Classification Of Drugs

The Vaughan-Williams2 classification of antiarrhythmic drugs is the most commonly used classification. Despite its many peculiarities the classification does provide a useful shorthand for referring to particular groups or actions of drugs.

Class I: sodium channel blockade. These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarisation. Another term for this property is membrane stabilising activity; it may contribute to stopping arrhythmias by limiting the responsiveness to excitation of cardiac cells. The class may be sub-classified as follows:

A. Drugs that lengthen action potential duration and refractoriness (adjunctive class III action), e.g. quinidine, disopyramide, procainamide

B. Drugs that shorten action potential duration and refractoriness, e.g. lignocaine (lidocaine) and mexiletine

C. Drugs that have negligible effect on action potential duration and refractoriness, e.g. flecainide, propafenone.

One value of the classification is that drugs in class IB are ineffective for supraventricular arrhythmias, whereas they all have some action in ventricular arrhythmias. The classification is not useful in explaining why the classes differ anatomically in their efficacy.

Class II: catecholamine blockade. Propranolol and other p-adrenoceptor antagonists reduce background sympathetic tone in the heart, reduce automatic discharge (phase 4) and protect against adrenergically stimulated ectopic pacemakers.

Class III: lengthening of refractoriness (without effect on sodium inflow in phase 0). Prolongation of the cardiac action potential and increased cellular refractoriness beyond a critical point may stop a reentrant circuit being completed and thereby prevent or halt a re-entrant arrhythmia (see above), e.g. amiodarone and sotalol. These drugs act by inhibiting IKr, the rapidly activating component of the delayed rectifier potassium current (phase 3). The gene, HERG (the human ether-a-go-go-related gene) encodes a major subunit of the protein responsible for IKr.

2 Vaughan Williams E M1992 Classifying antiarrhythmic actions: by facts or speculation. Journal of Clinical Pharmacology 32: 964-977.

These are the most commonly used antiarrhythmic drugs at this time; new agents in this class include dofetilide and azimilide.

Class IV: calcium channel blockade. These drugs depress the slow inward calcium current (phase 2) and prolong conduction and refractoriness particularly in the SA and AV nodes, which may explain their effectiveness in terminating paroxysmal supraventricular tachycardia, e.g. verapamil.

Although the antiarrhythmics have been entered into this classification according to a characteristic major action, most have other effects as well. For example, quinidine (class I) has major class III effects; propranolol (class II) has minor class I effects, and sotalol (class II) has major class III effects. Amiodarone has class I, II, III and IV effects but is usually classed under III.

CLASS IA (sodium channel blockade with lengthened refractoriness)

Disopyramide

Disopyramide was the most commonly used drug in this class but is much less so now. It has significant antimuscarinic activity. The drug was thought to be effective in ventricular arrhythmias, especially after myocardial infarction, and in supraventricular arrhythmias, although there are no clinical trials to support this idea.

Pharmacokinetics. Disopyramide is used orally (see Table 24.1) and is well absorbed. It is partly excreted unchanged and partly metabolised. The t1/, is 6 h.

Adverse reactions. The antimuscarinic activity is a significant problem and may lead to dry mouth, blurred vision, glaucoma and micturition hesitancy and retention. Gastrointestinal symptoms, rash and agranulocytosis occur. Effects on the cardiovascular system include hypotension and cardiac failure (negative inotropic effect)

Quinidine

Quinidine is considered the prototype class I drug, although it is now quite rarely used.3 In addition to its class IA activity, quinidine slightly enhances contractility of the myocardium (positive inotropic effect), and reduces vagus nerve activity on the heart (antimuscarinic effect). At therapeutic doses there is lengthening of ventricular systole which is positively inotropic.

Pharmacokinetics. Absorption of quinidine from the gut is rapid, 75% of the drug is metabolised and the remainder is eliminated unchanged in the urine (t1/, 7 h). Active metabolites may accumulate when renal function is impaired.

Adverse reactions. Quinidine must never be used alone to treat atrial fibrillation or flutter as its antimuscarinic action enhances AV conduction and the heart rate may accelerate. Other cardiac effects include serious ventricular tachyarrhythmias associated with electrocardiographic QT prolongation, i.e. torsades de pointes, the cause of 'quinidine syncope'. Plasma digoxin concentration is raised by quinidine (via displacement from tissue binding and impairment of renal excretion) and the dose of digoxin should be decreased when the drugs are used together. Noncardiac effects, called cinchonism, include diarrhoea and other gastrointestinal symptoms, rashes, thromobocytopenia and fever.

CLASS IB (sodium channel blockade with shortened refractoriness)

Lignocaine (lidocaine)

Lignocaine (lidocaine) is used principally for ven-

3 In 1912 K F Wenckebach, a Dutch physician (who described 'Wenckebach block') was visited by a merchant who wished to get rid of an attack of atrial fibrillation (he had recurrent attacks which, although they did not unduly inconvenience him, offended his notions of good order in life's affairs). On receiving a guarded prognosis, the merchant inquired why there were heart specialists if they could not accomplish what he himself had already achieved. In the face of Wenckebach's incredulity he promised to return the next day with a regular pulse, which he did, at the same time revealing that he had done it with quinine (an optical isomer of quinidine). Examination of quinine derivatives led to the introduction of quinidine in 1918 (Wenckebach K F 1923 Journal of the American Medical Association 81: 472).

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