpet marietta 45750, Urrameu, Vedran12, Wawoodworth, WikHead, Wikichange, Windchaser, Zenohockey, 210 ,55 anonymous edits Tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=462927920 Contributors: Andersat, Andrewr47, AnnaFrance, Antandrus, Antnoah, Aramis1250, Arcadian, ArrhythmiaAlliance, Artarro, Billyb, BjKa, BrianKnez, Can't sleep, clown will eat me, Capi, Chhind, Chrisbolt, Chzz, Coppermallow, Courcelles, Csigabi, DanMatan, Danhicks, Daonguyen95, Denisutku, Destynova, Discospinster, Dizzykids, Dorcots, Dreadstar, Dying, Energy Dome, Epeefleche, Eug, Facts707, Fallonso, Fdanonymous, Fratrep, GRAHAMUK, Gabbe, GermanX, Giftlite, Gilliam, Glane23, Grgcox, Hallbrianh, Hankwang, Harry Q. Hammer, Heyyoitsyou1, Hob, Hu12, Icairns, Imnotminkus, Indexer-larry, Iridescent, Isofox, J.delanoy, JamesAM, Jcmo, JeLuF, Jfdwolff, Jiwhit01, Jmh649, Jncraton, John Broughton, Joshuajohnlee, JulieADriver, Kgroneman, Ksheka, KuroiShiroi, Kyoko, LadyofShalott, Lbeben, Lester, Liljoe4195, Madhero88, Markaci, Markjohndaley, Mauvila, Metasquares, Modster, MoodyGroove, Ms. 45, Murtasa, Musiphil, Mynameiswill, NERVUN, Nick Number, Nkadhom, Nkrish, Obscurans, Ocatecir, Pascal666, Philobiomedic, Poindexter Propellerhead, R3dsh1ft, Renato Caniatti, Richard holt, Roger Roger, Ryoung54, SLATE, Savidan, Scohoust, SeanMack, Seaphoto, Sephiroth BCR, Shanes, Shattered Gnome, Shogunsassassin, Skagedal, Slawekb, Smalljim, Spoon!, SunCreator, TUF-KAT, Tabletop, TatRicanMamii23, TiCPU, Tiddly Tom, Tide rolls, Tomalak geretkal, Trafficone, Varlaam, Vedran12, Wayward, Wikidas, Wouterstomp, WriterHound, Zakksez, ZayZayEM, Zenosparadox, Zodon, Zorath, 178 ,12 ,55 anonymous edits Bradycardia Source: http://en.wikipedia.org/w/index.php?oldid=450352229 Contributors: 3R1C, Active Banana, Aff123a, AllyUnion, Altenmann, Andrewr47, Arcadian, ArrhythmiaAlliance, AstroHurricane001, AxelBoldt, Axl, Bobblewik, Brighterorange, Bryan Derksen, Calmer Waters, Can't sleep, clown will eat me, Card Zero, Cgerzee, Conti, Conversion script, Count Iblis, Countincr, Cswarren52, Darth Panda, Ddnile, Dr. Pathos, Eequor, Ekko, Eric Kvaalen, Ewen, Feathering my nest, Fismat, FreeBird, Fvasconcellos, Fwapper, Gobonobo, Graham87, Halosix, Hankwang, Happypatatoes, Ifrit, Intelligentsium, JBellis, JHunterJ, Jfdwolff, Jguy, Jmarchn, Jmh649, Johnteslade, Kay Dekker, Kelisi, Kgrad, KramerNL, Ksaraf, Ksheka, Laurusnobilis, Lenilucho, Looxix, Marek69, Markhu, Marumari, Matthew V Ball, Mesolimbo, Michael Hardy, MikeSy, Mitrius, Monachima505, Nbarth, Osnimf, Owhite9878, Permafrost, R'n'B, Renato Caniatti, Rhobite, Rich Farmbrough, Skagedal, Skinny McGee, StN, Stevenfruitsmaak, Stinkypie, Tarek, Tjajkovskij, Triona, Varlaam, Vedran12, Wikipediarules2221, Wouterstomp, Wtuvell, XHappy.BeeX, 101 ,55 anonymous edits Proarrhythmia Source: http://en.wikipedia.org/w/index.php?oldid=399373320 Contributors: AAAAA, Acdx, Arcadian, Facts707, Magioladitis, RDBrown, UtherSRG, Violncello, 2 anonymous edits Sinus rhythm Source: http://en.wikipedia.org/w/index.php?oldid=459129531 Contributors: Agateller, Angela, Arcadian, Atom cz, Beeswaxcandle, Bleakcomb, Bluenokkad, Cburnett, Ceyockey, CrookedAsterisk, Daniel Mahu, Dexenerator, Furby100, Fyrwoman49, G3pro, Gareth E Kegg, GregAsche, Jmarchn, Jpcallan, Kylet, LilHelpa, Mdf, Michael Hardy, Mnokel, MoraSique, MrDolomite, NCurse, Nealj0528, Pascal.Tesson, PigFlu Oink, Rubik-wuerfel, Scoo, Spiral5800, Tedder, Wouterstomp, 42 anonymous edits Sinus tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=459674932 Contributors: Andrewr47, Aramis1250, Arcadian, Blue bear sd, DabMachine, Darobian, Download, Frank Lofaro Jr., Fvasconcellos, Goodnightmush, Hallucegenia, Javsav, Lbeben, Lissyb12, LovelyLillith, MacGyverMagic, Mgiganteus1, MoodyGroove, Morostheou, OwenBlacker, Pascal666, Ph.eyes, TaintedMustard, Turdfergeson1, Vkohli, WereSpielChequers, WhatamIdoing, Woohookitty, , 27 anonymous edits Inappropriate sinus tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=451627197 Contributors: Arcadian, Clive TS, Debresser, Elsiedoll, FRANHORNE, Gurch, RDBrown, The Anome, Wikiwayman, Woohookitty, , 11 anonymous edits Sinus bradycardia Source: http://en.wikipedia.org/w/index.php?oldid=445785628 Contributors: Andrewjlockley, Arcadian, Chris the speller, Connormah, Frank Lofaro Jr., Fvasconcellos, JamesAM, Jmh649, Jwy, Lenilucho, M9aj, Mac Davis, Nagelfar, Pascal666, Ph.eyes, Rccoms, Turdfergeson1, Woohookitty, 19 anonymous edits Sick sinus syndrome Source: http://en.wikipedia.org/w/index.php?oldid=460387251 Contributors: Arcadian, Aristiana, Aunt Entropy, Barticus88, Darth Panda, Davodd, Det3574, Diberri, Dr. Vinzenz, FURRY BABY, FrugalFooker, Gaius Cornelius, Hehkuviini, JHeuser, Janus549, Japanese Searobin, Jazzmoney, Kellyolson, Ksheka, LiahFaile, Mantisia, Mnokel, MoodyGroove, Nephron, Nmg20, PFHLai, Runehawk, Stevenfruitsmaak, TehGrauniad, The wub, The.shrapnel, Wouterstomp, Zyryab, 19 anonymous edits Premature atrial contraction Source: http://en.wikipedia.org/w/index.php?oldid=453782600 Contributors: 09SentraSpecV, Aboalbiss, Arcadian, Berrie, Bobjgalindo, CDN99, DaSjieb, Deor, Diannaa, Dr.madanmjha, Feydey, Flywhc, FunkyDuffy, GrahamHardy, Hydnjo, Jengod, Johner, Kenmcl2, Kjkolb, LeadSongDog, LilHelpa, Lorien79, MastCell, MrMarmite, Nephron, Nirmalv, Philobiomedic, Rjwilmsi, Sbmehta, Sinusoidal, Spook`, Stoneguy, Toddst1, Weaseal, Zibbitech, 27 anonymous edits
