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Antiarrhythmic Drug Therapy (Part 1) Benefits and Hazards
IOday'S practice 01 cardiopulmOnary medicine Antiarrhythmic Drug Therapy (Part 1)* Benefits and Hazards Philip]. Podrid, M.D ., F.C.C.P.
ktiarrhythmic 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 Bvadrenergic 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 . ELECfROPHYSIOLOGIC EFFECTS
The antiarrhythmic drugs have been classified based on their physiologic effects, and the following four classes have been proposed:' Class I : Membrane-stabilizing or local anesthetic agents (reduce conductivity, excitability, and automaticity) IA: Moderate reduction in conductivity; prolongation of action potential duration (quinidine; disopyramide; procainam ide); QRS and QT prolonged IB: Little change in conductivity; shorten action potential duration (lidocaine; mexiletine; tocainide ; ethmozine); QRS and QT unaffected IC: Marked slowing of conduction; no change in action potential duration (encainide: flecainide ; propafenone ; lorcainide); QRS prolonged Class 2: l3-adrenergic blocking agents (propranolol; atenolol . plndolol, nadolol, timolol: aeebutolol: metoprolol , labetalol) Class 3: Select ive increase in action potential durat ion and refractory period (bretylium; sotalol, bethanidine; clofilium); QT prolonged Class 1: Calcium-channel blockers (verapamil: nifedipine; diltiazem ; beperdil) ·From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health, and the Cardiovascular Division, Department of Medicine, Brigham and Womens Hospital, Boston. Supported in part by grant HL-07776 from the National Heart, Lung, and Blood Institute and by the Rappaport International Program in Cardiology, Boston. Part 2 will appear in next month's issue of Chest . Reprint requests : Dr: Podrid, 221 Longwood Avenue , 80ston 02115
452
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.v' 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, disopyramide, and procainamide) prolong the action potential duration, while others (primarily lidocaine, mexiletine, and tocainide) shorten the duration. The drugs, encainide and flecainide, do not alter action potential duration . The l3-adrenergic blocking drugs exert their ant iarrhythmic 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. 4 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 involvAntiarrhythmic Drug Therapy (part I) (Philip J. Podrld)
Table i-Pharmacology
Drug Quinidine
Dosage*
Therapeutic Blood Level, f.Lglml
Half-Life, hr
MetaboUsm
200-400 mg qid, 300 mg tid
2-5
6-7
Hepatic; inactive metabolites
6-10
3
Hepatic to active metabolite (NAPA)t
2-4
6-7
1.5-5
15 min after 1 dose ; 2 hr with constant infusion
Hepatic to inactive metabolites
?
Drug effect up to 18 hr
Renal
?
15 min (IV); 2 hr (oral)
Hepatic to inactive metabolites 65% hepatic; 35% renal inactive metabolites 85% hepatic; inactive metabolites Hepatic; active metabolites Hepatic
Tocainide
(gIuconate) 500-1,000 mg qtd , 500-1,500 mg tid (sustained release) 100-200 mg tid or qid, 100-200 mg bid (sustained release) 100-200 mg IV (loading); 2-4 mglmin (continuous infusion) 10 mglkg IV (loading); 2-4 mglmin (continuous infusion) 15 mg (IV); 80-160 mg tid or qid (oral) 200-800 mg tid
Mexiletine
200-400 mg tid
Encainide Ethmozine
200-400 mg tid up to 15
Flecainide
mglkglday 100-200 mg bid
Procainamide
Disopyramide
Lidocaine
Bretylium
Verapamil
Lorcainide Propafenone Amiodarone
25-50 mg tid or qid
100-200 mg bid (oral); 400 mglday (IV) 150-300 mg tid Loading, 600-1,800 mg: maintenance, 200-600 mg
6-10
11
0.7-1.6
11.5
? ?
1.6-2.6 6-13
<1
-20
0.15-0.4
7.6
0.5-3 .0 1-2
6 30-60 days
35% hepatic; 65% renal as unchanged drug
75% hepatic; 25% renal inactive metabolites Hepatic; active metabolites Hepatic; metabolites activity Deiodination; hepatic; active metabolites
*qid, Four times daily ; tid, three times daily; bid , twice daily; and IV, intravenous. tNAPA, N-acetyl procainamide.
ing 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
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. 6 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 mglday 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 2JLglmi to 5JLglmi. 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 CHEST I 88 13 I SEPTEMBER. 1985
453
Table 2-Clinical Effects Drug QUinidine
Procainam ide
Disopyramtde Lidocaine Bretylium Verapamil
Hemodynamics
ECC
Side Effects"
Indication
Direct negative inotrope; peripheral vasodilatation and afterload reduction Direct negative inotrope; peripheral vasodilatation and afterload reduction Negative inotrope
P-R, QRS, and Q-T may prolong
CI ; hematologic; hepatic; fever; syncope
Ventricular and supraventricular arrhythmia
P-R, QRS, and Q-T may prolong
CI ; CNS ; lupus
Primarily ventricular arrhythmias
P-R, QRS,and Q-T may prolong None None
Anticholinergic; CHF
Ventricular and supraventricular arrhythmias Ventricular arrhythmia Refractory ventricular tachycardia or fibrillation Supraventricular tachycardia; rate control in atrial fibrillation and atrial flutter
None Increased cardiac output; hypotension Negative inotrope; peripheral vasodilatation and afterload reduction
Tocainide Mexiletine Encainide
None None None
Ethmozine
Mild negative inotrope
Flecainide
Negative inotrope
Lorcainide Propafenone
None Negative inotrope
Amiodarone
Negative inotrope; Q and blockade; peripheral vasodilatation and afterload reduction
Prolong P-R
None None Prolonged P-R and QRS May prolong P-R and QRS P·R and QRS prolongation None P-R prolongation ~
P-R and Q-T prolongation ; U waves
CNS ; CI CI; orthostatic hypotension CI ; headache; peripheral edema; CHF; conduction abnormalities CI ; CNS CI ; CNS CI ; CNS CI ; rash; CNS ; cholinergic CNS ; CI ; headache; visual disturbances CI; CNS ; sleep disorders CI ; CHF; conduction abnormalities microdeposits; CI ; CNS ; dermatologic; thyroid abnormalities; conduction abnormalities; pulmonary
Ventricular arrhythm ia Ventricular arrhythmia Ventricular and supraventricular arrhythmia Ventricular and ? supraventricular arrhythmia Ventricular and supraventricular arrhythm ia Ventricular arrhythmia Ventricular and supraventricular arrhythmia Ventricular and supraventricular arrh ythmia
·CI, gastrointestinal; CNS , central nervous system; and CHF, congestive heart failure . All drugs aggravate arrhythmia.
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. 9 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." Toxic Effects
Side effects due to therapy with quinidine are common . U 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 4S4
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 Antiantlythmlc Drug Therapy (part I) (Philip J. Podrld)
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 phenobarbital 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.
Clinical Use 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 l3-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 taehyarrhythmias. 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. DISOPYRAMIDE
Disopyramide is a membrane-active drug which affects all myocardial tissue and has electrophysiologic
effects similar to those of quinidine. 14 Disopyramide is available for oral use only, and the usual daily dosage is 300 to 800 mg in three or four divided doses. We have occasionally administered a loading dose of 300 mg to rapidly assess antiarrhythmic effect and achieve a steady-state level in a brief period of time . There is a long-acting preparation of disopyramide which can be administered twice daily. It is slowly absorbed, producing a steady-state level in the blood which is stable over a prolonged period of time . The half-life of disopyramide is six to seven hours, and therapeutic blood levels range from 2....g/ml to 4....g/ml. Only 35 percent of the drug is metabolized by the liver to inactive metabolites, while the remainder is cleared unchanged by the kidney. IS In the presence of renal insufficiency, the dosage must be reduced.
