Benzodiazepine (and Barbiturate) Comparison

Clinical Implications [2, 10]

• All benzodiazepines and barbiturates are metabolized by the liver.

  • Chlordiazepoxide, diazepam, midazolam, phenobarbital:

    Phase I metabolism (CYP450 system): Prolonged half-lives and durations of effect with hepatic dysfunction

  • Lorazepam:

    Phase II metabolism (glucuronidation): Less effect on pharmacokinetics with hepatic dysfunction.

Pharmacokinetics [1, 3-5, 10]

• Benzodiazepines exert primary action in central nervous system

• Drug permeability across the blood brain barrier influenced by the lipophilicity of molecule

  • A more lipophilic benzodiazepine will have a quicker onset once in systemic circulation.

    • IV speed of onset: Diazepam (fastest) > lorazepam (medium speed) > midazolam (slowest onset)

  • A more lipophilic benzodiazepine is more slowly absorbed following intramuscular administration, affecting the onset of action.

    • IM speed of onset: Midazolam (fastest) > lorazepam (medium speed)
    • Diazepam onset is variable because of unreliable IM absorption

  • A more lipophilic compound quickly diffuses out of the CNS and into lipid tissue, leading to short duration of action

    • Diazepam has a short duration of action with a single dose despite its long T_1/2.
    • With repeated dosing the concentration will accumulate saturating the lipid tissue and protein binding, resulting in a longer effect duration approaching the T_1/2.

References

1. Greenblatt DJ, Arendt RM, Abernethy DR et al. In vitro quantitation of benzodiazepine lipophilicity: relation to in vivo distribution. Br J Anaesth. 1983 Oct;55(10):985-9. PMID 6626413
2. Brunton LL, Knollmann BC, Hilal-Dandan R. Goodman & Gilman's the Pharmacological Basis of Therapeutics. Thirteenth ed. New York: McGraw Hill Medical; 2018.
3. Greenblatt DJ, Shader RI, Harmatz JS et al. Absorption rate, blood concentrations, and early response to oral chlordiazepoxide. Am J Psychiatry. 1977 May;134(5):559-62. PMID 848586
4. Greenblatt DJ, Harmatz JS, Friedman H et al. A large-sample study of diazepam pharmacokinetics. Ther Drug Monit. 1989b;11(6):652-657. PMID 2512694
5. Greenblatt DJ, Divoll M, Harmatz JS et al. Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci. 1982;71(2):248-252. PMID 6121043
6. Gale GD, Galloon S, Porter WR. Sublingual lorazepam: a better premedication? Br J Anaesth. 1983 Aug;55(8):761-5. PMID 6136288
7. Fresenius Kabi. Midazolam USP [package insert]. U.S. Food and Drug Administration website. Revised [2017].
8. Pentikäinen PJ, Välisalmi L, Himberg JJ et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol. 1989 Mar;29(3):272-7. PMID 2723115
9. Phenobarbital Sodium USP [package insert]. Boucherville, QC, Canada: Sandoz Canada Inc.; 2015
10. Greenblatt DJ, Shader RI, Divoll M et al. Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol. 1981;11 Suppl 1:11S-16S. PMID 6133528