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Wandering pacemaker Source: http://en.wikipedia.org/w/index.php?oldid=455626869 Contributors: Anim8cme, Arcadian, Black Kite, Cewvero, Cochise11, Mdclyburn.2013, MoodyGroove, Premeditated Chaos, Skysmith, Theda, 4 anonymous edits Multifocal atrial tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=441078123 Contributors: Arcadian, Esculapio, Greggsjm, IceCreamAntisocial, Keyvmarz, Middayexpress, Mrug, Pcheese2000, 7 anonymous edits Atrial flutter Source: http://en.wikipedia.org/w/index.php?oldid=448458356 Contributors: Alansohn, Arcadian, Arjayay, Axl, Bob K31416, Brighterorange, Bsadowski1, CBHA, CornmealZeal, Ddnile, Diberri, Draeco, Dreadstar, DRahier, Exploding Boy, Gimrudghk, GunnarK, Hadal, Hob, Hu12, Isaac elias, Jfdwolff, Jmh649, John of Reading, KieferSkunk, Ksheka, Mauvila, Mikael Hggstrm, MoodyGroove, PFHLai, Piano non troppo, Powers.andy, Rich Farmbrough, Rossumcapek, Shenme, St3vo, Svick, Theodore Kloba, Tocant, Toombes, 50 anonymous edits Atrial fibrillation Source: http://en.wikipedia.org/w/index.php?oldid=463867540 Contributors: A. B., A. Rad, AAAAA, Ahusni, Alex Pascual, Amadalvarez, Andrew73, AndyRudin, Anim8cme, Anthonyx310, Apers0n, Arcadian, Arfgab, Arjayay, ArrhythmiaAlliance, Aswang, Aszymanik, Atom cz, AustinKnight, Austria156, AxelBoldt, Axl, BService, Badagnani, Badgettrg, Balmainbug, Barnesjewish, Barticus88, Benbest, Biancamed, Bldavids, Bob K31416, Brighterorange, Burlywood, Caltas, Can't sleep, clown will eat me, Celian, Christianna1219, Cralize, Cucherat, Cybergoth, Dan D. Ric, Dancter, Danjeffers, Dantheman531, Ddnile, Diberri, Dlodge, DocJohnny, Doctormatt, Doctorwolfie, Dr saima aslam, DrJCPC, Dreadstar, Drpickem, Duswdav, ESkog, Ellusion, Emilyrader, Enigma55, Erianna, Erud, FHCPinehurst, Facts707, Faderrattnerb, FeatherPluma, Felix Folio Secundus, Francionyc, Freezor, Furqan Tejani, Fvasconcellos, Gak, Geoffrey Wickham, Glkelly, GoingBatty, Hadal, Hankwang, Harris4917, Hirohisat, Hu12, Ian Dalziel, IdidntgetwhereIamCJ, Ignoranceisbliss252, InvictaHOG, Iridescent, Iste Praetor, Jafib, JamesDriscoll, Jamesmcclelland, Jaquesk, Jean-Cedric Plourde, Jelohman, Jfdwolff, Jjalife, Jjwilson23, Jmh649, JonHarder, Jule3tid, Julius32, Kate, KerwinMD, Kinu, Klausner, Ksheka, Kwj2772, Lapappey, Laportechicago, Lbeben, Leaderofearth, LilHelpa, Luna Santin, Mailer diablo, Maryskole, Mattopaedia, Maxwvb, Mcth, Mediaforce, Mehrenberg, Mfwitten, Mikael Hggstrm, MollyNYC, MoodyGroove, Mwanner, N415Ros, Nbrysiewicz, Nlinton, Nneonneo, Ohnoitsjamie, OldakQuill, Oli Filth, Osm agha, PFHLai, Paiamshadi, Ph.eyes, Philobiomedic, Polyamorph, Powers.andy, Praetorian42, RJASE1, Randallwolf, RandomP, Raptor123211, Ravindar bethi, Rettetast, Rewster, RexNL, Rich Farmbrough, Riffle, Rjwilmsi, RodC, ST47, SarekOfVulcan, SciberDoc, Scottybowl, Sh111496, Shawnmichael19, SovereignRule, Spellcast, Squiggle, Stevenfruitsmaak, StopCyberBullies, Sweikart, T1n0, Tadler53033, TamePhysician, Tarek, TastyPoutine, The Anome, The Thing That Should Not Be, Tocant, Trudyjh, Ummel, Veinor, WLU, Walter S. Vaan Allen, Wkruse, Woohookitty, Woood, Wouterstomp, Writerite, WurzelT, Zyryab, 12, , 312 anonymous edits Supraventricular tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=463510390 Contributors: 2kool4scho0l, AdjustShift, Amizzo, Arcadian, ArrhythmiaAlliance, BService, Basalisk, Benstam, BigrTex, Biosfear, Bsoderberg, CME GBM, Captain Courageous, Ccacsmss, CesarB, Chwats, Cmdrjameson, Cutblood, Cybergoth, D'n, Deadles, Diberri, Dirac1933, Displaced, DrJCPC, Edward, ElPeste, Ellery, FRANHORNE, Facts707, Florian Huber, Franklinjefferson, Fratrep, Fxhomie, Gail, Gene Hobbs, Gracenotes, Hankwang, Headbomb, Hu12, Immunize, Inoculatedcities, Iridescent, J.delanoy, Jackfork, Jhcapps, Jmh649, Justen12189, Kauczuk, Kaufdropp, KennethToronto, Ksheka, L Kensington, LeadSongDog, Loren.wilton, Lyrl, MaffooClock, Malcolm Farmer, Markjohndaley, Mauvila, Mets501, Mikael Hggstrm, Mild Bill Hiccup, MoodyGroove, MrXow, Msaeed md, NawlinWiki, Nereocystis, Nick81, Nstanaway, Nuttycoconut, Paul Tyrrell, Philobiomedic, Professorial, Quirk, Ringbang, Ronhjones, SQGibbon, Seaira3, ShesGotSauce, Skr, Sky100010, SuperCoder, TamePhysician, The Anome, TheAllSeeingEye, Theodore Kloba, Thisisjonathanchan, ThujaSol, Tide rolls, Toddst1, Toombes, Travis.Thurston, Twisted86, VELVET, Vagus, Vedran12, Waggers, Wouterstomp, Zoicon5, 201 anonymous edits AV nodal reentrant tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=441574709 Contributors: Arcadian, Brjason, Calmer Waters, Ceccomaster, Facts707, Jfdwolff, K ahmad, Ksheka, Lbecque, Mikael Hggstrm, NCurse, Nikopoley, Popfossa, Rjwilmsi, Rmosler2100, Steinsky, Theodore Kloba, Toombes, Triquetra, WhatamIdoing, Woohookitty, Wouterstomp, 13 anonymous edits Junctional rhythm Source: http://en.wikipedia.org/w/index.php?oldid=450596179 Contributors: Ajutla, Arcadian, Immunize, Mikael