Antiarrhythmic Drugs

Dr Asmatanzeem Bepari
Assistant Professor of Pharmacology,

By the end of this lecture, the student should be able to

1. Outline the classification of antiarrhythmic drugs.
2. Describe the mechanisms of action of antiarrhythmic drugs.
3. Describe the pharmacological actions of antiarrhythmic drugs.
4. List the major side effects and therapeutic uses of antiarrhythmic
drugs.
PHYSIOLOGICAL CONSIDERATIONS

Autonomic Control
Cardiac Conduction
ARRHYTHMIA
¢ Definition: Abnormal cardiac rhythm, with change in rate or

regularity, monitored by electrocardiography (ECG)

¢ Symptoms in cardiac arrhythmias: Palpitations, dizziness,

syncope

¢ Classification of arrhythmias, according to:

— Site of origin of the abnormality: Atrial, junctional or ventricular.

— Rate:

¢ Tachycardia (↑) increase heart rate

¢ Bradycardia (↓) decrease heart rate

AIM OF ANTIARRHYTHMIC DRUGS

¢ To decrease automaticity of ectopic pacemakers more

than that of SA node.

¢ To reduce excitability and increase refractory (more in

depolarized than in normally polarized tissue).

¢ To selectively block sodium or calcium channels of

depolarized cells.
CLASSIFICATION OF ANTIARRHYTHMIC DRUGS

¢ Class I: Sodium Channel Blockers

— IA: Increase duration of action potential. Example: Quinidine,

Procainamide

— IB: Decrease duration of action potential. Example: Lidocaine

— IC: No effect on duration of action potential: Example: Flecainide

¢ Class II: Beta Adrenergic Blocker: Example: Propranolol,

Sotalol

¢ Class III: Potassium Channel Blockers: Example: Amiodarone

¢ Class IV: Calcium Channel Blocker: Example: Verapamil

¢ Others: Miscellaneous group: as Adenosine and Digitalis

CLASS I ANTIARRHYTHMIC DRUGS
Na+ channel blockers,

- block open state Na+ channel , therefore suppress A-V conduction and

prolong refractoriness.

- These actions serve to abolish ectopic pacemakers

- They are “use dependent or state dependent” in their action

(ie, they selectively depress tissue that is frequently depolarizing; or tissue that
is relatively depolarized during rest, eg, by ischemia).

Class 1A: Example: Quinidine, Procainamide

¢ Increase duration of action potential

¢ Have K+ channel blocking effect (nonspecific blockade of potassium

channels- class 3)

¢ Antimuscarinic & hypotensive effects

CLASS 1A: QUINIDINE:
n Decrease automaticity of ectopic pacemakers more than that of SA node

n Reduce conduction and excitability

n Increase refractory period (more in depolarized tissue than in normally

polarized tissue)

n Selectively block sodium of depolarized cells

Side effects of Quinidine

n Most common are:

n Diarrhea, Nausea, Vomiting

n Antimuscarinic actions.

n Neurological effects like ringing in ears, vertigo, deafness, visual

disturbances and mental changes (Cinchonism)

n Arrhythmias: therefore now it is rarely used

 Class 1A: Procainamide:
n Therapeutic Use:

Treatment of sustained ventricular arrhythmias associated with

acute myocardial infarction as second or third choice (after

amiodarone or lidocaine) in most coronary care units.

n Toxicity:

QT-interval prolongation, and induction of torsades de pointes

arrhythmia and syncope.

Chronic therapy causes: a syndrome resembling lupus

erythematosus and usually consisting of arthralgia and arthritis

Other adverse effects include nausea and diarrhea

CLASS 1B: LIDOCAINE:

n Cause suppression of automaticity in ectopic foci.

n Antagonize enhanced phase-4 depolarization in partially

depolarized or stretched PFs, and after-depolarizations

n Shorten the duration of action potential & refractory period.

n Lidocaine decreases APD in PF and ventricular muscle, but has

practically no effect on APD and ERP of atrial fibres.

n Effective in ventricular arrhythmias associated with cardiac

ischemia (myocardial infarction).

n PK: Must be given intravenously/ IM due to high first-pass

hepatic metabolism when given orally.

