Nimodipine


Article Author:
Joe M Das


Article Editor:
Patrick Zito


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Susan Johnson
Alexandra Caley


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Phillip Hynes
Tehmina Warsi


Updated:
12/3/2018 4:36:02 PM

Indications

Nimodipine (C21H26N2O7) is a second-generation 1,4-dihydropyridine calcium channel blocker. It was originally 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. Ophthalmic formulation of nimodipine is tried in the management of glaucoma[11]

The following findings have been derived from various trials regarding the use of nimodipine:

  1. Nimodipine should be given to patients with no neurological deficits after subarachnoid hemorrhage. This is 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 a 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. A beneficial effect of nimodipine was seen 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 equal in efficiency 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 is 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 a period of 21 days. (NEWTON trial, 2018)[21]

Mechanism of Action

During depolarization of smooth muscle cells of blood vessels, there is an influx of calcium ions. The main 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.

Administration

Oral

Nimodipine has to be started 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 are to be 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 is attained 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 drug is well tolerated and there is no hypotension, the dose can be increased 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 be continued for a minimum of 5 days and a maximum of 14 days. If the condition is treated surgically, nimodipine should be continued in the same dose for a minimum of 5 days.

Intravenous nimodipine can be administered with or without pre-treatment with nimodipine tablets. If it is given 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. Intravenous and oral forms of nimodipine should not be used 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.

Nimodipine is metabolized by the cytochrome P450 3A4 system. Drugs which 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. Grape juice is also an inhibitor of the cytochrome system and should not be given to a patient who is being treated with nimodipine.

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.

Adverse Effects

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

Contraindications

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 fully safe in pregnancy (Category C) and should be used only if there is a good benefit-risk ratio. Breastfeeding is contraindicated while taking the drug due to the chance of harmful effects on the baby. Safety in the pediatric population has not been fully established.

Monitoring

Blood pressure has to be monitored in patients receiving nimodipine as it can cause hypotension.

Toxicity

Symptoms

Sudden toxicity due to overdosage can cause hypotension, cardiac arrhythmias, nausea, and sometimes vomiting.

Treatment

Stop the drug as the first step. Emergency symptomatic management should be provided. If the toxicity is due to oral intake, gastric lavage can be done, and charcoal can be administered on an emergency basis. Hypotension is managed with inotrope and arrhythmias are treated in conjunction with a cardiologist. No specific antidote is available.

Enhancing Healthcare Team Outcomes

Nurses often use nimodipine in the intensive care unit (ICU) and on the neurosurgical floor. When administering this agent, it is important to be aware that it can produce hypotension. Careful monitoring of blood pressure is required after administration. In patients who cannot be fed orally, it can be given after extracting the contents in a syringe and feeding through a nasogastric tube. It should be labeled and kept separate to avoid its administration intravenously.


