Classifying Antiarrhythmic Drugs

To the extent that the clinical actions of drugs can be predicted, classifying drugs by common elec-trophysiological properties is useful. However, differences in pharmacological effects occur even among drugs that share the same classification, some of which may be responsible for the observed clinical differences in responses to drugs of the same broad "class" (Table 34-3). Another way of approaching therapy is to attempt to classify arrhythmia mechanisms and then to target drug therapy to the electrophysiological mechanism most likely to terminate or prevent the arrhythmia (Table 34-2).

Na+ CHANNEL BLOCK The extent of Na+ channel block depends critically on heart rate, membrane potential, and on drug-specific physicochemical characteristics that determine Trecovery. When Na+ channels are blocked, threshold for excitability is decreased; i.e., greater membrane depolarization is required to bring Na+ channels from the rest to open states. This change in threshold probably contributes to the clinical finding that Na+ channel blockers tend to increase both pacing threshold and the energy required for defibrillation. These deleterious effects may be important if antiarrhythmic drugs are used in patients with pacemakers or implanted defibrillators. Na+ channel block decreases conduction velocity in fast-response tissue and increases QRS duration. Usual doses of flecainide prolong QRS intervals by 25% or more during normal rhythm, whereas lidocaine increases QRS intervals only at very fast heart rates. Drugs with Trecovery values greater than 10 s (e.g., flecainide) also tend to prolong the PR interval; it is not known whether this represents additional Ca2+ channel block (see below) or block of fast-response tissue in the region of the AV node. Drug effects on the PR interval also are highly modified by autonomic effects. For example, quinidine actually tends to shorten the PR interval, largely as a result of its vagolytic properties. Action potential duration is either unaffected or shortened by Na+ channel block; some Na+ channel-blocking drugs do prolong cardiac action potentials, but usually by K+ channel block (Table 34-3).

Na+ channel block decreases automaticity and can inhibit triggered activity arising from DADs or EADs. Many Na+ channel blockers also decrease phase 4 slope. In anatomically defined reentry, Na+ channel blockers may decrease conduction sufficiently to extinguish the propagating reentrant wavefront. However, as described earlier, conduction slowing owing to Na+ channel block may exacerbate reentry. Thus, whether a given drug exacerbates or suppresses reentrant arrhythmias depends on the balance between its effects on refractoriness and on conduction in a particular reentrant circuit. Lidocaine and mexiletine have short Trecovery values and are not useful in atrial fibrillation or flutter, whereas quinidine, flecainide, propafenone, and similar agents are effective in some patients. Many of these agents owe part of their antiarrhythmic activity to blockade of K+ channels.

Na+ Channel-Blocker Toxicity Conduction slowing in potential reentrant circuits can account for toxicity of drugs that block the Na+ channel (Table 34-1). For example, Na+ channel block decreases conduction velocity and hence slows atrial flutter rate. Normal AV nodal function permits a greater number of impulses to penetrate the ventricle, and heart rate actually may increase. Thus, atrial flutter rate may drop from 300/min, with 2:1 or 4:1 AV conduction (i.e., a heart rate of 150 or 75 beats/min), to 220/min, with 1:1 transmission to the ventricle (i.e., a heart rate of 220 beats/min), with potentially disastrous consequences. This form of drug-induced arrhythmia is especially common with quinidine because it also increases AV nodal conduction through its vagolytic properties; flecainide and propafenone also have been implicated. Therapy with Na+ channel blockers in patients with reentrant ventricular tachycardia after myocardial infarction can increase the frequency and severity of arrhythmic episodes. Slowed conduction allows the reentrant wavefront to persist within the tachycardia circuit. Such drug-exacerbated arrhythmia can be very difficult to manage, and deaths owing to intractable drug-induced ventricular tachycardia have been reported. In this setting, Na+ infusion may be beneficial.

