Antiarrhythmic Drugs A practical guide – Part 5

Class I antiarrhythmic drugs 71 Several drug interactions have been seen with phenytoin. Pheny-toin increases plasma levels of theophylline, quinidine, disopyra-mide, lidocaine, and mexiletine. Phenytoin levels are increased by cimetidine, isoniazid, sulfonamides, and amiodarone. Plasma levels of phenytoin can be reduced by theophylline. Like other Class IB drugs, phenytoin rarely causes proarrhythmia. Class IC Class IC drugs generated much excitement in the early to late 1980s because they are very effective in suppressing both atrial and ven-tricular tachyarrhythmias and generally cause only mild end-organ toxicity. When the proarrhythmic potential of Class IC drugs was more fully appreciated, however, the drugs quickly fell out of favor and one (encainide) was taken off the market entirely. As shown in Figure 3.3, Class IC drugs have a relatively pro-nounced effect on the rapid sodium channel because of their slow sodium-channel-binding kinetics. Thus, they significantly slow con-duction velocity even at normal heart rates. They have only a mod-est effect on repolarization. Class IC drugs have similar effects on Figure 3.3 Effect of Class IC drugs on the cardiac action potential. Baseline action potential is displayed as a solid line; the dashed line indicates the effect of Class IC drugs. 72 Chapter 3 Table 3.5 Clinical pharmacology of Class IC drugs GI absorption Protein binding Elimination Half-life Therapeutic level Dosage range Flecainide >90% 40% 70% liver 30% kidneys 12–24 h 0.2–1.0 µg/mL 100–200 mg q12h Propafenone >90% 90% Liver 6–7 h 0.2–1.0 µg/mL 150–300 mg q8h Moricizine >90% >90% Liver (metabolized to >2 dozen compounds) Variable;usually3–12h — 200–300 mg q8h both atrial and ventricular tissue and are useful for both atrial and ventricular tachyarrhythmias. The major clinical features of Class IC antiarrhythmic drugs are summarized in Table 3.5, and the major electrophysiologic properties are shown in Table 3.6. Flecainide Flecainide was synthesized in 1972 and approved by the FDA in 1984. Clinical pharmacology Flecainide is well absorbed from the gastrointestinal tract, and peak plasma levels are reached 2–4 hours after an oral dose. Forty percent of the drug is protein bound. The drug is mainly metabolized by the liver (70%), but 30% is excreted unchanged by the kidneys. Flecainide has a long elimination half-life (12–24 h), so a steady state is not reached for 3–5 days after a change in oral dosage. Dosage The usual dosage is 100–400 mg/day orally, in divided doses. Gen-erally, the beginning dosage is 100 mg every 12 hours. Dosage can be increased by 50 mg/dose (at 3- to 5-day intervals) to a maximal dosage of 200 mg every 12 hours. Class I antiarrhythmic drugs 73 Table 3.6 Electrophysiologic effects of Class IC drugs Conduction velocity Refractory periods Automaticity Afterdepolarizations Flecainide Decrease + + + No change (may lengthen RP in atrium) – – Propafenone Decrease + + + No change Suppresses – Moricizine Decrease ++ Decrease + Suppresses Suppresses EADs and DADs Efficacy Atrial fibrillation/atrial ++ ++ + flutter AVN reentry ++ ++ + Macroreentry ++ ++ + PVCs + + + + + + ++ VT/VF ++ ++ ++ AVN, AV node; EADs, early afterdepolarizations; DADs, delayed afterdepolariza-tions; RP, refractory periods; PVCs, premature ventricular complexes; VT/VF, ven-tricular tachycardia and ventricular fibrillation. Electrophysiologic effects The major electrophysiologic feature of flecainide is a substantial slowing in conduction velocity. The prolonged slowing is directly related to the prolonged binding-unbinding time (i.e., the slow binding kinetics) of the drug. Although most Class IA agents have binding times in the range of 5 seconds, and Class IB drugs have binding times of approximately 0.3 seconds, flecainide has a binding time of 30 seconds. Thus, flecainide is virtually continuously bound to the sodium channel, and therefore produces slow conduction even at low heart rates (i.e., at rest). Flecainide subsequently has a dose-dependent effect on the electrocardiogram, manifested by 74 Chapter 3 a progressive prolongation of the PR and QRS intervals (reflecting its slowing of conduction velocity), with only a