Nimodipine

Summary

Synopsis

Nimodipine is a dihydropyridine calcium antagonist which has been shown to dilate cerebral arterioles and increase cerebral blood flow in animals and humans. It has potential in the treatment of a range of cerebrovascular disorders. Major interest to date, however, has focused on its use in the prevention and treatment of the delayed ischaemic neurological deficits that frequently occur in patients with subarachnoid haemorrhages as a result of sustained cerebral vasospasm.

Initial studies in which patients were treated with an intravenous infusion of nimodipine for up to 2 weeks, followed by oral treatment for 7 days, indicated that a higher proportion of patients than would normally be expected recovered with little or no permanent neurological damage. In a number of controlled studies oral nimodipine treatment for 3 weeks significantly decreased mortality rates and increased the number of patients who had a ‘good’ neurological outcome as compared with placebo treatment. In some of these trials fewer of the nimodipine-treated patients developed neurological deficits during the treatment period, but in none was there a significant effect on the incidence of angiographic vasospasm. It would seem that other pharmacological actions, such as increasing collateral blood flow to underperfused regions or a direct anti-ischaemic effect at the cellular level, may contribute to the clinical benefits obtained with nimodipine treatment. Preliminary results suggest that nimodipine is potentially useful in other cerebrovascular disorders, particularly ischaemic stroke.

To date, nimodipine has been well-tolerated, the only adverse effects of any significance being reductions in the blood pressure of some patients and reversible increases in liver enzymes during intravenous therapy. Thus, nimodipine has significant potential in the treatment of patients with subarachnoid haemorrhage. Wider clinical use should confirm its value as a significant addition to the very limited range of therapeutic choices currently available for patients with this disorder.

Pharmacodynamic Studies

Nimodipine is a dihydropyridine calcium antagonist which relaxes arterial smooth muscle in the presence of agonist-induced increased tone. In in vitro preparations it demonstrates a marked specificity for cerebral vessels. Following intravenous and intraperitoneal doses of nimodipine, dilation of cerebral arterioles has been demonstrated in vivo in animals, and similar results have been reported following the topical application of a nimodipine solution to exposed vessels. Several studies have shown that there is a preferential effect of nimodipine on arterioles with a diameter < 70 to 100μm. Direct observations of cerebral arteriole dilation have also been made in patients undergoing cranial surgery who received nimodipine 10 μg/kg as an intravenous infusion over 10 minutes. In animal studies intravenous or intracortical doses of nimodipine up to 0.1 μg/kg/min increased cerebral blood flow (CBF) by between 18 and 170% without significantly decreasing arterial blood pressure, although it would seem that this effect is only seen when cerebrovascular resistance is raised. Oral doses of nimodipine 40 to 80mg and intravenous doses of 15 to 30 μg/kg increased CBF by up to 18% in patients with subarachnoid haemorrhage (SAH), with no evidence of a ‘cerebral steal’ syndrome where blood flow is diverted to healthy tissue at the expense of ischaemic regions.

In patients with SAH infusion of nimodipine 1 mg/h, increased to 2 mg/h after 2 hours, had no significant effects on blood pressure or heart rate when given for up to 14 days, except in patients who were hypertensive before the start of treatment. However, if the infusion was started at the higher rate of 2 mg/h, systolic and diastolic blood pressures decreased over 3 to 4 hours by about 30 and 20mm Hg, respectively, partially recovered and then remained stable at this level for the duration of treatment.

When tested in non-primate animal models where experimental SAH was produced by injection of blood into the subarachnoid space, intrathecal administration of nimodipine was found to reverse both acute and delayed vasospasms of cerebral arteries. However, neither intrathecal nor intravenous doses of nimodipine up to 12 mg/kg 3 times daily had any effect on the occurrence of vasospasm or neurological deficits in primates subjected to experimental SAH by the surgical implantation of an autologous haematoma into the subarachnoid space. In animal models of total or partial cerebral ischaemia pretreatment with nimodipine increased post-ischaemic CBF values, reduced the extent of ischaemic damage, and improved neurological recovery in most studies, whereas only half the investigations where treatment was just given in the post-ischaemic stage were able to demonstrate any beneficial effects of nimodipine.

In healthy volunteers single oral doses up to 60mg produced modest improvements in self-rated alertness, and doses of 40 or 60mg given to elderly patients with mild cerebrovascular insufficiency tended to stabilise EEG determinants of vigilance.

Pharmacokinetic Properties

Intravenous infusions of nimodipine at rates of approximately 2 mg/h have resulted in mean steady-state plasma concentrations of 27 to 53 μg/L in patients with SAH, while single oral 60mg doses (in tablet form) given to healthy volunteers have produced maximum plasma concentrations of up to 31 μg/L within 1 hour of administration. Mean AUC values following 60mg oral doses have ranged from 42 to 125 μg/L · h, and other studies in volunteers showed reasonable linearity between oral dosage of nimodipine (up to 80mg) and both maximum plasma concentrations and AUC values. Despite the fact that nimodipine is well absorbed from the alimentary tract, considerable first-pass metabolism reduces the oral bioavailability to between 5 and 13% in volunteers and between 3 and 28% in patients with SAH.

