Pharmacology

Pharmacodynamics. The mechanism of nimodipine’s beneficial effect in patients with subarachnoid hemorrhage is not fully understood. It may have a preferential cerebral vasodilator action or a direct effect involving prevention of calcium overload in neurons by a blocking action on L-type voltage-sensitive calcium channels. Nimodipine may have a neuroprotective effect by entering the cell and inhibiting excessive calcium ion influx into the mitochondria. It increases the cerebral blood flow by reducing the resistance in small cerebral vessels; the increased perfusion is generally more pronounced in brain regions with preliminary damage and restricted circulation than in healthy regions. Cerebral vasodilation and neuroprotection occur at doses that have little or no effect on peripheral circulation. The improvement in cerebral circulation is particularly evident in patients with cerebral vasospasm after subarachnoid hemorrhage (Hunt and Hess grades I to III patients). Nimodipine improves reperfusion after stroke when administered within 12 hours of onset, but this benefit may be offset by reperfusion injury. Increased fibrinolytic activity has been observed in patients with aneurysmal subarachnoid hemorrhage following treatment with nimodipine. This is a nimodipine-induced decrease in the level of plasminogen activator inhibitor. Although nimodipine use is associated with improved outcome following subarachnoid hemorrhage, in some patients it can temporarily reduce brain tissue PO2.

Pharmacokinetics. Some of the important features of pharmacokinetics of nimodipine are:

	• The orally administered active substance nimodipine is almost completely absorbed. The unchanged active substance and its early "first pass" metabolites are detected in plasma as little as 10 to 15 minutes after the ingestion of the tablet. Following multiple-dose oral administration, the mean peak plasma concentrations (Cmax) are reached after 0.6 to 1.6 hours.
	• Nimodipine is widely distributed into body tissues after oral or intravenous administration. Plasma protein binding of unchanged nimodipine averages more than 95%. Nimodipine appears to distribute to a limited extent into cerebrospinal fluid.
	• Nimodipine concentrations appear to decline in a biphasic manner. The half-life is 1.2 to 1.8 hours after intravenous infusion and 5 to 10 hours after oral administration.
	• Nimodipine is extensively metabolized in the liver. All metabolites of nimodipine are either inactive or substantially less active than the parent drug.

Pharmacokinetic studies have reported an extensive variability of nimodipine concentrations in patients with subarachnoid hemorrhage. The observed variability may be attributed to practice variations in nimodipine administration, disease severity, administration of concomitant interacting drugs, and cytochrome P450 polymorphism (17).

Therapeutic drug monitoring. A method has been described for the determination of nimodipine in plasma and CSF of patients with subarachnoid hemorrhage using ultra high-performance liquid chromatography-tandem mass spectrometry (20). It is faster, simpler, and cheaper than other published analytical methods for nimodipine in plasma and the first validated one for nimodipine in CSF.

Novel formulations of nimodipine. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration (10). Lipid nanocapsules are in development for intranasal delivery of nimodipine into the brain.

Clinical trials

Although nimodipine ameliorated the ischemic consequences of subarachnoid hemorrhage in controlled clinical trials, no reversal of narrowing could be demonstrated on cerebral angiography. Various studies have shown that nimodipine is effective in delayed ischemic deficits of subarachnoid hemorrhage. The results of a randomized study suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing delayed ischemic neurologic deficits or cerebral vasospasm following subarachnoid hemorrhage (12). In a retrospective cross-sectional study on patients with aneurysmal subarachnoid hemorrhage treated by endovascular coiling, prophylactic administration of nimodipine reduced the rate of cerebral vasospasm and delayed cerebral ischemia (18).

A randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) on patients with aneurysmal subarachnoid hemorrhage showed that it was safe and tolerable up to 800 mg dose and reduced delayed onset of cerebral ischemia and use of rescue therapy (09). The 600 mg dose was selected for a pivotal phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy and safety study comparing EG-1962 to standard of care oral nimodipine in adults with aneurysmal subarachnoid hemorrhage (10). Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of greater than 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 hours of aneurysmal subarachnoid hemorrhage. An open-label, randomized, phase 2/3 study of intraventricular EG-1962 was stopped as it was considered unlikely to meet its primary endpoint (16). Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962, but internal carotid artery narrowing and occlusion in the basal cisterns did not occur.

Indications

Nimodipine is indicated for the prophylaxis and treatment of ischemic neurologic deficits caused by cerebral vasospasm after subarachnoid hemorrhage that follows ruptured intracranial aneurysm. The patients should be in good neurologic condition postictus, eg, Hunt and Hess grades I to III.

