Chemistry:Nimodipine

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Short description: Antihypertensive drug of the calcium channel blocker class
Nimodipine
Nimodipine structure.svg
Clinical data
Trade namesNimotop, Nymalize, others
AHFS/Drugs.comMonograph
MedlinePlusa689010
License data
Pregnancy
category
Routes of
administration		Intravenous, by mouth
Drug classDihydropyridine calcium channel blocker
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability13% (by mouth)
Protein binding95%
MetabolismHepatic
Elimination half-life8–9 hours
ExcretionFeces and Urine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC21H26N2O7
Molar mass418.446 g·mol−1
3D model (JSmol)
Melting point125 °C (257 °F)
  (verify)

Nimodipine, sold under the brand name Nimotop among others, is 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[2] and approved for medical use in the US in 1988.[3] It was approved for medical use in Germany in 1985.[4]

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.[5] 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.[6][7]

A 2003 trial (Belfort et al.) found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.[8]

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.[9] There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy.[10]

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),[6] but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative.

Contraindications

Nimodipine is associated with low blood pressure, flushing and sweating, edema, nausea and other gastrointestinal problems, most of which are known characteristics of calcium channel blockers. It is contraindicated in unstable angina or an episode of myocardial infarction more recently than one month.[citation needed]

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.[11]

Side-effects

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.[5]

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.[12]

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).[13]

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]

Mode 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.[14]

Nimodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[15]

Synthesis

Dihydropyridine calcium channel blocker. Prepn:[16] H. Meyer et al., U.S. Patent 3,799,934 (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.[17]

Enantiomers of nimodipine
(R)-Nimodipin Structural Formula V1.svg
(R)-Nimodipine
CAS number: 77940-92-2 		(S)-Nimodipin Structural Formula V1.svg
(S)-Nimodipine
CAS number: 77940-93-3

References

  1. ↑ "Nimodipine Use During Pregnancy". March 15, 2019. https://www.drugs.com/pregnancy/nimodipine.html. 
  2. ↑ Meyer H, Bossert F, Vater W, Stoepel KN, "New esters, their production, and their medicinal use", GB patent 1358951, published 1974-07-03
  3. ↑ "US FDA NDA 018869" (New drug approval from the US FDA). Food and Drug Administration of the United States (FDA). December 28, 1988. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018869. "Nimodipine (...) approved for the treatment of high blood pressure (...)" 
  4. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 464. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA464. 
  5. ↑ 5.0 5.1 "FDA approved Labeling text. Nimotop (nimodipine) Capsules For Oral Use". Food and Drug Administration. December 2005. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018869s014lbl.pdf. 
  6. ↑ 6.0 6.1 "Cerebral vasospasm after subarachnoid hemorrhage". Current Opinion in Critical Care 9 (2): 113–119. April 2003. doi:10.1097/00075198-200304000-00006. PMID 12657973. 
  7. ↑ "Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage". The New England Journal of Medicine 308 (11): 619–624. March 1983. doi:10.1056/NEJM198303173081103. PMID 6338383. 
  8. ↑ "A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia". The New England Journal of Medicine 348 (4): 304–311. January 2003. doi:10.1056/NEJMoa021180. PMID 12540643. 
  9. ↑ "Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review". The Lancet. Neurology 5 (12): 1029–1032. December 2006. doi:10.1016/S1474-4422(06)70582-8. PMID 17110283. 
  10. ↑ "Response to nimodipine in ultradian bipolar cycling after amygdalohippocampectomy". Journal of Clinical Psychopharmacology 32 (1): 146–148. February 2012. doi:10.1097/JCP.0b013e31823f9116. PMID 22217956. 
  11. ↑ "Information for Healthcare Professionals: Nimodipine (marketed as Nimotop)". Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm129297.htm. 
  12. ↑ "Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients". British Journal of Clinical Pharmacology 32 (3): 335–340. September 1991. doi:10.1111/j.1365-2125.1991.tb03908.x. PMID 1777370. 
  13. ↑ "Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes". Acta Pharmacologica Sinica 21 (8): 690–694. August 2000. PMID 11501176. http://www.chinaphar.com/1671-4083/21/690.pdf. Retrieved April 11, 2009. 
  14. ↑ Pharmacology. Edinburgh: Churchill Livingstone. 2003. ISBN 0-443-07145-4. 
  15. ↑ "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension 23 (5): 456–461. September 2014. doi:10.1097/MNH.0000000000000051. PMID 24992570. 
  16. ↑ 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]", DE patent 2117571, published 1972-10-19
  17. ↑ 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.

Further reading



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