Seizures and Benzodiazepines

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September 14, 2017 by jtreb

By: Matthew Yacobucci, PharmD, PGY1 Pharmacy Resident

Benzodiazepines (BZDs) are one of the most commonly prescribed pharmacologic agents in the United States (1,2).  These medications work by binding to the GABAA receptor, a ligand-gated chloride-selective ion channel, which, when agonized, produces an inhibitory effect, thus reducing the excitability of neurons(3).   BZDs are first line  treatment for seizures. The BZDs possess anxiolytic, amnestic, sedative, anticonvulsant, and muscle-relaxant properties.

Pharmacokinetics (PK), described as “what the body does to the drug,” can be broken into the following categories: 1) absorption, 2) distribution, 3) metabolism, and 4) excretion (3).  The PK of the various BZDs are summarized in Table 1.  In general, BZDs are well absorbed after oral administration(3).  The BZDs widely distribute in lipid-rich areas, such as the central nervous system and adipose tissue(3).

Below are few clinical pearls when considering which BZD to use for seizures:

Midazolam

  • It has a very rapid onset of action which is due to its lipophilic nature.
  • Midazolam is the preferred agent for intramuscular administration.
  • If midazolam is given in the setting of seizures, you must consider its short duration of anticonvulsant activity (15-30 mins).
  • Midazolam is only preferred in seizing patients who do not have IV access.

Lorazepam

  • Lorazepam is considered the BZD of choice for the treatment of seizures. It has been shown to have a lower rate of seizure recurrence compared to midazolam or diazepam, which is due to its hydrophilic nature(4).
  • Lorazepam IV may cause hypotension due to its diluent, propylene glycol, thus it should be diluted with an equal volume of normal saline, if time permits, prior to administration(4).
  • Lorazepam IM is not recommended for the treatment of acute seizures because of slow and incomplete absorption(5).

Diazepam

  • Do not administer diazepam intramuscularly; as it precipitates at the site of injection, which leads to slow and incomplete absorption(6).
  • Due to its very short duration of anti-convulsant action, diazepam is not recommended for the treatment of seizures in the emergency department, unless no other options are available.
  • Diazepam is the only BZD available as a rectal gel, which is an optimal route of administration for outpatient therapy.
  • Diazepam has active metabolites prolonging its durations of action, which is optimal for the treatment of some disease states (i.e., acute alcohol withdrawal)

Most BZDs are metabolized hepatically, with a few agents (chlordiazepoxide and diazepam) that have active metabolites.  The BZDs can be classified into short-acting, intermediate-acting, and long acting, based on the half-life of the individual agent. All BZDs are primarily excreted via the kidney(3).  Caution should be used when prescribing BZDs to patients with hepatic and/or renal dysfunction because of dose stacking and over sedation.

References

  1. Wick JY. The history of benzodiazepines. Consult Pharm. 2013 Sep;28(9):538-48.
  2. Cascade E, Kalali AH. Use of benzodiazepines in the treatment of anxiety. Psychiatry (Edgmont) 2008 Sep;5(9):21–22.
  3. Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects. The Ochsner Journal. 2013;13(2):214-223.
  4. Idrees U, Londner, M. Pharmacotherapy overview of seizure management in the adult emergency department. Journ Pharm Pract. 2005;18(5):394-411.
  5. Rey E, Tréluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes. Clin Pharmacokinet. 1999 Jun;36(6):409-24.
  6. Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for status epilepticus. J Emerg Med. 1999 Mar-Apr;17(2):323-8.

pharm table

 

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