Ca2 Channel Antagonists Ca2Antagonists Ca2 Channel Blockers CCAs

Fleckenstein, late Professor of Physiology at the University of Freiburg, Germany, observed that drugs could mimic the effects of calcium withdrawal from the medium surrounding the cells. He termed such drugs calcium antagonists (Figure 3 and Tables 3 and 4). The first compound reported by him to have such activity was verapamil, which is still used today in the treatment of hypertension. Subsequently, Fleckenstein found that nifedipine, discovered at Bayer AG in Germany,33 is ''the most potent and the most specific inhibitor of calcium entry into cells.'' In 1970 the first clinical studies with nifedipine were performed in patients with angina pectoris. The drug reduced the incidence of anginal attacks and was marketed for this purpose. Subsequently, nifedipine was found to reduce arterial pressure in patients with severe hypertension who did not previously respond to any other antihypertensive drugs available.

Sato and his associates at Tanabe Seiyaku Company in Japan discovered a chemically different CCA, diltiazem (Figure 3). All three first-generation CCAs, verapamil, nifedipine, and diltiazem, inhibit the same subunit (a1) of L-type voltage-dependent calcium channels, but bind to different sites in the subunit. The commercial success of the first three compounds prompted many pharmaceutical companies to initiate their own research programs for CCAs. Most of the second-generation CCAs were, like nifedipine, dihydropyridines (DHPs) (Tables 3 and 4). These DHPs differed from nifedipine in potency, duration of action, lipophilicity, and relative specificity for vascular rather than cardiac L-type calcium channels. Amlodipine has the longest duration of action and was the most successful of the second-generation DHPs; it is still widely used in the treatment of hypertension. In the late 1990s once-a-day formulations of most marketed CCAs became available; they provided better compliance, improved safety, and

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