Medical Pharmacology Topics   

Antiarrhythmic Drugs   Fast Na+ channel blockers      Intermediate Dissociation          Quinidine          Procainamide          Disopyramide      Fast Dissociation          Lidocaine          Phenytoin      Slow Dissociation          Flecainide   Beta Blockers          Propanolol          Atenol          Metoprolol          Esmolol   Prolong Repolarization          Amiodarone          Bretylium          Sotalol   Ca+2 Blockers          Verapamil          Diltiazen

Antiarrhythmic Drugs

Antiarrhythmic drugs are classified into for classes by the modified Vaughan Williams classification, according to what is thought to be their primary pharmacological action:

Class 1 - Drugs that block fast Na+ channels

Class 2 - Drugs that block beta adrenergic receptors

Class 3 - Drugs that prolong repolarization (K channel blockers)

Class 4 - Drugs that block Ca channels

Other agents not in these classes used as antiarrhythmics are digitalis, adenosine, and alpha adrenergic receptor antagonists.

Sodium Channel Blockers (Class 1 Antiarrhythmics)

The primary action of Class 1 drugs is a blockade of fast Na channels that open during phase 0 depolarization. These drugs affect fast response action potentials by decreasing the amplitude and rate of rise (Vmax) of the initial fast response, leading to slow conduction and conditions favorable for block. They have little effect on slow response action potentials (where fast Na+ channels are not involved).

The main therapeutic effects of Class 1 drugs are the termination of reentrant arrhythmias (because will slow down reetry, but can also create it!) and making the threshold potential less negative in Purkinje fibers, decreasing the slope of phase 4 depolarization, leading to decreased automaticity of Purkinje fibers. Class 1 drugs are used to treat reentrant arrhythmias, protect ventricles in supraventricular tachyarrhythmias and suppress abnormal ectopic automaticity.

Class 1 drugs are subdivided into three subclasses - A, B and C - based on significant differences in action due to differences in the kinetics of their interaction with fast Na+ channels. The drug is thought to bind to the open channel and dissociate from the channel in its rested state. Class 1B has the fastest dissociation kinetics, so drugs like lidocaine have the greatest effect at fast heart rates (because they tend to accumulate only at fast heart rates). Class 1C agents like feicaine have the slowest dissociation kinetics, and thus have considerable effects at normal and slow heart rates. Class 1A agents like quinidine, procainamide and disopyramide have intermediate dissociation kinetics, thus produce modestly enhanced effects at faster heart rates.

In addition to their intermediate-kinetics blocking of Na channels, which slows conduction, Class 1A drugs also increase the action potential duration and the effective refractory period by blocking K channels responsible for phase 3 repolarization. Class 1A drugs also have anticholinergic effects opposite to the ones just described at the AV node, increasing AV conduction velocity.

Quinidine and disopyramide have stronger muscarinic and alpha receptor blockade effects than procainamide, and will interact with digoxin by doubling its (effective?) plasma levels (digoxin inhibits the Na/K ATPase that pumps K inside the cell, in the end increasing intracellular Ca; I do not understand this).

Quinidine is mostly eliminated by the liver, while procainamide and dysopyramide ae eliminated by both the liver and kidneys. All three Class 1A antyarrythmics cause GI effects due to antimuscarinic blockade (mostly nausea and vominting). Disopyramide causes many ANS effects because of its strong muscarinic blockade (dry moouth, blurred vission, urinary retention, constipation, glaucoma). They all also depress cardiac contractility and have other cardiovascular effects. QUinidine can produce thrombocytopenia, cinchonism and syncope. Procainamide can also cause proarrhythmia (Torsade de Pointes) and a lupus-like autoimmune disorder due to its N-acetylated metabolite.

As Class 1A, Class 1B drugs like lidocaine (fastest dissociation kinetics) slow conduction by decreasing the slope of phase 0 (rate of initial depolarization) in atrial, ventricular and Purkinje fibers. In contrast to class 1A, class 1B drugs decrease action potential duration and refractory period.

Lidocaine has no adrenergic effects and has a rapid hepatic metabolism (half-life ~ 1.5 hrs), so it must be given intravenously. It has few side effects relate to its local anesthetic properties (drwsiness, tremors) and is used in the short-term management of life-threatening ventricular arrhythmias. Phenytoin is an anticonvulsant with limited use as antiarrhythmic.

