nimodipine

{{Short description|Antihypertensive drug of the calcium channel blocker class}}

{{Drugbox

| verifiedrevid = 462261185

| image = Nimodipine structure.svg

| tradename = Nimotop, Nymalize, others

| Drugs.com = {{drugs.com|monograph|nimodipine}}

| MedlinePlus = a689010

| DailyMedID = Nimodipine

| pregnancy_AU = C

| pregnancy_AU_comment = {{cite web | title=Nimodipine Use During Pregnancy | website=Drugs.com | date=March 15, 2019 | url=https://www.drugs.com/pregnancy/nimodipine.html | access-date=April 11, 2020}}

| pregnancy_category =

| routes_of_administration = By mouth, intravenous

| class = Dihydropyridine calcium channel blocker

| ATC_prefix = C08

| ATC_suffix = CA06

| ATC_supplemental =

| legal_AU =

| legal_AU_comment =

| legal_BR =

| legal_BR_comment =

| legal_CA =

| legal_CA_comment =

| legal_DE =

| legal_DE_comment =

| legal_NZ =

| legal_NZ_comment =

| legal_UK =

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_UN =

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| legal_status =

| bioavailability = 13% (by mouth)

| protein_bound = 95%

| metabolism = Hepatic

| elimination_half-life = 8–9 hours

| excretion = Feces and Urine

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 66085-59-4

| PubChem = 4497

| IUPHAR_ligand = 2523

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00393

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4341

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 57WA9QZ5WH

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00438

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1428

| IUPAC_name = 3-(2-Methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

| C = 21

| H = 26

| N = 2

| O = 7

| smiles = O=C(OC(C)C)\C1=C(\N/C(=C(/C(=O)OCCOC)C1c2cccc([N+]([O-])=O)c2)C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C21H26N2O7/c1-12(2)30-21(25)18-14(4)22-13(3)17(20(24)29-10-9-28-5)19(18)15-7-6-8-16(11-15)23(26)27/h6-8,11-12,19,22H,9-10H2,1-5H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = UIAGMCDKSXEBJQ-UHFFFAOYSA-N

| melting_point = 125

}}

Nimodipine, sold under the brand name Nimotop among others, is a calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage (a form of cerebral hemorrhage). It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication.

It was patented in 1971{{cite patent|country=GB|number=1358951|pubdate=1974-07-03|title=New esters, their production, and their medicinal use|assign=Bayer AG|inventor = Meyer H, Bossert F, Vater W, Stoepel KN }} and approved for medical use in the United States in 1988.{{cite web |title=US FDA NDA 018869 |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018869 |archive-url=https://web.archive.org/web/20170430081716/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018869 |url-status=dead |archive-date=April 30, 2017 |website=Drugs@FDA.gov Approved Drugs |publisher=Food and Drug Administration of the United States (FDA) |access-date=April 11, 2019 |format=New drug approval from the US FDA |date=December 28, 1988 |quote=Nimodipine (...) approved for the treatment of high blood pressure (...)}} It was approved for medical use in Germany in 1985.{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=464 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA464 }}

Medical use

Because it has some selectivity for cerebral vasculature, nimodipine's main use is in the prevention of cerebral vasospasm 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.{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018869s014lbl.pdf |archive-url=https://web.archive.org/web/20100315063859/http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018869s014lbl.pdf |url-status=dead |archive-date=March 15, 2010 |title=FDA approved Labeling text. Nimotop (nimodipine) Capsules For Oral Use |access-date=July 21, 2009 |date=December 2005 |publisher=Food and Drug Administration}} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage | journal = The New England Journal of Medicine | volume = 308 | issue = 11 | pages = 619–624 | date = March 1983 | pmid = 6338383 | doi = 10.1056/NEJM198303173081103 }}

A 2003 trial found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.{{cite journal | vauthors = Belfort MA, Anthony J, Saade GR, Allen JC | title = A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia | journal = The New England Journal of Medicine | volume = 348 | issue = 4 | pages = 304–311 | date = January 2003 | pmid = 12540643 | doi = 10.1056/NEJMoa021180 | doi-access = free }}