Electrocardiographic Changes Disopyramide may prolong the QRS or Q-T interval, and these changes are usually related to the level in the blood," however, similar to quinidine, there may be an idiosyncratic prolongation of the Q-T interval even with low levels in the blood. Prolongation of the Q-T interval has been associated with cardiac toxic effects. Like quinidine, disopyramide has a mild vagolytic effect which enhances atrioventricular nodal conduction, but counterbalancing this is a direct depressive effect. In most patients, there is no change in the P-R or atrio-His (A-H) interval. IS Disopyramide possesses significant negatively inotropic activity and will reduce cardiac output. 17 It does not have any direct effect on peripheral vascular resistance, but because of reduction in stroke volume, there is a reflex increase in peripheral vascular resistance. In our experience, disopyramide exacerbates congestive heart failure in 55 percent of the patients with a history ofleft ventricular dysfunction, while the incidence is 5 percent in those without a history of failure. 18 As evaluated with radionuclide angiography, disopyramide reduced the contractility in all abnormal myocardial segments, regardless of the underlying heart disease, while normal segments were unaffected."
Side Effects Side effects are common with disopyramide. The most frequent are anticholinergic, including dry mouth, dry eyes, blurred vision, constipation, vaginal dryness, and urinary retention. These are usually related to the dosage and blood level. Other side effects include nausea, vomiting, dizziness, and insomnia. The most serious adverse reactions are those affecting the cardiovascular system. There is a significant incidence of congestive heart failure in patients with cardiomegaly or a history of congestive heart failure. 18 Disturbances in atrioventricular nodal conduction CHEST I 88 13 I SEPTEMBER, 1985
455
have been reported. Similar to other drugs, disopyramide can aggravate ventricular arrhythmia. and "disopyramide syncope" associated with Q-T prolongation has been described." Electromechanical dissociation has occurred in patients with renal insufficiency when the serum level of the drug is very high. Disopyramide does not affect digoxin levels, and there is no interaction with warfarin. Caution is necessary when administering this drug with 13-adrenergic blocking agents or calcium antagonists which can also depress left ventricular function . Clinical Use
Disopyramide is effective for conversion and prevention of atrial fibrillation and is an alternative agent when quinidine is either poorly tolerated or ineffective. The drug may be effective for atrial flutter. but like quinidine. it may slow the atrial rate and result in an increase in the ventricular response. Blockade of atrioventricular nodal conduction is therefore necessary. The drug may be effective for preventing supraventricular tachycardia. The major use for disopyramide is in the treatment of ventricular arrhythmia. It is effective for suppression of all types of ventricular ectopy ; and in patients with a history of ventricular tachycardia and ventricular fibrillation. it will prevent a recurrence. Studies involving the administration of disopyramide or placebo in patients after a myocardial infarction have not demonstrated a reduction in mortality:" however, as with the studies involving other agents, the drug was randomly used without consideration of the baseline arrhythmia or the effect of the drug on its suppression. PROCAINAMIDE
Procainamide is a membrane-active drug possessing electrophysiologic properties similar to those of disopyramide and quinidine." It is available for oral and intravenous administration. The intravenous dosage is generally 100 mg infused every five minutes up to 1 to 1.5 g. The total dose administered should be titrated to its effect on arrhythmia, QRS widening, and the occurrence of side effects. The oral dosage is usually 3 to 6 g daily in four to six divided doses. Frequent dosing is necessary because of a short half-life, approximately three hours . There is a sustained-release preparation of procainamide available which permits dosing three or four times per day. The reported therapeutic plasma level is 6fJoglml to lOfJoglml. The drug is rapidly metabolized in the liver by acetylation to an active metabolite. N-acetyl procainamide." The presence of congestive heart failure or hepatic disease does not affect metabolism or blood levels, and a change in dosage is not necessary. Since the metabolite accumulates in the presence of renal insufficiency, reduction of dosage is necessary. Il3
Procainamide may cause prolongation in the P-R. QRS, and Q-T interval related to the blood level, although such changes occur less often than with quinidine." Like quinidine and disopyramide, procainamide exerts vagolytic effects on the atrioventricular node, but this is balanced by direct depression of atrioventricular nodal electrophysiologic properties. Procainamide exerts direct negatively inotropic activity, reducing left ventricular contractility.' however, it is a ganglionic blocker and causes peripheral vasodilatation. The decrease in afterload maintains cardiac output in most patients, and the precipitation of congestive heart failure is unusual. Side Effects
Side effects with procainamide are common. Z4 Often observed are gastrointestinal toxic effects, including nausea, vomiting, and anorexia. Central nervous system side effects include insomnia, fatigue, and tremors. Fever is a result of an allergic reaction. Agranulocytosis is a rare side effect, but there have been several reports of this complication with the use of the long-acting preparations. The most frequent side effect is the development of a positive antinuclear antibody titer or lupus erythematosus preparation. which occurs in up to 90 percent of the patients receiving the drug. 50 percent of whom will develop a lupus-like syndrome. 25 This generally occurs several months after initiation of procainamide therapy. and symptoms may persist for up to six months after the drug has been discontinued. Patients who have slow acetylation and have low levels of N-acetyl procainamide tend to have high antinuclear antibody titers early in therapy" and are more likely to develop lupus. Clinical Indications
Procainamide may be effective for some supraventricular arrhythmias. especially those occurring after surgery; however, it is less effective than quinidine and disopyramide and is not a first-line drug . The major role for procainamide is in the treatment of ventricular arrhythmia. The drug can be administered intravenously, and serious arrhythmias can be treated rapidly. Long-term oral therapy will prevent recurrence ofarrhythmia. Randomized studies with placebo or drug in patients after myocardial infarction have reported that procainamide appears to reduce mortality. but the number of patients studied is small. 25 LIDOCAINE
Lidocaine is a widely used antiarrhythmic drug which is effective for immediate suppression of serious ventricular arrhythmias occurring in a variety of clinical settings." It is only available for intravenous Antiarrhythmic Drug Therapy (part I) (Philip J. Podrtd)
use, since a short half-life precludes oral use. The dosage is 100 to 200 mg by bolus, followed by a continuous intravenous infusion of2 to 4 mg/min. The serum half-life of a single bolus of lidocaine is only 15 minutes, as it is rapidly distributed to peripheral stores . When a continuous intravenous infusion is initiated, more than one hour is required to achieve a steady-state level. During this time, levels oflidocaine may be subtherapeutic, and recurrent arrhythmia should be treated with additional boluses oflidocaine. During continuous infusion the drug is widely and rapidly distributed to peripheral stores, being avidly bound to adipose tissue ." With discontinuation of the intravenous infusion, the adipose stores will maintain blood levels for up to two hours. The drug is rapidly metabolized during a first-pass effect in the liver to inactive metabolites. In the presence of hepatic dysfunction or severe congestive failure, the dosage of lidocaine should be reduced. 29 Lidocaine does not alter the surface electrocardiogram; and the P-R, QRS, and Q-T intervals are not affected, making the drug safe in patients with conduction abnormalities. Lidocaine does not affect cardiac output or other hemodynamic parameters, and it can be safely administered to patients with congestive heart failure. Side Effects The majority of side effects caused by lidocaine are related to the infusion rate and serum level achieved. The most frequent toxic effects involve the central nervous system and include tremors, light-headedness, dizziness, increased agitation, changes in personality and mood, psychosis, lethargy, somnolence and, rarely, seizures . Gastrointestinal side effects include nausea and vomiting. Rarely, lidocaine may produce hypotension or rash. Clinical Indication The most important role for lidocaine is in the acute setting where rapid control of a serious ventricular arrhythmia is necessary. It is effective and safe in patients who have myocardial infarction, and its prophylactic use in this setting reduces the incidence of ventricular fibrillation. The drug is very effective in patients with serious ventricular arrhythmias associated with other clinical situations; however, it can only be administered intravenously, and if long-term therapy is necessary, another oral drug must be used . BRETYLIUM