Hggstrm, Nbrysiewicz, NeilN, Pascal.Tesson, Theonlyrealj, 8 anonymous edits Junctional tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=460374828 Contributors: Arcadian, Bearcat, Joshuajohnlee, Sisotp, Xezbeth WolffParkinsonWhite syndrome Source: http://en.wikipedia.org/w/index.php?oldid=464567279 Contributors: A Doon, ABCD, After Midnight, AjK, Andrew c, Antoshi, Arcadian, Arjayay, Axl, Bdve, Bellhalla, Biruitorul, Bobblewik, Cajolingwilhelm, Caleson, Captain Courageous, Chwats, Cpt ricard, Cybergoth, Dale Arnett, Danhicks, Ddrace, Delldot, Dodgerblue777, Doktorekg, Dr. Persi, Draeco, DragonFury, Dupz, Edward, EhJJ, Eleassar, Epbr123, Epguy, Eras-mus, Erebunium, Excalibre, FT2, FTWFTWFTWFTW, Facts707, Flowanda, Fullertonchris, Furqan Tejani, Fvasconcellos, Ginkgo100, Good Olfactory, Greensburger, Gypsydoctor, Hajisavvas, Halmstad, Hehkuviini, Illythr, JB82, Jaywhitely, Jfdwolff, Jiwhit01, Jmh649, John Darrow, Jusdafax, Kaiba, Kajerm, KingRaven44, Ksheka, Lapappey, Llywrch, Ludwigpnietzsche, M1ss1ontomars2k4, Makemi, Michael Hardy, Mikael Hggstrm, MikeCGU, MoodyGroove, Mrpeenut24, Mysteryone2011, Nehwyn, NiciVampireHeart, Nineblackalps, Nishkid64, Nixpix99, Nmg20, PDH, PFHLai, Pablothegreat85, Ph.eyes, Phil Boswell, Plucas58, Poindexter Propellerhead, Pythoness Mar, RDBrown, RainbowOfLight, RedWolf, Renice, Rhidica, Rich Farmbrough, Rick 50000, Ricky81682, Rjwilmsi, Rmky87, Rtiztik, Sallenmd, Secretaria, Sesamehoneytart, Sgamer1770, Shak-74M, Shi Hou, Singularity42, Sophie means wisdom, Student54, Swisse, Swizzlez, TJ Spyke, TO7010, Tameamseo, Temporaluser, Terminator50, Thatguyflint, TheFBH, Theodore Kloba, Tide rolls, Tionis, Tom Lck, Tommy2010, Toombes, Top Jim, Topbanana, Tsporr93, UNCPJP, VerbalHerbal, WhatamIdoing, Woohookitty, Yerpo, 256 anonymous edits LownGanongLevine syndrome Source: http://en.wikipedia.org/w/index.php?oldid=441081251 Contributors: Arcadian, Fvasconcellos, JHeuser, Jiwhit01, Jkanters, Jonathan Logan, LrdChaos, Michael Hardy, Nmg20, PrincessCaitlai, Shak-74M, 6 anonymous edits Premature ventricular contraction Source: http://en.wikipedia.org/w/index.php?oldid=461092419 Contributors: AAAAA, Acn20, Alex.tan, Arcadian, Aswang, AxelBoldt, Bellthorpe, Beno1000, Bob K31416, Bobtheowl2, Bookandcoffee, Brighterorange, Bubbachuck, Bunnyhop11, Bwrs, C6541, Chiptonius, Dabido3, Dark Formal, Derek Ross, DigbyDalton, Docsmack, Dr.satan257, Edokter, Exoity, Facts707, G vom s, GinaDana, Greentryst, Hehkuviini, Hennings64, JHeuser, JHunterJ, JL Hickman, JaGa, Jeff987, Jmh649, JohnI, Johner, Joshuajohnlee, Keenan Pepper, KeithJonsn, Kenmcl2, Kenw4077, Kinema, LeadSongDog, Leonard Finger, Lrothc, Mad Max, Madwong, Mister Matt, Nephron, Nihiltres, Nono64, OrangeGuutan, Orangeroof, Philobiomedic, R'dam, RDBrown, Relleh22hctac, Rewster, Rholton, Risk one, Saethwr, Scaife, Shell Kinney, Shirt58, Spalding, Squidward247, Stephenb, Tadc, Taylornate, Theresa knott, Tristanb, Vf38, W guice, Wadems, Wept, WhatamIdoing, Xezbeth, Yakushima, Zelphics, Zs35, 130 anonymous edits Ventricular tachycardia Source: http://en.wikipedia.org/w/index.php?oldid=463671700 Contributors: Acm95301, Alansohn, Andrei Cvhdsee Brazil, Arcadian, Aspects, Barticus88, Cfparker, ChrisCork, Davemck, Davidlawrence, Doctormatt, Doktorekg, Drphilharmonic, Facts707, Firsfron, Flyer22, Gaius Cornelius, Giraffedata, Grapetonix, Hehkuviini, Heron, Imnotminkus, J04n, Jfdwolff, Jiwhit01, Jjwilson23, Jkanters, Jmarchn, Jmh649, John Broughton, Joshkap18, Ksheka, Kwj2772, Laduree6th, Lwg9q, Minimac's Clone, Mokshu, Monitorer, MrPinkBullets, Orangeroof, Plasticup, R'n'B, Rjwilmsi, RobinHood70, Seanm028, Spiral5800, Stemonitis, Stephan Leeds, Swpb, Tocant, Toombes, UbiTerrarum, Vedran12, Vuo, Why Not A Duck, X!, Younesmaia, 65 ,12 anonymous edits Torsades de pointes Source: http://en.wikipedia.org/w/index.php?oldid=463864015 Contributors: AAAAA, Adisnake, Alexs, Andthu, Arcadian, Beeswaxcandle, Blanchette, Bob K31416, CWenger, Cecropia, Ceyockey, Chris the speller, Chrysaor, Citruscyanide, DabMachine, Delchicago, Displaced, Draeco, Drtriple, ER MD, Eastlaw, Eperotao, Flewis, Flopster2, Georghia, Hantla, Infaustos, JHeuser, Jag123, James McNally, Jfdwolff, Ksheka, Lucky 6.9, Mattingly23, Mfhulskemper, Mirams, Mmoneypenny, Monta100, MoodyGroove, NCurse, Nishantkumarnishu, Numero4, Nunh-huh, PFHLai, Panthro, Petersam, Poetsirrah!, RobinHood70, Salzaid, Sgpsaros, Signalhead, Sriram sh, Tomdeath1990, TyrS, Valerius Tygart, Versus22, Vuo, Wyvyrn, 50 anonymous edits Ventricular fibrillation Source: http://en.wikipedia.org/w/index.php?oldid=462263498 Contributors: Agoode, Andersat, Andrew73, Andylkl, Arcadian, ArchabacteriaNematoda, ArglebargleIV, Aswang, Athenscolumbia, Avoided, AxelBoldt, Bemoeial, Bobblewik, BrOnXbOmBr21, Captain-n00dle, Caspian, Chiu frederick, Crucis, Cynical, D Dinneen, Danny, Denelson83, Dimblethum, Discospinster, Dokane, Dougher, Dreadstar, Eleassar, Eleassar777, Etxrge, Eukesh, Frank Lofaro Jr., Gandalf grey, Gene Nygaard, Geoff B, Geoffrey Wickham, Gnusmas, Haham hanuka, Headbomb, Hehkuviini, Inoculatedcities, InvictaHOG, JNW, Jaganath, Jerry, Jfdwolff, Jmh649, Kate Carter, Kchishol1970, Kirill