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PHARMACOLOGY
A Study Guide
Pharmacology
Touro College of Osteopathic
Medicine
1
FACULTY
Arthur Prancan, Ph.D., Course Director
329 Touro College Building (646) 981-4612
Arthur.Prancan@touro.edu
2
Essential Objectives for Focused Learning
Drug Classification
Mechanism of Usefulness
Mechanism of Toxicity
Drug Classification
Mechanism of Action
Each drug involves itself in the biology of the patient or infective agents
This may not be the mechanism of usefulness, but it can start the ball rolling in the
right direction
Mechanism of Usefulness
For each application, how does the mechanism of action become useful?
Mechanism of Toxicity
3
DIURETIC AND ANTIDIURETIC MOA, USE, TOXICITY
4
Use: Hypertension, Hyperglycemia
Hydrochlorothiazide CHF, osteoporosis,
Increase of plasma
Indapamide nephrogenic diabetes cholesterol and
Chlorthalidone insipidus triglycerides
Sulfa sensitivity,
Photosensitivity, skin
rash
Hypercalcemia
Potassium-sparing Uses: Antagonize
Late distal tubule and Spironolactone is an aldosterone during
collecting duct aldosterone antagonist renin-angiotensin
and androgen hypertension and
Spironolactone and congestive heart failure.
antagonist.
Eplerenone (less Combine with Loops or
androgenic) Thiazides to offset
Triamterene and
Amiloride and hypokalemia.
amiloride
Triamterene Block sodium
transport, and retain Tox: Hyperkalemia and
potassium. Acidosis
Osmotic It is filtered at the Tox: Hyponatremia and
Mannitol glomerulus but poorly acute hypovolemia.
reabsorbed from the Hypotension
tubule. Thus mannitol
Use: Cerebral edema,
holds water in the
renal failure maintain
lumen by virtue of its
volume, dilute toxic
osmotic effect.
drugs.
5
Use: Both reduce urine vasopressin, not
volume. Desmopressin desmopressin.
preferred for
nephrogenic diabetes
insipidus no
vasoconstriction. V2
only.
6
Mechanisms for Side Effects of Diuretics
Nephron NaCl
Blood
Blood
Cell HOH
Na+ Na+
Na+
K+,H+
K+, H+ K+,H+
Hypokalemia Urine
Alkalosis
8
E. Hypovolemia and Hyponatremia (Loops and Thiazides)
These drugs enter the nephron via the organic acid excretion site in
the proximal tubule. That is where organic acids from filtered plasma
must enter the nephron, as well. Competition for these sites causes
accumulation of uric acid, causing hyperuricemia and contributing to
exacerbation of gouty arthritis. Other acids that do this: Lactic acid
during alcohol metabolism. Salicylic acid following deacetylation of
acetylsalicylic acid (aspirin). Gout-related ankle pain can become
worse when alcohol or aspirin are used to suppress the symptoms.
9
ANGIOTENSIN CONVERTING ENZYME INHIBITORS
ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) and ALISKIREN
Here are two classes of drugs which are used to treat high blood pressure and
congestive heart failure. The ACE inhibitors (ACEI) prevent synthesis of
angiotensin II while preserving bradykinin. Angiotensin II antagonists block
the receptor. The value of these drugs lies in their focus on a system that
offers compensatory regulation of vascular resistance, extracellular water
volume and the sympathetic nervous system.
ACE Inhibitors
ACE Inhibitor Subclass The ACE Inhibitors
ACTIONS OF ANGIOTENSIN II
10
conservation of sodium at the renal collecting tubule produces increased
extracellular and blood volume, and may cause loss of potassium.
ACTIONS OF BRADYKININ
11
POTENTIAL TOXICITIES OF THE ACE INHIBITORS
3. Acute renal failure is associated with ACE inhibitors in patients with bilateral
renal artery stenosis.
1. Pregnancy (second and third trimester). These drugs risk fetal renal failure and
hypotension.
