Pharmacology of the dihydropyridine calcium antagonists: relationship between lipophilicity and pharmacodynamic...

Importance of L-channels for calcium: Calcium L-channels, the specific target of calcium antagonists, appear to be the receptors for these therapeutic agents. Therefore, the accessibility of these channels/receptors to calcium antagonists is a major determinant of the response to these drugs in cardiovascular disorders, including essential hypertension. 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. Disadvantages of nifedipine: Within the series of dihydropyridine calcium antagonists, the first compound introduced was nifedipine, a relatively hydrophilic drug. Owing to its hydrophilic character the drug rapidly reaches the receptor, thus explaining the rapid onset of its vasodilator action. Accordingly, reflex tachycardia develops, which is not only triggered by the degree of vasodilation but also by the rapidity of its onset. In addition, nifedipine has a short duration of action, requiring 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 develop dihydropyridines with a slower onset and a longer duration of action. This may be achieved by drugs which are largely in the ionized state at a physiological pH (e.g. amlodipine) and therefore combine slowly with the receptor and bind firmly to various tissue compartments. Another logical approach is the use of highly lipophilic drugs such as lacidipine. Because of its physicochemical properties, the effect in equilibrium 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 dihydropyridine binding site, which has to be saturated before an equilibrium effect is reached. In addition, the persistence of the drug in this lipid compartment contributes to its long-lasting vasodilator effect.