Nimodipine is a dihydropyridine calcium antagonist which dilates cerebral blood vessels and increases cerebral blood flow in animals and humans. Preliminary findings reveal its potential benefit for the treatment of a wide range of cerebrovascular disorders, particularly for prophylaxis and treatment of delayed ischaemic neurological deficits resulting from cerebral vasospasm in patients with subarachnoid haemorrhage. Studies involving patients aged up to 79 years have confirmed these preliminary findings by showing that nimodipine reduces the incidence of severe ischaemic deficit after subarachnoid haemorrhage.
Initial results from studies of patients with acute ischaemic stroke indicate that nimodipine, started within 72 hours of onset, improved recovery, particularly in patients over 65 years. However, other investigators have found no marked difference in 6-month mortality or morbidity rates of stroke patients aged up to 97 years. Findings from other studies suggest that nimodipine may improve symptoms of cognitive dysfunction in elderly patients.
Nimodipine is well tolerated by both younger and older patients. The most frequently reported adverse event has been hypotension.
Thus, nimodipine therapy offers important benefits as part of the approach to management of patients with subarachnoid haemorrhage and has potential in other cerebral disorders, including stroke and impaired cognitive function, although confirmation of initial results in patients with cerebral impairment are required.
Nimodipine is a calcium antagonist of the 1,4-dihydropyridine class which relaxes arterial smooth muscle. In in vitro preparations it demonstrates marked specificity for cerebral vessels and in vivo it dilates cerebral blood vessels. In patients with cerebrovascular spasm following subarachnoid haemorrhage, single oral doses of nimodipine 40 to 80mg increased cerebral blood flow while intravenous doses of 15 to 30 µg/kg had an ‘inverse steal’ effect, increasing cerebral blood flow by up to 20% in ischaemic areas. In primate animal models of subarachnoid haemorrhage oral nimodipine had no significant effect on delayed vasospasm, although in nonprimate models intrathecal and intravenous nimodipine reversed both acute and delayed vasospasm.
Administration of nimodipine before cerebral ischaemic insult in animals consistently reduced the extent of ischaemic damage; however, only a few investigators have demonstrated any benefit in animal models when treatment was initiated after the event. In patients with acute ischaemic stroke administration of intravenous nimodipine 1 to 2 mg/h improved parameters of cerebral metabolism, such as regional glucose metabolism in noninfarcted areas, and oxygen metabolism in the dense ischaemic core and penumbra regions.
Infusion of nimodipine 1 mg/h, increased to 2 mg/h after 2 hours, had no significant effects on heart rate or blood pressure in normotensive patients with subarachnoid haemorrhage; however, higher initial doses (2 mg/h) resulted in transient decreases in systolic and diastolic blood pressures during the first 4 hours of treatment in hypertensive and normotensive patients with subarachnoid haemorrhage.
Single oral nimodipine doses of 40 to 80mg have improved alertness in healthy volunteers, and doses of 40mg stabilised EEG determinants of vigilance in elderly volunteers with minor impairments of cognitive function.
Absorption of nimodipine following oral administration is virtually complete, although as there is extensive first-pass hepatic metabolism bioavailability is relatively low; bioavailability was 5 to 13% in healthy volunteers and 3 to 28% in patients with subarachnoid haemorrhage. Maximum plasma nimodipine concentrations reached 20 to 80 µg/L following single oral 30 or 60mg doses in healthy volunteers and patients with subarachnoid haemorrhage or impaired cognitive function, and were achieved within 60 minutes. Steady-state plasma concentrations were attained within 12 to 18 hours of onset of intravenous infusion and were dose dependent; during intravenous infusion of 1 mg/h in healthy volunteers the plasma nimodipine concentration was 11.9 µg/L, and a plasma concentration of 26.6 µg/L was reached in patients with subarachnoid haemorrhage during infusion of 2 mg/h. Cerebrospinal fluid concentrations of nimodipine are lower than plasma concentrations.
Nimodipine is extensively metabolised in the liver by demethylation and dehydrogenation of the dihydropyridine nucleus. Approximately 50% of an administered dose is recovered as urinary metabolites within 4 days. Plasma elimination half-life values have ranged from 1.7 to 5.6 hours after oral administration and 0.9 to 1.5 hours following intravenous administration.
Patients with impaired renal function had reduced plasma clearance (0.23 vs 0.6 L/h) and longer elimination half-lives (22 vs 2.8h) than healthy volunteers. Clearance of nimodipine was also lower in patients with liver dysfunction (158 to 217 L/h) than in healthy volunteers (420 to 519 L/h), although there was no noticeable difference in half-life in these patients.