Lokshin, Kku, Kookygoose, Ksheka, Kwj2772, Lapappey, Liam Skoda, Light current, Looie496, Lwg9q, McSly, Mnokel, MoodyGroove, Nick Number, NuclearWarfare, Ohnoitsjamie, OmegaWiki, Orangeroof, Osnimf, PFHLai, Peter Gheeraert, Popbob12001, Pt, RDBrown, RJFJR, RedWolf, Revolver, Rich Farmbrough, RoyBoy, Sbrennan2, Shiggity, Sidhekin, Skagedal, Smlbstcbr, Someone else, Splintax, Sushi, Switchercat, T23c, Tabletop, Tarek, The Anome, Toytoy, Unara, Vic modi, Vmenkov, Vuo, WhatamIdoing, WhyBeNormal, Woohookitty, X!, Xernox123, Zazou, , 130 anonymous edits Accelerated idioventricular rhythm Source: http://en.wikipedia.org/w/index.php?oldid=463812591 Contributors: Arcadian, Beeswaxcandle, Brad, Pepemonbu, Wrongfooting, 6 anonymous edits First-degree atrioventricular block Source: http://en.wikipedia.org/w/index.php?oldid=441077285 Contributors: Adam Slack, Andrewjlockley, Arcadian, Axl, Bobjgalindo, Bryan Derksen, Crystallina, Darkmaster2004, Drphilharmonic, Jfdwolff, Ksheka, Kyoko, LOL, LUIGI FEDELE, Lectonar, Lou.weird, McSly, MoodyGroove, OwenX, Rjwilmsi, Rmhermen, Snalwibma, Taketa, That Guy, From That Show!, Wouterstomp, 38 anonymous edits Second-degree atrioventricular block Source: http://en.wikipedia.org/w/index.php?oldid=464402706 Contributors: Andrewjlockley, Animeronin, Arcadian, Bobjgalindo, Dmastad, Drparthnsy, Drphilharmonic, Hagerman, Hoverflysmiles, Jclemens, Ksheka, Lamaybe, MarshBruce, MoodyGroove, MrDolomite, Nmg20, Rudnick, Stadler981, Taketa, Trevor Wennblom, Tyler,
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Ulric1313, Woohookitty, Wouterstomp, 36 anonymous edits Third-degree atrioventricular block Source: http://en.wikipedia.org/w/index.php?oldid=446524115 Contributors: Andrewjlockley, Animeronin, Arcadian, Bearcat, Bryan Derksen, Compendium wmc, Cwbvb13, Drphilharmonic, I dream of horses, Isaac elias, Jarnex, Joshkap18, KieferSkunk, Ksheka, Malcolm Farmer, Maximus Rex, Mikeyankees, MoodyGroove, Ms1702, Nadavspi, SciberDoc, Stevenfruitsmaak, Taketa, The Anome, W guice, Wouterstomp, 51 anonymous edits Long QT syndrome Source: http://en.wikipedia.org/w/index.php?oldid=463377728 Contributors: Anilm11, AnjaManix, Annandale, Apers0n, Arcadian, Arhielanto, Atom cz, Belovedfreak, Bobblewik, Boghog, Brim, Cam27, Camw, Cherylpb, Cst17, David Shay, Doktorekg, DonSiano, Dpryan, DropDeadGorgias, Drphilharmonic, Erwinser, Gak, Gaussgauss, Gcgmd, Georghia, Gigemag76, HillbillyProfane, Ibidem, Iknowyourider, J.delanoy, JHeuser, Jfdwolff, Jkanters, Jmh649, JohnElder, Jonsilva, Ksheka, Lmitchell6, Looie496, Lradrama, Malcolm Farmer, MathiasFox, MichaK, Miranda, MoodyGroove, Morwan, Mr0t1633, Nagakurax, Nono64, Novangelis, Onebravemonkey, Ostmoe, PDH, PFHLai, Peiter, Pennycake, Pfortuny, Philip Trueman, RDBrown, Red Director, Renice, Rhcastilhos, Rich Farmbrough, Rjwilmsi, Rodhullandemu, RslaterIII, SJP, Sam Hocevar, Sceptre, Shadowjams, Shandris, ShesGotSauce, Sigveholmen, Silversin, SimonP, Someone else, Srich32977, StN, SunCreator, Swikid, Talon Artaine, Tcallis, The Anome, The Thing That Should Not Be, TogetherinParis, Tristanb, Txomin, Umpharm, VMS Mosaic, Wouterstomp, 194 anonymous edits Antiarrhythmic agent Source: http://en.wikipedia.org/w/index.php?oldid=458155834 Contributors: AAAAA, Abzs2k, Adamack42, Alex.tan, Angusrivers, Arcadian, ArcadianOnUnsecuredLoc, Atemus, Awanta, Axl, B. Wolterding, Bassem18, Benjaminevans82, Bialy Goethe, Bombyx, Cajolingwilhelm, Captain-n00dle, Cburnett, Cchrrisstiinaaa, Dancter, Diberri, Draeco, Eequor, Epolk, Eras-mus, Evlekis, Facts707, Fallschirmjger, Footprintx, Fvasconcellos, Haza-w, Hugh2414, Ilyabeylin1980, JHeuser, JackWasey, JamesAM, Jfdwolff, Jiwhit01, Jmh649, Kauczuk, Ksheka, Martpol, MayaSimFan, Mdtsa, Mikael Hggstrm, MikeSy, N313m, Newcastleunii, Niels Olson, Niteowlneils, Nowhereman86, Numero4, Orlandoturner, Porterea, Quasar Jarosz, QuickDuck, Quirk, RTaptap, Rdsmith4, Rjwilmsi, Salvadorjo, Sbmehta, Scarlett&Esther, Sgpsaros, Shano85, Tarek, Tbplante, Tony Lim, Travelbird, Txomin, UCLABruin, UberMD, Uthbrian, Veej209, Vrij, Wouterstomp, ZooFari, 152 anonymous edits Sodium channel blocker Source: http://en.wikipedia.org/w/index.php?oldid=460078994 Contributors: Arcadian, JWSurf, Looie496, Raymondwinn, Rich Farmbrough, Scottalter, ZooFari, , 4 anonymous edits Beta blocker Source: 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Vldscore, Walrus068, Wayne Slam, Winick88, Wouterstomp, 270 anonymous edits Potassium channel blocker Source: http://en.wikipedia.org/w/index.php?oldid=457770837 Contributors: Arcadian, ArcadianOnUnsecuredLoc, Dawndanielson, Fallschirmjger, Rich Farmbrough, Scarlett&Esther, Scottalter, Wingman4l7, , 2 anonymous edits Calcium channel blocker Source: http://en.wikipedia.org/w/index.php?oldid=462792773 Contributors: Ahoerstemeier, Amalgamator, Arcadian, Bobo192, Brighterorange, Cacycle, Calvero JP, Carlo Banez, Chowbok, Chris the speller, Chrispounds, Christopher Parham, DabMachine, Darobian, Diberri, Djsasso, DocJohnny, Eequor, Elonka, Erianna, Evox777, Fvasconcellos, Galaxiaad, Gekritzl, Gesundheit07, Jmarchn, Jmh649, Joel.geerling, Jubilee7, Jwpurple, KBlott, Kauczuk, Kpjas, Ksheka, Kurykh, Kyoko, Lbeben, Light