These drugs are angiotensin II antagonists at the AT-1 receptor, and can be used to
prevent or reverse AII actions at all sites of angiotensin action. Primary usefulness
is antihypertensive with some benefits seen in diabetic nephropathy and congestive
heart failure.
12
Side Effects: Because bradykinin is inactivated in the usual way, some side
effects associated with ACE inhibitors are not seen. No angioedema, no cough.
This is an advantage in some patients. All other actions listed for ACE Inhibitors
are seen with ARBs.
RENIN ANTAGONIST
Aliskiren
Vasodilators
Drug MOA Use Toxicity
Hydralazine Unknown Powerful Hypotension, headache,
Arteriole decrease in dizzy, high HR, chest pain,
Blood Pressure Drug-induced lupus
Minoxidil Open K+ Same Never alone due to potent
Channel hypotension and reflexive
Arteriole tachycardia, chest pain
Use with Beta Blocker
Hypertrichosis
Diazoxide Open K+ Same Hypotension, tachycardia,
Channel chest pain, hyperglycemia
Arteriole (see open K+ channel in
Beta Islet Cell)
Hypertrichosis
Sodium Nitric Oxide Unstable, short- Many of the above, except
Nitroprusside (NO) acting, iv for no hair growth. Mostly
Venules high BP low BP, high HR, dizziness,
Arterioles emergency. headache.
Fenoldopam D1 agonist Improves
Decreases
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arteriolar
resistance
14
NITRATES Same Atypical Note: MOA, USE
Long acting (hrs): Prinzmetals and TOXICITY
Nitroglycerin, oral Stop for all
6-8 coronary NITRATES are
Nitroglycerin, dermal spasm the SAME.
3-10
Isosorbide dinitrate, oral
2-6
Isosorbide mononitrate
6-10
BETA BLOCKERS Adrenergic Typical Fatigue
Non-Selective: Beta-1 Angina
Propranolol Receptor Only Drowsiness
Nadolol Less CNS Blocker Avoid in:
depression. (Also Beta-2)
Asthma Cardiac
Pindolol (ISA) No Diabetes depression
rebound, less Decrease HR, Peripheral
cardiodepression. SV Vascular AV Node
(Heart Work) Dis. depression
ARRHYTHMIAS
2. Identify the main ions that are associated with the phases of the
action potential in the pacemaker and in the Purkinje system.
7. Describe afterdepolarizations.
9. Characterize reentry.
17
Phase 0 Initiated by opening of sodium channels and entry of sodium into the cell via ion
channels and down a concentration gradient.
Phase 2 Calcium channels open and allow calcium entry via ion channels down the concentration
gradient.
Phase 3 Potassium channels open as calcium channels are closing, thereby creating the Phase 2-3
"shoulder". Most of Phase 3 is due to K+ conductance via ion channels
down a concentration gradient.
Phase 4 Potassium remains the major conductive ion as the sodium-potassium pump resets the
concentration gradient for each ion. Also, the Na+-Ca++ antiporter is busy re-
establishing the appropriate Ca+ concentrations.
NOTE: This is a busy phase for the cell, even though it is known as a "resting" phase. The
N+, K+ and Ca++ gradientn are re-established and maintained. A
pacemaker cell, such as SA or AV node, or even a Purkinje cell, is also
busy during Phase 4. This is the spontaneous depolarization phase for
these cells, wherein Ca++ "leaks" across the membrane, depolarizing the
cell until it reaches threshold and spontaneously fires itself. Because the
SA node does this first, it remains the only functional pacemaker in a
normal heart.
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19
20
21
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ANTIARRHYTHMIC DRUGS
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Ib Phenytoin Increases AV Nodal conduction. So, possible for
Digoxin tox. Dig. Causes AV depression and V.
extrasystole, tachycardia.
