Calcium antagonists. Some chemical-pharmacologic aspects.

Ca++ serves multiple roles as a regulator and initiator of cellular events. A variety of mechanisms serve to control cellular Ca++ levels and there exists a corresponding diversity of drugs which possess, with varying degrees of potency and selectivity, Ca++-antagonistic properties. Particular interest attaches to a group of agents designated as Ca++-channel or Ca++-entry blockers and includes verapamil, nifedipine, diltiazem, cinnarizine, and prenylamine. These agents function by blockade of the potential dependent Ca++-channel. However, their obvious chemical heterogeneity suggests that several sites and mechanisms of action may exist. A review of some basic questions concerning the action of the Ca++ channel antagonists is presented. The existence of discrete structure-activity relationships is consistent with the concept that these agents have specific sites of action, rather than serving, for example, as, nonspecific membrane-stabilizing agents. This view is further supported by their selectivity of action seen both in tissue selectivity and selectivity of antagonism of agonist responses. Studies of the relationship of these compounds to Ca++ show that they appear to function competitively against Ca++ and to block cellular Ca++ uptake. Moreover, both contractile responses and cellular Ca++ uptake appear equisensitive to these antagonists, providing further evidence that inhibition of Ca++ uptake underlies their inhibition of mechanical response. Of particular importance is the question of selectivity of action. It is quite clear that the Ca++ channel antagonists do not show equal activity toward all Ca++ channels and that major differences in selectivity occur between cardiac and smooth muscle. It is possible that selectivity of antagonism may occur between different vascular beds. Furthermore, Ca++ channels controlling stimulus-secretion coupling appear to be less sensitive to these antagonists than the channels involved in excitation-contraction coupling. Finally, the actions of Ca++ antagonists on non-Ca++-mediated processes, including Na+-dependent and receptor-binding events, are noted. These actions are seen at higher concentrations than those needed to inhibit Ca++ channel events, and their contribution to the therapeutic actions exerted by these antagonists is unknown.