Nimodipine Reappraised: An Old Drug With a Future

Abstract

Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine's role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

Keywords: Delayed cerebral ischemia; L-type calcium channel; nimodipine; subarachnoid hemorrhage; sustained release delivery; vasospasm..

Fig. (1)

Proposed model by which Nimodipine and other L-type calcium channel blockade may mitigate the harmful effects of SD through both direct mechanisms limiting SD initiation and propagation as well as the microvascular response to SD. This leads to less severe metabolic stress to vulnerable cells in compromised regions. The four vertical panels (separated by dashed lines) in the chart demonstrate the effects of SD (green arrows) across the ischemic spectrum of perfusion from irreversible core to normally perfused brain (See CBF chart at the top). As SD passes from initiation in core or penumbra into vulnerable brain, neurons and astrocytes are further depolarized and penetrating arterioles (red) transiently constrict (spreading ischemia), causing progression of injury. In normal brain, SD dissipates, causes reversible metabolic stress to neurons, and vasodilation (spreading hyperemia.) Under conditions of adequate l-type calcium channel blockade with nimodipine, SD is initiated less frequently and propagates less efficiently by neurons and astrocytes, leading to fewer and less severe SD. The microvascular constriction is reversed through a process that involves smooth muscle cells, but may also be mediated through effects in pericytes and perivascular astrocytes. Normal brain is therefore able to compensate with the metabolic challenge and even in conditions of vasospasm, this lack of metabolic stress to potentially vulnerable brain lessens the burden of delayed cerebral ischemia. Metabolic stress to neurons and astrocytes is demonstrated in each vulnerable zone before and after SD.

Fig. (2)

Mechanism for reduction of delayed cerebral ischemia (DCI) with nimodipine even in the presence of large vessel vasospasm. Such a model explains the clinically beneficial effect without consistently limiting large vessel vasospasm. Under control conditions (A), SD (green arrows) propagates from core (black zone) and vulnerable regions (grey zone), causing additional ischemia both adjacent to the core insult and in distant regions with compromised perfusion due to large vessel vasospasm. Under conditions of L-type calcium channel blockade with nimodipine (B), some SD may still be initiated but is less frequent and less severe as outlined in Fig. 1. This then leads to less risk of DCI (grey area) both locally and in remote tissue, even in the case of large vessel vasospasm.

Fig. (3)

Pharmakokinetic analysis of plasma and serum nimodipine concentrations in the NEWTON 1 study [97], averaged across all doses. Intrathecal delivery of EG-1962 is compared to standard of care oral nimodipine. Note that CSF concentration (A) of nimodipine is nearly unmeasurable in the standard of care oral administration group. In plasma (B), concentrations of nimodipine in the oral group were higher, potentially increasing the risk of hypotensive transient events. The inset to the right (C) is a scanning electron micrograph of the microparticles used for delivery of the nimodipine crystals, which are embedded in the clefts of the particles (white arrows). This allows for slow sustained release of the nimodipine as measured by persistent nimodipine presence in serum even to 30 days after subarachnoid hemorrhage [161].