Ic Flecainide, Very potent Na blockers. Limited usefulness,
Encainide and My cause Ventricular except in very short
Moriczine Arrhythmias. duration.
24
Class IV CALCIUM CHANNEL BLOCKERS
Class Drugs Usefulness/Actions Toxicity
IV Verapamil Block calcium channel AV depression
Diltiazem in arteriole, SA, AV, SA asystole
Ventricle. Constipation
Vasodilation, no reflex. Dizzy-low BP
Suppress rate of
conduction at AV node,
protect ventricle during
atrial arrhythmias.
Drug of choice vs AV
origin atrial
tachycardia.
SPECIAL CLASS
Drugs Usefulness Toxicity
Digoxin AV Nodal Depressant Ventricular extrasystoles
Used to protect Ventricle leading to V. tach and fib.
from Atrium during A. AV nodal block
tach, and A. fib. when a
drug may unload the AV
Node.
Adenosine Action = 8 sec. iv to stop Bronchoconstrictor, cough.
A. tach due to reentry in Anti-asthmatic theophylline is
AV Node. an adenosine antagonist
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ANTIARRHYTHMIC CLINICAL APPLICATION OVERVIEW
1. Impulse-conducting pathways (sodium channel depolarizing cells) in
atrium or ventricle respond to Class I and to Class III. Most
tachycardia is a reentry of the wall in atrium or ventricle. Sodium
channel blockers decrease depolarization velocity and stop the rapid
response to a repeat signal. Potassium channel blockers expand the
Action Potential Duration (APD) to increase Effective Refractory
Period (ERP). The cell is not ready to fire when adjacent cell action is
taking place. In both cases, the rapid recycling of action is extinguished.
2. Arrhythmias of calcium conductance depolarization in SA Node and
AV Node respond to drugs in Class II and Class IV. The nodal
pacemaker tissues depolarize slowly via calcium conductance, driven by
Beta-1 agonists and suppressed by Beta-1 blockers and calcium channel
blockers. Muscarinic agonists also suppress these sites by stimulating
K+ conductance.
3. The Sympathetic Nervous System acts via Norepinephrine at Beta-1
receptors, causing increase in Heart Rate at SA Node, increase in AV
conduction velocity at AV Node and increased ventricular contractility
and arrhythmias. All of these are suppressed by Class II Beta Blockers.
ATRIAL ARRHYTHMIAS
1. Digoxin is used to protect the ventricle by causing AV nodal depression.
Also verapamil or a Beta-Blocker.
2. Ectopic focus or active sites are sodium depolarization actions and are
suppressed by Class Ia.
3. Reentry in the atrium wall is a conducting pathway. Blocked by Class
Ia or by Class III.
SUPRAVENTRICULAR TACHYCARDIA
1. AV Node reentry. AV nodal depressants stop the recycling action:
verapamil (IV), propranolol (II), digoxin or adenosine.
2. AV Node Reciprocating with the Accessory Pathway, Wolff-Parkinson-
White. Avoid AV nodal depression. Avoid the drugs in 1. Use
procainamide (Ia) or cardioversion.
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PREMATURE VENTRICULAR CONTRACTIONS (PVC)
1. Extra Systoles, Early After Depolarizations (EADs), Delayed After
Depolarizations (DADs).
2. Caused by high calcium via digoxin or SANS, high sodium via
aldosterone or low potassium via diuretics.
3. Stop and prevent with lidocaine (Ib) or amiodarone (III).
4. Use Beta Blockers (II) if a high Sympathetic NS Activity as in
hyperthyroidism.
VENTRICULAR TACHYCARDIA
1. Ectopic depolarizations or a reentry in a conducting circuit.
2. Life threatening, use cardioversion.
3. Lidocaine (Ib)
4. Class Ia or Class III
VENTRICULAR FIBRILLATION
1. Cardioversion to synchronize depolarizations.
2. Stabilize with Class Ib, Ia or III.
DIGITALIS-INDUCED ARRHYTHMIAS
1. Phenytoin (Ib) increases AV conduction against digoxin-induced AV
depression. It also suppresses extrasystoles.
