Nimodipine (C21H26N2O7) is a second-generation 1,4-dihydropyridine calcium channel blocker. It was initially invented for the management of systemic hypertension.

The FDA approved the use of nimodipine for the first time in 1988. However, its use is restricted mainly to the management of vasospasm following subarachnoid hemorrhage.

1. Prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage (FDA-approved use)[1]
2. In the treatment of diffuse brain injury along with hyperbaric oxygen therapy[2]
3. In assisting the recovery after cranial nerve injury[3]
4. In the treatment of frequent migraine; nimodipine with Yufeng Ningxin tablets[4]
5. Migraine prophylaxis[5]
6. Peripheral vertigo and Meniere disease[6]
7. Nimodipine reduces the development of postoperative delirium in elderly patients under general anesthesia[7]
8. Drug-resistant epilepsy[8]
9. Orgasmic headache[9] and bath-related headache[10]
10. The ophthalmic formulation of nimodipine is a potential agent in the management of glaucoma[11]

The following findings derive from various trials regarding the use of nimodipine:

1. Nimodipine should be given to patients with no neurological deficits after subarachnoid hemorrhage to reduce the onset of new neurological deficits due to vasospasm. (Cerebral arterial spasm controlled trial of nimodipine in patients with subarachnoid hemorrhage, 1983)[1]
2. Nimodipine 60 mg every 4 hours given orally was well tolerated and reduced cerebral infarction. It also improved the outcome after subarachnoid hemorrhage. (British aneurysm nimodipine trial, 1989)[12]
3. There is no statistically-proven benefit of nimodipine in head injury patients. (The British/Finnish Co-operative Head Injury Trial Group, 1990)[13]
4. Nimodipine has no role in improving the functional outcome in acute ischemic hemispheric stroke. (A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke, 1994)[14]
5. There is no benefit of nimodipine in the treatment of head injury patients. (Nimodipine in traumatic subarachnoid hemorrhage: a re-analysis of the HIT I and HIT II trials, 1996)[15]
6. Nimodipine has got only a very minimal role in the prophylaxis of migraine without aura. European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Migraine-Nimodipine European Study Group (MINES), 1989.[16]
7. Researchers noted a beneficial effect with nimodipine in acute cerebral ischemia. (A randomized, double-blind controlled study of nimodipine in acute cerebral ischemic stroke, 1998). [17]
8. Nimodipine may be effective in patients with small vessel subcortical vascular dementia. (Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial, 2000)[18]
9. Early supplementation of nimodipine in stroke patients does not have any beneficial effect. (Very Early Nimodipine Use in Stroke (VENUS), 2001)[19]
10. Oral and intravenous nimodipine are equally efficient in preventing vasospasm following subarachnoid hemorrhage. (Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration, 2009)[20]
11. Nimodipine has a potential neuroprotective effect by preventing calcium overload in ischemic neurons. However, this gets outweighed by its harmful hemodynamic effects in the ischemic area in the treatment of acute ischemic stroke. (Intravenous Nimodipine West European Stroke Trial (INWEST), 1994)
12. A new product named EG-1962 is undergoing phase 3 clinical trial for the use in subarachnoid hemorrhage patients. It comprises a Nimodipine suspended with a biodegradable polymer. It can be given intraventricularly as a single dose and releases nimodipine into the intraventricular and subarachnoid space over 21 days. (NEWTON trial, 2018)[21]

During the depolarization of smooth muscle cells of blood vessels, there is an influx of calcium ions. The primary function of nimodipine is to block voltage-gated L-type calcium channels in their inactive conformation, avoiding this influx, to prevent vasoconstriction. It has a preference to act on cerebral blood vessels since it is lipophilic and can cross the blood-brain barrier.

Oral

Nimodipine should start as early as possible or within 96 hours of the diagnosis of subarachnoid hemorrhage. Nimodipine is usually available as capsules of 30 mg. 1It has to be given at least 1 hour before or 2 hours after meals. The adult recommended dose for adults is 60 mg (two 30-mg capsules) every 4 hours for 21 consecutive days.