Bretylium is an antiarrhythmic agent derived from guanethidine. It depletes catecholamines and thus exerts antisympathetic activity. The direct electrophysiologic effects of the drug are a prolongation of the action potential duration and increase of the refractory period.30
Bretylium is only available for intravenous use, and the usual dose is 10 mg/kg by bolus, followed by a continuous intravenous infusion of2 to 4 mg/min. The antiarrhythmic effect of the drug may be observed for several hours after a single dose, and a continuous infusion may not be necessary. Bretylium does not substantially change the QRS interval, but there may be slight prolongation of the P-R and Q-T intervals because of the drug's antisympathetic effect. Bretylium has a direct positively inotropic effect, but the mechanism is unclear. After the initial bolus, there may be a hypertensive response and a sinus tachycardia due to elevated levels of circulating catecholamtnes," however, with continuous infusion, catecholamines are depleted, resulting in a decrease in peripheral vascular resistance which may cause hypotension and an augmentation in cardiac output. Toxic Effects The major side effects of bretylium result from its antisympathetic activity. The most frequent is the development of orthostatic hypotension, which may persist for a prolonged period after the drug is discontinued . Other side effects include nausea and vomiting. Clinical Indication Bretylium is often administered for sustained ventricular tachyarrhythmias refractory to intravenous therapy with lidocaine or procainamide." When used in patients with refractory ventricular fibrillation, bretylium may produce spontaneous defibrillation without the need for electrical reversion." In our experience, it is most effective for ventricular tachycardias with rapid rates, while slower ventricular tachycardias revert less often . After the termination of the ventricular tachyarrhythmia, there may be frequent ventricular premature beats due to elevated levels of circulating catecholamines . For continued long-term therapy an oral antiarrhythmic agent must be administered. CALCIUM ANTAGONISTS
There are three calcium-channel blocking drugs available, but only verapamil possesses significant clinical antiarrhythmic effects. Since the drug affects calcium ion fluxes in the sinus and atrioventricular nodes, the major use for verapamil is for therapy of arrhythmias which involve the atrioventricular node, specificallyjunctional tachycardia and atrial flutter and fibrillation.3< Verapamil is available for both intravenous and oral use. The intravenous dosage is 5 mg every three to five minutes up to 15 mg. The oral dosage is 80 to 160 mg three to four times per day. There is rapid metabolism due to a first-pass effect in the liver, accounting for the CHEST I 88 I 3 I SEPTEMBER. 1985
457
disparity in the intravenous and oral dosages. The halflife of the intravenous drug is only 15 minutes, while the effect of the oral drug may last up to six hours. The metabolites are not active. 35 Verapamil is a direct negatively inotropic agent, but it also produces peripheral vasodilatation and a reduction in afterload which maintains cardiac output," however, in the presence of severe left ventricular dysfunction , or when peripheral resistance is already reduced, verapamil may precipitate hypotension or congestive heart failure. Verapamil is directly negatively chronotropic and may depress sinus rate and prolong recovery time of the sinus node ; however, the reduction in peripheral vascular resistance usually leads to a reflex increase in sympathetic tone, which maintains sinus rate. The drug slowsconduction through and prolongs the refractory period of the atrioventricular node, resulting in an increase of the P-R interval. It does not alter QRS or Q-T intervals. Toxic Effects
The most common side effects include nausea, vomiting, and constipation. As a result of vasodilatation, dizziness, headaches, and peripheral edema occur. The most serious side effects are those which affect the cardiovascular system including hypotension, bradycardia, conduction disturbances, and congestive heart failure. There is a dose-related interaction between digoxin and verapamil which is similar to that with quinidine and is a result of a reduction in digoxin clearance." Beta-adrenergic blockers and verapamil may have additive effects on the sinus and atrioventricular nodes and on left ventricular function. There have been reports of cardiovascular collapse when verapamil is administered along with disopyramide. When used in patients with atrial fibrillation, regularization of the R-R intervals due to atrioventricular nodal blockade may be observed, especially at night, when vagal tone is high, or with concomitant digoxin therapy. Clinical Indications
Verapamil is primarily useful for supraventricular arrhythmias. With intravenous use, 90 percent of supraventricular tachycardias will revert," and orally administered verapamil may be effective for preventing supraventricular tachycardia. The drug generally does not revert atrial Butter or atrial fibrillation but will slow the ventricular response rate ." Oral verapamil is very effective for improving rate control in patients with chronic atrial fibrillation." Verapamil is ineffective for the treatment of ventricular arrhythmia.40 BETA-ADRENERGIC BLOCKERS
In the United States, there are now eight ~-adre nergic blockers available which include propranolol, 458
nadolol, timolol , metoprolol, pindolol , atenolol, acebutolol, and labetalol. Only propranolol is approved for arrhythmia, but each of the ~-adrenergic blocking agents may be effective. In general, these drugs are not first-line agents for the treatment of arrhythmia except in specific cases in which catecholamines induce or maintain the arrhythmia. 41 Usual doses of beta-adrenergic blockers have no direct antiarrhythmic effect on myocardial tissue but interfere with the action of catecholamines on the heart. 42 Although each of these drugs share similar antiarrhythmic activity, they differ in potency, potential for membrane stabilization, the presence of intrinsic sympathomimetic activity, cardioselectivity, and lipid solubility (Table 3). The dose of the individual drug is best guided by its physiologic effect, specifically the reduction of resting and exercise heart rates. Metabolism varies and is dependent upon lipid solubility. Those drugs which are lipid-soluble , such as propranolol and metoprolol, undergo rapid first-pass metabolism by the liver and have a short half-life, while others, such as atenolol and nadolol, are not lipid-soluble . They are not metabolized but are cleared by the kidney unchanged. Each of the ~-adrenergic blockers are indirectly negatively inotropic agents resulting from blockade of catecholamine effect on the heart. The amount of myocardial depression varies among the agents, and those with intrinsic sympathomimetic activity have less of an effect.43 Each l3-adrenergic blocker is negatively chronotropic and will decrease resting heart rate, although those agents with intrinsic sympathomimetic activity have less of an effect.43 A prolongation of P-R interval associated with the reduction in heart rate is common. There is no change in the QRS interval, while the Q-T interval may shorten. Toxic Effects
Although the frequency and intensity of side effects vary among the agents, adverse reactions associated with this class of drugs are diverse . Most serious are those of the cardiovascular system and include conTable 3-Beta-Adrenergic Blocker Pharmacology Cardia-
Drug
