Because it has some selectivity for cerebral vasculature, nimodipine's main use is in the prevention of cerebralvasospasm and resultant ischemia, a complication of subarachnoid hemorrhage (a form of cerebral bleed), specifically from ruptured intracranial berry aneurysms irrespective of the patient's post-ictus neurological condition.[6] Its administration begins within 4 days of a subarachnoid hemorrhage and is continued for three weeks. If blood pressure drops by over 5%, dosage is adjusted. There is still controversy regarding the use of intravenous nimodipine on a routine basis.[7][8]
A 2003 trial (Belfort et al.) found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.[9]
Nimodipine is not regularly used to treat head injury. Several investigations have been performed evaluating its use for traumatic subarachnoid hemorrhage; a systematic review of 4 trials did not suggest any significant benefit to the patients that receive nimodipine therapy.[10] There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy.[11]
The regular dosage is 60 mg tablets every four hours. If the patient is unable to take tablets orally, it was previously given via intravenous infusion at a rate of 1–2 mg/hour (lower dosage if the body weight is <70 kg or blood pressure is too low),[7] but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative.
While nimodipine was occasionally administered intravenously in the past, the FDA released an alert in January 2006, warning that it had received reports of the approved oral preparation being used intravenously, leading to severe complications; this was despite warnings on the box that this should not be done.[12]
The FDA has classified the side effects into groups based on dosages levels at q4h. For the high dosage group (90 mg) less than 1% of the group experienced adverse conditions including itching, gastrointestinal hemorrhage, thrombocytopenia, neurological deterioration, vomiting, diaphoresis, congestive heart failure, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, deep vein thrombosis.[6]
After oral administration, it reaches peak plasma concentrations within one and a half hours. Patients taking enzyme-inducing anticonvulsants have lower plasma concentrations, while patients taking sodium valproate were markedly higher.[13]
Nimodipine is metabolized in the first pass metabolism. The dihydropyridine ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by cytochrome P450 isoform 3A (CYP3A). This can be completely inhibited however, by troleandomycin (an antibiotic) or ketoconazole (an antifungal drug).[14]
Studies in non-human mammals using radioactive labeling have found that 40–50% of the dose is excreted via urine. The residue level in the body was never more than 1.5% in monkeys.[citation needed]
Nimodipine binds specifically to L-type voltage-gated calcium channels. There are numerous theories about its mechanism in preventing vasospasm, but none are conclusive.[15]
The key acetoacetate (2) for the synthesis of nimodipine (5) is obtained by alkylation of sodium acetoacetate with 2-methoxyethyl chloride, Aldol condensationofmeta-nitrobenzene (1) and the subsequent reaction of the intermediate with enamine (4) gives nimodipine.
Nimodipine contains a stereocenter and can exist as either of two enantiomers. The pharmaceutical drug is a racemate, an equal mixture of the (R)- and (S)- forms.[18]
^GB 1358951, Meyer H, Bossert F, Vater W, Stoepel KN, "New esters, their production, and their medicinal use", published 1974-07-03, assigned to Bayer AG
^"US FDA NDA 018869"(New drug approval from the US FDA). Drugs@FDA.gov Approved Drugs. Food and Drug Administration of the United States (FDA). December 28, 1988. Retrieved April 11, 2019. Nimodipine (...) approved for the treatment of high blood pressure (...)
^Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, et al. (March 1983). "Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage". The New England Journal of Medicine. 308 (11): 619–624. doi:10.1056/NEJM198303173081103. PMID6338383.
^Vergouwen MD, Vermeulen M, Roos YB (December 2006). "Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review". The Lancet. Neurology. 5 (12): 1029–1032. doi:10.1016/S1474-4422(06)70582-8. PMID17110283. S2CID43488740.
^De León OA (February 2012). "Response to nimodipine in ultradian bipolar cycling after amygdalohippocampectomy". Journal of Clinical Psychopharmacology. 32 (1): 146–148. doi:10.1097/JCP.0b013e31823f9116. PMID22217956.
^DE 2117571, Meyer H, Bossert F, Vater W, Stoepel KN, "Unsymmetrische 1,4-Dihydropyridincarbonsäureester, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimitell I [Asymmetrical 1,4-dihydropyridine carboxylic acid esters, process for their preparation and their use as pharmaceuticals I]", published 1972-10-19, assigned to Bayer AG
^Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN978-3-946057-10-9, S. 204.
Use as cerebral vasodilator: GB 2018134, "Cerebral therapeutic agent", assigned to Bayer AG; eidem, US 4406906, Meyer H, Bossert F, Kazda S, Hoffmeister F, Vater W, issued September 27, 1983, assigned to Bayer AG
