The clinical pharmacology and therapeutic applications of the antiarrhythmic drugs

Abstract

The mechanisms of action and therapeutic applications of the commonly employed and new antiarrhythmic agents are best understood by consideration of the basic electrophysiologic properties of heart muscle affected by these drugs. Thus, each of these agents depresses disorders of impulse formation by reducing diastolic depolarization and thereby diminishing automaticity and inhibits disorders of impulse conduction by altering conduction velocity and refractory period and thereby disrupting re-entry mechanisms. Accompanying these antiarrhythmic actions, quinidine, procaine amide (Pronestyl), propranolol (Inderal), and potassium worsen atrioventricular block; whereas lidocaine (Xylocaine) usually does not influence nodal conduction velocity, and diphenylhydantoin accelerates this property in the atrioventricular node. Quinidine and procaine amide directly prolong refractory period; in contrast, lidocaine, diphenylhydantOin, and proprarwlol directly reduce this period. Quinidine and procaine amide are useful in most types of supraventricular and ventricular tachyarrhythmias. Propranolol is particularly effective against supraventricular arrhythmias; however, lidocaine is only moderately effective in disorders of atrial rhythm but markedly suppresses ventricular tachyarrhythmias. Diphenylhydantoin (Dilantin) and bretylium (Darenthin) are most beneficial in terminating disorders of ventricular rhythm and, in the case of bretylium, particularly those due to re-entry mechanisms. Diphenylhydantoin, propranolol, and lidocaine possess electrophysiologic properties that are particularly salutary in the treatment of digitalis toxicity. In general, antiarrhythmic agents have depressant effects on cardiac contractility which are related to dose, speed of administration, and extent of myocardial disease.In con/'rast, bretylium possesses positive inotropic actions, and potassium within normal serum concentrations has no effect on contractile state. It is suggested that the fundamental subcellular actions of antiarrhythmic agents occur as a consequence of their binding to the cell membrane; in this manner, altered transmembrane fluxes of sodium and potassium ions underlie the electrophysiologic effects, and those of calcium ions underUe the contractile properties of these agents. From these observations, the thorough understanding of basic and applied pharmacology of the antiarrhythmic agents prOVides for their more iudicious use in patients.

Selected Cardiovascular and Central Properties of Three Lidocaine Analogs

“…The effec tiveness of lidocaine in blocking nerve conduc tion and depressing overall cardiac excitability may have the common denominator of being able to interfere with ionic fluxes in the vicinity of tlie cell membrane. This is supported from observations that show lidocaine's action is to alter cell membrane characteristics (Mason et al, 1970), to displace membrane-bound cal cium, to alter membrane conformation (Seeman, 1974), and to reduce sodium and potas sium migration across the cell membrane (Goodman and Gilman, 1975).…”

Antiarrhythmic Drugs: Electrophysiological Actions

“…However, the direct effects of propranolol on membrane responsiveness and conduction also may suppress certain arrhythmias. Mason et al (14) have recently suggested that, depending on the clinical circumstances in which the drug is used, either of the two actions of propranolol, antiadrenergic or di rect "quinidine-like" effects, can be of importance. This, we feel, is an ac curate estimation of the current understanding of the antiarrhythmic effects of propranolol.…”

“…Bretylium is such a drug and also dem onstrates weak local anesthetic activity. Bretylium has attracted recent at tention because of reports that it is apparently successful in treating a num ber of arrhythmias in man including those induced by myocardial infarc tion, digitalis intoxication, and open heart surgery (14) . Leveque in 1965 (125 ) reported that bretylium was effective against atrial fibrillation in duced in dogs rendered hypokalemic by pretreatment with insulin and glu cose.…”

“…We have limited ourselves to describing a comparatively few of the many papers pub lished in this area in recent years. The reader is referred to the comprehen sive review by Szekeres & Papp (13) for a complete survey of antiar rhythmic drugs and to several recent reviews for clinical indications for their use and toxic manifestations (4,10,14,15). Several papers and mono graphs provide a full description of the techniques mentioned above and a review of the changes in transmembrane potential that accompany excita tion in heart (3) and the ionic basis for these changes (16,17).…”

The Effect of Propranolol and Verapamil On Atrial and Atrioventricular Refractory Periods in Man

“…[13][14][15][16] In recent years these problems have been extensively studied in experiments with advanced electrophysiological techniques, and the results reviewed in a number of excellent surveys. [16][17][18][19] Studies on atrial refractory period in man can conveniently be performed by the extra stimulus method. 'o…”