In noncomparative studies, nimodipine administered by constant intravenous infusion for up to 14 days, followed by a period of oral therapy in some patients, provided protection against delayed ischaemic deterioration during the risk period for symptomatic vasospasm in both young and elderly patients undergoing surgery following subarachnoid haemorrhage. Neurological outcome, assessed at the end of treatment or after ⩽ 3 years, was considered to be good in 60 to 77% of patients. Recovery was best in patients not severely affected by the haemorrhage, and in those with internal carotid artery complex or middle cerebral artery aneurysms. However, the incidence of angiographically diagnosed vasospasm remained unaltered by nimodipine therapy. The beneficial effects of nimodipine (oral or intravenous administration) have also been demonstrated in placebo controlled studies of patients with subarachnoid haemorrhage. Significantly fewer nimodipine recipients than placebo-treated patients died or had permanent neurological deficits, and fewer nimodipine recipients had cerebral infarcts. The incidence of death resulting from delayed ischaemic deficit was also lower in nimodipine treated patients. It therefore appears that nimodipine reduces the incidence of severe deficits, rather than facilitates recovery from severe deficits.
Oral nimodipine 120 mg/day, initiated within 72 hours of acute ischaemic stroke and continued for 21 to 28 days, has been associated with significantly improved neurological outcome in small numbers of elderly patients, and overall mortality rates in studies evaluating the effects of nimodipine in patients with acute ischaemic stroke aged 35 to 79 years (7.9 to 25%) have been lower than those for placebo-treated patients of the same age range (12 to 29%). Overall analysis of results from placebo controlled studies suggests nimodipine may be of greater benefit in patients older than 65 years and is more likely to be beneficial when treatment has been initiated within 12 hours of the ischaemic event. However, study findings also suggest that while oral nimodipine improves neurological function in some patients with more severe impairment, it has no marked effect in patients with only mild impairment.
Results from studies in patients with cognitive impairment of varying aetiologies indicate that oral treatment with nimodipine 90 mg/day may ameliorate the most common symptoms of cognitive dysfunction in elderly patients. However, improvements are more likely to be observed in patients with cerebral dysfunction of vascular origin than in patients with other diagnoses. In addition, preliminary evidence suggests that nimodipine therapy may protect against anoxic-ischaemic brain injury following cardiac arrest and may also be beneficial in elderly patients with head injury.
In clinical trials nimodipine was generally well tolerated. The most frequently reported adverse event was hypotension, which occurred in up to 5% of patients with subarachnoid haemorrhage, approximately 3% of patients with acute ischaemic stroke and 19% of patients with impaired cognitive function. Headache has also been reported in up to 1% of participants with subarachnoid haemorrhage, and headache and/or dizziness were the adverse events reported most frequently by patients with acute ischaemic stroke or impaired cognitive function. Overall, in controlled comparative studies up to 21 % of patients with subarachnoid haemorrhage treated with nimodipine had adverse events compared with up to 25% of placebo recipients.
Instances of increased serum concentrations of liver enzymes have occurred during oral and intravenous nimodipine therapy. Other events reported during therapy with nimodipine include abdominal disorders, rash, dizziness, nausea and vomiting, flushing, perspiration, bradycardia, extrasystoles, intrapulmonary venous shunt, and anxiety with confusion.
Dosage and Administration
In patients with subarachnoid haemorrhage nimodipine treatment should be initiated as soon as possible after the first haemorrhage (or the development of vasospasm-related neurological deficit), and continued for up to 21 days. Nimodipine may be administered as an oral 60mg dose every 4 hours or, alternatively, initiated as an intravenous infusion of 0.5 to 1 mg/h, increasing over 2 hours to 2 mg/h if the blood pressure remains stable. Intravenous therapy should be maintained for 5 to 14 days and followed, if necessary, by oral therapy with 60mg every 4 hours for a total of 21 days.
For patients with unstable blood pressure, impaired liver function or low bodyweight, a lower starting dose should be considered. Renal and liver function should be monitored during treatment.
Oral nimodipine 120 mg/day for up to 28 days has also been administered to patients after an acute ischaemic stroke, and a dosage of 90 mg/day has been used to treat patients with impaired cognitive function of varying aetiologies.
KeywordsCerebral Blood Flow Nimodipine Cerebral Vasospasm Nimo Impaired Cognitive Function
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