current, Mensch, MiPe, Mikael Hggstrm, MikeVitale, Mitartep, Ocdcntx, Pbergson, Ringbang, Robbrad3, Rritter.rn, Ryan Pedigo, Salvadorjo, Sdfromage, Sephiroth BCR, Sonett72, Szalzala, Tarawneh, Teamabby, Techelf, Thomasballard, Tide rolls, Tkjtkj, Tmallard, Tristanb, Uthbrian, Wasbeer, WereSpielChequers, Wi11y 0n wh3315!, Winterheart, Wisdom89, 107 anonymous edits Procainamide Source: http://en.wikipedia.org/w/index.php?oldid=464528749 Contributors: Anastrophe, Anilverma, Arcadian, ArcadianOnUnsecuredLoc, Beetstra, Bhmunos, Bwhack, Ceyockey, Chamedic, Chowbok, Clicketyclack, Deflective, Eras-mus, Fvasconcellos, Gxcf1, Jiwhit01, J, Kristenq, Ksaraf, Kwamikagami, Louisajb, Paddles, Rbaselt, Rich Farmbrough, Rjwilmsi, Salvadorjo, Scottalter, Stevenfruitsmaak, Su-no-G, Swizzlez, Tarek, Terrace4, Viriditas, Zorkun, , 21 anonymous edits Quinidine Source: http://en.wikipedia.org/w/index.php?oldid=464348071 Contributors: Acsmith23, Alsiola vet, Anilverma, Arcadian, Beetstra, Benjah-bmm27, Ceyockey, ChemNerd, Choosebrad, Copperman, Edgar181, Element16, Eras-mus, FelixP, Gliu, Gor n bein, Hans Frrum, Harbinary, Hengsheng120, Heron, Jfdwolff, Kauczuk, Kimiko Moon, Kristenq, Ksheka, L Kensington, Louisajb, MayaSimFan, Mikael Hggstrm, Mykhal, Onco p53, P-kun80, Panoramix303, Penarc, Rifleman 82, RingMaruf, Salvadorjo, Scodocs2, Scottalter, Selket, Uthbrian, Where next Columbus?, WriterHound, Yakushima, Zfr, , 34 anonymous edits Disopyramide Source: http://en.wikipedia.org/w/index.php?oldid=460796372 Contributors: Anypodetos, Arcadian, Beetstra, Bikeable, ChemNerd, Chowbok, Divine Knight, Fvasconcellos, Hengsheng120, Kdiwavvou, Louisajb, MayaSimFan, MichaK (usurped), Pashihiko, Pearle, Rayc, Rwjosep, Sbmehta, Scottalter, Stemonitis, Terrace4, Unixer, Yakushima, Yid, , 5 anonymous edits Lidocaine Source: http://en.wikipedia.org/w/index.php?oldid=464757878 Contributors: 4wajzkd02, Acdx, Adamrush, Aghochikyan, Alex.tan, Alison, Almazi, Alvis, Anastrophe, Andersat, Andrew73, Anonabyss, Arcadian, Aschwole, Atmamatma, Babyblade6, Beardoc, Beetstra, Bejnar, Bemoeial, Benjah-bmm27, Bignoter, Bov, Brambleclawx, Bubba73, C6541, Cacycle, Calabe1992, Captain 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RODERICKMOLASAR, Rajasekhar1961, Rbaselt, Rebroad, Rich Farmbrough, Rifleman 82, Rjwilmsi, Rotellam1, Rror, Russthomas1515, Salvadorjo, Sam Hocevar, Samir, Scottalter, Selket, Smokefoot, Sneakums, StoneColdCrazy, Swamp Ig, TangentCube, Tarek, Techelf, Terrace4, The Rhymesmith, Thickycat, Tmobsterdon, Triggtay, Uncle Dick, Vipinhari, Vuo, Wakablogger2, Whkoh, Wimvandorst, Woodsstock, Ymousa, Zetawoof, Zirland, ~K, , 261 anonymous edits Phenytoin Source: http://en.wikipedia.org/w/index.php?oldid=463035684 Contributors: ABCD, Adambisset, Aesculapian, Agjchs, Alessandra Napolitano, Amcarroll32, Ansell, Arcadian, ArthurMcGill, Aschwole, Axl, Bayerischermann, Be4u92, Beetstra, Ben Webber, Boblegrand, Captain-n00dle, CaroleHenson, Casforty, ChemNerd, Chowbok, Colin, CyberSkull, Dachshund, Daevatgl, Danielgrad, Davidmpye, Dekimasu, Dethomas, Diberri, Drphilharmonic, Dscush, Dvavasour, E. Ripley, Eclipseracer786, Enix150, Ettrig, Facts707, Firsfron, Fvasconcellos, Galaxiaad, Gjohar, Gor n bein, Guy Harris, Hardy, Hnc, Ibkhayyat, Ikkyu2, Jaknouse, Jandalhandler, Jddriessen, Jfdwolff, John R Rodgers, Kitetrimmer, Knocky7, Ksheka, Laportechicago, Lipothymia, Lmatt, MLHarris, Magsato, Mauvila, Maxxicum, Metalhead94, MiPe, Michaeltwilliams, Mykhal, Mysid, Nikai, Nmebrown, Ohnoitsjamie, Paiamshadi, Pashihiko, Patxi lurra, Pdauwe, Pdeitiker, Peryeat, Quadralabs, Quinsareth, RDBrown, Retornaire, Rich Farmbrough, Rich257, Rifleman 82, Rmky87, Salvadorjo, SandyGeorgia, Selket, SemperBlotto, Shoy, SilkTork, Soulblade, St3vo, Staciabb, Staffordkendall, SteveTaylor, Su-no-G, Szalzala, Tabletop, Tatterfly, Tins128, Tophtucker, Treecko 09, Tsiaojian lee, Uthbrian, Varlaam, Vivchawda, Wa1ter, Wapcaplet, Wavehunter, WiccaIrish, Will Beback Auto, Wspencer11, Wwallacee, Xezbeth, Yandman, 105 anonymous edits Mexiletine Source: http://en.wikipedia.org/w/index.php?oldid=462324445 Contributors: Andrew c, Arcadian, Axl, Beetstra, Carlo Banez, Chowbok, Copperman, D8888, Eldaverino, Funkhauser, Fvasconcellos, J, Lisaharvey5, Marcheshakker, MayaSimFan, Mikael Hggstrm, Pashihiko, Scottalter, Welsh, , 11 anonymous edits Flecainide Source: http://en.wikipedia.org/w/index.php?oldid=450383390 Contributors: AAAAA, Anthony, Arcadian, Audry2, Beetstra, BetterWorld, Bob K31416, CMBJ, Cacycle, ChemNerd, Chowbok, Chris the speller, Deflective, Donm3546, Dowlingj, Edgar181, Everyking, FrancioDoc, Fvasconcellos, Gentgeen, Gor n bein, Gronky, Ibkhayyat, Jfdwolff, J, Kelly Martin, Ksheka, Kwamikagami, Louisajb, Lucky 6.9, Master of Puppets, MattKingston, Mutt Lunker, Mykhal, Open2universe, Owen, Pashihiko, Penarc, Physchim62, Pne, Rbrwr, Rhobite, SWAdair, Salvadorjo, Sam Hocevar, Scottalter, Selket, SunCreator, Travelbird, , 54 anonymous edits Propafenone Source: http://en.wikipedia.org/w/index.php?oldid=456801566 Contributors: Arcadian, Beetstra, Benvolio, Chowbok, Chrysaor, Deflective, Derek.cashman, Edward, Fredrik, Gggh, Gor n bein, Identifier, Kaal, Ksheka, Kwamikagami, Lasqueti10, MayaSimFan, Mykhal, PFHLai, Salvadorjo, Scottalter, Selket, SimonP, Snubcube, Statkit1, Terrace4, Theodore Kloba, Xenophon777, , 29 anonymous edits