ACTION POTENTIAL PROLONGATION Most drugs that prolong the action potential do so by blocking K+ currents, usually /Rr, although enhanced inward Na+ current also can cause prolongation. Enhanced inward current may underlie QT prolongation (and arrhythmia suppression) by ibutilide. Block of cardiac K+ channels increases action potential duration and reduces normal auto-maticity. Increased action potential duration, seen as an increase in QT interval, increases refractoriness and therefore should be an effective way of treating reentry. Experimentally, K+ channel block produces a series of desirable effects: reduced defibrillation energy requirement, inhibition of ventricular fibrillation owing to acute ischemia, and increased contractility. Most K+ channel blocking drugs also interact with p adrenergic receptors (sotalol) or other channels (e.g., amiodarone and quinidine) (see Table 34-3). Amiodarone and sotalol appear to be at least as effective as drugs with predominant Na+ channel-blocking properties in both atrial and ventricular arrhythmias. "Pure" action potential-prolonging drugs (e.g., dofetilide and ibutilide) also are available.

Toxicity of Drugs That Prolong QT Interval Most of these agents disproportionately prolong cardiac action potentials when underlying heart rate is slow and can cause torsades de pointes (Table 34-1). While this effect usually is seen with QT-prolonging antiarrhythmic drugs, it can occur more rarely with drugs that are used for noncardiac indications. For such agents, the risk of torsades de pointes may become apparent only after widespread use postmarketing. For unknown reasons, drug-induced torsades de pointes associated with antiarrhythmic drugs is significantly more common in women.

Ca2+ CHANNEL BLOCK The major electrophysiological effects resulting from block of cardiac Ca2+ channels are in slow-response tissues, the sinus and AV nodes. Dihydropyridines such as nifedipine, which are used commonly in angina and hypertension, preferentially block Ca2+ channels in vascular smooth muscle; their cardiac effects, such as heart rate acceleration, result principally from reflex sympathetic activation secondary to peripheral vasodilation. Only verapamil, diltiazem, and bepridil block Ca2+ channels in cardiac cells at clinically used doses. These drugs generally slow heart rate, although hypotension can cause reflex sympathetic activation and tachycardia. The velocity of AV nodal conduction decreases, so the PR interval increases. AV nodal block occurs as a result of decremental conduction and increased AV nodal refractoriness, which form the basis for the use of Ca2+ channel blockers in reentrant arrhythmias whose circuit involves the AV node, such as AV reentrant tachycardia.

Another important indication for antiarrhythmic therapy is to reduce ventricular rate in atrial flutter or fibrillation. Rare forms of ventricular tachycardia appear to be DAD-mediated and respond to verapamil. Parenteral verapamil and diltiazem are approved for rapid conversion of PSVTs to sinus rhythm and for temporary control of rapid ventricular rate in atrial flutter or fibrillation. Oral verapamil may be used in conjunction with digoxin to control ventricular rate in chronic atrial flutter or fibrillation and for prophylaxis of repetitive PSVT. Unlike p adrenergic receptor antagonists, Ca2+ channel blockers have not been shown to reduce mortality after myocar-dial infarction.

Toxicity of Ca2+ Channel Blockers The major adverse effect of intravenous verapamil or dil-tiazem is hypotension, particularly with bolus administration. This is a particular problem if the drugs are used mistakenly in patients with ventricular tachycardia misdiagnosed as AV nodal reentrant tachycardia. Hypotension also is frequent in patients receiving other vasodilators, including quinidine, and in patients with underlying left ventricular dysfunction, which the drugs can exacerbate. Severe sinus bradycardia or AV block also occurs, especially in patients also receiving p blockers. With oral therapy, these adverse effects tend to be less severe.

