En fråga gällande Bensodiazepiner

Fråga: Jag har en fråga gällande Bensodiazepiner. Det är välkänt inom kliniken att stora skillnader finns mellan olika benso-preparat avseende ekvipotens, elimination och farmakokinetik. Jag har däremot svårt att hitta något bra underlag för skillnader mellan olika bensodiazepiner avseende klinisk effekt. Jag tänker främst på ångestlindring, sedation, muskelrelaxerande egenskap och beroendepotential. Min fråga är alltså om det vetenskapliga och/eller biokemiska underlaget för skillnader i klinisk effekt mellan olika bensodiazepiner, ffa avseende anxiolytisk effekt, sedation, muskelrelaxantia och beroendepotential. Utöver detta vore det jätteintressant om du/ni finner någon vetenskaplig grund för insättande av särskilt bensopreparat vid särskilda diagnoser eller tillstånd. Ett exempel är att Lorazepam allmänt betraktas som förstahandspreparat vid katatoni (istället för något annat benso-preparat).

Svar: Due to the large size of the question, we have only been able to do a brief overview of the field and attach reviews and book chapters for further reading. If a more detailed evaluation is required, we suggest contacting SBU and their "Upplysningstjänst" (1), who can possibly be of assistance.

Benzodiazepines (BZDs) are a class of drugs that share a common chemical structure and have antianxiety, antiepileptic, muscle relaxant, and hypnotic effects. Although similarities exist among all BZDs, differences exist in some of their pharmacologic properties (2) The BZD receptors have been classified into several types, based on a subunit isoforms and clinical effects related to each type. Not all BZDs interact with the same BZ receptor or with equal affinity to a specific receptor. These differences in a subunit isoforms, BZ receptor type affinity, and location within the central nervous system account for the different effects of the various BZDs (3)

There are major differences in potency between different BZDs and BZDs can be characterized by their relative potency. The first BZDs were low to medium potency. These include long-acting chlordiazepoxide, the first BZD discovered, as well as oxazepam and temazepam and they became first-line agents for conditions such as insomnia and anxiety. High-potency BZDs such as alprazolam, lorazepam, and clonazepam showed improved therapeutic effects as well as faster onset of action, making them the preferred BZDs for most applications (3). Previously BZDs were thought to differ only in terms of their pharmacokinetics however certain BZDs seem to have unique properties. Alprazolam has documented antidepressant and antipanic properties, and diazepam may be more selective as a skeletal muscle relaxant than other benzodiazepines (4). (for more readings please refer to reference (5)).

Based on their elimination half-lives, BZDs are classified as long acting, short acting, or intermediate acting. Long-acting BZDs (40-250 hours), such as chlordiazepoxide, clobazam, clorazepate, and diazepam, have long elimination half-lives and are commonly used to treat chronic anxiety. Short-acting BZDs (1-12 hours), including alprazolam, lorazepam, and oxazepam, have short elimination half-lives. These agents are commonly used to treat insomnia, breakthrough anxiety, and infrequent panic attacks (2, 3). For more readings on indication and doses please refer to references (6, 7).

Marketing of different benzodiazepines as hypnotics or anxiolytics is governed more by commercial than by pharmacological factors (7).

Regarding the dependence potential of BZDs we attach a previous evaluation on the subject by ULIC in 2015 (attachment No. 1) (for more readings please refer to reference (8)).

For general readings about BZDs please refer to attached files (attachment No. 2, 3).

1. https://www.sbu.se/sv/var-metod/fraga-upplysningstjansten/
2. Michael Kaplan E, DuPont RL. Benzodiazepines and anxiety disorders: a review for the practicing physician. Curr Med Res Opin. 2005 Jun;21(6):941-50.
3. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013 Summer;13(2):214-23.
4. https://www.sciencedirect.com/topics/neuroscience/benzodiazepines
5. Calculating equivalent doses of oral benzodiazepines. NHS, 2014. http://www.sussexpartnership.nhs.uk/sites/default/files/documents/bdz_equivalent_doses_spt_guidance_update_-_0714.pdf
6. Micromedex, 2018. Class Comparison: Benzodiazepines.
7. Guidelines for the Rational Use of Benzodiazepines. https://www.benzo.org.uk/asgr.htm
8. UpToDate, 2018. https://www.uptodate.com/contents/benzodiazepine-use-disorder-epidemiology-pathogenesis-clinical-manifestations-course-and-diagnosis?search=benzodiazepines%20comparison&;amp;source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2