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Moricizine Source: http://en.wikipedia.org/w/index.php?oldid=462452696 Contributors: Alahmmed, Anypodetos, Arcadian, Beetstra, ChemNerd, Identifier, KBi, Leyo, MichaK, Noahvale, P-kun80, Pashihiko, Scottalter, Selket, 1 anonymous edits Propranolol Source: http://en.wikipedia.org/w/index.php?oldid=464481254 Contributors: ABCD, Academic Challenger, Acdx, Adrian, Alexf, Almazi, AndrewHowse, Andyjsmith, Ansell, Arcadian, Arteyu, Aschwole, Astanhope, Aunt Entropy, Aurista25, Autiger, Axitamm, Barticus88, Be4u92, Beetstra, Benjah-bmm27, Bhadani, Boghog, Bumm13, Cacycle, Camembert, Can't sleep, clown will eat me, Casforty, Cburnett, Charleswallacecharleswallace, ChemNerd, Chiaotzu87, Chris Capoccia, Clarince63, Coredesat, Crabbylucy, Cybercobra, Davidruben, Deglr6328, Deiz, DiamonDie, Dpuder, Dryman, Dvmedis, Eequor, El3ctr0nika, Embe111, Enix150, Excirial, Fiddledeedee, Fogeltje, Fredspry, Fvasconcellos, Ginkgo100, GlowBee, Goodnightmush, Gor n bein, GraybeardBiochemist, HazyM, Headcrash, Infoporfin, J.delanoy, J04n, Jclemens, Jeff Silvers, Jesundevil, Jfdwolff, Jfurr1981, Joshuajohnlee, Joyous!, Jsellick100, Julesd, Justo, J, Kosebamse, Ksheka, Kwamikagami, Kyanha, Light current, LilHelpa, Literaturegeek, Mais oui!, Malick78, Mattcaplan, MayaSimFan, Memestream, Mike2vil, Mod.torrentrealm, Necropedal, Nolelover, Nono64, Nutsterrt, OGoncho, Obeso24, Opiance, Oxfordwang, P-kun80, Parhamr, Ph.eyes, Poppy, Quinyu, RDBrown, Rapsar, Red Stone, RedWolf, Richwales, Rjwilmsi, Ronpedia, Ruja, Rutigor, SDC, Shadowjams, Somersetlevels, Spellmaster, SunCreator, Susan Mason, Sverdrup, Sweettooth4, Tarotcards, Techelf, TimVickers, Toddst1, Todiwan, Untrue Believer, Uthbrian, VicusT, Vlad, Vldscore, Where next Columbus?, Whoosher, Wouterstomp, Wtaber, Ztras, , 248 anonymous edits Esmolol Source: http://en.wikipedia.org/w/index.php?oldid=461238199 Contributors: Albmont, Arcadian, Axl, Beetstra, Bignoter, Bobjgalindo, Bwhack, Dachannien, Danierrr, Davidruben, GeeJo, Gor n bein, Jfdwolff, Jfurr1981, J, LilHelpa, Look2See1, Louisajb, Mrug, Mysid, Pashihiko, Peryeat, Polylerus, Pt, Rhadamante, Rich Farmbrough, Wouterstomp, , 9 anonymous edits Timolol Source: http://en.wikipedia.org/w/index.php?oldid=463226407 Contributors: Arcadian, Beetstra, Boucmat, Colibri37, Dachannien, Davidruben, Edgar181, Fuhghettaboutit, Fvasconcellos, GeeJo, Gor n bein, Gubernator, J, Kauczuk, Michael Daly, Noelfirl, Nono64, Od Mishehu, P-kun80, Pashihiko, Rcawsey, Senseiwa, Stephen, Stuver, Techelf, Terrace4, UNV, W guice, Wolfling, WolfmanSF, Woohookitty, Yid, , 24 anonymous edits Metoprolol Source: http://en.wikipedia.org/w/index.php?oldid=462216570 Contributors: Alexf, Arcadian, Aschwole, Asicwizard, BBuchbinder, Barticus88, Beetstra, Boris.brus, CBM, Cacycle, Casforty, Ceyockey, ChemNerd, Chowbok, DaveChem, Davidruben, Deflective, Deli nk, Dhotwagner, Drues, Edgar181, Eequor, Eribro, Evan C, Exert, Facts707, Fedt, Forever Dusk, Fvasconcellos, G-my, GJeffery, GeeJo, GeorgeLouis, Glane23, 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Contributors: Andr Teixeira Lima, Arcadian, Aublea1, Beetstra, Carlo Banez, Casforty, ChemNerd, Davidruben, Deli nk, Drugsmedia, Edgar181, Emw, Fvasconcellos, GeeJo, Gronky, Immunize, Janke, J, Marwan soft, Maxxicum, MayaSimFan, Mikael Hggstrm, Mike Doughney, Oaktree b, Omar Safi, Orioneight, Quinyu, Rbaselt, Rich Farmbrough, Slashme, Walkerma, WhatamIdoing, Wouterstomp, ZZuluZ, , 31 anonymous edits Amiodarone Source: http://en.wikipedia.org/w/index.php?oldid=464387673 Contributors: AGlossop, Appraiser, Arcadian, Barticus88, Beetstra, Bignoter, Bobjgalindo, Bporopat, Brian Sayrs, Burchclay, Bwhack, CXCV, Cacycle, Casforty, ChemNerd, Chowbok, Davidruben, Diberri, DocKrin, Donaldal, Dr.saptarshi, Dreadstar, Edgar181, Eeekster, Eequor, Epolk, Faderrattnerb, Fan2012, Fuzbaby, Gaius Cornelius, Gentgeen, Gor n bein, Harbinary, HazyM, Headbomb, Hu12, Ibkhayyat, Iridescent, Irishguy, Janke, Jeffq, Jesup, Jfdwolff, Jlabarbera, Jmh649, Jonnyjwalton, J, KnowledgeOfSelf, Ksheka, Leechungsr, Louisajb, MayaSimFan, Mellery, Mhockstein, Michael Hardy, Mulder2010, Mykhal, Natalie Erin, Nbauman, Nickj, Optweb, PFHLai, Pashihiko, Peter.C, Power piglet, RDBrown, Rich Farmbrough, Rjwilmsi, Salvadorjo, Scottalter, Selket, Sethillion, SimonWaters, Stevenfruitsmaak, SunCreator, Tabletop, Theodore Kloba, Tsai the wanderer, Vochee, Wikipedia brown, Xarr, , 116 anonymous edits Sotalol Source: http://en.wikipedia.org/w/index.php?oldid=461651789 Contributors: Arcadian, Axl, Bearcat, Beetstra, Biscuittin, Carlo Banez, ChemNerd, Cmcnicoll, Dachannien, Davidruben, Dipyourwiki, Doctormatt, Facts707, Fvasconcellos, GeeJo, JorStuScho, J, Katnap01, Kav381, Kristenq, Ksheka, MayaSimFan, Od Mishehu, Pashihiko, Rejaneeshsr, Rich Farmbrough, Sam Hocevar, Scottalter, Sneakers55, Tarek, Terrace4, Wouterstomp, Yeeshayl, , 16 anonymous edits Ibutilide Source: http://en.wikipedia.org/w/index.php?oldid=451181814 