Off-label uses

Novel methods of administration of nimodipine for vasospasm. Besides oral administration, several novel methods for the delivery of nimodipine have been developed:

Intraarterial. Selective continuous intraarterial nimodipine treatment has been shown to be effective for refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage (32). Based on data collected from 42 patients, nimodipine has been recommended as an effective and safe intraarterial agent for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (04). Another retrospective study has shown beneficial effects in some patients with low-dose intraarterial nimodipine and the authors consider it as a valid adjunct for the endovascular treatment of cerebral vasospasm (05). A retrospective review from an institution where intraarterial nimodipine has been used since 2009 concluded that the treatment appears to be effective in reversing angiographic cerebral vasospasm, but it is not always effective in reversing clinical deterioration as several other factors, including treatment delay, affect the outcome (02). Results of another study showed that continuous intraarterial nimodipine infusion is an effective treatment for patients with severe cerebral vasospasm who fail to respond to hypertensive hypervolemic therapy and oral nimodipine alone, but emphasized that multimodal neuromonitoring should be done, and the dosage as well as the time of infusion should be determined, for each patient (03). A case control study concluded that angiographic reversal of vasospasm is seen in most patients following intraarterial nimodipine, but this does not always result in a long-lasting clinical response and is not a major advantage over the conventional hemodynamic therapy (07).

Intranasal administration. Lipid nanocapsules have been evaluated for particle size, drug payload, and in vitro drug release. In a study, the in vivo pharmacokinetic behavior of lipid nanoparticles loaded with nimodipine in blood and brain was compared with nimodipine solution after intravenous administration in rats (21). Results showed that they were capable of delivering the same amount of nimodipine to the brain with lower drug levels in blood. Lipid nanoparticles could provide an effective systemic delivery of nimodipine into the brain, with lower frequency of administration and minimal side effects.

Cisternal and intraventricular administration. Cisternal lavage with nimodipine by stereotactic catheter ventriculocisternostomy is a novel rescue therapy for the prevention of delayed cerebral infarction due to cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (22).

Stroke. Development of nimodipine for the indication of ischemic stroke was stopped after reaching phase III because the results revealed no evidence of efficacy of nimodipine in acute ischemic stroke.

Dementia. There is no convincing evidence to show that nimodipine is a useful treatment for unclassified dementia, Alzheimer disease, vascular dementia, or mixed Alzheimer and vascular dementia. A multicenter randomized clinical trial in China is evaluating the benefits and safety of nimodipine, administered within 1 week of onset of ischemic stroke, in preventing/treating mild cognitive impairment (31).

Epilepsy. Nimodipine was shown to have an anticonvulsive effect on penicillin-induced epileptiform activity in experimental animals. The explanation of this anticonvulsive effect is the calcium channel blocking effect of nimodipine to prevent excessive calcium influx into neurons, which is the initial step toward a seizure. A systematic review of randomized placebo-controlled add-on trials of calcium antagonists, including nimodipine in drug-resistant epilepsy, did not show efficacy (11).

Bipolar mood disorder. Nimodipine has been found to have a beneficial effect in ultrarapid-cycling bipolar depression.

Vestibular vertigo. Nimodipine has been reported to be effective in reducing the frequency of vestibular vertigo.

Urge incontinence. Treatment of geriatric urge incontinence with 30 mg nimodipine twice daily did not result in a significant improvement of incontinent episodes.

Call-Fleming syndrome. Calcium channel blockers such as nimodipine have been tried for the treatment of Call-Fleming syndrome, which is characterized by sudden onset of headache and focal neurologic deficits associated with segmental cerebral vasoconstriction.

Headache. Patients with primary thunderclap headache have been treated effectively with nimodipine. Intravenous nimodipine has been used for headache of reversible cerebral angiopathy. Responsiveness to nimodipine has been reported in a patient with thunderclap headache triggered by micturition (08).

Severe traumatic brain injury. In a study of patients with severe head trauma nimodipine was shown to improve cerebral metabolism and outcome, indicating a neuroprotective effect (01).

Vasospasm following traumatic subarachnoid hemorrhage. This can be successfully treated with intraarterial infusion of nimodipine.

Reversible cerebral vasoconstriction syndrome. Nimodipine relieves the headache component of this syndrome but has no definite effect on the hemorrhagic and ischemic complications.

Protection against iron toxicity of the brain. An experimental study has shown that nimodipine, as an L-type voltage-gated calcium channel blocker, may serve as a protective agent against iron overload, particularly in neuron cell types highly susceptible to iron toxicity (15).

