Canadian Health&Care Mall: Antiarrhythmic Drug Therapy
Antiarrhythmic drugs remain the most widely used therapy for the management of arrhythmia. There are now seven antiarrhythmic drugs approved for oral or intravenous use in the United States, as well as several P-adrenergic blocking agents which are useful for some arrhythmias. There are many other agents in various stages of clinical investigation which may be available for use in the next few years. Each antiarrhythmic drug has a unique structure, the pharmacology and toxicity are varied, and the effect on arrhythmia in a given patient is unpredictable. It is therefore important to review this diverse class of drugs and present data about the benefits and potential hazards of their use.
The antiarrhythmic drugs have been classified based on their physiologic effects, and the following four classes have been proposed:
|Class 1: Membrane-stabilizing or local anesthetic agents (reduce conductivity, excitability, and automaticity)|
|1A: Moderate reduction in conductivity; prolongation of action potential duration (quinidine; disopyramide; procainamide); QRS and QT prolonged|
|IB: Little change in conductivity; shorten action potential duration (lidocaine; mexiletine; tocainide; eth-mozine); QRS and QT unaffected|
|1C: Marked slowing of conduction; no change in action potential duration (encainide; flecainide; propafenone; lorcainide); QRS prolonged|
|Class 2: ^-adrenergic blocking agents (propranolol; atenolol; pindolol; nadolol; timolol; acebutolol; metoprolol; labetalol)|
|Class 3: Selective increase in action potential duration and refractory period (bretylium; sotalol; bethanidine; clofilium); QT prolonged|
|Class 1: Calcium-channel blockers (verapamil; nifedipine; diltiazem; beperdil)|
The majority of the antiarrhythmic drugs in use for suppressing ventricular and supraventricular arrhythmias are classified as membrane-stabilizing or local anesthetic agents. Their major electrophysiologic effect is interference with rapid sodium conductance into the myocardial cell. As a result, there is a reduction in the velocity (dv/dt) of the action potential upstroke (phase 0) and a decrease in the maximum amplitude achieved (phase 1). The decrease in dv/dt of phase 0 results in a reduction in the velocity of impulse conduction through the myocardium. The local anesthetic drugs also prolong phase 3 repolarization of the action potential or the refractory period, especially when compared to the action potential duration. This increase in the ratio of the effective refractory period to action potential duration results in a decrease in membrane excitability. Lastly, the membrane-stabilizing drugs reduce the rate of spontaneous depolarization (phase 4), thereby reducing automaticity. The reduction in conductivity, excitability, and automaticity constitute the primary electrophysiologic effects of membrane-active drugs. The magnitude of these effects differ among the various agents. Moreover, some of these agents (such as quinidine, disopyr-amide, and procainamide) prolong the action potential duration, while others (primarily lidocaine, mex-iletine, and tocainide) shorten the duration. The drugs, encainide and flecainide, do not alter action potential duration. Follow the link bloghealthcaremall and find the information interesting to be read.
The P-adrenergic blocking drugs exert their antiarrhythmic effects by interfering with the effect of catecholamines on the heart. These drugs have no direct effect on the myocardium, although at very high concentration and in ischemic tissue, some of these agents may exert local anesthetic activity, depressing conduction and excitability.
The calcium-channel blocking drugs interfere with the slow fluxes of calcium ion into myocardial tissue. Therefore they exert effects in those tissues dependent upon calcium ion conductance, primarily the sinus node, atrioventricular node, and tissue of the atrioventricular annulus. Clinically, the arrhythmias involving the atrioventricular node respond to these agents.
The last class of antiarrhythmic drug includes those which directly prolong the action potential duration and refractory period but do not interfere with sodium conductance. The drugs of this class include bretylium and amiodarone.
Since each antiarrhythmic drug is unique, it is appropriate to review the pharmacology, toxicity, and specific indications for each of these agents (Tables 1 and 2).
Quinidine has been in clinical use as an antiarrhythmic drug since 1917 and is effective for both ventricular and supraventricular arrhythmias. It is a membrane-active drug and exerts electrophysiologic effects in all cardiac tissue. Additionally, it has mild vagolytic activity which may be important in the atrioventricular node.
