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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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- American Nimodipine Study Group. Clinical trial of nimodipine in acute ischaemic stroke. Stroke 23: 3–8, 1992Google Scholar
- Ameriso SF, Wenby RB, Meiselman HJ, Fisher M. Nimodipine and the evolution of hemorheological variables after acute ischemic stroke. Journal of Stroke and Cerebrovascular Diseases 2: 22–25, 1992Google Scholar
- Baumel B, Eisner LS, Karukin M, MacNamara R, Raphan H. Nimodipine in the treatment of Alzheimer’s disease. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp 366–373, Springer-Verlag, Berlin, Heidleberg, 1989Google Scholar
- Bianchi AP, Viglianesi MS. Hemorheological effects of dihydropyridine calcium entry blockers. Abstract. Naunyn-Schmiedeberg’s Archives of Pharmacology 330 (Suppl. V): R37, 1985Google Scholar
- Bormann B, v. Boldt J, Kling D, Mulch J, Weidler B, et al. Influence of nimodipine on cardiovascular parameters during coronary surgery. Neurochirurgia 28: 79–83, 1985Google Scholar
- Bogousslavsky J, Regli F, Zumstein V, Köbberling W. Double-blind study of nimodipine in non-severe stroke. European Journal of Neurology 30: 23–26, 1990Google Scholar
- Cummings JL, Jarvik LF. Dementia. In Cassel CK et al. (Eds) Geriatric medicine, 2nd ed., pp. 428–448, Springer-Verlag, New York, 1990Google Scholar
- Engel RR, Satzger W. Methodological problems in assessing therapeutic efficacy in patients with dementia. Drugs & Aging 2: 79–85, 1992Google Scholar
- Fischhof PK, Wagner G, Littschauer L, Rüther E, Apecechea M, et al. Therapeutic results with nimodipine in primary degenerative dementia and multi-infarct dementia. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp 350–359, Springer-Verlag, Berlin, Heidelberg, 1989Google Scholar
- Forsman M, Olsnes BT, Semb G, Steen PA. Effects of nimodipine on cerebral blood flow and neuropsychological outcome after cardiac surgery. British Journal of Anaesthesia 1990 65: 514–520, 1990Google Scholar
- Hilgert D, Eicher H, Liebl D, Platt D, Becker C, et al. Nimodipin-Therapie multimorbider geriatrischer Patienten mit hirnorganischem psychosyndrom — Pharmakodynamik und kinetik. Medizinische Welt 43: 20–26, 1992Google Scholar
- James IM, Savage IT. Nimodipine on cerebral blood flow and altertness in man. In Lechner & Ladurner (Eds) Progress in pathophysiology, diagnosis and therapy of cerebrovascular diseases. pp. 142–149, Excerpta Medica, 1984Google Scholar
- Kamath B, Lettieri J, Krol G, Raemusch K, Yeh S, et al. Phar-macokinetics and metabolism of radiolabeled nimodipine. Pharmacological Research 4 (Suppl. 2): S80, 1987Google Scholar
- Kanowski S, Fischhof P, Hiersemenzel J, Röhmel J, Kern U. Therapeutic efficacy of nootropic drugs — a discussion of clinical phase III studies with nimodipine as a model. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp. 339–349, Springer-Verlag, Berlin, Heidelberg, 1989Google Scholar
- Kapoula O, Lehrl S, Fischer B, Burkard G, Schuback G. Nimodipin bei Hirnleistungsstörungen im Alter — eine placebokontrollierte Doppelblindstudie in ärztlichen Praxen. Geriatrie & Rehabilitation 3: 135–146, 1990Google Scholar
- Kirch W, Rämsch KD, Dührsen U, Ohnhaus EE. Clinical pharmacokinetics of nimodipine in normal and impaired renal function. International Journal of Clinical Pharmacology Research IV: 381–384, 1984Google Scholar
- Kraaier V, van Huffelen AC, Wieneke GH, Keppel Hesselink JM. Nimodipine tested in a human model of cerebral ischaemia: electroencephalographic and transcranial Doppler ultrasound investigations in normal subjects during standardized hyperventilation. European Journal of Clinical Pharmacology 40: 17–21, 1991PubMedGoogle Scholar
- Ljunggren B, Brandt L, Säveland H. Management of aneurysmal subarachnoid hemorrhage. In Vincent JL (Ed.). Update in intensive care and emergency medicine, pp. 179–184, Springer Verlag, Berlin, 1985Google Scholar