BetaBlocking Potency
Acehutolol Atenolol Labetalol Metoprolol Nadolol Pindolol Propranolol Timolol
0.3 1 0.7 0.8 1 4-7 1 6
+ +
selectivity
0
+ 0 0 0 0
ISA*
Membrane StabiIizing
Lipid Solubility
+
+
0 0 Weak Weak 0 Weak Strong 0
0 0 0 0
++ 0 0
0
+ ::t
0
+ ++ 0
*ISA, Intrinsic sympathomimetic activity. Antiarrhythmic Drug Therapy (part I) (Philip J. Podrtd)
gestive heart failure, conduction abnormalities, hypotension, symptomatic bradycardia, and vasoconstriction resulting in claudication and Raynaud's phenomenon. Bronchospasm and provocation of asthma may occur in patients with a history of pulmonary problems. Gastrointestinal side effects include nausea, vomiting, and diarrhea or constipation . Toxic effects on the central nervous system include depression, dizziness, insomnia, nightmares, fatigue, and changes in mood and personality. A change in urinary function and impotency are common . Clinical Indications
Beta-adrenergic blockers are not first-line agents for the treatment of any specific arrhythmia, except in cases where the arrhythmia is associated with elevated catecholamine levels such as occurs with hyperthyroidism, exercise, or in the postoperative state . Catecholamine-induced sinus tachycardia , atrial tachycardia, atrial fibrillation, atrial flutter, junctional tachycardia, and ventricular arrhythmia may respond. In our experience, l3-adrenergic blockers are most effective when used as adjunct therapy in combination with membrane-stabilizing agents, resulting in a synergistic effect.44 As with calcium blocking drugs, l3-adrenergic blockers are effective for controlling the ventricular rate during atrial fibrillation or atrial flutter. There are a number of studies which demonstrate that most of the l3-adrenergic blockers administered prophylactically to patients after a recent myocardial infarction will reduce cardiac mortality, especially the incidence of sudden death .~.46 The mechanism of this protective effect is unknown . REFERENCES 1 Vaughan Williams EM . Classification of antiarrhythmic drugs. In : Sandoe E, Flensted-Jensen E, Olsen E, eds. Symposium on cardiac arrhythmias. Sodertalje, Sweden: AB Astra, 1970:449-72 2 Chen CM, Gettes LS, Katzung BG. Effect of lidocaine and quinidine on steady state characteristics and recovery kinetics of dv-/dt",... in guinea pig ventricular myocardium. Circ Res 1975; 37:20-9 3 Rosen MR, Wit AL. Electropharmacology of antiarrhythmic drugs . Am Heart J 1983; 106:829-39 4 Coltart DJ, Gibson DG, Shand DG. Plasma propranolol levels associated with suppression of ventricular ectopic beats. Br Med J 1971;1:490-91 5 Hoffman BF, Rosen MR, Wit AL. Electrophysiology and pharmacology of cardiac arrhythmias: 7. cardiac effects of quinidine and proeainamide . Am Heart J 1975;90:117-22 6 Josephson ME, Seides SF, Batsford Wp, Weisfogel BM, Akhtar M, Caracts AR, et al, The electrophysiologic effects of intramuscular quinidine on the atrioventricular conducting system in man. Am Heart J 1977; 87:55-64 7 Anglakos ET, Hastings EP. The influence of quinidine and proeainamide on myocardial contractility in vivo. Am J Cardiel 1960; 6:791-98 8 Ferrer MI, Harvey M, Werko L, Dresdale DT, Cournand A, Richards DW. Some effects of quinidine sulfate on the heart and circulation in man. Am Heart J 1948; 36:816-37
9 Heissenbuttel RH, Bigger JT. The effect of oral quinidine on intraventricular conduction in man : correlation of plasma quinidine with changes in QRS duration . Am Heart J 1970; 80:453-57 10 Selzer AH, Wray AW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias . Circulation 1964; 30:17-26 11 Cohen IJ, Hershel J, Cohen SI. Adverse reactions to quinidine in hospitalized patients : findings based in data from the Boston Collaborative Drug Surveillance Program. Prog Cardiovasc Dis 1977; 20:151-63 12 Bigger JT. The quinidine-digoxin interaction. Am Heart J 1982; 51:73-8 13 Holmberg S, Bergman H. Prophylactic quinidine treatment in myocardial infarction. Acta Med Scand 1967; 181:297-304 14 Sekiya A, Vaughan Williams EM. A comparison of the antifibrillatory actions and effects on intracellular cardiac potentials of pronethalol , disopyramide and quinidine. Br J Pharmacal 1963; 21:473-81 15 Karim A. Pharmacokinetics of Norpace. Angiology 1975; 26(suppl 1):85-92 16 Josephson ME, CaractaAR, Law S1; Gallagher JJ, Damato AN. Electrophysiological evaluation of disopyramide in man. Am Heart J 1973; 86:771-80 17 Jensen GB, Sigard B, Uhrenholt A. Circulatory effects of intravenous disopyramide in heart failure. J Intern Med Res 1976; 4(suppl 1):42-5 18 Podrid PJ, Schoeneberger A, Lown B. Congestive heart failure caused by oral disopyramide . N Eng) J Med 1980; 302:614-17 19 KoweyPR, Friedman RL, Podrid PJ, Zielonka J, Lown B, Wynn J, et al. Use of radionuclide ventriculography for assessment of changes in myocardial performance induced by disopyramide phosphate. Am Heart J 1982; 104:769-74 20 Meltzer RS, Robert WE, McMorrow M. Atypical ventricular tachycardia as a manifestation of disopyramide toxicity. Am J Cardiel 1978; 42:1049 21 Jennings G, Jones MBA, Besterman EMM , Model DG, Turner pp, Kidner PH. Oral disopyramide in prophylaxis ofarrhythmias following myocardial infarction. Lancet 1976; 1:51-4 22 Giardina EGV, Dreyfuss J, Bigger IT, Shaw JM, Schreiber EC. Metabolism of proeainamide in normal cardiac subjects . Clin Pharmacal Ther 1970; 19:339-51 23 Drayer DE , Lowenthal DT, Woosley RL, Nies AS, Schwartz A, Reidenberg MM. Cumulation of N-acetyl proeainamide-an active metabolite of proeainamide in patients with impaired renal function. Clin Pharmacal Ther 1977; 22:63-9 24 Koch Weser J, Klein SM. Proeainamide dosage schedules, plasma concentrations and clinical effects. JAMA 1971; 215:
1454-60 25 Koswosky B, Taylor PJ, Lown B, Ritchie RF. Long term use of proeainamide following acute myocardial infarction. Circulation 1973; 42:1204-10 26 Woosley RL, Drayer DE, Reidenberg MM, Nies AS, Carr K, Vates JA. Effect of acetylator phenotype on the rate at which proeainamide induces antinuclear antibodies and the lupus syndrome . N Eng) J Med 1978; 298:1157-59 27 Lown B, Vassaux C. Lidocaine in acute myocardial infarction. Am Heart J 1968; 76:586-87 28 Benowitz N, Forsyth RP, Melman KL, Rowland M. Lidocaine disposition kinetics in monkeys and man: 1. prediction by a perfusion model. Clin Pharmacal Ther 1974; 16:87-92 29 Thomson PD, Melman KL, Richardson JA, Cohen K, Steinbrunn W, Cudihee R, et al, Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans . Ann Intern Med 1973; 78:499-504 30 Bacaner MB. Quantitative comparison of bretylium with other antifibrillatory drugs. Am J Cardioll968; 21:504-12 CHEST I 88 13 I SEPTEMBER, 1985
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31 Chatterjee K, Mandel WJ, Vyden JK, Parmley WW, Forrester JS. Cardiovascular effects ofbretylium tosylate in acute myocardial infarction. JAMA 1983; 223:757-60 32 Bacaner MB. Treatment of ventricular fibrillation and other acute arrhythmias with bretylium tosylate. Am J Cardioll968; 21:43035 33 Arcidiancono R. Use ofbretylium tosylate in ventricular fibrillation . Clin Ther 1978; 84:253-66 34 Sung RL, Elser B, McAllister RG. Intravenous verapamil for termination of reentrant supraventricular tachycardias. Ann Intern Med 1980; 93:682-89 35 Rosen MR, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias: 6. cardiac effects of verapamil. Am Heart J 1975; 89:665-73 36 Singh BN, Hecht HS, Nademanee K. Electrophysiologic and hemodynamic actions of slow channel blocking compounds. Prog Cardiovasc Dis 1982; 25:103-32 37 Klein HD, Lang R, Weiss E , Desegni E , Libhober L, Guerrero J, et aI. The influence of verapamil on serum digoxin concentration. Circulation 1982; 65:998-1003 38 Schamroth L. Immediate effects of intravenous verapamil on atrial fibrillation . Cardiovasc Res 1981; 5:419-24 39 Klein HD, Pauzner H , Di Segni E , David D, Kaplinsky E . The beneficial effects of verapamil in chronic atrial fibrillation . Arch Intern Med 1979; 139:74749 40 Wellens HJJ, Bar FW, Lie KI, Durrer DR, Dohmen HJ. Effects
480
41
42
43
44
45
46
