Classification Systems for Antiarrhythmic Drugs

There are two accepted classification systems for antiarrhythmic drugs. The first, and most widely used, was created by Vaughan Williams and Singh,19 and modified by Harrison and others. The second is known as the Sicilian Gambit.20

1. The Vaughan Williams-Singh classification has a number of advantages in that all drugs in a particular class tend to have the same clinical utility and similar, if not identical, actions on particular ion channels. The classification system has been found to be useful both experimentally and clinically with predictive utility, particularly in terms of clinical effectiveness and potential toxicity.

2. The Sicilian Gambit attempts to be more precise in its classification, but it ends up with almost every single drug being a special case which undermines any real attempt at classification. It does, however, fully describe the pharmacological spectrum of action of each antiarrhythmic drug.

In the following, drugs are considered on the basis of their classification with each class considered in terms of: (a) mechanism(s) and site of action; (b) structure-activity relationships (SARs) and basic pharmacophores; and (c) effectiveness, toxicity, and side effects. Emphasis is placed on comparisons within classifications with respect to particular drugs, their current limitations, and possible future directions in terms of making better drugs in the class. Antiarrhythmic classes 1-5: actions, effectiveness, toxicity

The Vaughan Williams-Singh classification originally divided drugs into classes on the basis of their actions on action potential shape in atria, or on ^-adrenoceptors. Modifications to the classification system became possible with an increased understanding of the ionic currents responsible for the action potentials found in the heart. In addition, clinical experience allowed for the clinical actions of the different classes of antiarrhythmic drugs on the ECG, and other clinical electrophysiological characteristics in man, to be accommodated within the classification system. The classes include (1) sodium channel blockers, (2) b-adrenoceptor blockers, (3) potassium channel blockers, (4) calcium channel blockers, and (5) selective bradycardic drugs. Class 1 antiarrhythmic drugs are all sodium channel blockers

All Class 1 drugs block cardiac sodium channels. However, on the basis of the frequency-dependent nature of the block, and the presence or absence of concomitant potassium channel blocking actions resulting in action potential prolongation, Class 1 is divided into subclasses: 1a, 1b, and 1c. Class 1a: quinidine, procainamide, disopyramide

• Mechanism: Class 1a drugs block sodium channels with moderate frequency dependence and also block potassium channels (IKr, Ito). Some also block muscarinic receptors. Their ion channel blocking actions result in ECG changes including a widened QRS complex and QT duration on the ECG, as well as delayed AV conduction (PR prolongation). Blockade of muscarinic receptors, by blocking the actions of parasympathetic nerves on the heart, can cause an apparent paradoxical increase in heart rate and AV conduction.

• Effectiveness: Class 1a drugs are currently used to treat life-threatening sustained VT, but their use is associated with dangerous arrhythmias, especially in the presence of cardiac damage. Therefore, they are probably too dangerous for regular use in ventricular arrhythmias, but can be used together with an implantable cardioverter defibrillator (ICD). Quinidine and disopyramide (Figure 4) are also used to treat atrial flutter or fibrillation, while procainamide (Figure 4) is used to treat AF, but this does not have FDA approval for this use.

• Toxicity: Class 1a drugs all have subclass-wide adverse effects and toxicity profiles. They include ventricular arrhythmias and muscarinic antagonism, as well as nausea, vomiting, and diarrhea (in up to 30% of patients). Individual drugs can have their own unique toxicity such as the cinchona syndrome with quinidine, and an allergic systemic lupus-like syndrome with procainamide.

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4 Lidocaine 5 Mexiletine

Figure 5 Examples of class 1b antiarrhythmics.

6 Tocainide Class 1b: lidocaine, mexiletine, tocainide

• Mechanism: Class 1b drugs are selective sodium channel blockers with marked positive frequency dependence. As a result of this frequency dependence, they have few effects on the ECG at normal heart rates since they only block sodium channels when heart rate is high, or in ischemic cardiac tissue. All drugs in this subclass have low molecular weights, and high lipid solubility. The latter, combined with high frequency dependence, results in central nervous system (CNS) penetration and resulting CNS toxicity.

• Effectiveness: Class 1b drugs like lidocaine (Figure 5) have been used intravenously for the acute termination of ventricular arrhythmias, such as life-threatening VT, since they are mostly ineffective against atrial arrhythmias. Unlike lidocaine which undergoes rapid first-pass metabolism, mexiletine and tocainide (Figure 5) are orally effective. While there is evidence that such drugs reduce the incidence of VF in patients undergoing myocardial infarction, there is little evidence that they reduce mortality. Thus, they reduce the incidence of VF but cause death as a result of asystole (absence of heart beat) resulting in no change in mortality.

• Toxicity: The toxicity of class 1b drugs includes loss of SA and AV node pacing resulting in a lack of a heart beat (asystole). CNS symptoms are common, and include initial paresthesias with subsequent convulsions. This is a result of their easy penetration (low molecular weight and high lipid solubility) into CNS tissue and nerves plus the very high frequency of CNS neuronal firing. Class 1c: flecainide, encainide, propafenone, moricizine

• Mechanism: Class 1c drugs block sodium channels, but they have very limited frequency dependence and limited other pharmacological actions.

• Effectiveness: Class 1c drugs like flecainide and propafenone (Figure 6) are used to terminate paroxysmal AV nodal tachycardia, AV re-entrant tachycardia, and paroxysmal atrial flutter and fibrillation. They, and moricizine (Figure 6), are also indicated for the management of sustained VT, but only if it is judged to be life-threatening. However, they can be dangerous in ventricular arrhythmias, especially when there is cardiac damage, as was shown so graphically in the Cardiac Arrhythmia Suppression Trial (CAST),17 resulting in the voluntary withdrawal of encainide (Figure 6) from the market.

• Toxicity: The toxicity of class 1c drugs includes arrhythmias and cardiovascular depression. Class 2: p-adrenoceptor blockers: propranolol, atenolol, metoprolol, and many others

• Mechanism: There are many P-adrenoceptor blockers that vary slightly pharmacologically with some having limited specificity for cardiac P-adrenoceptors. Propranolol is the prototype while atenolol and metoprolol have some selectivity for the P-adrenoceptor (Figure 7). Some P-adrenoceptor blockers are also partial agonists.

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