Nifedipine. Relationship between pharmacokinetics and pharmacodynamics

The availability of specific chemical assays and the development of appropriate biological models have made it feasible to study the relationship between the pharmacokinetics and the pharmacodynamics of nifedipine, a relationship that is presumed to be sigmoidal for most effects. In healthy volunteers the haemodynamic effects of a single dose of nifedipine are markedly influenced by the pharmaceutical preparation and the rate of drug input. When the plasma concentration of nifedipine increases rapidly, such as after an intravenous bolus injection or rapidly disintegrating capsules, there is a marked increase in heart rate and little or even no effect on blood pressure. On the other hand, when the drug is given as a slow intravenous infusion or as a sustained release tablet and when the capsules are taken together with food, the decrease in blood pressure is accompanied by few or no changes in heart rate. Furthermore, it has been shown that not only haemodynamic effects of nifedipine, but also oesophageal motor function may be used as a quantifiable pharmacological effect. For patients with angina pectoris, a plasma concentration range that is associated with optimal treatment has not been defined, since large inter-individual variations in the nifedipine plasma concentration were observed in effectively treated patients. For patients with hypertension, significant sigmoidally shaped correlations between blood pressure reduction and nifedipine plasma concentrations following single or multiple doses have been demonstrated. The concentration-effect parameters were very similar to those found for normotensive subjects. After 6 weeks of treatment the potency of the drug had decreased, which might indicate the development of some tolerance. In patients with severe renal impairment, the maximal effect of nifedipine on diastolic blood pressure was more than doubled, which cannot be explained by differences in pharmacokinetics; therefore these patients appear to be more sensitive at the pharmacodynamic level. In patients with liver cirrhosis, the pharmacokinetics of nifedipine were quite different due to reduced protein binding and reduced enzyme activity; in patients with a portacaval shunt, considerable increased bypassing of the liver during the first pass after oral administration was observed. When corrected for free drug concentrations, the concentration-effect relationship for these patients is essentially the same as that found for healthy subjects.(ABSTRACT TRUNCATED AT 400 WORDS)