Nimodipine

Nimodipine is a dihydropyridine calcium channel blocker with particular cerebrovascular effect. Nimodipine increases cerebral perfusion, particularly in poorly perfused areas, by arterial dilatation, an effect which is proportionately greater in smaller than in larger vessels.

Vasoconstrictions provoked in vitro by various vasoactive substances (e.g. serotonin, prostaglandins and histamine) or by blood and blood degradation products can be prevented or reduced by up to 75% by nimodipine.

The intravenous nimodipine solution is 100% available to the tissues as the peripheral venous blood takes the drug to the lungs and heart and from there to all organs.

Absorption

After oral ingestion, absorption is rapid. Peak plasma concentrations are observed 30 to 60 minutes following oral administration. Despite high gastrointestinal absorption of nimodipine, the absolute bioavailability is 5–15%, which is attributed to extensive first pass metabolism (about 85–95%).

Distribution

The distribution volume (V_ss, 2 compartment model) for i.v. administration is calculated to be 0.9–2.3 l/kg body weight. The total (systemic) clearance is 0.8–1.6 l/h/kg. Nimodipine is 97–99% bound to plasma proteins.

Biotransformation

The cytochrome P450 3A4 system plays a major role in the metabolic elimination of nimodipine. Nimodipine is eliminated as metabolites, mainly by dehydrogenation of the dihydropyridine ring and oxidative O-demethylation. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups, and glucuronidation as a conjugation reaction are other important metabolic steps. The three primary metabolites occurring in plasma show no or only therapeutically negligible residual activity.

Elimination

Effects on liver enzymes by induction or inhibition are unknown. In humans the metabolites are excreted about 50% renally and 30% in the bile.

Linearity/non-linearity

For oral administration, the peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg). The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hours. The terminal half-life is 5-10 hours, and is not relevant for establishing the recommended dosing interval for the medicinal product.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. However, several preclinical findings may be of relevance to the prescribing physician. In chronic repeat dose toxicity studies in dogs, doses of 1 and 2.5 mg/kg/day were shown to be tolerated without adverse effect. However, at the higher dose of 6.25 mg/kg/day significant changes in ECGs were noted due to disturbances in myocardial blood flow, but there was no indication of histopathological damage to the heart. In pregnant rats, doses of 30 mg/kg/day and higher inhibited fetal growth and resulted in reduced fetal weights. At 100 mg/kg/day embryolethality occurred. No evidence of teratogenicity was observed. In rabbits, equivocal evidence of teratogenicity was seen in one study at doses up to 10 mg/kg/day. In two subsequent studies (one at 30 mg/kg/day), these findings were not reproduced. In one peri-postnatal study in rats, mortality and delayed physical development were observed at doses of 10 mg/kg/day and higher. The findings were not confirmed in subsequent studies.