Synopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics.

Verapamil: A Review of its Pharmacological Properties and Therapeutic Use

The present status, clinical experience, side effects, clinical pharmacology and electrophysiologic actions of seven new antiarrhythmic agents are reviewed. The drugs selected for comment are amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide and verapamil. Each drug has been shown to have clinical efficacy in suppressing cardiac arrhythmias.

New antiarrhythmic agents: amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil.

The extent and consequence of misdiagnosis of wide complex tachycardia (QRS, 120 ms or more; heart rate, 100 or more beats/min) presenting emergently were assessed. Forty-six consecutive episodes of wide complex tachycardia were reviewed and their tachycardia mechanisms subsequently established. All 8 episodes of supraventricular tachycardia with aberrant conduction were correctly diagnosed, whereas 15 of 38 episodes of ventricular tachycardia (39%) were misdiagnosed as supraventricular tachycardia at the time initial therapy was given. Ventriculoatrial dissociation was evident in 11 (73%) of the electrocardiograms of misdiagnosed ventricular tachycardia. Patients with misdiagnosed episodes had poorer outcomes than those with episodes correctly diagnosed (p = 0.0003). Verapamil was administered to patients in 13 of the 15 episodes of misdiagnosed ventricular tachycardia; hemodynamic deterioration occurred in all 13 episodes. Wide complex tachycardia is often incorrectly diagnosed as supraventricular tachycardia when, in fact, the 12-lead electrocardiogram strongly suggests ventricular tachycardia. Verapamil is commonly administered in these circumstances and is frequently associated with a poor outcome.

Wide Complex Tachycardia: Misdiagnosis and Outcome After Emergent Therapy

The effects of verapamil, 0.145 mg/kg body weight, administered intravenously in a bolus injection followed by 0.005 mg/kg per min, on cardiovascular hemodynamics and on ventricular ejection fraction, determined with gated cardiac blood pool scanning, were studted in 25 patients, 8 with acute myocardial infarction and 17 with symptomatic coronary artery disease who were undergoing diagnostic cardiac catheterization. The mean (± standard deviation) plasma verapamil level, determined with a gas liquid chromatographic technique utilizing a nitrogen detector, was 161 ± 47 ng/ml (n = 8) during steady state conditions of drug infusion. In 15 patients with stable coronary artery disease having a normal or moderately reduced ejection fraction, verapamil reduced mean arterial pressure (−16 percent, probability [p] < 0.001), systemic vascular resistance (−23 percent, p < 0.001), stroke work index (−13 percent, p < 0.02), with no significant change in pulmonary vascular resistance, ejection fraction or heart rate; cardiac index was increased (+11 percent, p < 0.001) as was the stroke volume index (+7 percent, p < 0.01) and mean capillary wedge pressure (+10 percent, p < 0.01). In the seven patients with uncomplicated infarction, there was no effect on ejection fraction, heart rate or pulmonary vascular resistance. There was a decrease in systemic vascular resistance (−22 percent, p < 0.01) and mean arterial pressure (−16 percent, p < 0.01) with an increase in cardiac index (+27 percent, p < 0.05), stroke volume index (+4 percent, p < 0.05) and mean capillary wedge pressure (+17 percent, p < 0.02). In three patients, one wlth acute infarction and two with coronary artery disease, having a severely reduced ejection fraction and elevated mean capillary wedge pressure (20 mm Hg or greater), mean arterial pressure decreased markedly with a fall in stroke volume index and an abrupt increase in the mean pulmonary capillary wedge pressure. These findings were associated with clinical evidence of heart failure and dyspnea.

It is concluded that (1) in patients with cardiac disease having a mild to moderate decrease in left ventricular ejection fraction accompanied by a normal or mildly elevated mean pulmonary capillary wedge pressure, the intrinsic depressant effect of verapamil is offset almost entirely by its potent vasodilator proporties, but (2) in patients with a severely reduced ejection fraction and a high pulmonary capillary wedge pressure, the depressant effects of the compound become clinically apparent with sudden further increases in pulmonary capillary wedge pressure and a decrease in stroke volume and mean arterial pressure.

Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease

New perspectives in the pharmacologic therapy of cardiac arrhythmias.

Verapamil (Isoptin®) caused a dose-dependent peripheral vasodilation, increase in myocardial contractility, and tachycardia in the anaesthetized dog. Propranolol pre-treatment blocked the cardiac stimulation following verapamil but the vasodilation was unaltered. Inflation of a thoracic aortic balloon prevented the fall in intravascular pressure and reduced the tachycardia and positive inotropic responses. These experiments suggest that clinical doses of verapamil cause peripheral vasodilation which leads to a sympathetic reflex induced increase in heart rate and myocardial contractility. Verapamil also had a direct myocardial depressant action which became evident at doses above the range used clinically. The drug increased the PR interval in conscious dogs for up to 60 minutes. This effect was partly mediated through cholinergic stimulation and partly through a direct depression on atrioventricular conduction.

P. Dhumma-Upakorn

Papers

Cardiovascular action of verapamil in the dog with particular reference to myocardial contractility and atrioventricular conduction