Nimodipine

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. 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.

A 2003 trial found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.

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

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

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, 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.

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).

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.

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.

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

Synthesis

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.

References

References

1. (March 15, 2019). "Nimodipine Use During Pregnancy".
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3. (December 28, 1988). "US FDA NDA 018869". Food and Drug Administration of the United States (FDA).
4. (2006). "Analogue-based Drug Discovery". John Wiley & Sons.
5. (December 2005). "FDA approved Labeling text. Nimotop (nimodipine) Capsules For Oral Use". [[Food and Drug Administration (United States).
6. (March 1983). "Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage". The New England Journal of Medicine.
7. (January 2003). "A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia". The New England Journal of Medicine.
8. (December 2006). "Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review". The Lancet. Neurology.
9. (February 2012). "Response to nimodipine in ultradian bipolar cycling after amygdalohippocampectomy". Journal of Clinical Psychopharmacology.
10. (April 2003). "Cerebral vasospasm after subarachnoid hemorrhage". Current Opinion in Critical Care.
11. (September 1991). "Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients". British Journal of Clinical Pharmacology.
12. (August 2000). "Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes". Acta Pharmacologica Sinica.
13. (2003). "Pharmacology". Churchill Livingstone.
14. (September 2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension.
15. "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]".
16. 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.