of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with recurrent ventricular tachycardia. Am J CardioI1977; 40:579-85 Podrid PJ, Lawn B. Use of beta-adrenergic blocking agents for cardiac arrhythmias. In : Kostis JP, DeFelice EA, eds . Beta blockers in the treatment of cardiovascular disease. New York: Raven Press, 1984:121-54 Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias: 9. cardiac electrophysiologic effects of beta-adrenergic receptor stimulation and blockade: part C. Am Heart J 1975; 90:797-803 Frishman W, Davis R, Strom J, EI Rayam A, Stampfer M, Rebner H, et al, Clinical pharmacology of the new beta-adrenergic blocking drugs: part 5. pindolol (LB-46) therapy for supraventricular arrhythmia: a viable alternative to propranolol in patients with bronchospasm. Am Heart J 1979; 98:393-98 Hirsowitz GS, Podrid P, Lampert S, Stein J, Lawn B. The use of beta blocking agents as adjunct therapy in the treatment of malignant ventricular arrhythmia. J Am Coli Card 1984; 3:619 Beta Blocker Heart Attack Thai Research Group. A randomized trial of propranolol on patients with acute myocardial infarction: 1. mortality results. JAMA 1982; 297:1707-14 Norwegian Multicenter Study Group. TImolol induced reduction in mortality and reinfarction in patients surviving an acute myocardial infarction. N Eng! J Med 1981; 304:801-06
Antiarrhythmic Drug Therapy (part I) (Philip J. Podrld)
ktiarrhythmic 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 Bvadrenergic 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 . ELECfROPHYSIOLOGIC EFFECTS
The antiarrhythmic drugs have been classified based on their physiologic effects, and the following four classes have been proposed:' Class I : Membrane-stabilizing or local anesthetic agents (reduce conductivity, excitability, and automaticity) IA: Moderate reduction in conductivity; prolongation of action potential duration (quinidine; disopyramide; procainam ide); QRS and QT prolonged IB: Little change in conductivity; shorten action potential duration (lidocaine; mexiletine; tocainide ; ethmozine); QRS and QT unaffected IC: Marked slowing of conduction; no change in action potential duration (encainide: flecainide ; propafenone ; lorcainide); QRS prolonged Class 2: l3-adrenergic blocking agents (propranolol; atenolol . plndolol, nadolol, timolol: aeebutolol: metoprolol , labetalol) Class 3: Select ive increase in action potential durat ion and refractory period (bretylium; sotalol, bethanidine; clofilium); QT prolonged Class 1: Calcium-channel blockers (verapamil: nifedipine; diltiazem ; beperdil) ·From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health, and the Cardiovascular Division, Department of Medicine, Brigham and Womens Hospital, Boston. Supported in part by grant HL-07776 from the National Heart, Lung, and Blood Institute and by the Rappaport International Program in Cardiology, Boston. Part 2 will appear in next month's issue of Chest . Reprint requests : Dr: Podrid, 221 Longwood Avenue , 80ston 02115
452
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.v' 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, disopyramide, and procainamide) prolong the action potential duration, while others (primarily lidocaine, mexiletine, and tocainide) shorten the duration. The drugs, encainide and flecainide, do not alter action potential duration . The l3-adrenergic blocking drugs exert their ant iarrhythmic 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. 4 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 involvAntiarrhythmic Drug Therapy (part I) (Philip J. Podrld)
Table i-Pharmacology
Drug Quinidine
Dosage*
Therapeutic Blood Level, f.Lglml
Half-Life, hr
MetaboUsm
200-400 mg qid, 300 mg tid
2-5
6-7
Hepatic; inactive metabolites
6-10
3
Hepatic to active metabolite (NAPA)t
2-4
6-7
1.5-5
15 min after 1 dose ; 2 hr with constant infusion
Hepatic to inactive metabolites
?
Drug effect up to 18 hr
Renal
?
15 min (IV); 2 hr (oral)
Hepatic to inactive metabolites 65% hepatic; 35% renal inactive metabolites 85% hepatic; inactive metabolites Hepatic; active metabolites Hepatic
Tocainide
(gIuconate) 500-1,000 mg qtd , 500-1,500 mg tid (sustained release) 100-200 mg tid or qid, 100-200 mg bid (sustained release) 100-200 mg IV (loading); 2-4 mglmin (continuous infusion) 10 mglkg IV (loading); 2-4 mglmin (continuous infusion) 15 mg (IV); 80-160 mg tid or qid (oral) 200-800 mg tid
Mexiletine
200-400 mg tid
Encainide Ethmozine
200-400 mg tid up to 15
Flecainide
mglkglday 100-200 mg bid
Procainamide
Disopyramide
Lidocaine
Bretylium
Verapamil
Lorcainide Propafenone Amiodarone
25-50 mg tid or qid
100-200 mg bid (oral); 400 mglday (IV) 150-300 mg tid Loading, 600-1,800 mg: maintenance, 200-600 mg
6-10
11
0.7-1.6
11.5
? ?
1.6-2.6 6-13
<1
-20
0.15-0.4
7.6
0.5-3 .0 1-2
6 30-60 days
35% hepatic; 65% renal as unchanged drug
75% hepatic; 25% renal inactive metabolites Hepatic; active metabolites Hepatic; metabolites activity Deiodination; hepatic; active metabolites
*qid, Four times daily ; tid, three times daily; bid , twice daily; and IV, intravenous. tNAPA, N-acetyl procainamide.
ing 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
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. 6 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 mglday 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 2JLglmi to 5JLglmi. 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 CHEST I 88 13 I SEPTEMBER. 1985
453
Table 2-Clinical Effects Drug QUinidine
Procainam ide
Disopyramtde Lidocaine Bretylium Verapamil
Hemodynamics
ECC
Side Effects"
Indication
Direct negative inotrope; peripheral vasodilatation and afterload reduction Direct negative inotrope; peripheral vasodilatation and afterload reduction Negative inotrope
P-R, QRS, and Q-T may prolong
CI ; hematologic; hepatic; fever; syncope
Ventricular and supraventricular arrhythmia
P-R, QRS, and Q-T may prolong
CI ; CNS ; lupus
Primarily ventricular arrhythmias
P-R, QRS,and Q-T may prolong None None
Anticholinergic; CHF
Ventricular and supraventricular arrhythmias Ventricular arrhythmia Refractory ventricular tachycardia or fibrillation Supraventricular tachycardia; rate control in atrial fibrillation and atrial flutter
None Increased cardiac output; hypotension Negative inotrope; peripheral vasodilatation and afterload reduction
Tocainide Mexiletine Encainide
None None None
Ethmozine
Mild negative inotrope
Flecainide
Negative inotrope
Lorcainide Propafenone
None Negative inotrope
Amiodarone
Negative inotrope; Q and blockade; peripheral vasodilatation and afterload reduction
Prolong P-R
None None Prolonged P-R and QRS May prolong P-R and QRS P·R and QRS prolongation None P-R prolongation ~
P-R and Q-T prolongation ; U waves
CNS ; CI CI; orthostatic hypotension CI ; headache; peripheral edema; CHF; conduction abnormalities CI ; CNS CI ; CNS CI ; CNS CI ; rash; CNS ; cholinergic CNS ; CI ; headache; visual disturbances CI; CNS ; sleep disorders CI ; CHF; conduction abnormalities microdeposits; CI ; CNS ; dermatologic; thyroid abnormalities; conduction abnormalities; pulmonary
Ventricular arrhythm ia Ventricular arrhythmia Ventricular and supraventricular arrhythmia Ventricular and ? supraventricular arrhythmia Ventricular and supraventricular arrhythm ia Ventricular arrhythmia Ventricular and supraventricular arrhythmia Ventricular and supraventricular arrh ythmia
·CI, gastrointestinal; CNS , central nervous system; and CHF, congestive heart failure . All drugs aggravate arrhythmia.
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. 9 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." Toxic Effects
Side effects due to therapy with quinidine are common . U 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 4S4
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 Antiantlythmlc Drug Therapy (part I) (Philip J. Podrld)
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 phenobarbital 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.
Clinical Use 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 l3-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 taehyarrhythmias. 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. DISOPYRAMIDE
Disopyramide is a membrane-active drug which affects all myocardial tissue and has electrophysiologic
effects similar to those of quinidine. 14 Disopyramide is available for oral use only, and the usual daily dosage is 300 to 800 mg in three or four divided doses. We have occasionally administered a loading dose of 300 mg to rapidly assess antiarrhythmic effect and achieve a steady-state level in a brief period of time . There is a long-acting preparation of disopyramide which can be administered twice daily. It is slowly absorbed, producing a steady-state level in the blood which is stable over a prolonged period of time . The half-life of disopyramide is six to seven hours, and therapeutic blood levels range from 2....g/ml to 4....g/ml. Only 35 percent of the drug is metabolized by the liver to inactive metabolites, while the remainder is cleared unchanged by the kidney. IS In the presence of renal insufficiency, the dosage must be reduced.
