Antiarrhythmic agent

The cardiac action potential

Relative ion flow in cardiac myocyte in relation to features of the ECG.

Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.

While the use of antiarrhythmic agents to suppress atrial arrhythmias (atrial fibrillation and atrial flutter) is still in practice, it is unclear whether suppression of atrial arrhythmias will prolong life.^[1][2]

In the past, it was believed that following myocardial infarction (heart attack), suppression of ventricular arrhythmias would prolong life. However, large clinical trials such as CAST and CAPS found that suppression of these arrhythmias would ironically increase mortality,^[3][4] which may happen due to the proarrhythmic effect these drugs may have.^[4]

In individuals with atrial fibrillation, antiarrhythmics are still used to suppress arrhythmias. This is often done to relieve the symptoms that may be associated with the loss of the atrial component to ventricular filling (atrial kick) that is due to atrial fibrillation or flutter.

In individuals with ventricular arrhythmias, antiarrhythmic agents are often still in use to suppress arrhythmias. In this case, the patient may have frequent arrhythmic events or be at high risk for ventricular arrhythmias. Antiarrhythmic agents may be considered the first-line therapy in the prevention of sudden death in certain forms of structural heart disease, and failure of these agents to suppress arrhythmias may lead to implantation of an implantable cardioverter-defibrillator (ICD).

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.

Vaughan Williams antiarrhythmic classification

The Vaughan Williams classification, introduced in 1970,^[5] 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 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 VW classification system for the effects of drug metabolites. Procainamide—a class Ia agent whose metabolite N-acetyl procainamide (NAPA) has a class III action—is 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 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.

Overview table

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 1 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 2 agents like propranolol also have a membrane stabilizing effect.)

Class I agents are divided into three groups (1a, 1b and 1c) based upon their effect on the length of the action potential.^[8][9]

• 1A lengthens the action potential (right shift)
• 1B shortens the action potential (left shift)
• 1C does not significantly affect the action potential (no shift)

Class Ia agent decreasing Vmax, thereby increasing action potential duration.

Class Ib

Class Ic

Class II agents

Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β₁-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

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.^[10] 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 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".^[11] 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^[12]
• Magnesium sulfate,^[13] which has been used for torsades de pointes.^[14][15]

Sicilian Gambit classification

Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.^[16][17][18]

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.^[19]

Trials

The Cardiac Arrhythmia Suppression Trial (CAST trial) ^[20] (published in 1989) was a medical study that demonstrated that some class 1 anti-arrhythmic drugs were not helpful to people suffering from ventricular premature depolarization. Specifically, for populations of recent heart attack survivors, the study observed lower mortality in a control population than in populations treated with encainide, flecainide or moricizine (all class 1c drugs). The Cardiac Arrhythmia Pilot Study (CAPS, published in 1986) was another study to investigate arrhythmias.

Other major trials examining antiarrhythmic drugs include Antiarrhythmics Versus Implantable Defibrillators (AVID), and the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM), which compared antiarrhythmic drugs with drugs which controlled inappropriately rapid and irregular heart rate. In both trials, the arrhythmic drugs were less effective than the alternative.^[21]

Mnemonics

Mnemonic for Class I-IV agents: SoBe PoCa (SOBE as in South Beach or the drink, POCA as in Polka)

Also - remembering that of all anti-arrhythmics "some block potassium channels" can help you:

• Class I "Some" = S = Sodium
• Class II "Block" = B =Beta blockers
• Class III "Potassium" = Potassium channel blockers
• Class IV "Channels" = C =Calcium channel blockers

Specific drugs:

• Class I agents:
  • Class IA “Double Quarter Pounder” (Disopyramide, Quinidine, Procainamide)
  • Class IB “Lettuce, Tomato, Mayo, Pickles” (Lidocaine, Tocainide, Mexilitine, Phenytoin)
  • Class IC “More Fries Please” (Moricizine, Flecainide, Propafenone).

• Class III agents: "A Big Dog Is Scary" (Amiodarone, Bretylium, Dofetilide, Ibutilide, Sotalol).

• Class IV: Calcium channel blockers are verapamil and diltiazem. NB: Nifedipine is not cardioselective and is therefore not a class IV anti-arrhythmic even though dihydropyridines are considered Ca2+ channel blockers].

See also

• Action potential
  • Cardiac action potential
• Electrocardiogram
• Proarrhythmic agent

References