- Melina D, Guerrera G, Colivicchi F, Santoliquido A, Cardillo C, et al. Anthihypertensive effect of nimodipine in elderly patients with chronic cerebrovascular disease: a preliminary report. Current Therapeutic Research 48: 70–80, 1990Google Scholar
- Murphy JJ. The role of calcium antagonists in the treatment of cerebrovascular disease. Drugs & Aging 2: 1–6, 1992Google Scholar
- Newberg Milde L, Milde JH, Michenfelder JP. Delayed treatment with nimodipine improves cerebral blood flow after complete cerebral ischaemia in the dog. Journal of Cerebral Blood Flow and Metabolism 6: 332–337, 1986Google Scholar
- Philippon BL, Chacornac R, Salord F, Kayayan R. FCBF Study of the effects of two calcium blockers during subarachnoid hemorrhage. Stroke 21 (Suppl. 8): 1129, 1990Google Scholar
- Philipon J, Grob R, Dagreou F, Guggiari M, Rivierez M, et al. Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine. Acta Neurochirurgica 82: 110–114, 1986Google Scholar
- Pickard JD, Murray GD, Illingworth R, Shaw MDM, Teasdale GM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. British Medical Journal 298: 33–59, 1989Google Scholar
- Pittera A, Ciancitto S. Effect of oral nimodipine on cerebral blood flow in patients with chronic cerebrovascular disorders: a supra-aortic Doppler ultrasound open study. Current Therapeutic Research 48: 716–729, 1990Google Scholar
- Powell M. Subarachnoid haemorrhage. Prescriber’s Journal 30: 173–179, 1990Google Scholar
- Rämsch K-D, Graefe K-H, Sommer J. Pharmacokinetics and metabolism of nimodipine. In Betz et al. (Eds) Nimodipine: pharmacological and clinical properties, pp. 147–161 Schattauer Verlag. Stuttgart, 1985bGoogle Scholar
- Rämsch K-D, Lücker PW, Wetzelsburger N. Pharmacokinetics of intravenously and orally administered nimodipine. Clinical Pharmacology and Therapeutics 41: 216, 1987Google Scholar
- Rudin M, Sauter A. Dihydropyridine calcium antagonists reduce the consumption of high-energy phosphates in the rat brain. A study using combined P/H magnetic resonance spectroscopy and P saturation transfer. Journal of Pharmacology and Experimental Therapeutics 251: 700–706, 1989PubMedGoogle Scholar
- Schmage N, Boehme K, Dycka J, Schmitz H. Nimodipine for psychogeriatric use: methods, strategies, and considerations based on experience with clinical trials. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp 374–381, Springer-Verlag, Berlin, Heidelberg, 1989Google Scholar
- Schuurman T, Traber J. Old rats as an animal model for senile dementia: behavioural effects of nimodipine. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp 296–307, Springer-Verlag, Berlin, Heidelberg, 1989Google Scholar
- Scriabine A, van der Kerckhoff W. Pharmacology of nimodipine: a review. Annals of the New York Academy of Science 522: 698–706, 1988Google Scholar
- Talley PW, Sundt Jr TM, Anderson RE. Improvement of cortical perfusion, intracellular pH, and electrocorticography by nimodipine during transient focal cerebral ischaemia. Neurosurgery 24: 80–87, 1989Google Scholar
- Tedeschi D. Calcium regulation in brain aging by nimodipine: a multicenter trial in Italy. Current Therapeutic Research 50: 553–563, 1991Google Scholar
- Tettenborn D, Dycka J. Prevention and treatment of delayed ischemic dysfunction in patients with aneurysmal subarachnoid hemorrhage. Stroke 21 (Suppl. IV): 85–89, 1990Google Scholar
- Tettenborn D, Dycka J, Kurtz N, Porto L. Safety profile of nimodipine in patients with subarachnoid hemorrhage. In Scriabine et al. (Eds) Nimodipine. Pharmacological and clinical results in cerebral ischaemia, pp 111–123, Springer-Verlag, Berlin, Heidleberg, 1991Google Scholar
- Tobares N, Pedromingo A, Bigorra J. Nimodipine treatment improves cognitive functions in vascular dementia. In Bergener & Reisberg (Eds) Diagnosis and treatment of senile dementia, pp. 360–365, Springer-Verlag, Berlin, Heidelberg, 1989Google Scholar
- Trust Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 336: 1205–1209, 1990Google Scholar
- Wronski J, Abraszko R, Berny W, Mierzwa T. Clinical experiences with nimodipine treatment in patients after SAH and aneurysm surgery. Zentrablatt für Neurochirugie 51: 21–23, 1990Google Scholar