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Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy

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Abstract

Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed.

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Authors and Affiliations

  1. Department of Neurology, Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA

    Sima I. Patel

  2. MINCEP Epilepsy Care through University of Minnesota Health, 5775 Wayzata Blvd, Minneapolis, MN, 55416, USA

    Sima I. Patel & Ilo E. Leppik

  3. Department of Experimental and Clinical Pharmacology, College of Pharmacy, Minneapolis, USA

    Angela K. Birnbaum, James C. Cloyd & Ilo E. Leppik

  4. Department of Neurology, Medical School, Minneapolis, MN, USA

    Ilo E. Leppik

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  1. Sima I. Patel
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  2. Angela K. Birnbaum
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  3. James C. Cloyd
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  4. Ilo E. Leppik
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Correspondence to Sima I. Patel.

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Funding

Supported in part by NIH NINSD NS 16308 and K01 NS050309. No funding was received from industry for the preparation of this manuscript.

Disclosures

AKB, JCC and IEL hold a patent on intravenous carbamazepine. JCC holds a patent on intravenous topiramate. SIP has no conflicts of interest.

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Patel, S.I., Birnbaum, A.K., Cloyd, J.C. et al. Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy. CNS Drugs 29, 1009–1022 (2015). https://doi.org/10.1007/s40263-015-0289-0

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