Verapamil (calan, isoptin, verelan, covera-hs) is prescribed as a racemate. l-Verapamil is a more potent calcium channel blocker than is d-verapamil. However, with oral therapy, the l-enantiomer undergoes more extensive first-pass hepatic metabolism. For this reason, a given concentration of verapamil prolongs the PR interval to a greater extent when administered intravenously (where concentrations of the l- and d-enantiomers are equivalent) than when administered orally. Diltiazem (cardizem, tiazac, dilacor xr, and others) also undergoes extensive first-pass hepatic metabolism, and both drugs have metabolites that exert Ca2+ channel-blocking actions. Adverse effects during therapy with verapamil or diltiazem are determined largely by underlying heart disease and concomitant therapy; plasma concentrations of these agents are not measured routinely. Both drugs can increase serum digoxin concentration, although the magnitude of this effect is variable; excess slowing of ventricular response may occur in patients with atrial fibrillation. constipation can occur with oral verapamil.

BLOCK OF p ADRENERGIC RECEPTORS p Adrenergic stimulation increases the magnitude of the Ca2+ current and slows its inactivation, increases the magnitude of repolarizing K+ and Cl- currents, increases pacemaker current (thereby increasing sinus rate), and under pathophysiological conditions, can increase both DAD- and EAD-mediated arrhythmias. The increases in plasma Epi associated with severe stress (e.g., acute myocardial infarction or resuscitation from cardiac arrest) lower serum K+, especially in patients receiving chronic diuretic therapy. p Adrenergic receptor antagonists inhibit these effects and can be antiarrhythmic by reducing heart rate, decreasing intracellular Ca2+ overload, and inhibiting afterdepolarization-mediated automaticity. Epi-induced hypokalemia appears to be mediated by b2 adrenergic receptors and is blocked by "noncardioselective" antagonists such as propranolol (see Chapter 10). In acutely ischemic tissue, p blockers increase the energy required to fibrillate the heart, an antiarrhythmic action. These effects may contribute to the reduced mortality observed in trials of acute and chronic therapy with p blockers after myocardial infarction.

As with Ca2+ channel blockers and digitalis, p blockers slow AV nodal conduction and prolong AV nodal refractoriness; hence, they are useful in terminating reentrant arrhythmias that involve the AV node and in controlling ventricular response in atrial fibrillation or flutter. In some patients, including many with the congenital long QT syndrome, arrhythmias are triggered by physical or emotional stress; p blockers may be useful in these cases. p adrenergic receptor antagonists also reportedly are effective in controlling arrhythmias owing to Na+ channel blockers; this effect may be due in part to slowing of the heart rate, which then decreases the extent of rate-dependent conduction slowing by Na+ channel block.

Selected p Adrenergic Receptor Blockers The p antagonists likely share antiarrhythmic properties. Some, such as propranolol, also exert Na+ channel-blocking ("membrane stabilizing") effects at high concentrations, but the clinical significance of this effect is uncertain. Drugs with intrinsic sympathomimetic activity may be less useful as antiarrhythmics. Sotalol (see below) is more effective for many arrhythmias than are other p blockers probably because of its K+ channel-blocking actions. Esmolol is a p1 selective agent that is metabolized by erythrocyte esterases and so has a very short elimination t1/2 (9 minutes). Intravenous esmolol is useful when immediate p adrenergic blockade is desired (e.g., for rate control of rapidly conducted atrial fibrillation). Because of esmolol's very rapid elimination, adverse effects due to p adrenergic blockade—should they occur—dissipate rapidly.

Toxicity of p Adrenergic Blockers Adverse effects of p blockade include fatigue, bron-chospasm, hypotension, impotence, depression, aggravation of heart failure, worsening of symptoms owing to peripheral vascular disease, and masking of the symptoms of hypoglycemia in diabetic patients. In patients with arrhythmias owing to excess sympathetic stimulation (e.g., pheochromocytoma or clonidine withdrawal), p blockers can cause unopposed a adrenergic stimulation, resulting in severe hypertension and/or a adrenergic-mediated arrhythmias. In such patients, arrhythmias should be treated with both a and p adrenergic antagonists or with a drug such as labetalol that combines a and p blocking properties. Abrupt discontinuation of chronic p blocker therapy can lead to "rebound" symptoms, including hypertension, increased angina, and arrhythmias; thus, p receptor antagonist therapy is tapered over 2 weeks.

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