In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

Abstract

ObjectiveTo investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods.MethodsFive healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted.ResultsPlasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine.ConclusionNimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

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“…Nimodipine, although Ltype calcium channel blocker, has more pronounced neuroprotective effects 52 . Nimodipine is highly lipophilic, crosses the blood-brain barrier, and reaches the brain where it causes a reduction in vasospasm in subarachnoid hemorrhage.…”

“…Nimodipine administered before hemorrhage does cause an inhibition in the nitric oxide activity and acts as a protectant. Nimodipine also exhibits anti-convulsive actions and is also beneficial in improving cognitive and behavioral symptoms in organic brain syndrome, thereby slowing the progression of dementia [52][53][54][55][56][57] . It is useful in cluster headache as it relieves vasospasm 55 .…”

“…Nimodipine has a less pronounced cardiovascular effect, but studies have shown it lowers the blood pressure in a small group of patients, where it causes hypotension [52][53][54][55][56][57] . However, further trials are required to suggest its use in hypertension.…”

Neuropharmacology in the ICU: Monitoring the Therapeutic Response and Neurological Hemodynamic Impact of Our Therapeutic Decisions in Real Time

“…The impact of these agents on the cerebrovasculature may ultimately result in decreased cerebral tissue oxygenation and poor outcomes. In addition, acute/chronic comorbidities (e.g., chronic hypertension, renal insufficiency, or hepatic failure), hyperthermia/hypothermia, alterations in acid/base status, and even volume status can alter the pharmacokinetics of these drugs [2]. In patients with aneurysmal SAH, tailoring therapy can be challenging as cerebral vasospasm along with other pathophysiologic mechanisms are thought to contribute to morbidity and mortality in these patients [3][4][5][6].…”