Nimodipine is a calcium antagonist belonging to the 1,4-dihydropyridine group. On account of its highly lipophilic nature, the substance easily penetrates the blood-brain barrier. In animal studies, nimodipine binds with high affinity and selectivity to calcium-ion channels of the L-type, thus blocking the influx of calcium ions through the membrane. In pathological states associated with the increased influx of calcium ions into the nerve cells eg, cerebral ischemia, nimodipine is believed to improve the stability and functional capacity of these cells.
Investigations carried out in patients with acute cerebral circulatory disturbances have shown that nimodipine dilates the cerebral vessels and increases cerebral circulation, the increased perfusion being generally more pronounced in areas of the brain with preliminary damage and restricted circulation than in healthy areas. The improvement is particularly noticeable in patients with cerebral vasospasm after subarachnoid haemorrhage. Nimodipine produces significant reductions in ischemic neurological deficits caused by vasospasm and in mortality.
Selective blockade of calcium-ion channels in certain areas of the brain eg, the hippocampus and cortex may possibly explain the positive effect of nimodipine on learning and memory deficits observed in various animal models. The same molecular mechanism probably underlies the cerebral vasodilative and blood flow-promoting effect of nimodipine observed in animals and humans. The exact mechanism by which the molecular effects of nimodipine produce the improvements in disturbed brain function that have been demonstrated in neurophysical and clinical test models will be the subject of future investigations.
Absorption: The orally administered active substance, nimodipine, is practically completely absorbed. The unchanged active substance and its early first-pass metabolites are detected in plasma as little as 10-15 min after ingestion of the tablet. Following multiple-dose oral administration (3 x 30 mg/day), the mean peak plasma concentrations (Cmax
) are 7.3-43.2 ng/mL in elderly individuals, these being reached after 0.6-1.6 hrs (tmax
). The peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg).
Using continuous infusions of 0.03 mg/kg/hr, mean steady-state plasma concentrations of 17.6-26.6 ng/mL are achieved. After IV bolus injections, the plasma nimodipine concentrations fall biphasically with half-lives of 5-10 min and about 60 min. The distribution volume (Vss
, 2-compartment model) for IV administration is calculated to be 0.9-1.6 L/kg/body weight. The total (systemic) clearance is 0.6-1.9 L/hr/kg.
Protein-Binding and Distribution: Nimodipine is 97-99% bound to plasma proteins. Nimodipine added to whole blood is roughly equally distributed between the erythrocytes and the plasma. In animal studies, nimodipine has been shown to penetrate the placental barrier. In lactating rats it has also been shown to pass into the milk. It is probable that both these processes also occur in humans, although no data is as yet available.
After oral and IV administration, nimodipine can be detected in the CSF in concentrations about 0.5% of the measured plasma concentrations. These correspond roughly to the free concentration in plasma.
Metabolism, Elimination and Excretion: Nimodipine is eliminated metabolically, mainly by dehydrogenation of the dihydropyridine ring and oxidative ester cleavage. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups and glucuronidation as a conjugation reaction are further important metabolic steps. The 3 primary metabolites occurring in plasma show no or only therapeutically unimportant residual activity.
Effects on liver enzymes by induction or inhibition are unknown. In humans, the metabolites are excreted about 50% renally and 30% in the bile.
The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hrs. The terminal half-life of 5-10 hrs is of no importance for establishing the dosage interval in the package insert.
Bioavailability: On the basis of the high metabolization during the first-pass through the liver (about 85-90%) the absolute bioavailability is 10-15%.
Acute Toxicity (LD50
): See table.
Click on icon to see table/diagram/image
Chronic Toxicity: The systemic tolerability of nimodipine at doses up to 6.25 mg/kg/day was studied in dogs in a study lasting 1 year. Doses up to 2.5 mg/kg proved harmless; 6.25 mg/kg produced slight though reversible ECG changes as a result of disturbances to the myocardial blood flow. However, no histopathological changes in the heart or in other organs were detected at this dose. Rats given daily doses of nimodipine up to about 90 mg/kg/day in feed for a period of 2 years tolerated these doses without harm.
Oncogenic and Mutagenic Potential: A lifetime study in which rats received nimodipine at doses of up to 1800 ppm (about 90 mg/kg/day) in their feed for 2 years yielded no evidence of an oncogenic potential. Similarly, a long-term study in which mice received 500 mg/kg/day orally for 21 months produced no evidence that nimodipine has an oncogenic potential.
Nimodipine has been the subject of extensive mutagenicity testing. Tests for the induction of genetic and chromosomal mutations have yielded no relevant evidence of mutagenic effects.
Reproduction Toxicity: The fertility of male and female rats and subsequent generations was unimpaired at doses up to 30 mg/kg/day.
Administration of 10 mg/kg/day to pregnant rats during embryogenesis showed no harmful effects. Doses ≥30 mg/kg/day inhibited growth, causing reduced fetal weight, and at 100 mg/kg/day increased numbers of embryos died in utero
. No teratogenic effects were observed.
Embryotoxicity studies in rabbits with doses up to 10 mg/kg/day orally yielded no evidence of teratogenic or other embryotoxic effects.
To investigate perinatal and postnatal development, studies were conducted in rats with doses up to 30 mg/kg/day. In 1 study, increased perinatal and postnatal mortality and delayed physical development were observed with ≥10 mg/kg/day. These findings were not confirmed in subsequent studies.
No findings are available from use during pregnancy and lactation in humans.