 CLASS 1B: LIDOCAINE:

n Side effects:

¨ Neurological effects: Drowsiness, twitchings convulsions

¨ Arrhythmia

¨ Hypotension

Therapeutic Use:

Drug of choice for termination of ventricular tachycardia

and ventricular fibrillation in the setting of acute

myocardial ischemia
 CLASS 1C: FLECAINIDE:

n Has no effect on duration of action potential & refractory period.

n most potent Na+ channel blockers with more prominent action on

open state and the longest recovery times (> 10S).

n Used for treating supraventricular arrhythmias.

n Pro-arrhythmic.

n Worsens heart failure and increase mortality in myocardial

infarction.
CLASS II ANTIARRHYTHMIC DRUGS

¢ Beta-adrenergic blockers: example: Propranolol

Heart Sympathetic Parasympathetic

Chronotropy (rate) +++ ___

Inotropy (contractility) +++ _

Dromotropy
++ ___
(conduction velocity)
CLASS II: BETA-ADRENERGIC BLOCKERS
¢ Beta-blockers decrease sympathetic effect, leading to decrease heart

automaticity and conductivity (prolong ERP of A-V node)

¢ Esmolol, a very short-acting β blocker for intravenous

administration, is used in acute arrhythmias.

¢ Propranolol, metoprolol, are used chronically to prevent

arrhythmias.

¢ Indications:

— Supraventricular (PSVT) and ventricular arrhythmias

— Decrease mortality in myocardial infarction

— Prophylaxis against recurrent tachyarrhythmias caused by

increased sympathetic activity.

CLASS III: POTASSIUM CHANNEL BLOCKERS
¢ Example: Amiodarone

¢ Pharmacological actions:

— Prolongs duration of action potential by blocking K+ channels.

— Also block sodium channels.

— Partially inhibits myocardial Ca2+ channels, has noncompetitive β

adrenergic blocking property

— Slows sinus rate and atrioventricular conduction

— Causes peripheral vascular dilation.

The broad spectrum of actions account for its relatively high efficacy
CLASS III: POTASSIUM CHANNEL BLOCKERS

¢ Side effects of Amiodarone:

— Nausea, gastrointestinal upset

— Thyroid disorders: Hypo- or hyperthyroidism.

— Photosensitization and sun burn like skin pigmentation

— Pulmonary fibrosis that may be fatal.

— Peripheral neuropathy

— Corneal microdeposits
 CLASS III: POTASSIUM CHANNEL BLOCKERS

¢ Drug interactions of Amiodarone:

— Cytochrome P450 enzyme inhibitor and may result in high levels of

drugs, Eg: statins, digoxin, and warfarin.

— The dose of warfarin should be reduced by one third to one half

following initiation of amiodarone, and prothrombin times should
be closely monitored.

¢ Pharmacokinetics:

— Extremely long half-life. Toxicity may persist after drug is stopped.

¢ Therapeutic uses: Atrial Fibrillation is most common use

— Also other Ventricular and supraventricular arrhythmias,

including PSVT, Atrial Flutter

CLASS IV: CALCIUM CHANNEL BLOCKERS
¢ Example: Verapamil

¢ Their effect is more marked in tissues that:

— Depend on calcium current for firing, as SA and AV nodes.

— cause a state- and use-dependent selective depression of calcium

current

¢ Directly slows SA node and prolongs AV conduction.

¢ Side effects:

— AV block, sinus arrest and cardiac failure.

— Constipation and peripheral edema.

¢ Therapeutic uses:

— Supraventricular tachycardia: nodal arrythmias

— Reduces ventricular rate in atrial fibrillation (AF).

OTHERS: ADENOSINE
¢ Half life less than 10 sec. (very short duration of action).

¢ Pharmacological actions:

— activates K+ channels and causes membrane hyperpolarization

through interaction with A1 type of adenosine GPCRs on SA

node (pacemaker depression → bradycardia), A-V node

(prolongation of ERP → slowing of conduction) and atrium.

— Inhibition of cAMP-induced calcium influx in A-V node

— Inhibits AV nodal conduction and Increases AV nodal refractory

period.

¢ Toxicity: Flushing (20%) and shortness of breath.

¢ Advantages of adenosine for termination of PSVT are:

• Efficacy equivalent to or better than verapamil.

• Action lasts < 1 min; adverse effects (even cardiac arrest, if it

occurs) are transient.

• No haemodynamic deterioration; can be given to patients with

hypotension, CHF or those receiving β blockers. Verapamil is

contraindicated in these situations.

• Safe in wide QRS tachycardia (verapamil is unsafe)

THERAPEUTIC USES OF ANTIARRHYTHMIC
DRUGS

Type of arrhythmias Drugs

Supraventricular Verapamil (IV)

Adenosine and digoxin (others)

Ventricular Lidocaine (IB)

Ventricular and Amiodarone (III)

supraventricular Beta-blockers (II)
Procainamide(I)
NONPHARMACOLOGIC TREATMENT OF
ARRHYTHMIAS

These methods include

(1) external defibrillation

(2) implanted defibrillators

(3) implanted pacemakers and

(4)radiofrequency ablation or cryoablation of

arrhythmogenic foci via a catheter.

REFERENCES
1. Katzung Basic and clinical pharmacology

2. Pharmacotherapy: A Pathophysiologic Approach, 8e

3. Goodman and Gilman's The Pharmacological Basis of

Therapeutics