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Nimodipine - Questions

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Nimodipine - References

References

Allen GS,Ahn HS,Preziosi TJ,Battye R,Boone SC,Boone SC,Chou SN,Kelly DL,Weir BK,Crabbe RA,Lavik PJ,Rosenbloom SB,Dorsey FC,Ingram CR,Mellits DE,Bertsch LA,Boisvert DP,Hundley MB,Johnson RK,Strom JA,Transou CR, Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage. The New England journal of medicine. 1983 Mar 17     [PubMed]
Sun J,Zheng J,Wang F,Zhang G,Wu J, Effect of hyperbaric oxygen combined with nimodipine on treatment of diffuse brain injury. Experimental and therapeutic medicine. 2018 Jun     [PubMed]
Scheller C,Wienke A,Tatagiba M,Gharabaghi A,Ramina KF,Ganslandt O,Bischoff B,Zenk J,Engelhorn T,Matthies C,Westermaier T,Antoniadis G,Pedro MT,Rohde V,von Eckardstein K,Kretschmer T,Kornhuber M,Steighardt J,Richter M,Barker FG 2nd,Strauss C, Prophylactic nimodipine treatment for cochlear and facial nerve preservation after vestibular schwannoma surgery: a randomized multicenter Phase III trial. Journal of neurosurgery. 2016 Mar     [PubMed]
Mu H,Wang L, Efficacy of Nimodipine Plus Yufeng Ningxin Tablets for Patients with Frequent Migraine. Pharmacology. 2018     [PubMed]
Leone M,Frediani F,Patruno G,Valentini S,Bussone G, Is nimodipine useful in migraine prophylaxis? Further considerations. Headache. 1990 May     [PubMed]
Sin JH,Shafeeq H,Levy ZD, Nimodipine for the treatment of otolaryngic indications. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2018 Sep 15     [PubMed]
Li YN,Zhang Q,Yin CP,Guo YY,Huo SP,Wang L,Wang QJ, Effects of nimodipine on postoperative delirium in elderly under general anesthesia: A prospective, randomized, controlled clinical trial. Medicine. 2017 May     [PubMed]
Pelliccia A,Sciaretta A,Matricardi M, Nimodipine treatment for drug-resistant childhood epilepsy. Developmental medicine and child neurology. 1990 Dec     [PubMed]
Du L,Yang Y,Wu J,Zhang H, Orgasmic headache treated with nimodipine. The journal of sexual medicine. 2014 Jan     [PubMed]
Kumpinsky A,Nahas SJ, Bath-Related Headache. Current pain and headache reports. 2018 Aug 2     [PubMed]
Maria DN,Abd-Elgawad AH,Soliman OA,El-Dahan MS,Jablonski MM, Nimodipine Ophthalmic Formulations for Management of Glaucoma. Pharmaceutical research. 2017 Apr     [PubMed]
Pickard JD,Murray GD,Illingworth R,Shaw MD,Teasdale GM,Foy PM,Humphrey PR,Lang DA,Nelson R,Richards P, Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ (Clinical research ed.). 1989 Mar 11     [PubMed]
Teasdale G,Bailey I,Bell A,Gray J,Gullan R,Heiskanan U,Marks PV,Marsh H,Mendelow AD,Murray G, The effect of nimodipine on outcome after head injury: a prospective randomised control trial. The British/Finnish Co-operative Head Injury Trial Group. Acta neurochirurgica. Supplementum. 1990     [PubMed]
Kaste M,Fogelholm R,Erilä T,Palomäki H,Murros K,Rissanen A,Sarna S, A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Stroke. 1994 Jul     [PubMed]
Murray GD,Teasdale GM,Schmitz H, Nimodipine in traumatic subarachnoid haemorrhage: a re-analysis of the HIT I and HIT II trials. Acta neurochirurgica. 1996     [PubMed]
European multicenter trial of nimodipine in the prophylaxis of classic migraine (migraine with aura). Migraine-Nimodipine European Study Group (MINES). Headache. 1989 Nov     [PubMed]
Nag D,Garg RK,Varma M, A randomized double-blind controlled study of nimodipine in acute cerebral ischemic stroke. Indian journal of physiology and pharmacology. 1998 Oct     [PubMed]
Pantoni L,Rossi R,Inzitari D,Bianchi C,Beneke M,Erkinjuntti T,Wallin A, Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial. Journal of the neurological sciences. 2000 Apr 15     [PubMed]
Horn J,de Haan RJ,Vermeulen M,Limburg M, Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke. 2001 Feb     [PubMed]
Kronvall E,Undrén P,Romner B,Säveland H,Cronqvist M,Nilsson OG, Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration. Journal of neurosurgery. 2009 Jan     [PubMed]
Hänggi D,Etminan N,Mayer SA,Aldrich EF,Diringer MN,Schmutzhard E,Faleck HJ,Ng D,Saville BR,Macdonald RL, Clinical Trial Protocol: 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 [NEWTON-2 (Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After SubarachNoid Hemorrhage)]. Neurocritical care. 2018 Jul 16     [PubMed]

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