Electrocardiographic Changes Disopyramide may prolong the QRS or Q-T interval, and these changes are usually related to the level in the blood," however, similar to quinidine, there may be an idiosyncratic prolongation of the Q-T interval even with low levels in the blood. Prolongation of the Q-T interval has been associated with cardiac toxic effects. Like quinidine, disopyramide has a mild vagolytic effect which enhances atrioventricular nodal conduction, but counterbalancing this is a direct depressive effect. In most patients, there is no change in the P-R or atrio-His (A-H) interval. IS Disopyramide possesses significant negatively inotropic activity and will reduce cardiac output. 17 It does not have any direct effect on peripheral vascular resistance, but because of reduction in stroke volume, there is a reflex increase in peripheral vascular resistance. In our experience, disopyramide exacerbates congestive heart failure in 55 percent of the patients with a history ofleft ventricular dysfunction, while the incidence is 5 percent in those without a history of failure. 18 As evaluated with radionuclide angiography, disopyramide reduced the contractility in all abnormal myocardial segments, regardless of the underlying heart disease, while normal segments were unaffected."
Side Effects Side effects are common with disopyramide. The most frequent are anticholinergic, including dry mouth, dry eyes, blurred vision, constipation, vaginal dryness, and urinary retention. These are usually related to the dosage and blood level. Other side effects include nausea, vomiting, dizziness, and insomnia. The most serious adverse reactions are those affecting the cardiovascular system. There is a significant incidence of congestive heart failure in patients with cardiomegaly or a history of congestive heart failure. 18 Disturbances in atrioventricular nodal conduction CHEST I 88 13 I SEPTEMBER, 1985
455
have been reported. Similar to other drugs, disopyramide can aggravate ventricular arrhythmia. and "disopyramide syncope" associated with Q-T prolongation has been described." Electromechanical dissociation has occurred in patients with renal insufficiency when the serum level of the drug is very high. Disopyramide does not affect digoxin levels, and there is no interaction with warfarin. Caution is necessary when administering this drug with 13-adrenergic blocking agents or calcium antagonists which can also depress left ventricular function . Clinical Use
Disopyramide is effective for conversion and prevention of atrial fibrillation and is an alternative agent when quinidine is either poorly tolerated or ineffective. The drug may be effective for atrial flutter. but like quinidine. it may slow the atrial rate and result in an increase in the ventricular response. Blockade of atrioventricular nodal conduction is therefore necessary. The drug may be effective for preventing supraventricular tachycardia. The major use for disopyramide is in the treatment of ventricular arrhythmia. It is effective for suppression of all types of ventricular ectopy ; and in patients with a history of ventricular tachycardia and ventricular fibrillation. it will prevent a recurrence. Studies involving the administration of disopyramide or placebo in patients after a myocardial infarction have not demonstrated a reduction in mortality:" however, as with the studies involving other agents, the drug was randomly used without consideration of the baseline arrhythmia or the effect of the drug on its suppression. PROCAINAMIDE
Procainamide is a membrane-active drug possessing electrophysiologic properties similar to those of disopyramide and quinidine." It is available for oral and intravenous administration. The intravenous dosage is generally 100 mg infused every five minutes up to 1 to 1.5 g. The total dose administered should be titrated to its effect on arrhythmia, QRS widening, and the occurrence of side effects. The oral dosage is usually 3 to 6 g daily in four to six divided doses. Frequent dosing is necessary because of a short half-life, approximately three hours . There is a sustained-release preparation of procainamide available which permits dosing three or four times per day. The reported therapeutic plasma level is 6fJoglml to lOfJoglml. The drug is rapidly metabolized in the liver by acetylation to an active metabolite. N-acetyl procainamide." The presence of congestive heart failure or hepatic disease does not affect metabolism or blood levels, and a change in dosage is not necessary. Since the metabolite accumulates in the presence of renal insufficiency, reduction of dosage is necessary. Il3
Procainamide may cause prolongation in the P-R. QRS, and Q-T interval related to the blood level, although such changes occur less often than with quinidine." Like quinidine and disopyramide, procainamide exerts vagolytic effects on the atrioventricular node, but this is balanced by direct depression of atrioventricular nodal electrophysiologic properties. Procainamide exerts direct negatively inotropic activity, reducing left ventricular contractility.' however, it is a ganglionic blocker and causes peripheral vasodilatation. The decrease in afterload maintains cardiac output in most patients, and the precipitation of congestive heart failure is unusual. Side Effects
Side effects with procainamide are common. Z4 Often observed are gastrointestinal toxic effects, including nausea, vomiting, and anorexia. Central nervous system side effects include insomnia, fatigue, and tremors. Fever is a result of an allergic reaction. Agranulocytosis is a rare side effect, but there have been several reports of this complication with the use of the long-acting preparations. The most frequent side effect is the development of a positive antinuclear antibody titer or lupus erythematosus preparation. which occurs in up to 90 percent of the patients receiving the drug. 50 percent of whom will develop a lupus-like syndrome. 25 This generally occurs several months after initiation of procainamide therapy. and symptoms may persist for up to six months after the drug has been discontinued. Patients who have slow acetylation and have low levels of N-acetyl procainamide tend to have high antinuclear antibody titers early in therapy" and are more likely to develop lupus. Clinical Indications
Procainamide may be effective for some supraventricular arrhythmias. especially those occurring after surgery; however, it is less effective than quinidine and disopyramide and is not a first-line drug . The major role for procainamide is in the treatment of ventricular arrhythmia. The drug can be administered intravenously, and serious arrhythmias can be treated rapidly. Long-term oral therapy will prevent recurrence ofarrhythmia. Randomized studies with placebo or drug in patients after myocardial infarction have reported that procainamide appears to reduce mortality. but the number of patients studied is small. 25 LIDOCAINE
Lidocaine is a widely used antiarrhythmic drug which is effective for immediate suppression of serious ventricular arrhythmias occurring in a variety of clinical settings." It is only available for intravenous Antiarrhythmic Drug Therapy (part I) (Philip J. Podrtd)
use, since a short half-life precludes oral use. The dosage is 100 to 200 mg by bolus, followed by a continuous intravenous infusion of2 to 4 mg/min. The serum half-life of a single bolus of lidocaine is only 15 minutes, as it is rapidly distributed to peripheral stores . When a continuous intravenous infusion is initiated, more than one hour is required to achieve a steady-state level. During this time, levels oflidocaine may be subtherapeutic, and recurrent arrhythmia should be treated with additional boluses oflidocaine. During continuous infusion the drug is widely and rapidly distributed to peripheral stores, being avidly bound to adipose tissue ." With discontinuation of the intravenous infusion, the adipose stores will maintain blood levels for up to two hours. The drug is rapidly metabolized during a first-pass effect in the liver to inactive metabolites. In the presence of hepatic dysfunction or severe congestive failure, the dosage of lidocaine should be reduced. 29 Lidocaine does not alter the surface electrocardiogram; and the P-R, QRS, and Q-T intervals are not affected, making the drug safe in patients with conduction abnormalities. Lidocaine does not affect cardiac output or other hemodynamic parameters, and it can be safely administered to patients with congestive heart failure. Side Effects The majority of side effects caused by lidocaine are related to the infusion rate and serum level achieved. The most frequent toxic effects involve the central nervous system and include tremors, light-headedness, dizziness, increased agitation, changes in personality and mood, psychosis, lethargy, somnolence and, rarely, seizures . Gastrointestinal side effects include nausea and vomiting. Rarely, lidocaine may produce hypotension or rash. Clinical Indication The most important role for lidocaine is in the acute setting where rapid control of a serious ventricular arrhythmia is necessary. It is effective and safe in patients who have myocardial infarction, and its prophylactic use in this setting reduces the incidence of ventricular fibrillation. The drug is very effective in patients with serious ventricular arrhythmias associated with other clinical situations; however, it can only be administered intravenously, and if long-term therapy is necessary, another oral drug must be used . BRETYLIUM