Neuroprotection in whole brain radiation. An experimental study in rats exposed to brain radiation has shown that nimodipine alleviates delayed cognitive deficits due to neuron apoptosis likely by regulation of Bax/Bcl-2 and BDNF in the hippocampus (30).

A subtype of daily persistent headache starting with a thunderclap headache. This subtype responds to nimodipine, which decreases the CSF tumor necrosis factor alpha levels causing cerebral artery vasospasm (23).

Orgasmic headache. Nimodipine has been used to relieve as well as prevent the recurrence of headache during sexual activity accompanied by spasm of the middle cerebral arteries bilaterally (13).

Cranial nerve injuries. Nimodipine has been used for treatment of vocal fold (cord) paralysis, which is commonly due to recurrent laryngeal nerve injury. A retrospective study has shown that nimodipine treatment for acute vocal fold paralysis yielded equal recovery rates regardless of whether the medication was started within 15 days of onset or between 15 to 30 days or after 30 days (28). A systematic review and meta-analysis of open clinical studies supports the positive effect of nimodipine on vocal fold and facial motion recovery after injury (14).

Promotion of neuroregeneration. Nimodipine has been shown to attenuate spinal cord degeneration in experimental autoimmune encephalomyelitis and promote remyelination in a mouse model of multiple sclerosis (26). Because it combines features of immunomodulation with beneficial effects on neuroregeneration, nimodipine may have broad therapeutic implications for chronic neuroinflammatory diseases.

Contraindications

Nimodipine is contraindicated in patients with a known hypersensitivity to the drug.

Nimodipine is contraindicated in the management of prolonged familial hemiplegic migraine attacks as it prolongs the attacks (19).

Goals and duration of treatment

Nimodipine administration should be started within 96 hours after the onset of subarachnoid hemorrhage and should be continued for 3 weeks. The goal is prevention of neurologic deficits associated with vasospasm. A retrospective study has shown that administration of nimodipine 3 to 7 days following oral therapy after bleeding can be the alternative regimen, with no significant difference in outcome in patients who did not start nimodipine within 96 hours of onset of subarachnoid hemorrhage (25). Results of another retrospective study suggest that a more limited 14-day course of nimodipine therapy after a subarachnoid hemorrhage, as compared to a 21-day course, may be reasonable and efficacious in patients with a higher Glasgow Coma Scale score and lower Hunt-Hess grade of subarachnoid hemorrhage on presentation (27). Oral nimodipine administration has been shown to improve clinical outcome of patients after aneurysmal subarachnoid hemorrhage, and routine administration is recommended for patients (06).

Dosing

The recommended dosage is 60 mg taken 6 times per day. Nimodipine 120 mg tablets in micro particles with programmed action produces stable plasma levels with only 1 administration every 24 hours. This formulation would be more suitable when nimodipine chronic therapy is indicated.

Special considerations

Nimodipine should be used with care when cerebral edema or severely raised intracranial pressure is present.

Pediatric. Safety and effectiveness in children have not been established.

Geriatric. Clearance of nimodipine may be decreased substantially in elderly patients with hepatic dysfunction or renal impairment.

Pregnancy. Animal studies have shown no consistent evidence of teratogenic activity. Nimodipine has the potential to produce fetal hypoxia associated with maternal hypotension. There are no adequate and well-controlled studies in pregnant women to assess directly the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nimodipine itself has been shown to appear in human breast milk; therefore, nursing mothers are advised not to breast feed their babies when taking the drug.

Anesthesia. There are no special precautions for anesthesia.

Interactions

The use of nimodipine is not generally recommended in patients taking antihypertensive drugs, including other calcium channel blockers, as it may potentiate the effects of these medications.

With concomitant administration of anticonvulsants, nimodipine serum concentration may be considerably lowered due to the induction of drug-metabolizing enzymes.

Concomitant use of cimetidine raises nimodipine plasma concentrations. This effect may be mediated by the known inhibition of hepatic cytochrome P-450 by cimetidine, which could decrease first-pass metabolism of nimodipine.

Efficacy of nimodipine may be reduced when concomitantly administered with rifampicin because of the enzyme-inducing effect of rifampicin.

Adverse effects

The most commonly reported adverse reactions that are possibly related to oral nimodipine were decreased blood pressure, nausea, bradycardia, rash, edema, and diarrhea. The adverse reactions in cases of intravenous nimodipine were hypotension, abnormal liver function tests, and headache. Two cases of vasogenic edema have been reported following intraarterial administration of nimodipine for cerebral vasospasm refractory to medical treatments, and this may have been a result of reperfusion following relief of vasospasm (24).

Management. Management of adverse effects is symptomatic and supportive.