Contributors: Anypodetos, Arcadian, Beetstra, ChemNerd, Deli nk, Fvasconcellos, Gak, Looie496, Moatgenelex, Pashihiko, Rjwilmsi, Scottalter, Stevenfruitsmaak, Wolingfeng, , 10 anonymous edits Dofetilide Source: http://en.wikipedia.org/w/index.php?oldid=457791434 Contributors: Anodyne, Arcadian, Beetstra, ChemNerd, Chowbok, Chrysaor, Cybernetic, Diberri, Epolk, Fvasconcellos, HkCaGu, Ksheka, Levophed, Lkinkade, Louisajb, Niteowlneils, Nunh-huh, Pashihiko, Rich Farmbrough, Scottalter, Selket, , 10 anonymous edits E-4031 Source: http://en.wikipedia.org/w/index.php?oldid=451224766 Contributors: Edgar181, JGGBorst, Katharineamy, Scarlett&Esther, Scottalter, , 1 anonymous edits Verapamil Source: http://en.wikipedia.org/w/index.php?oldid=462062143 Contributors: Aegoodall, AmadeoV, Aramgutang, Arcadian, Axl, BD2412, BMRR, Beetstra, Bluemoose, BorisTM, Burningrome, CDN99, Casforty, ChemNerd, Colonies Chris, Copperman, Dirac1933, Draeco, Duncan Wils, Edgar181, Eequor, Flopster2, Fnielsen, Freestyle-69, Fvasconcellos, GeeJo, Gimrudghk, Gor n bein, Headbomb, Hetoi, Iantnm, Jfdwolff, J, Kpjas, Ksheka, Kyoko, Louisajb, Nick04, Nirmos, Oaktree b, Oda Mari, P-kun80, Potkettle, Pyfan, Rafael000, Rbaselt, Rich Farmbrough, Rifleman 82, Ringbang, Rjwilmsi, Rmcmullenmd, Rmky87, Ronhjones, Ropers, Salvadorjo, Sarahjarchowchoy, Sbmehta, Selket, Shanedphillips, SimonP, Skwsm, StacyMGA, Stepa, Su-no-G, Szuba daruba, Teddy111, Terrace4, Theo10011, Thioxane, Top Sock Puppet, Triddle, WLU, Where next Columbus?, Whywhenwhohow, WriterHound, Wwallacee, Yid, Zuiram, , 67 anonymous edits Diltiazem Source: http://en.wikipedia.org/w/index.php?oldid=463920982 Contributors: Alex.tan, AltheaJ, Aquaphone, Aramgutang, Arcadian, Arostron, Beetstra, Bloodleech, Casforty, Ceyockey, Chowbok, Chris Capoccia, Colonies Chris, DoC352, Dtsang, Edgar181, Eequor, Foobaz, Frap, Fvasconcellos, GeeJo, Gor n bein, Grendelkhan, HazyM, Hudson Stern, Isnow, Javsav, JeremySavage, Joel2013, J, Leechungsr, MaFi0s0, MeekMark, Meodipt, Mykhal, Nathan, Nbauman, Nephron, Netguyvikas, Oaktree b, Pashihiko, Pdavis68, Pgeoff, Phlebzero, Rjwilmsi, SMcCandlish, Sbmehta, Selket, Sgpsaros, SimonP, Su-no-G, Tcw31, Terrace4, Tristanb, Vikrant42, , 55 anonymous edits Adenosine Source: http://en.wikipedia.org/w/index.php?oldid=463628433 Contributors: 2over0, Adenosine, Alnokta, Altimmons, Ambix, Andres, AndrewHowse, Ansell, Arcadian, Axel Driken, AxelBoldt, Bababen, Beetstra, Blafreniere, BobKawanaka, Bobjgalindo, Boppet, Brjason, Brumpton, CDrecche, Cacycle, Casforty, Chem-awb, ChemNerd, Cibjr, Cliff, CommonsDelinker, Dcirovic, Dddstone, Dma, Dmodlin71, DrAlvi, Edgar181, Edsanville, El3ctr0nika, Eras-mus, Euchiasmus, Excirial, Firsfron, Foobar, Freestyle-69, Genrethan, Gigs, Goodnightmush, Hairy Dude, Hengsheng120, Iamnotanorange, Icey, Itub, JTG 1624, JesseChisholm, Jiwhit01, Jtoomim, Kostisl, Ksheka, Lhynard, Lir, LittleHow, Lkinkade, Louisajb, Malcolm Farmer, Medic-ben, Melissahoward, Mgtoohey, Mikael Hggstrm, Mike2vil, Monobeg, Mrwilly123, Niteowlneils, Nono64, Northfox, Ocaasi, OldZeb, PFHLai, Panoramix303, Pashihiko, Peruvianllama, Peter Znamenskiy, Philthecow, Physchim62, Podwich, PuzzletChung, RainbowOfLight, Random832, Raul654, Reillyd, Rich Farmbrough, Rjwilmsi, Rmosler2100, RobesFSU1, RussBlau, SColombo, SeattleLaurelhurst, Selket, Sesamehoneytart, Shultzc, Stack, Stewartadcock, Tabor, Tbone, TheKMan, Theodore Kloba, Tins128, Uthbrian, Vargster, Vedran12, Vojtech.dostal, Walkerma, Wnt, Wolfmankurd, Xpher, Yikrazuul, Zorknot, 140 anonymous edits Digoxin Source: http://en.wikipedia.org/w/index.php?oldid=462112766 Contributors: Adamack42, Adambein, Alansohn, Alliegm, Anonywiki, Arcadian, Axl, Beetstra, Belovedfreak, Bob K31416, Bobblewik, Boghog, Brockert, Cajolingwilhelm, Casforty, Ceyockey, Chester Markel, Chowbok, Chris the speller, Colin, Danaldine1980, Danny, Darios, DavidLon, Davidnricks, Deflective, Deli nk, Deuter1000, Divine Beauty, Doktorekg, Donreed, Dr.einsteinium, Dr.n3no3, Edgar181, Eloy, Eras-mus, Eric-Wester, Fvasconcellos, Fyrael, Gene Nygaard, Ghaly, Gor n bein, GunnarK, HazyM, Hmoobrojhmoobntshav, Hoffmeier, Hraefen, IcedNut, Iohannes Animosus, Isnow, J Milburn, JamesAM, Janek78, Jfdwolff, Jmh649, Jmknox, John Quincy Adding Machine, JohnOwens, JohnnyCalifornia, Joonasl, Julius86, Jyril, Kilbosh, Kitb, Ksheka, Kupirijo, Kwamikagami, Leyo, Louisajb, Luke poa, Martinor, Mfullenkamp, Mikael Hggstrm, N5iln, Netha Hussain, Nieren, Oizys, Okyea, Pashihiko, Pharmproof, Piercetheorganist, Plrk, Pontificalibus, Power.corrupts, Pwnage8, Pzieba, RDBrown, Reaper X, Reinoutr, Rifleman 82, Rjwilmsi, Rudimae, SMcCandlish, Sacerdos79, Sebwite, Simaan, Someone else, Speciate, StaraBlazkova, Su-no-G, Suleyman Habeeb, SunCreator, T1980, Tahmmo, Techelf, TheAngriestPharmacist, Vchimpanzee, WLU, WhatamIdoing, Where next Columbus?, Wiccan Quagga, Wildwoodfrusciante, William Avery, WolfmanSF, WriterHound, Wsiegmund, , 146 anonymous edits Artificial pacemaker Source: http://en.wikipedia.org/w/index.php?oldid=463343831 Contributors: 12barney, 168..., ABF, 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Cardiac Electrophysiology