2. Procainamide (Ia) has no AV nodal action. Therefore, no added AV
nodal depression and suppression of extrasystoles.
3. Must avoid AV depressants: Class II, Class III (Class II and IV
activity), Class IV and adenosine.
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What About Digoxin and Adenosine?
1. Digoxin is antiarrhythmic because it suppresses AV Node.
2. Protects Ventricle. # 1 job in cardiology.
3. Adenosine, injectable, super short action, stops AV Node reentry right
now.
4. Bronchial irritant.
SYMPATHOLYTICS
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Alpha-1 Adrenergic Agonists
Agonist Receptor Actions Uses
Norepinephrine Alpha-1, Beta-1 Vasoconstrictive increase in blood
pressure.
Epinephrine Alpha-1, Beta-1, Beta-2 Vasoconstrictive benefit to retain local
anesthetics in the injection site. Other
uses are Beta-1 and 2 related.
Ephedrine Alpha-1, Beta-1, Beta-2 Vasoconstrictive decongestant in past;
as herb, included in weight-control
mixtures, now banned due to Beta-1
cardiac toxicity.
Pseudoephedrine Alpha-1, Beta-1 Vasoconstrictive decongestant
Phenylephrine Alpha-1 Vasoconstrictive decongestant
Vasoconstrictor in cases of hypotension
due to anesthesia in surgery. Raise BP
Methoxamine Alpha-1 Vasoconstrictor in cases of hypotension
due to anesthesia in surgery. Raise BP
Alpha-1 Adrenergic Antagonists
Antagonist Receptor Actions Uses
Prazosin, Doxazosin Alpha-1 Anti hypertensive
Terazosin Alpha-1 Anti hypertensive
Benign Prostatic Hypertrophy (BPH)
Tamsulosin, Alfuzosin Alpha-1 Benign Prostatic Hypertrophy (BPH)
Phentolamine Alpha-1, Alpha-2 Diagnostic for
Short-acting, Pheochromocytoma Management
Phenoxybenzamine Alpha-1, Alpha-2 Management of Pheochromocytoma
Long-act.,
30
Alpha-2 Adrenergic Receptor Antagonists
Antagonist Receptor Actions Uses
Yohimbine Alpha-2 Improve SANS
Phentolamine Alpha-1, Alpha-2 Anti hypertensive
Alpha-2 block increases
reflexive tachycardia
when BP becomes too
low
Phenoxybenzamine Alpha-1, Alpha-2 Anti hypertensive
Alpha-2 block increases
reflexive tachycardia
when BP becomes too
31
Beta-1 and 2 Adrenergic Agonists (Nonselective)
Agonist Receptor Actions Uses
Norepinephrine Alpha-1, Beta-1 Vasoconstrictive increase in blood pressure.
Epinephrine Alpha-1, Beta-1, Beta-2 Vasoconstrictive benefit to retain local
anesthetics in the injection site. Cardiac
Stimulant (Beta-1). Bronchodilator (Beta-
Ephedrine Alpha-1, Beta-1, Beta-2 Vasoconstrictive decongestant in past; as herb,
included in weight-control mixtures, now
banned due to Beta-1 cardiac toxicity. Some
use as a long-acting bronchodilator (Beta-2)
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Beta-1 Adrenergic Antagonists (Cardioselective)
Antagonist Receptor Uses
Atenolol Beta- Antihypertensive, Antianginal
Metoprolol Beta- Antihypertensive, Antianginal
Acebutolol Beta- Antihypertensive, Antiarrhythmic
33
Nicotinic Antagonist (Ganglionic Blocker)
34
Muscarinic M-2 Receptors
Site of Action Receptor Stimulation Receptor Blockade
Cardiac Slowed rate of Allows increased heart
Pacemaker SA pacemaker depolarization, rate
Node lower heart rate
Cardiac AV Allows increased
Slowed rate of impulse
Node impulse conductance
conductance A to V.