Quinidine sulfate is most often administered by the oral route, and the usual dosage is 300 mg four times per day, although up to 1,600 mg/day has been used. The intravenous and intramuscular preparations are rarely used. The half-life of quinidine sulfate is six to seven hours. In general, four half-lives (or 24 hours) are required to establish a steady-state therapeutic level in the blood, which is reported to be 2|ig/ml to 5fig/ml. We have observed that the administration of a single large dose of quinidine (600 mg) results in therapeutic levels in the blood within two hours. A longer acting preparation of the drug, quinidine gluconate, can be administered two or three times daily. It is more slowly absorbed and produces blood levels which are lower than those resulting from quinidine sulfate, although levels are maintained for a longer duration. Quinidine is metabolized by the liver to inactive metabolites which are excreted in the urine. Usually the dosage does not have to be altered in the presence of mild hepatic or renal disease or in patients with congestive heart failure.
In studies in animals, quinidine has direct negatively inotropic effects; however, the drug also exerts ganglionic blocking activity and causes peripheral vasodilation and a reduction in afterload. With clinical use, quinidine does not significantly change cardiac output or other hemodynamic parameters. When quinidine is administered parenterally, hypotension resulting from vasodilatation has been reported. The drug exerts vagolytic activity which can potentially enhance conduction through the atrioventricular node; however, this is counterbalanced by its direct depressive effect on conduction, and usually there is no change in the electrophysiologic parameters of the atrioventricular node. As a result of the reduction in membrane conductivity, there is a prolongation of the QRS interval directly related to dosage and blood level. The most frequent electrocardiographic change is prolongation of the Q-T interval and flattening on the T wave, reflecting the drugs effects on repolarization. Although usually related to the blood level, Q-T prolongation may occur even when a low dosage is administered. Significant Q-T prolongation may be associated with toxic effects.
Side effects due to therapy with quinidine are common. The most frequent involve the gastrointestinal tract and include nausea, vomiting, diarrhea, and anorexia. Occasionally, these symptoms can be prevented by administration of an aluminum-containing antacid which will not interfere with absorption. In some patients, quinidine gluconate may be better tolerated. Other gastrointestinal side effects include granulomatous hepatitis and abdominal discomfort. Cinchonism is dose-related and manifests with tinnitus, nystagmus, and dizziness. Quinidine may cause a myasthenic-like state associated with profound weakness or a viral-like syndrome associated with myalgias, fever, and diaphoresis.
More serious side effects which necessitate discontinuation of the drug include fever, an allergic reaction; thrombocytopenia and hemolytic anemia, which are immunologic reactions; and quinidine-induced syncope. This latter side effect often occurs in association with Q-T prolongation, with “therapeutic” blood levels, and is a result of nonsustained ventricular fibrillation or rapid atypical ventricular tachycardia known as torsades de pointes. Aggravation of arrhythmia may occur even in the absence of QRS or Q-T prolongation. If ventricular tachycardia or ventricular fibrillation occur in association with QRS and Q-T prolongation, treatment involves a rapid lowering of the level of the drug in the blood by alkalinization using sodium bicarbonate or lactate which enhances protein-binding of the drug. Alternatively, an infusion of catecholamines such as isoproterenol will enhance the depressed conduction and shorten the prolonged refractory period. If necessary, overdrive pacing may be effective.
There are several drug interactions which have been described with quinidine. It is protein-bound and displaces warfarin, prolonging the prothrombin time. Metabolism of quinidine may be enhanced by phe-nobarbital or phenytoin which induce hepatic enzymes. Quinidine reduces the renal excretion of digoxin, prolonging its half-life, and may displace digoxin from peripheral binding sites. Reduction of the digoxin dosage may be necessary when therapy with quinidine is used concomitantly.
Quinidine is effective therapy for ventricular and supraventricular arrhythmias. It will revert or prevent atrial fibrillation (AF). Often, quinidine is administered with digoxin because of its vagolytic effect and the potential for an increase in rate response; however, the direct depressant effect offsets this, and atrioventricular nodal conduction usually is unaltered; therefore, quinidine can be administered alone for AF without the risk of rate acceleration. The drug may be of benefit for atrial flutter. In this situation, quinidine may decrease the atrial rate; and with a reduction in concealed conduction within the atrioventricular node, there may be an increase in the ventricular response rate. For example, when the atrial rate is 300 impulses per minute, there is 2:1 atrioventricular block and a ventricular response rate of 150 impulses per minute. During quinidine therapy the atrial rate may be decreased to 180 to 200 beats per minute, which is slow enough to permit 1:1 atrioventricular nodal conduction, resulting in an increased ventricular response rate. Therefore, concomitant therapy with digoxin, a P-adrenergic blocker, or a calcium-blocking drug is necessary when quinidine is administered for atrial flutter. Quinidine may be of benefit for termination and prevention of some atrial or junctional tachycardias, including those associated with preexcitation syndromes.