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Cardiac Electrophysiology

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Cardiac Electrophysiology

Anatomy, Pathophysiology and Medical Intervention

Anatomy and Physiology

Sinus Rhythms and Dysrythmias

Atrioventricular Node Dysrythmias

Calcium channel blocker

Type III Antiarrythmics

Drawing of the ECG, with labels of intervals

Anatomy and Physiology

Isolated conduction system of the heart

systema conducens cordis

Electrical conduction system of the heart

Depolarization and the ECG

Purkinje fibers/ventricular myocardium: QRS complex

Ventricular repolarization: T wave

Cardiac action potential

Intra- and extracellular ion concentrations (mmol/L)

Na+, Ca2+ INaCa Na+, K+ Ca2+ INaK IpCa

Ca2+-transporting ATPase ATP1B

Resting membrane potential

Phases of the cardiac action potential

Cardiac action potential

Cardiac action potential

Regulation by the autonomic nervous system

Dog Cardiac Muscle 400X Latin textus muscularis striatus cardiacus

Code TH H2.00.05.2.02001 [1]

Role of calcium in contraction

Regeneration of heart muscle cells

Plan of upper portions of glossopharyngeal, vagus, and accessory nerves.

The vagus nerve and the heart

Medical treatment involving the vagus nerve

Physical and emotional effects

Effects of vagus nerve lesions

Transverse section of thorax, showing relations of pulmonary artery

The arch of the aorta, and its branches

The tracheobronchial lymph glands

Section of the medulla oblongata at about the middle of the olive

Hind- and mid-brains; postero-lateral view

The thyroid gland and its relations

The thymus of a full-term fetus, exposed in situ

Sinus node dysfunction

Heart; conduction system

Schematic representation of the atrioventricular bundle

Image showing Bachmann's bundle

Bachmann's bundle and the atrial conduction system

Isolated Heart conduction system showing AV node

Isolated Heart conduction system showing Bundle of His

His Bundle Pacing

Isolated Heart conduction system showing purkinje fibers

The QRS complex is the large peak.

Scope of practice, tests and procedures

Clinical cardiac electrophysiology

Surgical Procedures: Pacemaker and Defibrillator implantation and follow up

EKG graph paper

Unipolar vs. bipolar leads

Augmented limb leads

Waves and intervals

Schematic representation of normal ECG

Animation of a normal ECG wave.

Feature RR interval P wave

Duration 0.6 to 1.2s

QRS complex J-point

Vectors and views

Clinical lead groups