Bretylium is an antiarrhythmic agent derived from guanethidine. It depletes catecholamines and thus exerts antisympathetic activity. The direct electrophysiologic effects of the drug are a prolongation of the action potential duration and increase of the refractory period.30
Bretylium is only available for intravenous use, and the usual dose is 10 mg/kg by bolus, followed by a continuous intravenous infusion of2 to 4 mg/min. The antiarrhythmic effect of the drug may be observed for several hours after a single dose, and a continuous infusion may not be necessary. Bretylium does not substantially change the QRS interval, but there may be slight prolongation of the P-R and Q-T intervals because of the drug's antisympathetic effect. Bretylium has a direct positively inotropic effect, but the mechanism is unclear. After the initial bolus, there may be a hypertensive response and a sinus tachycardia due to elevated levels of circulating catecholamtnes," however, with continuous infusion, catecholamines are depleted, resulting in a decrease in peripheral vascular resistance which may cause hypotension and an augmentation in cardiac output. Toxic Effects The major side effects of bretylium result from its antisympathetic activity. The most frequent is the development of orthostatic hypotension, which may persist for a prolonged period after the drug is discontinued . Other side effects include nausea and vomiting. Clinical Indication Bretylium is often administered for sustained ventricular tachyarrhythmias refractory to intravenous therapy with lidocaine or procainamide." When used in patients with refractory ventricular fibrillation, bretylium may produce spontaneous defibrillation without the need for electrical reversion." In our experience, it is most effective for ventricular tachycardias with rapid rates, while slower ventricular tachycardias revert less often . After the termination of the ventricular tachyarrhythmia, there may be frequent ventricular premature beats due to elevated levels of circulating catecholamines . For continued long-term therapy an oral antiarrhythmic agent must be administered. CALCIUM ANTAGONISTS
There are three calcium-channel blocking drugs available, but only verapamil possesses significant clinical antiarrhythmic effects. Since the drug affects calcium ion fluxes in the sinus and atrioventricular nodes, the major use for verapamil is for therapy of arrhythmias which involve the atrioventricular node, specificallyjunctional tachycardia and atrial flutter and fibrillation.3< Verapamil is available for both intravenous and oral use. The intravenous dosage is 5 mg every three to five minutes up to 15 mg. The oral dosage is 80 to 160 mg three to four times per day. There is rapid metabolism due to a first-pass effect in the liver, accounting for the CHEST I 88 I 3 I SEPTEMBER. 1985
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disparity in the intravenous and oral dosages. The halflife of the intravenous drug is only 15 minutes, while the effect of the oral drug may last up to six hours. The metabolites are not active. 35 Verapamil is a direct negatively inotropic agent, but it also produces peripheral vasodilatation and a reduction in afterload which maintains cardiac output," however, in the presence of severe left ventricular dysfunction , or when peripheral resistance is already reduced, verapamil may precipitate hypotension or congestive heart failure. Verapamil is directly negatively chronotropic and may depress sinus rate and prolong recovery time of the sinus node ; however, the reduction in peripheral vascular resistance usually leads to a reflex increase in sympathetic tone, which maintains sinus rate. The drug slowsconduction through and prolongs the refractory period of the atrioventricular node, resulting in an increase of the P-R interval. It does not alter QRS or Q-T intervals. Toxic Effects
The most common side effects include nausea, vomiting, and constipation. As a result of vasodilatation, dizziness, headaches, and peripheral edema occur. The most serious side effects are those which affect the cardiovascular system including hypotension, bradycardia, conduction disturbances, and congestive heart failure. There is a dose-related interaction between digoxin and verapamil which is similar to that with quinidine and is a result of a reduction in digoxin clearance." Beta-adrenergic blockers and verapamil may have additive effects on the sinus and atrioventricular nodes and on left ventricular function. There have been reports of cardiovascular collapse when verapamil is administered along with disopyramide. When used in patients with atrial fibrillation, regularization of the R-R intervals due to atrioventricular nodal blockade may be observed, especially at night, when vagal tone is high, or with concomitant digoxin therapy. Clinical Indications
Verapamil is primarily useful for supraventricular arrhythmias. With intravenous use, 90 percent of supraventricular tachycardias will revert," and orally administered verapamil may be effective for preventing supraventricular tachycardia. The drug generally does not revert atrial Butter or atrial fibrillation but will slow the ventricular response rate ." Oral verapamil is very effective for improving rate control in patients with chronic atrial fibrillation." Verapamil is ineffective for the treatment of ventricular arrhythmia.40 BETA-ADRENERGIC BLOCKERS
In the United States, there are now eight ~-adre nergic blockers available which include propranolol, 458
nadolol, timolol , metoprolol, pindolol , atenolol, acebutolol, and labetalol. Only propranolol is approved for arrhythmia, but each of the ~-adrenergic blocking agents may be effective. In general, these drugs are not first-line agents for the treatment of arrhythmia except in specific cases in which catecholamines induce or maintain the arrhythmia. 41 Usual doses of beta-adrenergic blockers have no direct antiarrhythmic effect on myocardial tissue but interfere with the action of catecholamines on the heart. 42 Although each of these drugs share similar antiarrhythmic activity, they differ in potency, potential for membrane stabilization, the presence of intrinsic sympathomimetic activity, cardioselectivity, and lipid solubility (Table 3). The dose of the individual drug is best guided by its physiologic effect, specifically the reduction of resting and exercise heart rates. Metabolism varies and is dependent upon lipid solubility. Those drugs which are lipid-soluble , such as propranolol and metoprolol, undergo rapid first-pass metabolism by the liver and have a short half-life, while others, such as atenolol and nadolol, are not lipid-soluble . They are not metabolized but are cleared by the kidney unchanged. Each of the ~-adrenergic blockers are indirectly negatively inotropic agents resulting from blockade of catecholamine effect on the heart. The amount of myocardial depression varies among the agents, and those with intrinsic sympathomimetic activity have less of an effect.43 Each l3-adrenergic blocker is negatively chronotropic and will decrease resting heart rate, although those agents with intrinsic sympathomimetic activity have less of an effect.43 A prolongation of P-R interval associated with the reduction in heart rate is common. There is no change in the QRS interval, while the Q-T interval may shorten. Toxic Effects
Although the frequency and intensity of side effects vary among the agents, adverse reactions associated with this class of drugs are diverse . Most serious are those of the cardiovascular system and include conTable 3-Beta-Adrenergic Blocker Pharmacology Cardia-
Drug
BetaBlocking Potency
Acehutolol Atenolol Labetalol Metoprolol Nadolol Pindolol Propranolol Timolol
0.3 1 0.7 0.8 1 4-7 1 6
+ +
selectivity
0
+ 0 0 0 0
ISA*
Membrane StabiIizing
Lipid Solubility
+
+
0 0 Weak Weak 0 Weak Strong 0
0 0 0 0
++ 0 0
0
+ ::t
0
+ ++ 0
*ISA, Intrinsic sympathomimetic activity. Antiarrhythmic Drug Therapy (part I) (Philip J. Podrtd)
