Future Prospects of the Development of Calcium Antagonists

In considering the mechanism of action of the calcium antagonists, it is important to realize that there are three distinct receptor types and that the new classification divides these three drugs as members of the dihydropyridine, phenylalkylamines and benzothiazipines, respectively. The World Health Organization as well as the International Union of Pharmacology and Cardiology have adopted this classification. Unlike every other class of drugs, such as the alpha and beta adrenergic blocking agents, diuretics, etc., the calcium antagonists need to be thought of as three distinct drug classes. The reason they share some, but not all of the pharmacological profile is that they all act at specific receptor domains present in one large protein of 165 daltons present in all excitable tissue. This protein along with several other subunits make up what is known as the voltage-dependent calcium channel (the so-called "L"type, L-VDCC). The mechanism of action of the three drugs involve first a specfic binding and then an inhibition of the movement of calcium into the cell Some of these drugs, such as diltiazem, may have other interesting intracellular effects perhaps associated with protection of the mitochondria during ischemic insults. The nature of the receptor is being explored by molecular genetic techniques, and we have recently cloned two of the major subunits; some of the data will be presented.