Cerebral Pharmacokinetic/-dynamics of Nimodipine

Bleedings from brain aneurysms (bulging of brain arteries) usually cause severe neurological deficits. Initially, the bleeding of the aneurysm itself leads to serious brain damage. However, several days after this kind of brain bleeding many patients suffer stroke due to mechanisms still not fully understood. To date, there is no clearly defined and efficient treatment to prevent these delayed onset strokes. Several studies have already shown that the drug nimodipine can reduce the incidence of these strokes and thus improve the neurological long-term outcome. However, its clinical application remains controversial and the exact mode of action of nimodipine is still unknown. It is believed that the drug, with its dilating effect on arteries, might counteract the spasms of brain arteries that are often observed after this type of brain bleeding. It is also discussed that nimodipine might prevent the death of brain cells. However, it is still unknown whether the drug can even penetrate into the brain in order to achieve its neuron-protective effect. Nimodipine can be administered as a tablet, via the vein or directly into the arteries supplying the brain. However, the superiority of either route of administration and the most effective dosage is unclear. Therefore, the aim of this study is to determine whether and at which dose nimodipine can penetrate into the brain and to investigate the effects of nimodipine on brain oxygen supply and brain metabolism depending on the route of administration and dosing. To this end, we measure nimodipine concentrations simultaneously in blood, cerebrospinal fluid and directly in the brain using special brain probes (microdialysis) of 30 patients suffering severe brain bleedings from an aneurysm. Nimdoipine concentrations are determined at different administration routes (pills, vein, artery) and doses. In addition, during drug administration the intracranial pressure, the brain oxygen supply, the brain metabolism as well as the blood pressure and the heart function are monitored in order to determine the effects of nimodipine on body and brain. Our results will not only define the mode of action of nimodipine, but also determine its effectiveness and best route of administration to prevent delayed-onset strokes following brain bleedings from an aneurysm.

Our study has shown that administration of nimodipine through the veins may be more effective than oral administration in protecting the brain after a specific type of brain hemorrhage called subarachnoid hemorrhage. This is important because preventing damage to the brain in these patients can improve their chances of recovery and long-term health. We compared two methods of nimodipine delivery: oral administration and intravenous infusion. We found that significantly higher concentrations of the drug were achieved in both the blood and cerebrospinal fluid (the fluid surrounding the brain) during intravenous administration compared to oral administration. This suggests that intravenous nimodipine may be better at preventing brain damage, as higher levels in the cerebrospinal fluid are likely more effective at stopping reduced blood flow to the brain. However, we also found that only small amounts of nimodipine were detected in the actual brain tissue with both methods of administration. This indicates that the protective effects of nimodipine happen mainly in the fluid around the brain rather than directly in the brain tissue itself. It seems that the drug works by widening blood vessels in the cerebrospinal fluid space, rather than directly protecting the brain cells. This is an important finding because it clarifies how nimodipine works and suggests that intravenous administration provides a more consistent and higher exposure of the medication to the critical areas of the brain that need protection. Our results indicate that using intravenous nimodipine might be more effective than the currently recommended oral administration and could lead to better outcomes for patients after subarachnoid hemorrhage. While our findings support the use of intravenous nimodipine, more research is needed to confirm whether these higher levels in the cerebrospinal fluid actually result in fewer cases of delayed brain ischemia (a dangerous condition caused by reduced blood flow) and improved long-term recovery. Future clinical studies will be necessary to investigate this further.