PHARMACOLOGY OF THE DIHYDROPYRIDINE CALCIUM-ANTAGONISTS - RELATIONSHIP BETWEEN LIPOPHILICITY AND PHARMACODYNAMIC RESPONSES

Importance of L-channels for calcium: Calcium L-channels, the specific target of calcium antagonists, appear to be the receptors for these t herapeutic agents. Therefore, the accessibility of these channels/rece ptors to calcium antagonists is a major determinant of the response to these drugs in cardiovascular disorders, including essential hyperten sion. As with numerous other drugs, the concentration at the receptor level and its time-course largely determine not only the intensity but also the rate of onset and the duration of the drug's effect. Disadva ntages of nifedipine: Within the series of dihydropyridine calcium ant agonists, the first compound introduced was nifedipine, a relatively h ydrophilic drug. Owing to its hydrophilic character the drug rapidly r eaches the receptor, thus explaining the rapid onset of its vasodilato r action. Accordingly, reflex tachycardia develops, which is not only triggered by the degree of vasodilation but also by the rapidity of it s onset. In addition, nifedipine has a short duration of action, requi ring the use of special galenic formulations to allow one dose a day. New dihydropyridine calcium antagonists: In view of the disadvantages of the hydrophilic calcium antagonists, attempts have been made to dev elop dihydropyridines with a slower onset and a longer duration of act ion. This may be achieved by drugs which are largely in the ionized st ate at a physiological pH (e.g. amlodipine) and therefore combine slow ly with the receptor and bind firmly to various tissue compartments. A nother logical approach is the use of highly lipophilic drugs such as lacidipine. Because of its physicochemical properties, the effect in e quilibrium is reached very slowly, after up to 5 h in isolated tissues and after more than 2 h after intravenous administration. Lacidipine appears to slowly enter a lipid compartment surrounding the dihydropyr idine binding site, which has to be saturated before an equilibrium ef fect is reached. In addition, the persistence of the drug in this lipi d compartment contributes to its long-lasting vasodilator effect.