30 - Benzodiazepines

Benzodiazepines:

© SPMM Course Benzodiazepines: Drug Duration of action Effect Diazepam, chlordiazepoxide, clonazepam, flurazepam Long-acting Can have more than 200hrs t1/2 in genetically slow metabolizers. Also, toxicity can take 1 – 2 weeks to be evident when higher doses are given. Lorazepam, oxazepam, temazepam, Alprazolam Intermediate or short acting Severe withdrawal phenomena but the lesser risk of daytime impairment and daytime sedation. Rebound insomnia and anterograde amnesia more often seen in short t1/2. Lorazepam t1/2 15 hours; temazepam somewhat shorter – 10 hours. Triazolam Very short acting Used in anaesthesia Diazepam is well absorbed orally - oral bioavailability nearly 100%. Peak plasma concentration is reached in 15 - 90 minutes after oral administration; has a second peak at 6 - 12 hours due to enterohepatic recirculation. Diazepam is widely distributed - highly lipophilic (so CSF concentration more or less equals plasma concentration) with 95-99% plasma protein binding. It has a slow elimination t½ 30 h (ranges between 20 - 100 h). It also takes a long time to reach steady state (5 -6 days). It gets extensively metabolized in the liver with 3 active metabolites: Nordiazepam or desmethyldiazepam (principal metabolite – could accumulate due to long t1/2), Oxazepam and Temazepam. “Z”-hypnotics  Zolpidem, zaleplon, and eszopiclone are quickly and completely absorbed when given orally. Food may delay absorption by an hour.  Lack of active metabolites of zolpidem, zaleplon, and eszopiclone avoid the accumulation and hang over effects.  NICE's appraisal committee concluded that no compelling evidence of a clinically useful difference exists between the Z-drugs and short-acting benzodiazepines in terms of effectiveness, adverse effects, or potential for misuse or dependence. But this is controversial. Z HYPNOTICS

Zopiclone / Eszopiclone (enantiaomer) Onset within 45 mins; half-life 4 to 5 hours (acts up to 8 hours) Benzodiazepine receptor selective for alpha 1 subunit; eszopiclone is the only Z-hypnotic indicated for sleep maintenance therapy (US FDA) – others are used for initiation problems. Zaleplon Onset within 30 mins; half-life 1 to 2 hours (acts up to 4 hours). Shorter half-life and quick onset – makes it suitable for those with sleep initiation problems; not so helpful for the maintenance of sleep. Zolpidem Onset within 30 mins; half-life 1 to 4 hours (acts up to 6 hours). Shorter half-life and quick onset – makes it suitable for those with sleep initiation problems; not so helpful for the maintenance of sleep. Less hangover effect.

© SPMM Course Notes prepared using excerpts from:

 Chadwick, B. et al. Potentially hazardous drug interactions with psychotropics. Advances in Psychiatric Treatment (2005) 11: 440-449  Davis, J et al (2006) Switch or stay? Am J Psychiatry 163:2032-2033,  De Leon, J. (2004) Psychopharmacology: Atypical Antipsychotic Dosing: The Effect of Smoking and Caffeine. Psychiatric Services. 55 (5): 491-493.  Lieberman & Tasman, Handbook of Psychiatric Drugs.  Mendelson WB, et al. The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev. 2004;8:7-17.  Palaniyappan, L., Insole, L. & Ferrier, IN. The safety and efficacy of antidepressant combinations: A review. Adv Psych Treatment. In press.  Puri, BK. Drugs in psychiatry- Oxford Medical Publications; ; 13-37  Sandson NB, Armstrong SC, Cozza KL: Med-Psych Drug-Drug Interactions Update An Overview of Psychotropic Drug-Drug Interactions. Psychosomatics 2005;46:464–494.  Schrier, RW. Diseases of the Kidney & Urinary Tract: Clinicopathologic Foundations of Medicine. Lippincott-Wilkins, 2007 Pg 301  Tamminga, C & Davis, JM Schizophrenia Bulletin vol. 33 no. 4 pp. 937–946, 2007  Taylor D. Psychopharmacology and adverse effects of antipsychotic long-acting injections: a review. The British Journal of Psychiatry Nov 2009, 195 (52) S13-S19  http://www.drugs.com/pro/fluvoxamine.html  Phipps A & Turkington, D. Psychiatry in the renal unit. http://apt.rcpsych.org/content/7/6/426

DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information