A to V.
35
Muscarinic Antagonists (M-2, M-3)
Antagonist Receptor Uses
Actions
Atropine M-2, M-3 Opthalmic: Mydriasis and
Plus Cycloplegia. GI, Bladder
others relaxation.
Counteracts Anticholinesterase
Tropicamide M-3 Opthalmic: Mydriasis and Cycloplegia.
Cyclopentolat
e
Scopolamine M-3 Motion sickness
Ipratropium M-3 Bronchodilator in asthma and COPD
37
Antiplatelet Aspirin Acetylates
COX GI distress,
Clopidogrel bleeding
Blocks ADP
Abciximab
Heparin: reverse bleeding with protamine sulfate; Warfarin use vitamin K
B. Control of Arrhythmias
1. Acute MI can be accompanied by ventricular extra-systoles,
which can become ventricular tachycardia or fibrillation. Class lb
lidocaine is short-acting, iv administered, relatively non-toxic
drug that effectively suppresses arrhythmias in ischemic ventricle.
Class III, amiodarone is also useful.
38
1. Volume Management. Reduction of intravascular volume can
decrease left ventricular filling pressure. Furosemide can rapidly
improve vascular compliance, increasing venous capacitance,
reducing venous return and ultimately decreasing ventricular filling
pressure.
39
D. Low Blood Pressure and Low Cardiac Output. Shock Syndromes. This is
acute heart failure with high ventricular filling pressure. The goals are to
improve cardiac output and to reduce venous volume and pressure.
40
E.. Right Ventricle Infarction and Failure. Low blood pressure and low
cardiac output. This problem is focused on the right ventricle and its inability
to move sufficient blood volume to the left ventricle, allowing cardiac output
and blood pressure to suffer. The goal in this area is to improve left ventricle
filling pressure.
1.Volume replacement. Adding circulating volume can drive volume and pressure
through the ineffective right ventricle to the left side of the heart,
improving cardiac output and blood pressure.
41
CONGESTIVE HEART FAILURE
Drug MOA Use Toxicity
Thiazide Diuretics Block sodium Loss of body Hypokalemia
recovery at Distal water. Resolve Alkalosis
Hydrochlorothiazide Convoluted peripheral Hyperuricemia
Chlorthalidone Tubule. Sodium edema, lung Hyperglycemia
Indapamide and water congestion and Hypercalcemia
diuresis. expanded blood
volume.
Loop Diuretics Block sodium Rapid loss of Hypokalemia
Furosemide recovery at body water. Alkalosis
Torsemide ascending Loop Resolve Hyperuricemia
Bumetanide of Henle. peripheral Hyperglycemia
Ethacrynic Acid Sodium and edema, lung Hypocalcemia
(No S, Ototox.) water diuresis. congestion and
expanded blood
volume.
Potassium Sparing Aldosterone Stops volume Hyperkalemia
diuretics Antagonist expansion by Acidosis
Block sodium Aldosterone as
Spironolactone recovery at it drives
Eplerenone collecting tubule, recovery of
less potassium sodium and
loss in exchange water at
collecting
tubule.
Potassium Sparing Not Aldo. In combination, Hyperkalemia
diuretics Antagonist they counteract Acidosis
Block sodium hypokalemia of
Amiloride recovery at Loop and
Triamterene collecting tubule, Thiazide
less potassium diuretics.
loss in exchange.
ACE Inhibitors Block Decrease Hypotension
Prils Angiotensin II vascular Hyperkalemia
Captopril synthesis resistance and Cough
Lisinopril aldosterone Angioedema
Enalapril Retain release
Ramipril Bradykinin (BK) (Volume
42
expansion).
Add a
vasodilator.