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.{{cite journal | vauthors = Vergouwen MD, Vermeulen M, Roos YB | title = Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review | journal = The Lancet. Neurology | volume = 5 | issue = 12 | pages = 1029–1032 | date = December 2006 | pmid = 17110283 | doi = 10.1016/S1474-4422(06)70582-8 | s2cid = 43488740 }} There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy.{{cite journal | vauthors = De León OA | title = Response to nimodipine in ultradian bipolar cycling after amygdalohippocampectomy | journal = Journal of Clinical Psychopharmacology | volume = 32 | issue = 1 | pages = 146–148 | date = February 2012 | pmid = 22217956 | doi = 10.1097/JCP.0b013e31823f9116 }}

=Dosage=

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),{{cite journal | vauthors = Janjua N, Mayer SA | title = Cerebral vasospasm after subarachnoid hemorrhage | journal = Current Opinion in Critical Care | volume = 9 | issue = 2 | pages = 113–119 | date = April 2003 | pmid = 12657973 | doi = 10.1097/00075198-200304000-00006 | author2-link = Stephan A. Mayer | s2cid = 495267 }} but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative.

Contraindications

Side effects

The US Food and Drug Administration (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,{{Clarify|reason=Clarify meaning of "q4h" and "neurological deterioration"|date=March 2025}} vomiting, diaphoresis, congestive heart failure, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, and deep vein thrombosis.

Pharmacokinetics

=Absorption=

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.{{cite journal | vauthors = Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H, Caresia L, Mück W, Barzaghi N, Gatti G | display-authors = 6 | title = Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients | journal = British Journal of Clinical Pharmacology | volume = 32 | issue = 3 | pages = 335–340 | date = September 1991 | pmid = 1777370 | pmc = 1368527 | doi = 10.1111/j.1365-2125.1991.tb03908.x }}

=Metabolism=

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).{{cite journal | vauthors = Liu XQ, Ren YL, Qian ZY, Wang GJ | title = Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes | journal = Acta Pharmacologica Sinica | volume = 21 | issue = 8 | pages = 690–694 | date = August 2000 | pmid = 11501176 | url = http://www.chinaphar.com/1671-4083/21/690.pdf | access-date = April 11, 2009 | archive-date = July 8, 2011 | archive-url = https://web.archive.org/web/20110708145218/http://www.chinaphar.com/1671-4083/21/690.pdf | url-status = dead }}

=Excretion=

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|date=January 2014}}

Mechanism of action

Nimodipine binds specifically to L-type voltage-gated calcium channels. There are numerous theories about its mechanism in preventing vasospasm, but none are conclusive.{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=0-443-07145-4 }}

Nimodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.{{cite journal | vauthors = Luther JM | title = Is there a new dawn for selective mineralocorticoid receptor antagonism? | journal = Current Opinion in Nephrology and Hypertension | volume = 23 | issue = 5 | pages = 456–461 | date = September 2014 | pmid = 24992570 | pmc = 4248353 | doi = 10.1097/MNH.0000000000000051 }}

Synthesis

File:Nimodipine synthesis.svg calcium channel blocker. Prepn:{{Cite patent|country=DE|number=2117571|pubdate=1972-10-19|title=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]|assign=Bayer AG |inventor = Meyer H, Bossert F, Vater W, Stoepel KN }} H. Meyer et al., {{US patent|3799934}} (1974 to Bayer).]]

The key acetoacetate (2) for the synthesis of nimodipine (5) is obtained by alkylation of sodium acetoacetate with 2-methoxyethyl chloride, Aldol condensation of meta-nitrobenzene (1) and the subsequent reaction of the intermediate with enamine (4) gives nimodipine.

Stereochemistry

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.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, {{ISBN|978-3-946057-10-9}}, S. 204.

class="wikitable" style="text-align:center"

class="hintergrundfarbe6"

! colspan="2"| Enantiomers of nimodipine

200 px
(R)-Nimodipine
CAS number: 77940-92-2

| 200 px
(S)-Nimodipine
CAS number: 77940-93-3