gestive heart failure, conduction abnormalities, hypotension, symptomatic bradycardia, and vasoconstriction resulting in claudication and Raynaud's phenomenon. Bronchospasm and provocation of asthma may occur in patients with a history of pulmonary problems. Gastrointestinal side effects include nausea, vomiting, and diarrhea or constipation . Toxic effects on the central nervous system include depression, dizziness, insomnia, nightmares, fatigue, and changes in mood and personality. A change in urinary function and impotency are common . Clinical Indications
Beta-adrenergic blockers are not first-line agents for the treatment of any specific arrhythmia, except in cases where the arrhythmia is associated with elevated catecholamine levels such as occurs with hyperthyroidism, exercise, or in the postoperative state . Catecholamine-induced sinus tachycardia , atrial tachycardia, atrial fibrillation, atrial flutter, junctional tachycardia, and ventricular arrhythmia may respond. In our experience, l3-adrenergic blockers are most effective when used as adjunct therapy in combination with membrane-stabilizing agents, resulting in a synergistic effect.44 As with calcium blocking drugs, l3-adrenergic blockers are effective for controlling the ventricular rate during atrial fibrillation or atrial flutter. There are a number of studies which demonstrate that most of the l3-adrenergic blockers administered prophylactically to patients after a recent myocardial infarction will reduce cardiac mortality, especially the incidence of sudden death .~.46 The mechanism of this protective effect is unknown . REFERENCES 1 Vaughan Williams EM . Classification of antiarrhythmic drugs. In : Sandoe E, Flensted-Jensen E, Olsen E, eds. Symposium on cardiac arrhythmias. Sodertalje, Sweden: AB Astra, 1970:449-72 2 Chen CM, Gettes LS, Katzung BG. Effect of lidocaine and quinidine on steady state characteristics and recovery kinetics of dv-/dt",... in guinea pig ventricular myocardium. Circ Res 1975; 37:20-9 3 Rosen MR, Wit AL. Electropharmacology of antiarrhythmic drugs . Am Heart J 1983; 106:829-39 4 Coltart DJ, Gibson DG, Shand DG. Plasma propranolol levels associated with suppression of ventricular ectopic beats. Br Med J 1971;1:490-91 5 Hoffman BF, Rosen MR, Wit AL. Electrophysiology and pharmacology of cardiac arrhythmias: 7. cardiac effects of quinidine and proeainamide . Am Heart J 1975;90:117-22 6 Josephson ME, Seides SF, Batsford Wp, Weisfogel BM, Akhtar M, Caracts AR, et al, The electrophysiologic effects of intramuscular quinidine on the atrioventricular conducting system in man. Am Heart J 1977; 87:55-64 7 Anglakos ET, Hastings EP. The influence of quinidine and proeainamide on myocardial contractility in vivo. Am J Cardiel 1960; 6:791-98 8 Ferrer MI, Harvey M, Werko L, Dresdale DT, Cournand A, Richards DW. Some effects of quinidine sulfate on the heart and circulation in man. Am Heart J 1948; 36:816-37
9 Heissenbuttel RH, Bigger JT. The effect of oral quinidine on intraventricular conduction in man : correlation of plasma quinidine with changes in QRS duration . Am Heart J 1970; 80:453-57 10 Selzer AH, Wray AW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias . Circulation 1964; 30:17-26 11 Cohen IJ, Hershel J, Cohen SI. Adverse reactions to quinidine in hospitalized patients : findings based in data from the Boston Collaborative Drug Surveillance Program. Prog Cardiovasc Dis 1977; 20:151-63 12 Bigger JT. The quinidine-digoxin interaction. Am Heart J 1982; 51:73-8 13 Holmberg S, Bergman H. Prophylactic quinidine treatment in myocardial infarction. Acta Med Scand 1967; 181:297-304 14 Sekiya A, Vaughan Williams EM. A comparison of the antifibrillatory actions and effects on intracellular cardiac potentials of pronethalol , disopyramide and quinidine. Br J Pharmacal 1963; 21:473-81 15 Karim A. Pharmacokinetics of Norpace. Angiology 1975; 26(suppl 1):85-92 16 Josephson ME, CaractaAR, Law S1; Gallagher JJ, Damato AN. Electrophysiological evaluation of disopyramide in man. Am Heart J 1973; 86:771-80 17 Jensen GB, Sigard B, Uhrenholt A. Circulatory effects of intravenous disopyramide in heart failure. J Intern Med Res 1976; 4(suppl 1):42-5 18 Podrid PJ, Schoeneberger A, Lown B. Congestive heart failure caused by oral disopyramide . N Eng) J Med 1980; 302:614-17 19 KoweyPR, Friedman RL, Podrid PJ, Zielonka J, Lown B, Wynn J, et al. Use of radionuclide ventriculography for assessment of changes in myocardial performance induced by disopyramide phosphate. Am Heart J 1982; 104:769-74 20 Meltzer RS, Robert WE, McMorrow M. Atypical ventricular tachycardia as a manifestation of disopyramide toxicity. Am J Cardiel 1978; 42:1049 21 Jennings G, Jones MBA, Besterman EMM , Model DG, Turner pp, Kidner PH. Oral disopyramide in prophylaxis ofarrhythmias following myocardial infarction. Lancet 1976; 1:51-4 22 Giardina EGV, Dreyfuss J, Bigger IT, Shaw JM, Schreiber EC. Metabolism of proeainamide in normal cardiac subjects . Clin Pharmacal Ther 1970; 19:339-51 23 Drayer DE , Lowenthal DT, Woosley RL, Nies AS, Schwartz A, Reidenberg MM. Cumulation of N-acetyl proeainamide-an active metabolite of proeainamide in patients with impaired renal function. Clin Pharmacal Ther 1977; 22:63-9 24 Koch Weser J, Klein SM. Proeainamide dosage schedules, plasma concentrations and clinical effects. JAMA 1971; 215:
1454-60 25 Koswosky B, Taylor PJ, Lown B, Ritchie RF. Long term use of proeainamide following acute myocardial infarction. Circulation 1973; 42:1204-10 26 Woosley RL, Drayer DE, Reidenberg MM, Nies AS, Carr K, Vates JA. Effect of acetylator phenotype on the rate at which proeainamide induces antinuclear antibodies and the lupus syndrome . N Eng) J Med 1978; 298:1157-59 27 Lown B, Vassaux C. Lidocaine in acute myocardial infarction. Am Heart J 1968; 76:586-87 28 Benowitz N, Forsyth RP, Melman KL, Rowland M. Lidocaine disposition kinetics in monkeys and man: 1. prediction by a perfusion model. Clin Pharmacal Ther 1974; 16:87-92 29 Thomson PD, Melman KL, Richardson JA, Cohen K, Steinbrunn W, Cudihee R, et al, Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans . Ann Intern Med 1973; 78:499-504 30 Bacaner MB. Quantitative comparison of bretylium with other antifibrillatory drugs. Am J Cardioll968; 21:504-12 CHEST I 88 13 I SEPTEMBER, 1985
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31 Chatterjee K, Mandel WJ, Vyden JK, Parmley WW, Forrester JS. Cardiovascular effects ofbretylium tosylate in acute myocardial infarction. JAMA 1983; 223:757-60 32 Bacaner MB. Treatment of ventricular fibrillation and other acute arrhythmias with bretylium tosylate. Am J Cardioll968; 21:43035 33 Arcidiancono R. Use ofbretylium tosylate in ventricular fibrillation . Clin Ther 1978; 84:253-66 34 Sung RL, Elser B, McAllister RG. Intravenous verapamil for termination of reentrant supraventricular tachycardias. Ann Intern Med 1980; 93:682-89 35 Rosen MR, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias: 6. cardiac effects of verapamil. Am Heart J 1975; 89:665-73 36 Singh BN, Hecht HS, Nademanee K. Electrophysiologic and hemodynamic actions of slow channel blocking compounds. Prog Cardiovasc Dis 1982; 25:103-32 37 Klein HD, Lang R, Weiss E , Desegni E , Libhober L, Guerrero J, et aI. The influence of verapamil on serum digoxin concentration. Circulation 1982; 65:998-1003 38 Schamroth L. Immediate effects of intravenous verapamil on atrial fibrillation . Cardiovasc Res 1981; 5:419-24 39 Klein HD, Pauzner H , Di Segni E , David D, Kaplinsky E . The beneficial effects of verapamil in chronic atrial fibrillation . Arch Intern Med 1979; 139:74749 40 Wellens HJJ, Bar FW, Lie KI, Durrer DR, Dohmen HJ. Effects
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of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with recurrent ventricular tachycardia. Am J CardioI1977; 40:579-85 Podrid PJ, Lawn B. Use of beta-adrenergic blocking agents for cardiac arrhythmias. In : Kostis JP, DeFelice EA, eds . Beta blockers in the treatment of cardiovascular disease. New York: Raven Press, 1984:121-54 Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias: 9. cardiac electrophysiologic effects of beta-adrenergic receptor stimulation and blockade: part C. Am Heart J 1975; 90:797-803 Frishman W, Davis R, Strom J, EI Rayam A, Stampfer M, Rebner H, et al, Clinical pharmacology of the new beta-adrenergic blocking drugs: part 5. pindolol (LB-46) therapy for supraventricular arrhythmia: a viable alternative to propranolol in patients with bronchospasm. Am Heart J 1979; 98:393-98 Hirsowitz GS, Podrid P, Lampert S, Stein J, Lawn B. The use of beta blocking agents as adjunct therapy in the treatment of malignant ventricular arrhythmia. J Am Coli Card 1984; 3:619 Beta Blocker Heart Attack Thai Research Group. A randomized trial of propranolol on patients with acute myocardial infarction: 1. mortality results. JAMA 1982; 297:1707-14 Norwegian Multicenter Study Group. TImolol induced reduction in mortality and reinfarction in patients surviving an acute myocardial infarction. N Eng! J Med 1981; 304:801-06
Antiarrhythmic Drug Therapy (part I) (Philip J. Podrld)