Following intravenous administration there is an initial rapid distribution of nimodipine into the central compartment (half-life = 7 minutes, initial volume of distribution = 0.43 L/kg), presumably followed by a slower distribution into tissue sites. The volume of distribution at steady-state has been estimated at between 0.94 and 2.3 L/kg following intravenous administration. Only a small proportion of circulating nimodipine passes into the cerebrospinal fluid — a CSF concentration of 0.3 μg/L corresponded to a plasma concentration of 77 μg/L in SAH patients — reflecting the fact that nimodipine is extensively (about 98%) bound by plasma proteins.

The primary stages in the metabolism of nimodipine are demethylation and dehydrogenation of the dihydropyridine nucleus to produce an inactive pyridine analogue which is then further metabolised to a variety of plasma and urinary species. Approximately 50% of an oral dose is excreted as metabolites in the urine within 4 days. The elimination half-life of nimodipine following intravenous administration was 0.9 to 1.5 hours, while oral studies in volunteers produced longer values of between 1.7 and 7.2 hours.

Patients with liver disease have impaired clearance of nimodipine (mean total clearances of 158 to 217 L/h vs 420 to 519 L/h in healthy controls) but this only produced a noticeable increase in elimination half-life when nimodipine was given sublingually (18 vs 6.2 hours in controls). Similarly, the elimination half-life was much longer in elderly patients with renal failure (22 hours) compared with younger volunteers (3 hours), but it is not known whether this is due to impaired renal function or the effects of increasing age.

Therapeutic Trials

In non-comparative studies of patients with SAH who, in addition to standard treatment, received intravenous nimodipine 1 to 2 mg/h for 7 to 14 days, followed by oral treatment of 45 to 60mg every 4 hours for up to 7 days, overall neurological outcome (assessed at the end of treatment or after up to 3 years) was considered good in 60 to 78% of patients and mortality rates were 2 to 13%. In other, independent series of patients who underwent standard therapeutic procedures only, good recovery was obtained in 42 to 56% of those studied and 28 to 39% of patients died. A limited number of double-blind randomised trials have compared the effects of oral treatment with nimodipine 0.35 mg/kg to 90mg every 4 hours for 21 days with those of placebo treatment. Some of these assessed overall neurological outcome in all patients at 3 months and it was reported that there was a significant reduction in mortality (4 vs 24%; p < 0.01) or an increase in the percentage of patients who had little or no permanent neurological damage (29 vs 10%; p < 0.01) in the groups who received nimodipine. Furthermore, in 1 study fewer patients receiving nimodipine developed delayed neurological deficits during the treatment period (8% vs 29% for placebo). In the largest such trial to date (n = 554), nimodipine reduced the incidence of cerebral infarction by 34% (p < 0.005) and of poor outcomes by 40% (p < 0.001) versus placebo. The other studies concentrated on those patients who developed vasospasm-related neurological deficits during treatment; in 1 of these trials nimodipine reduced the incidence of deficits, the severity of neurological impairment was consistently reduced, and in 1 study there was a slight decrease in mortality. Similar results have been obtained with intravenous administration. In none of the comparative studies did nimodipine treatment actually reduce the incidence of angiographic cerebral vasospasm, and it is possible that the clinical benefits of nimodipine are the result of increased collateral blood supply to ischaemic tissues or a direct antiischaemic effect at the cellular level.

Preliminary studies have shown that oral treatment with nimodipine 120 mg/day for 28 days significantly reduced mortality and improved neurological recovery of patients who had suffered an acute ischaemic stroke. Additionally, the results of a number of small scale trials indicate that prophylactic treatment with nimodipine 120 mg/day reduces the frequency of migraine attacks in patients with common or classical disease, and may also lessen the duration and severity of attacks.

Adverse Effects

Nimodipine is generally well-tolerated, with hypotension being the only adverse effect reported more frequently than with placebo treatment. The incidence of hypotension in studies of patients with SAH was 4.7 to 8%, while a total of 21% of patients who received nimodipine noted adverse effects of any type, compared with 25% of patients who received placebo in 1 double-blind comparative study. Increased serum concentrations of liver enzymes have been observed in patients during intravenous treatment with nimodipine; these have always been reversible and are thought to be produced by ethanol in the intravenous formulation rather than nimodipine per se. There have been single reports of confusion with psychosis and possible myocardial ischaemia during nimodipine treatment.

Dosage and Administration

Treatment of patients with SAH should be started as soon after the initial haemorrhage or the development of neurological deficit as possible. Oral treatment can be given at a dosage of 60mg every 4 hours for 21 days. Alternatively, treatment can initially be an intravenous infusion of 1 mg/h. Provided that blood pressure remains stable this can be increased after 2 hours to 2 mg/h, then continued for 5 to 14 days, and followed by oral treatment of 60mg every 4 hours for up to 7 days. If treatment is started prior to surgery it should be continued for at least 5 days after the operation. For patients with low bodyweight, unstable blood pressure or impaired liver function a lower starting dose of intravenous nimodipine 0.5 mg/h (or 30mg orally every 4 hours) may be more suitable. Renal function should be monitored in patients known to have kidney disease.