Quinidine is an effective agent for suppressing ventricular premature beats and preventing ventricular tachycardia and ventricular fibrillation in those with a previous history of these sustained tachyarrhythmias. Quinidine has not been demonstrated to be of benefit for preventing sudden death in patients after myocardial infarction; however, in these studies, placebo or a fixed dosage of drug was randomly administered regardless of baseline arrhythmia or the efficacy of the drug for suppression of arrhythmias.
|Drug||Dosage*||Therapeutic Blood Level,M’g/ml||Half-Life,hr||Metabolism|
|Quinidine||200-400 mg qid; 300 mg tid (gluconate)||2-5||6-7||Hepatic; inactive metabolites|
|Procainamide||500-1,000 mg qid; 500-1,500 mg tid (sustained release)||6-10||3||Hepatic to active metabolite (NAPA)t|
|Disopyramide||100-200 mg tid or qid; 100-200 mg bid (sustained release)||2-4||6-7||35% hepatic; 65% renal as unchanged drug|
|Lidocaine||100-200 mg IV (loading); 2-4 mg/min (continuous infusion)||1.5-5||15 min after 1 dose; 2 hr with constant infusion||Hepatic to inactive metabolites|
|Bretylium||10 mg/kg IV (loading); 2-4 mg/min (continuous infusion)||?||Drug effect up to 18 hr||Renal|
|Verapamil||15 mg (IV); 80-160 mg tid or qid (oral)||?||15 min (IV); 2 hr (oral)||Hepatic to inactive metabolites|
|Tocainide||200-800 mg tid||6-10||11||65% hepatic; 35% renal inactive metabolites|
|Mexiletine||200-400 mg tid||0.7-1.6||11.5||85% hepatic; inactive metabolites|
|Encainide||25-50 mg tid or qid||?||1.6-2.6||Hepatic; active metabolites|
|Ethmozine||200-400 mg tid up to 15 mg/kg/day||?||6-13||Hepatic|
|Flecainide||100-200 mg bid||<1||-20||75% hepatic; 25% renal inactive metabolites|
|Lorcainide||100-200 mg bid (oral); 400 mg/day (IV)||0.15-0.4||7.6||Hepatic; active metabolites|
|Propafenone||150-300 mg tid||0.5-3.0||6||Hepatic; metabolites activity|
|Amiodarone||Loading, 600-1,800 mg; maintenance, 200-600 mg||1-2||30-60 days||Deiodination; hepatic; active metabolites|
Table 2—Clinical Effects
|Quinidine||Direct negative inotrope;||P-R, QRS, and Q-T||GI; hematologic; hepatic;||Ventricular and supraventricular|
|peripheral vasodilatation||may prolong||fever; syncope||arrhythmia|
|and afterload reduction|
|Procainamide||Direct negative inotrope;||P-R, QRS, and Q-T||GI; CNS; lupus||Primarily ventricular|
|peripheral vasodilatation||may prolong||arrhythmias|
|and afterload reduction|
|Disopyramide||Negative inotrope||P-R, QRS,and Q-T may prolong||Anticholinergic; CHF||Ventricular and supraventricular arrhythmias|
|Lidocaine||None||None||CNS; GI||Ventricular arrhythmia|
|Bretylium||Increased cardiac output;||None||GI; orthostatic||Refractory ventricular|
|hypotension||hypotension||tachycardia or fibrillation|
|Verapamil||Negative inotrope;||Prolong P-R||GI; headache; peripheral||Supraventricular tachycardia;|
|peripheral vasodilatation||edema; CHF;||rate control in atrial|
|and afterload reduction||conductionabnormalities||fibrillation and atrial flutter|
|Tocainide||None||None||GI; CNS||Ventricular arrhythmia|
|Mexiletine||None||None||GI; CNS||Ventricular arrhythmia|
|Encainide||None||Prolonged P-R and QRS||GI; CNS||Ventricular and supraventricular arrhythmia|
|Ethmozine||Mild negative inotrope||May prolong P-R||GI; rash; CNS;||Ventricular and ?|
|and QRS||cholinergic||supraventricular arrhythmia|
|Flecainide||Negative inotrope||P-R and QRS||CNS; GI; headache;||Ventricular and supraventricular|
|Lorcainide||None||None||GI; CNS; sleep disorders||Ventricular arrhythmia|
|Propafenone||Negative inotrope||P-R prolongation||GI; CHF; conduction abnormalities||Ventricular and supraventricular arrhythmia|
|Amiodarone||Negative inotrope; a and p||P-R and Q-T||microdeposits; GI; CNS;||Ventricular and supraventricular|
|blockade; peripheral||prolongation; U||dermatologic; thyroid||arrhythmia|