Nimodipine

Nimodipine (C21H26N2O7) is a second-generation 1,4-dihydropyridine calcium channel blocker. It was initially 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.

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

The primary function of nimodipine is to block voltage-gated L-type calcium channels in their inactive conformation, avoiding this influx.

It has a preference to act on cerebral blood vessels since it is lipophilic and can cross the blood-brain barrier.

The mechanisms by which mortality and morbidity are reduced are still controversial and essentially unknown.

Nimodipine does not reduce the incidence or severity of radiological cerebral vasospasm detected by angiography in humans or primates.

Hypotheses 

• There is modification of microcirculatory flow e.g. by dilation of pial conducting vessels (leptomeningeal collaterals) or by decreased platelet aggregation 
• Decreased intracellular calcium accumulation and therefore decreased neuronal cell death
• Some other direct neuronal protective effect.
• Nimodipine increases endogenous fibrinolytic activity, which may reduce the incidence of microthrombosis
• Nimodipine may antagonise cortical spreading depolarisation / ischaemia

Yes.

Nimodipine reduces the relative risk of a poor neurological outcome and delayed cerebral ischaemia after aSAH, with a relative risk of 0.67 (95% CI 0.55 to 0.81) compared to placebo, 

The NNT is 19 patients to prevent one poor neurological outcome.

This comes from a 2007 Cochrane Systematic review. The biggest contributor to this meta-analysis was the 1989 British Aneurysm Nimodipine Trial (BRANT) which was a prospective multicentre UK RCT using oral nimodipine vrs placebo in 554 patients and showed a reduction in DCI and poor neurological outcomes.

PO or IV

If PO 60 mg every 4 hours for 21 days

If IV 20 mcg/kg/hr 

Two RCT’s comparing PO versus IV nimodipine have been performed, in 2009 and 2012, neither showing any difference in outcomes. 

Pros of PO: 

10 times cheaper

Less hypotension

No CVC and associated complications

Pros of IV: 

More guaranteed absorption, can be given with ileus / nausea

Stable pharmacokinetic properties

Theoretically less fluctuations in BP

CYP3A4

The drug is extensively metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme and has a high first-pass metabolism. 

Therefore, concomitant administration of nimodipine with strong inducers (eg, phenytoin, carbamazepine, phenobarbital, rifampin) or inhibitors (eg, protease inhibitors, azole antifungals, macrolides like erythromycin, amiodarone, verapamil, diltiazem, grapefruit juice) of CYP3A4 should generally be avoided.

Adverse Effects

Common: 

• Hypotension requiring vasopressor support
• Constipation
• Alcohol effect from vehicle

Less common

• Headache, vertigo, flushing, nausea, pedal edema, rash, and palpitations.