Use Dependence.

Some drugs exert greater inhibitory effects on the upstroke of the action potential at more rapid rates of stimulation and after longer periods of stimulation, a characteristic called use dependence. Use dependence means that depression of max is greater after the channel has been “used” (i.e., after action potential depolarization rather than after a rest period). Agents in class IB exhibit fast kinetics of onset and offset or use-dependent block of the fast channel; that is, they bind and dissociate quickly from receptors. Class IC drugs have slow kinetics, and class IA drugs are intermediate. With increased time spent in diastole (slower rate), a greater proportion of receptors become drug free, and the drug exerts less effect. Unhealthy cells with reduced (i.e., abnormal) membrane potentials recover more slowly from drug actions than do healthier cells with more negative (i.e., normal) membrane potentials.

Reverse Use Dependence.

Some drugs exert greater effects at slow rates than at fast rates, a property known as reverse use dependence. This is particularly true for drugs that lengthen repolarization. The QT interval becomes more prolonged at slow rather than at fast rates. This effect is not what the ideal antiarrhythmic agent would do because prolongation of refractoriness should be increased at fast rates to interrupt or to prevent a tachycardia and should be minimal at slow rates to avoid precipitation of torsades de pointes.

Mechanisms of Arrhythmia Suppression.

Given the fact that enhanced automaticity, triggered activity, or reentry can cause cardiac arrhythmias (see Chapter 33), mechanisms by which antiarrhythmic agents suppress arrhythmias can be postulated (see Table 35-2). Antiarrhythmic agents can slow the spontaneous discharge frequency of an automatic pacemaker by depressing the slope of diastolic depolarization, shifting the threshold voltage toward zero, or hyperpolarizing the resting membrane potential. Mechanisms whereby different drugs suppress normal or abnormal automaticity may not be the same. In general, however, most antiarrhythmic agents in therapeutic doses depress the automatic firing rate of spontaneously discharging ectopic sites while minimally affecting the discharge rate of the normal sinus node. Slow channel blockers such as verapamil, beta blockers such as propranolol, and some antiarrhythmic agents such as amiodarone also depress spontaneous discharge of the sinus node, whereas drugs that exert vagolytic effects, such as disopyramide and quinidine, can increase the sinus discharge rate. Drugs can also suppress early or delayed afterdepolarizations and eliminate triggered arrhythmias related to these mechanisms.

Reentry depends critically on the interrelationships between refractoriness and conduction velocity, the presence of unidirectional block in one of the pathways, and other factors that influence refractoriness and conduction, such as excitability (see Chapter 33). An antiarrhythmic agent can stop ongoing reentry that is already present or prevent it from starting if the drug depresses or, alternately, improves conduction. For example, improving conduction can (1) eliminate a unidirectional block so that reentry cannot begin or (2) facilitate conduction in the reentrant loop so that the returning wave front reenters too quickly, encounters cells that are still refractory, and is extinguished. A drug that depresses conduction can transform a unidirectional block into a bidirectional block and thus terminate reentry or prevent it from starting by creating an area of complete block in the reentrant pathway. Conversely, a drug that slows conduction without producing block or lengthening refractoriness significantly can promote reentry. Finally, most antiarrhythmic agents share the ability to prolong refractoriness relative to their effects on APD; that is, the ratio of the effective refractory period (ERP) to APD exceeds 1.0. If a drug prolongs the refractoriness of fibers in the reentrant pathway, the pathway may not recover excitability in time to be depolarized by the reentering impulse, and reentrant propagation ceases. The different types of reentry (see Chapter 33) influence the effects and effectiveness of a drug.

In considering the properties of a drug, it is important that the situation or model from which conclusions are drawn be defined with care. Electrophysiologic, hemodynamic, autonomic, pharmacokinetic, and adverse effects may all differ in normal subjects as compared with patients, in normal tissue as compared with abnormal tissue, in cardiac muscle as compared with specialized conduction fibers, and in atrium as opposed to ventricular muscle (Table 35-4).

Drug Metabolites.

Drug metabolites can add to or alter the effects of the parent compound by exerting similar actions, competing with the parent compound, or mediating drug toxicity. Quinidine has at least four active metabolites but none with a potency exceeding that of the parent drug and none implicated in causing torsades de pointes. About 50% of procainamide is metabolized to N-acetylprocainamide (NAPA), which prolongs repolarization and is a less effective antiarrhythmic drug but competes with procainamide for renotubular secretory sites and can increase the parent drug’s elimination half-life. Lidocaine’s metabolite can compete with lidocaine for sodium channels and partially reverse block produced by lidocaine.

Pharmacogenetics.

Genetically determined metabolic pathways account for many of the differences in patients’ responses to some drugs (see Chapter 9).² The genetically determined activity of hepatic N-acetyltransferase regulates the development of antinuclear antibodies and lupus syndrome in response to procainamide. Slow acetylator phenotypes appear to be more prone than rapid acetylators to the development of lupus. The enzyme cytochrome P-450 (CYP450) is needed to metabolize propafenone, to hydroxylate several beta blockers, and to biotransform flecainide. Lack of this enzyme (in ≈7% of patients) reduces metabolism of the parent compound and thereby leads to increased plasma concentrations of the parent drug and reduced concentrations of metabolites. Propafenone is metabolized by CYP450 to a compound with slightly less antiarrhythmic and beta-adrenergic blocking effects, as well as fewer central nervous system side effects. Thus, poor metabolizers may experience more heart rate slowing and neurotoxicity than extensive metabolizers do.

Drugs such as rifampin, phenobarbital, and phenytoin induce the synthesis of larger amounts of CYP450, which leads to lower concentrations of the parent drugs because of extensive metabolism, whereas erythromycin, clarithromycin, fluoxetine, and grapefruit juice inhibit enzyme activity, which leads to accumulation of the parent compound. Cisapride, a gastric motility agent, blocks the delayed rectifier current I_Kr but does not prolong the QT interval significantly in most patients because of extensive metabolism. In patients who take an inhibitor of CYP450 (such as erythromycin) along with cisapride, the latter drug could accumulate and lead to QT prolongation and torsades de pointes.