Benzodiazepines and Z-drugs
R. Hamish McAllister-Williams, MD, PhD, FRCPsych
Professor of Affective Disorders Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service BENZODIAZEPINES Clinical Pharmacology
•Archetypal anxiolytics in preclinical models – all anxiolytics tested against this standard
•BDZs widely used clinically •How do they work?
•Problems of tolerance, addiction and withdrawal •Why is this? A lesson from schizophrenia? Affinity for dopamine receptors & clinical potency
-7 IC50 10 (mol/l) Promazine Chlorpromazine Clozapine Trazodone Thioridazine 10-8 Molindone Prochlorperazine Moperone Trifluperazine Thiothixene 10-9 Droperidol Haloperidol Fluphenazine Pimozide Trifluperidol Benperidol 10-10 Spiroperidol
0.1 1 10 100 1000 Range and average clinical dose for controlling schizophrenia (mg/day) Benzodiazepine receptor binding affinity and clinical dose
60 chlordiazepoxide 50 Dose 40 mg/d diazepam oxazepam 30
20
10 triazolam lorazepam 0 0 0.5 1 1.5 2 2.5 3 3.5 Log10 affinity (nM)
Adapted from – Dorow RG, Seidler J & Schneider HH, Br J Clin Pharmac (1982), 13, 561-565. GABA-A receptor electron microscopy
Nayeem N, Green TP, Martin JL, et al (1994) Journal of Neurochemistry, 62, 815-818. GABA-A Receptor subunits
Five GABA-A receptor subunits make up a single receptor
2- as 2- bs 1- g BDZs bind here GABA/BZD receptor chloride ionophore complex
GABA GABA-A muscimol agonist sites
GABAA site Benzodiazepine Agonists: + + ethanol e.g. Diazepam anticonvulsant chloral anxiolytic Cl - sedative/hypnotic BDZ site Barbiturate barbiturates amnestic site heminevrin
Neurosteroid site
pregnenalones Propofol/ (progesterone derivatives) anaethetics Neurosteroids chloride channel
GABA A receptor
BZ binding site within membrane
8-19 Stahl S M, Essential Psychopharmacology (2000) GABA BZ
8-21 Stahl S M, Essential Psychopharmacology (2000) BZ GABA
BZ
Stahl S M, Essential Psychopharmacology 8-22 (2000) GABA BZ
GABA
BZ
8-23 Stahl S M, Essential Psychopharmacology (2000) GABA
BZ GABA GABA
BZ flumazenil BZs vs cyclopyrrolones (Z-drugs): Structure
Diazepam Zopiclone
Zolpidem Temazepam Z-drugs vs BZs Z-drugs vs BZs BZs vs Z-drugs: half lives
Drug Half life (hours) Chlordiazepoxide 5-30 [36-200] Clonazepam 18-50 Diazepam 20-100 [36-200] Lorazepam 10-20 Nitrazepam 15-38 Oxazepam 4-15 Temazepam 8-22 Zolpidem 2-3 Zopiclone 5-6 Are GABA-A receptors altered in anxiety disorders ? Benzodiazepine receptors in panic disorder PET 11C- flumazenil
Normal control Panic disorder Malizia et al Arch gen Psych 1998; 55; 715-720 Benzodiazepine receptors in GAD
Controls (grand average)
123I-NNC SPECT
deficit
patients (grand average)
Decreased BDZ receptor binding of [123I]NNC 13-8241 in left temporal pole
Tiihonen et al 1997 PTSD: Iomazenil SPECT
Bremner et al
Am J Psychiatry 2000; 157:1120–1126 Is it possible to make better drugs that are e.g. less addictive? Why does tolerance occur? Different subunit combinations make many different GABA-A receptors in the brain
GABA-A subunits family tree
axbxg a a b g a b g axbx x b a b g b abx b abg abxg a a bg a b x abxg a abg a a a a a abg g abg g g GABAA alpha subunits are differentially distributed in rat brain a
• Alpha 1 most abundant – esp in cortex • Alpha 2 & Alpha 5 rarer, mainly found in hippocampus
Möhler H, Fritschy JM, Rudolph U. J Pharmacol Exp Ther. 2002; 300:2-8.
Subunit mRNA expression GABA-A receptor subtypes
The a subunit composition of the receptor defines the pharmacology
a a g a g g a g
b b b b b b b b a a a a
zolpidem g a g a
b b b b a a
Sedation Anxiolysis? Amnestic? Tolerance/resistant? BDZ sensitive BDZ insensitive Benzodiazepine receptor adaptation leads to anxiety
Rebound anxiety worse more
Symptoms
treatment Brain Receptor GABA adaptation function
less better
Benzodiazepines undermine their own action and this leads to problems on withdrawal Changing the benzodiazepine receptor
g a
b b a
a a a
BDZ tolerance may be explained by a subunit exchange reducing GABAA receptor sensitivity GABA-A receptor subtypes
The a subunit composition of the receptor defines the pharmacology
a a g a g g a g
b b b b b b b b a a a a
zolpidem g a g a
b b b b a a
Sedation Anxiolysis? Amnestic? Tolerance/resistant? BDZ sensitive BDZ insensitive
Summary
• Benzodiazepines act on GABAA receptor complexes – Alone they have no effect on chloride conductance (this makes them relatively safe c.f. barbiturates) – Flumazenil is a benzodiazepine antagonist • The major difference between BZs (and with Z-drugs) is their half lives and whether they have active metabolites • BZ binding sites are abnormal in a range of anxiety disorders
• GABAA complexes can come in a variety of conformations – This leads to functional differences and may explain tolerance and withdrawal effects Clinical Context and Use of BZs British National Formulary: benzodiazepines
1. Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling or causing the patient unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness. 2. The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate. 3. Benzodiazepines should be used to treat insomnia only when it is severe, disabling or causing the patient extreme distress.
British National Formulary. BMJ Group and Pharmaceutical Press. March 2011. Benzodiazepines in GAD - Europe
90 80 70 60 50 40 30
% of of % respondents 20 10 0 1st Line 2nd Line 3rd Line Never/NA
BZD SSRI SNRI TCA Pregabalin Atypical • 501 psychiatrists, questionnaire survey, management of GAD • 81.4% patients received benzodiazepines before referral • a first-line treatment in 26% of patients • treatment duration less than 6 weeks in 78.9% respondents
Baldwin et al. World J Biol Psychiatry. 2012 Oct;13(7):510-6. BZ’s use in anxiety disorders (BAP Guidelines 2014)
• BZs have proven efficacy in the treatment of GAD, panic and SAD. – can cause troublesome sedation and cognitive impairment, tolerance and dependence (especially in predisposed patients) • BZs reserved for the further treatment of patients who have not responded to at least 3 previous treatments – but concerns about potential problems in long term use should not prevent their use in patients with persistent, severe, distressing, and impairing anxiety symptoms
Baldwin et al. 2014 J Psychopharm 28(5):403-39 See www.bap.org.uk Clinical Summary • In general avoid long term (> 4 weeks) use of benzodiazepines – However don’t avoid using BZs in well selected refractory patients JUST on the basis of general guidance • The main clinical differentiation between BZs (and Z-drugs) relates to their half life – There may also be some selectivity differences as well (e.g. Zolpidem)