Class 1C drugs like flecainide have the slowest dissociation kinetics, so they have considerable effect at normal or low heart rates. They greatly slow conduction and have marked effects on Vmax at normal heart rates. Most class 1C drugs have little effect on action potential duration or refractoriness.

Beta Blockers (Class 2 Antiarrhythmics)

Class 2 antiarrhythmics are b-adrenergic antagonist. Sympathetic activity may contribute to many forms of arrhythmia. Stimulation of b-receptors increases cAMP in myocardial cells, and this in turn promotes phosphorylation of Ca channels and facilitate Ca influx. Beta blockade decreases the rate of phase 4 depolarization in automatic cells, slows conduction through the AV node (by blocking SNA enhancement of Ca channels) and reduce myocardial contractility and oxygen demand. These effects translate into decreased heart rate and ectopic automaticity, and enhanced AV block.

Chronic treatment with beta blockers may cause up-regulation of cardiac beta receptors, thus rapid withdrawal is associated with arrhythmias resulting from enhanced catecholamine sensitivity (a beneficial effect when treating congestive heart failure).

Propanolol is the beta blocker often used to treat arrhythmias. It has the potential to block Na+ channels, although it is unclear whether this effect is evident at therapeutic concentrations. It is used to treat supraventricular tachyarrhythmias (to control ventricular rate by promoting AV block), various atrial and ventricular arrhythmias and prevention of sudden death in post-myocardial infarction patients. The goal is to control ventricular rate by enhancing or promoting AV block. <aqui>

Class 3 antiarrhythmics like amidarone, sotalol and betylium prolong the action potential (delay repolarization) and increase refractoriness in atrial and ventricular muscle and in Purkinje fibers, usually (?) by K channel blockade. Amiodarone also blocks Na and Ca channels, leading to decreased slope of phase 4 depolarization in the sinus node, the rate of increase of fast response action potentials and AV node conduction. It has few side effects with short-term use but fatal pulmonary fibrosis is seen occasionally with long-term, high dose treatment. Amidarone also has some non-competitive antagonist effects on adrenergic receptors.

Sotalol can also be considere a Class 2 agent because it is a beta blocker. It decreases automaticity and slows AV conduction and has some autonomic side effects. Sotalol is used to treat life-threatening ventricular tachycardia and supraventricular tachyarrythmias

Bretylium reduces the heterogeneicity of repolarization times by prolonging action potential duration to a greater degree in normal tissue than in damage tissue (where the action potential duration is already increased). It also interfers with catecholamine storage and may cause transient increases in SA automaticity and AV conduction by release of catecholamines (action similar to guanethamine), leading to initial transient hypertension and worsen arrhythmias. Bretylium is used in emergency treatment of sustained ventricular fibrillation.

Ca Channel Blokers (Class 4 Antiarrythmics)

Class 4 antiarrhythmics like verapamil and diltiazem block L-type Ca in the myocardium and smooth muscle. They affect slow response action potentials (SA and AV nodes, damage cells) by decreasing the slope of phase 4 depolarization (decreases heart rate), decreasing Vmax, and the amplitude of phase 0 (decreased conduction).

As with Na channel blockers, Ca channel blockers exhibit "use dependence", i.e. they are more effective at faster rates. Ca channel blockers also decrease contractility, therefore they are contraindicated in patients with chronic heart failure. They may also relax vascular smooth muscle, causing decreased arterial pressure and baroreflex response that may increase heart rate

Class 4 antiarrhythmics are used to treat supraventricular arrhythmias.

Other Antiarrythmics

Miscellaneous antiarrhythmic agents include adenosine, a-adrenergic antagonists and the digitalis glycosides. Adenosine acts through G-protein coupled receptors to exert a vagomimetic effect, slowing down AV conduction and inhibiting delayed afterpolarizations (half-life of seconds, usually causes transient asystole). Alpha receptor agonists like phenylephrine act indirectly through the baroreflex.

Digitalis glycosides block the Na/K ATPase, reducing the concentration gradients for these ions across the plasma membrane. This causes depolarization, resulting in slowed conduction and increased refractory period. At the same time, digitalis depolarizes baroreceptor nerve ending, resulting in their sensitization. Increased firing of the baroreceptors results in decreased sympathetic tone and increased parasympathetic activity, both of which further slow AV conduction. The cardiac glycosides are used to treat atrial fibrilation and heart failure. The digitalis glycosides are discussed further in the "Cardiac Failure" section.

Continue to "Cardiac Failure" or take a quiz: [Q1].

Need more practice? Answer the review questions below.

Questions coming soon