If the patient is not conscious enough to swallow the nimodipine capsule, a hole can be made in both ends of it using an 18-gauge needle, and the contents get extracted into a syringe. Then it can be fed through a nasogastric tube and washed down with 30 ml of normal saline (0.9%).

Bioavailability following parenteral administration is 100%, while that following oral administration is 3% to 30% due to the extensive first-pass metabolism. Bioavailability increases in patients with cirrhosis liver, making it necessary to reduce the dose in such patients. After oral administration, peak plasma concentration occurs within 1 hour. The elimination half-life is longer (8 to 9 hours) as compared to the rate of initial elimination (1 to 2 hours), making the biological half-life 1.7 to 9 hours. Hence the drug has to be administered frequently (every 4 hours). Nimodipine does not accumulate in the body even after continuous administration for a week. It is over 95% attached to plasma proteins, which is concentration-independent. Excretion is via kidneys in the form of metabolites.

Intravenous

Nimodipine should be given intravenously via a central venous catheter at a starting dose of 1 mg/hr (15 mcg/kg per hour equivalent to 5 ml per hour) for the first 2 hours. If the patient tolerates the drug well and there is no hypotension, the dose can increase to 2 mg per hour (30 mcg/kg per hour equivalent to 10 ml per hour) after the first 2 hours. Two hours for 2 mg nimodipine, i.e., 10 ml nimodipine solution per hour (about 30 microgram/kg per hour).

If the patient's body weight is less than 70 kg or the patient has hypotension, nimodipine should be started at a dose of 0.5 mg per hour (2.5 ml of solution per hour) or less, if necessary.

Duration of Treatment

Aneurysmal subarachnoid hemorrhage

Treatment via intravenous route should be started via intravenous route as soon as possible after the onset of clinical vasospasm and should continue for a minimum of 5 days and a maximum of 14 days. If the condition has surgical treatment, nimodipine should continue at the same dose for a minimum of 5 days.

The administration of intravenous nimodipine can be with or without pre-treatment with nimodipine tablets. If giving the drug following administration of oral form, the total duration of treatment should not exceed a maximum of 21 days. Intravenous nimodipine should not be given for a period longer than 14 days. Patients should not take the intravenous and oral forms of nimodipine concomitantly.

During surgery, a freshly prepared dilute solution of nimodipine (20 ml of a dilute solution of nimodipine: 1 ml of nimodipine concentrated intravenous infusion solution and 19 ml of Ringer solution) warmed up to blood temperature may be instilled intracisternally. This dilution must be used immediately after preparation.

The cytochrome P450 3A4 system metabolizes nimodipine. Drugs that inhibit this enzyme can lead to increased plasma concentrations of nimodipine. Such drugs include macrolide antibiotics like erythromycin, protease inhibitors like ritonavir, azole antimycotics like ketoconazole, antidepressants like fluoxetine, quinupristin/dalfopristin, cimetidine, and valproic acid. Grapefruit juice is also an inhibitor of the cytochrome system, and a patient who is getting treated with nimodipine should avoid it.

Intraventricular

The outcome, dosage, and duration of intraventricular administration of nimodipine are not yet clear. The NEWTON trial is going on to identify these factors.

Nimodipine is usually well tolerated orally, but its use correlates with some side effects, related to the vasodilating property. The main adverse effects of the drug are headache, vertigo, flushing, nausea, diarrhea, pedal edema, rash, and palpitations.

A previous history of a hypersensitivity reaction to nimodipine is an absolute contraindication. Liver failure and hypotension are relative contraindications for administering nimodipine.

The drug is not entirely safe in pregnancy (Category C under the previous FDA system), and pregnant patients should only use it if there is a strong benefit-risk ratio. Breastfeeding is contraindicated while taking the drug due to the chance of harmful effects on the baby. Research has not yet fully established safety in the pediatric population.