Pharmacological basis for the therapeutic applications of slow-channel blocking drugs

Excitation-contraction coupling in cardiac muscle as well as in smooth muscle is mediated by the transmembrane fluxes of calcium. In the case of cardiac muscle, this transfer occurs through the slow-inward channel. Agents that selectively inhibit the myocardial slow-channel also block calcium entry in smooth muscle cells, particularly in arteries. Thus, such selective inhibitors of the slow channel, exemplified by verapamil, nifedipine, and diltiazem, produce a marked negative inotropic effect in cardiac muscle; in whole animals or in man, such a propensity is largely nullified or even reversed by the profound vasodilator effects of these compounds. The drugs known as calcium antagonists are chemically heterogeneous and they may exhibit associated pharmacological properties such as noncompetitive sympathetic inhibition while having varying potencies for inhibiting the calcium influx in smooth muscle and in the heart and nodal tissues. These similarities and differences influence the net electrophysiologic and hemodynamic effects of calcium antagonists in man. Electrophysiologically, the main effect is a depressant one on the AV node in which most agents of the class lengthen AV conduction and enhance refractoriness, a property that is relevant in the termination of PSVT and to the slowing of the ventricular response in atrial flutter and fibrillation. The effective refractory periods of atrial, ventricular, and His-Purkinje tissues or the bypass tracts are not altered by calcium antagonists, but conduction may be improved in ischemic tissues. On the surface ECG, the only effect is the short-term lengthening of the PR interval with no change in the QRS or Q-Tc intervals. The sinus frequency is variably affected relative to the competing influences of the direct effect, reflex response to hypotension and of sympathetic antagonism. The sinus node recovery time is affected little normally, but may be prolonged dramatically in the sick sinus syndrome. Hemodynamically, as a class of drugs, calcium antagonists produce a complex interplay of simultaneous changes in preload, afterload, contractility, coronary flow, and heart rate. The net hemodynamic effect that becomes apparent will be dependent on the agent used, on the cardiac condition and the level of ventricular function present, on the intactness of the autonomic nervous system, and on the route of drug administration. An appreciation of the electrophysiological and hemodynamic actions of calcium antagonists relative to their individual pharmacologic properties permits the rational choice of the appropriate agent in the control of a wide spectrum of cardiocirculatory disorders.