Antiarrhythmic Drugs

PRESENT BY:
1. ALICIA KUAN LEE CHING 1507591
2. ANG YONG XIN 1403680
3. CHAN CHUN KEAT 1503102
4. LEE SU XIAN 1507723
UDDD3224 PHARMACOLOGY 5. SOH KAE SIANG 1507031
Cardiac arrhythmia
 Irregular pattern of heartbeat or changes in the
sequence of electrical impulses

 Different types of arrhythmias available:

1. Tachycardia
2. Bradycardia
3. Atrial or ventricular fibrillation
4. Conduction disorders
5. Premature contraction
Factors that caused Arrhythmias
 Smoking
 Heavy alcohol use
 Drugs abuse
 Excessive coffee consumption
 Emotional stress
 Congenital heart defects
 Coronary heart disease
 Heart failure
Complications of
Arrhythmias
 Stroke
- Blood clots happen as the heart is not pumped properly
- Block the brain artery once the blood clots dislodges
 Heart failure
- Prolonged tachycardia or bradycardia
- Blood volume is not sufficient to pump to the body and
organs
Class I
Antiarrhythmics
Mechanism of Action

 Sodium channel blocker

Mechanism of Action

 Blocks fast sodium ion channel

which are responsible for rapid
depolarization (phase 0) of
fast response cardiac action
potentials.
 Result decrease amplitude of
action potential.
 Used to suppress tachycardia
Blocks Na+ ion Decrease action
(higher heart rate). channel potential amplitude
 Classification

Class 1A Class 1B Class 1C

 Classified
based on
electrophysiologic effects
 Refinement of the Vaughan
Williams classification system
Comparison of Class IA, IB and IC
 Three classes have different efficacy
for reducing the slope of phase 0.
(Greatest) IC > IA > IB (Lowest)

 Effective refractory period (ERP) -

related to drug actions on
potassium channels involved in
phase 3 repolarization of action
potentials.
(Greatest) IA > IC > IB (Lowest)
Normal ECG
wave
Classes Example Effect Pharmacodynamics

Class Procainamide Increase QRS interval Blocks sodium channel

IA Hydrochloride (Intermediate) Intermediate potassium channel block
Quinidine Gluconate Increase QT interval Prolong repolarization and refractoriness of
Disopyramide Phosphate isolated myocardial tissue
Block rapid inward sodium current

Class Lidocaine Hydrochloride Increase QRS interval Blocks sodium channel

IB Mexiletine Hydrochloride (Weakest) Rapid kinetics
Increase QT interval Shorten action potential
(weaker than IA) Modest inhibition to rapid sodium inward
current

Class Flecainide Acetate Increase QRS interval Blocks sodium channel

IC Propafenone (Strongest) Slow kinetics
Hydrochloride Slows down conduction
Little effect on repolarization
Routes of administration, Pharmacokinetics and Toxicity
Class IA
Class Route of Pharmacokinetics Toxicity
administration & t1/2

Class IA
- Procainamide Oral, Intravenous, 99% metabolized to N- Hypotension
Hydrochloride Intramuscular acetyl-procainamide Long term therapy leads to reversible
(3-5 hours) (hepatic) (CYP2D6) lupus-related symptoms
Renal elimination

- Quinidine Oral 85% metabolized to 3- Headaches, dizziness and tinnitus

gluconate (2-3 hours) Hydroxyquinidine Idiosyncratic and immunologic
reaction (rare)

- Disopyramide Oral 40-60% metabolized to Heart failure in patient with pre-existing

Phosphate (6-9 hours) N-desisopropyl depression of ventricular function
disopyramide Symptomatic adverse effect (Urinary
retention, dry mouth, blurred vision,
constipation)
Routes of administration, Pharmacokinetics and Toxicity
Class IB
Class Route of Pharmacokinetics Toxicity
administration & t1/2

Class IB
- Lidocaine Intravenous 95% metabolized to Adverse effect similar to
Hydrochloride Oral (extensive monoethylglycine local anesthetic which
first pass effect) xylidide and glycine are neurologic
(1.5-2 hours) xylidide

- Mexiletine Oral 80% metabolized to Adverse effect is

Hydrochloride (8-17 hours) monoethylglycine neurologic including
xylidide and glycine tremor, blurred vision,
xylidide (inactive) lethargy and nausea
Routes of administration, Pharmacokinetics and Toxicity

Class IC
Class Route of Pharmacokinetics Toxicity
administration
and t1/2
Class IC
- Flecainide Oral Undergo hepatic and Proarrhythmic effect
Acetate (20 hours) kidney metabolism

- Propafenone Oral 99% metabolized to 5- Adverse effect such as

hydrochloride (3-8 hours) Hydroxypropafenone metallic taste,
constipation and
arrhythmia exacerbation
Class II
Antiarrhythmics
β-Adrenoceptor Blocking Drugs
 Examples:

 Propranolol

 Esmolol

 Not widely used - relatively small effect

 Route of Administration

 IV

 Orally
Mechanism of Action
 Beta-blockers divided into two classes:
 non-selective blockers (block both β1and β2 receptors)

 selective β1 blockers

 Depend on the specific mechanism of individual arrhythmia

 reentry and promoted by decreased conduction velocity and shortened
refractoriness

 tachycardia and ischemia

 early or delayed after-depolarizations

Propranolol
 Prototype of the beta-adrenergic receptor antagonists

 Competitive, non-selective beta-blocker without intrinsic

sympathomimetic activity

 L-isomer is responsible for adrenergic blocking activity

 Competes with sympathomimetic neurotransmitters

1. binding at beta(1)-adrenergic receptors in the heart

2. inhibiting sympathetic stimulation

 Propranolol
 Almost fully absorbed from the gastrointestinal tract.