ARBS Block Relieve effects Hypotension
Sartans Angiotensin II of angiotensin II Hyperkalemia
Losartan Receptors and aldosterone (Advantage: No
Valsartan BK)
Vasodilators Arteriolar Relieve Cardiac Hypotension
vasodilator workload:
Hydralazine Afterload
Venular dilation
Isosorbide dinitrate Preload
Beta Blockers Beta-1 Suppress high Heart Failure
Antagonists heart rate and Cardiodepressant
Atenolol potential for V. AV Nodal
Metoprolol arrhythmias Depression
43
(Alpha-1: NE,
Epi)
Phosphodiesterase Increase cAMP, Improve
Inhibitors Beta-1 cardiac cardiac
signal contractility
Inamrinone
Milrinone Cardiotonic
Brain Natriuritic cGMP Lower Preload
Peptide (BNP) Relax Smooth and Afterload
Muscle
Nesiritide Vasodilate IV short-term
Arterioles and
Venules
44
ANTIHYPERTENSIVE THERAPY
The Eighth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) provides
the current guideline for hypertension prevention and management. It supplements JNC7,
which has a comprehensive recommendation. The following are the reports key
messages:
In persons older than 60 years, the guideline is to maintain BP less than 150/90
mmHg. Younger than 60, the goal is less than 140/90 mmHg. For all patients with
kidney disease or diabetes, goal is 140/90 mmHg.
45
Drugs Used For Hyperlipidemia
Drug Use MOA Toxicity
BILE ACID RESINS LDL-C blood Bind bile acids in Nausea, bloating, constipation or
levels decrease the gut and diarrhea. These drugs have a gritty
Cholestyramin 30%. prevent their texture and must be mixed well in 8
eColestipol resbsorption. ounces of water.
Colesevalam Not to be used in Interfere with drug and vitamin
patients with These drugs are absorption:
high not absorbed. thiazides, digoxin, warfarin, estrogens,
triglycerides and fat-soluble vitamins. Drugs and
Oral vitamins must be spaced several
Bioavailability is hours when giving a bile acid resin.
zero
Effective against Decreases Intense flushing and itching, which is
hypertriglyceridem production of reversible and preventable with
NIACIN ia VLDL in the liver. aspirin. Peptic ulcer, Hyperglycemia,
Hyperuricemia (gout).
Decreases VLDL Myositis and
(TG) assembly. Rhabdomyolysis can also occur.
HMG CoA Circulating HMG CoA Hepatic toxicity (increased liver function
REDUCTASE LDL-C reductase is the tests)
INHIBITORS decreases by rate-limiting step Myopathy, and
25- 45%. in cholesterol Rhabdomyolysis.
Lovastatin, synthesis by liver. Drug interactions: enzyme inhibitors
Simvastatin, Statins The statin drugs (erythromycin, ketoconazole) and
Pravastatin, stimulate and competitively grapefruit juice may increase levels and
Fluvastatin, increase LDL bind this enzyme toxicity of the Statin drug. These drugs
Atorvastatin, receptors. and decrease should never be used in pregnancy.
Rosuvastatin LDL
FIBRATES Triglyceride PPAR-alpha Myositis, gallstones, and liver toxicity.
levels decrease by agonist which (Especially when given with a statin
Gemfibrozi 35%. Degrade drug).
increases
lFenofibrat VLDL(TG). lipoprotein lipase
e
activity.
Fibrates
degrade VLDL-
triglycerides.
Inhibitor of intestinal Reduction of LDL Inhibits Small increase in hepatic dysfunction
sterol absorption intestinal when given with a statin drug.
absorption of GI distress
Ezetimibe (Zetia) cholesterol and
For homozygous Oral availability
familial Inhibits VLDL
Lomitapide
hyperlipidemia, assembly
LDL over 500
46
For homozygous Injected weekly
familial Inhibits apoB
Mipomersen
hyperlipidemia, synthesis
LDL over 500
47