In the coming weeks we will live update how we will incorporate the new 4-factor PCC products into our institutional formulary and practice.
Exciting developments to come!
Month: April 2013
Nimodipine Shortage: What About Nicardipine
Drug shortages continue to wreak havoc on health care in US hospitals. It seems every day there is yet another drug, more critical to medicine than the last, that’s unavailable due to shortages. Over the past few weeks, nimodipine has been going, going, gone. Now reaching for alternatives, in this case, is proving difficult as a result of limited data on alternatives leaving many in a troubling situation. Nicardipine, diltiazem, magnesium and other investigational agents are now being considered. This discussion implies other treatment modalities are consistent with normal practices (ie, surgical intervention, triple-H therapy).
It’s important to consider the therapeutic goals of these treatments: reducing the occurrence of cerebral vasospasm after subarachnoid hemorrhage. Though nimodipine has not conclusively been shown to prevent vasospasm, it has demonstrated reduction in cerebral ischemia and reduction in the incidence of poor neurological outcome at 3 months.1 Thus, when reviewing the data supporting these other treatments; cerebral vasospasm is essentially a surrogate marker for secondary cerebral ischemia and poor neurological outcomes.
Nicardipine would seem logical as an alternative to nimodipine. From the same class of CCB, similar pharmacokinetics and the availability of an IV dosage form in the US. However, the clinical, randomized data has not shown an improvement in neurological outcome in SAH patients. In a randomized-placebo controlled trial conducted in the early 1990’s, nicardipine reduced the incidence of symptomatic vasospasm vs placebo.2 At three months, there was no difference in GOS and NIHSS. While this study didn’t show an overall benefit for nicardipine, it is important to note that the study was stopped early and therefore underpowered, because nimodipine became commercially available in the USA during enrollment. The resulting power of the study was not the original 0.9, but 0.7. In addition, fewer patients in the nicardipine arm received adjuvant therapy for symptomatic vasospasm vs placebo, potentially reflecting under-treatment of those patients. What I walk away with from this study is that nicardipine 1) does not worsen outcomes vs placebo and 2) has not been adequately studied to say there is no benefit. At worse, it is certainly an option if nimodipine is not available. A follow up study was published, but only compared high vs low dose nicardipine, with no placebo (or nimodipine) arm.3
It’s been postulated that nimodipine may have some other, yet to be identified, effect other than its calcium channel blockade.4This could be an explanation why nicardipine has not shown a similar benefit. A newer CCB of the same class, clevidipine, has not been studied in the setting of SAH, and it is not know whether it would have outcomes resembling nimodipine, or nicardipine; certainly an area for future study.
After SAH, there are multiple pathophysiologic events that lead to cerebral vasospasm. With the old cliché, that ‘the exact mechanism is poorly understood,’ it seems that vasospasm results from depletion of nitric oxide, or the existence of extravasated oxyhemoglobin disrupting vascular endothelium-smooth muscle communication causing the production of endothelin-1 as well as a myriad of inflammatory cytokines.4 To me, it would seem that rather than address each pathophysiological derangement individually (statins, ET-1 antagonists, methylene blue??); there might be more appropriate ‘global’ therapies that may play a role.
Ultimately, there is no good answer to the nimodipine shortage with our current understanding and existing data. I can’t help but consider the situation we are in now with nimodipine and what is to come with other medications with unique actions and therapeutic niches. Why can’t there be an IV acetaminophen shortage?
Reference:
- Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al.: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid hemorrhage: British aneurysm nimodipine trial. BMJ 1989, 298:636-642
- Haley EC Jr, Kassell NF, Torner JC, Truskowski LL, Germanson TP. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1994 May;80(5):788-96
- Haley EC Jr, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993 Apr;78(4):537-47
- Siasios I, Kapsalaki EZ, Fountas KN. Cerebral Vasospasm Pharmacological Treatment: An Update. Neurology Research International;13: 1-20
Cocaethylene: Not Your Old Coca-Cola
We all know that the effects produced from the toxic ingestion of cocaine and alcohol as separate entities are excessive stimulation and pronounced depression, respectively. So what are the effects of the toxic ingestion of both compounds together?
Enter cocaethylene…and it is far from the Coca-Cola produced during your great grandmother’s time.
Cocaethylene (also known as ethylbenzoylecgonine) is produced from the concomitant ingestion of cocaine and alcohol. It is formed by the liver through a transesterification reaction of cocaine that occurs in the presence of ethanol through the activity of the nonspecific enzyme, cocaine carboxylesterase.
Like cocaine, cocaethylene blocks the reuptake of dopamine in the central nervous system and increases the extracellular concentration of dopamine in the accumbens nucleus, which produces euphoria and other similar effects. This effect may potentiate the toxicity of cocaine. However, cocaethylene has very little activity on the serotonergic system. In addition, the half-life of cocaethylene is longer than that of cocaine (nearly 2 hours for cocaethylene, compared to 40 minutes for cocaine), which can lead to prolonged toxicity. In addition, the LD50 of cocaethylene is lower than that of cocaine, which can be of potential concern in the patient who presents with concomitant ingestion of cocaine and alcohol.
The order of ingestion is important here, as the ingestion of ethanol preceding the ingestion of cocaine will not only lead to the formation of cocaethylene, but will also increase the plasma levels of cocaine and lead to a prolonged euphoric effect.
In terms of manifestations of toxicity, animal models have demonstrated that cocaethylene has myocardial depression effects and can decrease stroke volume, contractility, and mean arterial pressure. In addition, it has also been shown to increase the incidence of EKG abnormalities and lead to life-threatening dysrhythmias in a dose-dependent manner as a result of its greater potent effects on sodium channel blockade. It has also been shown to have inhibitory properties on the potassium and calcium channels in the heart, and one case report has described a patient who experienced QTc prolongation and Torsades de Pointes as a result of a dual ingestion of cocaine and ethanol.
It is difficult to extrapolate the effects that cocaethylene has demonstrated in animal studies to human patients, but it is important to be mindful of the effects of the combination of cocaine and alcohol and the potential for the formation of cocaethylene in the setting of such a dual ingestion.
References:
Jatlow P. Cocaethylene: pharmacologic activity and clinical significance. Ther Drug Monit 1993; 15:533-536. [PMID: 8122289]
Andrews P. Cocaethylene toxicity. J Addict Dis 1997; 16:75-84. [PMID: 9243342]
Hearn WL, Rose S, Wagner J, et al. Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol Biochem Behav 1991; 39:531-533. [PMID: 1946594]
Wilson LD, French S. Cocaethylene’s effects on coronary artery blood flow and cardiac function in a canine model. J Toxicol Clin Toxicol 2002; 40:535-546. [PMID: 12215047]
Wilson LD, Henning RJ, Suttheimer C, et al. Cocaethylene causes dose-dependent reductions in cardiac function in anesthetized dogs. J Cardiovasc Pharm 1995;26:965-973. [PMID: 8606535]
Wilson LD, Jeromin J, Garvey L, et al. Cocaine, ethanol, and cocaethylene cardiotoxicity in an animal model of cocaine and ethanol abuse. Acad Emerg Med 2001;8:211-222. [PMID: 11229942]
Xu YQ, Crumb WJ, Clarkson CW. Cocaethylene, a metabolite of cocaine and ethanol, is a potent blocker of cardiac sodium channels. J Pharmacol Exp Ther 1994; 271:319-325. [PMID: 7965731]
EM PharmD 
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