 Plasma concentrations attained are quite variable

among individuals.

 The bioavailability through oral administration

yielded only 25 ± 8%.

 The half-life is 4 hours.

 The metabolism of propranolol

 N-desisopropylpropranolol → CYP 1A2

 4'-hydroxypropanolol → CYP 2D6

Side Effects and Toxicity
Side Effects and Toxicity
Side Effects and Toxicity
Side Effects and Toxicity
Class III
Antiarrhythmics
Class III Antiarrhythmics
(K+ channel blockers)

Amiodarone

Dronedarone
Ibutilide
Class III

Dofetilide Sotalol
Mechanism of Action (Amiodarone)
 inhibit K+ channels (block IKr)
→ prolong QT interval
→ prolong ventricular action
potential
→ prolong effective refractory
period (ERP)
Pharmacokinetics

• bioavailability 35-65%
• t1/2 = extremely long (weeks)
Amiodarone (distributes extensively in adipose tissue)
• metabolized by CYP3A4

• bioavailability ~4% (with high fat meal ~15%)

Dronedarone • t1/2 = 24 hr
 Toxicity & Side Effects
(Amiodarone)

Torsades de pointes
Gray-blue
discoloration
Hypothyroidism/
Pulmonary fibrosis hyperthyroidism

Bradycardia
Optic neuropathy
(corneal deposits)
Hepatotoxicity
Class IV
Antiarrhythmics
Class IV Antiarrhythmics
(Ca2+ channel blockers)
Verapamil Diltiazem
Pharmacokinetics
• half-life of 4–7 hours

Verapamil • bioavailability ~ 20% (after liver metabolism)

• IV route, initial 5 mg over 2–5 minutes,
followed by second 5 mg few minutes later.
After that, doses of 5–10 mg can be given
every 4–6 hours, or a continuous infusion of
0.4 µg/kg/min may be used
• Oral route, 120 mg to 640 mg daily,
separated into 3-4 doses
Verapamil
• blocks inactivated &
activated L-type
calcium channels
• slows nodal conduction
• Increase PR interval
• suppresses
afterdepolarizations
Toxicity & Side Effects
 Hemodynamic collapse
 Ventricular fibrillation

 AV block
 Peripheral oedema
 Lassitude
Other
Antiarrhythmic
Drugs
Other Antiarrhythmic Drugs

Magnesium
Adenosine
Sulphate
Adenosine

Mechanism of Actions
 Adenosine receptors
- A1 (Atria)
- A2A (Coronary Blood Vessels)
 Activate inward rectifier K+ current
Inhibit calcium current
- Suppress calcium dependent action potentials
Route of Administration Pharmacokinetics
 Intravenous
Half Life

Pharmacodynamics <10
 Antagonist seconds

Block A1 receptors  Present of adenosine

deaminase
Side Effects
Decreased:
1. AV 1. Shortness of breath
conduction
2. Firing of SA 2. Chest burning
and AV nodes 3. Atrial ventricular
(AV) blockage
Dilation of blood
4. Atrial fibrillation
vessels
Magnesium Sulphate
Mechanism of Actions
 A crucial role:
1. Resting membrane potential
2. Repolarization phase (cardiac pacemaker and non-pacemaker
action potentials)
 Interacts with:
1. Na+/K+-ATPase
2. Sodium channels
3. Potassium channels
4. Calcium channels
 Route of Administration Pharmacokinetics
 Intravenous Duration
 Intramuscular
• Intravenous:
Pharmacodynamics ~30 min
• Intramuscular:
between 3-4 hrs
Anticonvulsant Electrolyte
replenisher
drug Side Effects
Treat
Relieve muscle
pre-eclampsia Overdose Adverse effects
contraction
and eclampsia
in pregnant
women Muscle • Depression in CNS
weakness and respiratory
• Changes in ECG
• Diarrhea
• Urinary retention
• Hypotension
Conclusion  Different drug affects different ion
channels.
Class I

• Na+ channel blockers  Caution has to be taken before the

administration of the drug into
Class II
patients, especially those with pre-
• β-receptor blockers
existing disease.
Class III
 Adverse effects could also occur and
• K+ channel blockers
therefore dosage has to be
Class IV
controlled.
• Ca2+ channel blockers
THANK YOU
Electrophysiologic effects
 Electrophysiologic effects is the study of the electrical
properties of biological cells and tissues. It involves
measurements of voltage changes or electric current or
manipulations on a wide variety of scales from single ion
channel proteins to whole organs like the heart.

 the study of the production of electrical activity and the

effects of that electrical activity on the body.
 Proarrhythmic effect

 Defined as 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
Torsades de pointes

 Torsades de pointes is a specific form of polymorphic

ventricular tachycardia in patients with a long QT interval.
 It is characterized by rapid, irregular QRS complexes, which
appear to be twisting around the ECG baseline.
 This arrhythmia may cease spontaneously or degenerate into
ventricular fibrillation.
 Due to medications and electrolyte disorders such as
hypokalemia and hypomagnesemia)
Nystagmus
 Due to lidocaine toxicity
 vision condition in which the eyes make repetitive,
uncontrolled movements.
 result in reduced vision and depth perception and can
affect balance and coordination
 can occur from side to side, up and down, or in a
circular patterned coordination.