minor effect on the QT interval (reflecting its minimal effect on refractory periods). The drug depresses conduction in all areas of the heart. Hemodynamic effects Flecainide has a pronounced negative inotropic effect similar to that of disopyramide. The drug should not be given to patients with a history of congestive heart failure or with significantly depressed left ventricular ejection fraction. Therapeutic uses As one might predict from the universal nature of the drug’s elec-trophysiologic properties, flecainide has an effect on both atrial and ventricular tachyarrhythmias. It has been shown to be effective for terminating and preventing atrial fibrillation and atrial flutter; if the arrhythmias recur, flecainide can slow the ventricular response. Be-cause it affects accessory pathway function, flecainide is useful in the treatment of bypass-tract-mediated tachyarrhythmias. The drug has a profound suppressive effect on premature ventricular complexes and nonsustained ventricular tachycardia. It has been reported to suppress approximately 20–25% of inducible sustained ventricular tachycardias in the electrophysiology laboratory. Flecainide is unsurpassed in suppressing premature ventricular complexes and nonsustained ventricular tachycardias, but it should not be used for this indication in patients who have underlying heart disease. This finding was made apparent by results of the Cardiac Ar-rhythmia Suppression Trial (CAST [1]), which tested the proposition that suppression of ventricular ectopy after myocardial infarction would reduce mortality. Patients receiving flecainide or encainide in this trial had significantly higher mortality rates than did patients receiving placebo. The significant difference in mortality has been attributed to the proarrhythmic properties of the Class IC drugs. Adverse effects and interactions Flecainide is generally better tolerated than most antiarrhythmic agents. Mild-to-moderate visual disturbances are the most common side effect, usually manifesting as blurred vision. Occasionally, gas-trointestinal symptoms occur. However, no significant organ toxicity has been reported. Class I antiarrhythmic drugs 75 By far the most serious adverse effect of flecainide (and of all Class IC drugs) is its significant proarrhythmic potential (see the comparison to other Class I drugs in Table 3.7). Proarrhythmia with IC agents takes the form of exacerbation of reentrant ventricular tachycardia; torsades de pointes is not seen. Thus, the risk of proar-rhythmia with flecainide is mainly limited to patients who have the potential for developing reentrant ventricular arrhythmias, that is, patients with underlying cardiac disease. CAST revealed that proar-rhythmiawithClassICdrugsisespeciallylikelyduringtimesofacute myocardial ischemia. It is likely that ischemia potentiates the effect of these drugs just as it does with both Class IA and IB drugs. In any case, flecainide and other Class IC drugs appear to have a tendency to convert an episode of angina to an episode of sudden death. Class IC drugs should be avoided in patients with known or suspected coronary artery disease. Flecainide levels may be increased by amiodarone, cimetidine, propranolol, and quinidine. Flecainide may modestly increase digoxin levels. Encainide Encainide is a Class IC drug whose electrophysiologic and clinical properties are very similar to those of flecainide. Encainide was re-moved from the market after CAST and is no longer available. Propafenone Propafenone was developed in the late 1960s and released for use in the United States in 1989. Clinical pharmacology Propafenone is well absorbed from the gastrointestinal tract and achieves peak blood levels 2–3 hours after an oral dose. It is subject to extensive first-pass hepatic metabolism that results in nonlinear kinetics—as the dosage of the drug is increased, hepatic metabolism becomes saturated; thus, a relatively small increase in dosage can produce a relatively large increase in drug levels. The drug is 90% protein bound and is metabolized by the liver. The elimination half-life is 6 or 7 hours after a steady state is reached. Generally, 3 days at a stable drug dosage achieves steady-state blood levels. ... - tailieumienphi.vn