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Transcript
Zzzzzzz…. Benzodiazepines, ‘Z-drugs’ and tranquillisation Dr David Middleton (ST4) Introduction • Anxiety • Classification of anxiolytic and hypnotic medications • Benzodiazepines – – – – action uses pharmacokinetics adverse effects • Alternatives to benzodiazepines • Tranquillisation • Exam questions Anxiety • Normal fear response to threatening stimuli: – – – – – autonomic reflexes (e.g. sweating) arousal corticosteroid secretion emotional responses behavioural responses (e.g. fight or flight) Anxiety • Becomes ‘abnormal’ when responses occur independent of external stimuli – anticipation – spectrum between ‘normal’ and ‘pathological’ – becomes a disorder when it interferes with functioning • Important neurotransmitter systems: – GABA, 5-HT and noradrenaline Anxiety disorders • Generalised anxiety disorder – enduring anxiety state without clear precipitant • Phobias – specific fear of objects or situations • Panic disorder – discrete attacks of anxiety with somatic symptoms • Post-traumatic stress disorder – recall of distressing experiences • Obsessive compulsive disorder – rituals driven by irrational anxiety Classification of anxiolytic and hypnotic drugs • Benzodiazepines – used as anxiolytic and hypnotic agents • Buspirone – 5-HT1A receptor partial agonist – non-sedating • β-adrenoceptor antagonists – e.g. propranolol – good for prominent physical symptoms – block peripheral sympathetic responses Classification of anxiolytic and hypnotic drugs • Zolpidem – acts like a benzodiazepine – used as hypnotic, minimal anxiolytic action • Barbiturates – rarely used except in anaesthesia/epilepsy • Others – chloral hydrate, rarely used Benzodiazepines - history • Identified in 1957 during systematic screening of muscle-relaxants • ‘taming’ effect on test animals • Chlordiazepoxide in 1960, diazepam in 1962 • Began to replace barbiturates • Physical dependence thought to be only in high dose but later (1981) in therapeutic doses Benzodiazepines - structure • Seven-membered ring fused to an aromatic ring • Four substituent groups • Some variation in pharmacological activity – e.g. anticonvulsant>sedation • Differences in pharmacokinetics are more important clinically Benzodiazepines - action • Selective action on GABAA receptors (fast inhibitory synaptic transmission in CNS) • Open GABA-activated chloride channels in the presence of GABA (c.f. barbiturates) • Bind specifically to regulatory site of the receptor not at the GABA-binding site • Allosteric action i.e. increase affinity of GABA for the receptor • Do not affect glycine or glutamate receptors GABAA receptor GABAA receptor structure • • • • Pentameric assembly of subunits , and subunits Three or more isoforms of each Commonest type (50% of total): two 1 , two 2 and one 2 • 1 subunit: sedative, amnesic and anticonvulsant effects • 2 subunit: anxiolytic and muscle relaxant effects • Selective benzodiazepines in the future? GABAA receptor subunits Benzodiazepine receptors • Benzodiazepine binding site lies between 1 and 2 subunits • Type I benzodiazepine receptors: – cerebellum – induction and maintenance of sleep • Type II benzodiazepine receptors: – spinal cord and limbic regions – muscle relaxant, anxiolytic and anticonvulsant effects Diazepam - pharmacokinetics Bioavailability Almost complete orally Peak concentration 30-90 minutes Protein binding 90-95% Renal excretion Negligible for unchanged drug Metabolism Phase I to active metabolite, desmethyldiazepam Phase II for inactivation of metabolites Elimination half-life •Young adults 20 hours •Elderly 30-100 hours •Desmethyldiazepam 30-90 hours Diazepam - pharmacokinetics • Absorption following IM erratic • Highly lipid soluble – diffuses into CNS rapidly – found in breast milk – crosses placenta • Newborn infants metabolise benzodiazepines slowly, can accumulate to cause respiratory depression • Reports of cleft lip and cleft palate Benzodiazepines - metabolism • Phase I – functional groups altered e.g. hydroxylation – produces active metabolite in some cases e.g. diazepam to desmethyldiazepam – causes ‘hangover’ effect if used as hypnotics – affected by age, liver disease or enzymeinducing drugs • Phase II – functional groups added to drug or metabolite – conjugation (e.g. combining with sulphate or glucuronic acid) usually inactivates compound – phase II only preferable in hypnotics Pharmacological properties of anxiolytics and hypnotics Drug Absorption t1/2 of drug Metabolic t1/2 of phases metabolites Diazepam Rapid 20-100 I + II 30-90 Chlordiazepoxide Intermediate 5-30 I + II 30-90 Alprazolam Intermediate 5-15 I + II Low concn Lorazepam Intermediate 10-20 II only None Nitrazepam Intermediate 24 I + II 30-90 Flurazepam Rapid 2 I + II 36-120 Temazepam Slow 10 II only None Zolpidem Rapid 2 II only None Zaleplon Rapid 1 II only None Zopiclone Rapid 3-4 I + II 3-6 Diazepam – adverse effects Common Occasional Rare Drowsiness Dry mouth Amnesia Dizziness Blurred vision Restlessness Psychomotor impairment Gastrointestinal upset Ataxia Headache Reduced BP Skin rash Benzodiazepines - uses • Reduction of anxiety – mainly generalised anxiety disorder or acute anxiety states – better response: • somatic and psychological symptoms, clear stressors and short duration – poorer response: • depressive, phobic and hypochondriacal symptoms – use for shortest possible duration – smallest effective dose – not more than 4 weeks Benzodiazepines - uses • Sedation and sleep – decrease time taken to get to sleep and increase total sleep – effect declines if taken regularly for >2 weeks – minimal long-term reduction in REM sleep (but reduces from 25% to 10-15% in first two weeks’ use) – rebound increase in REM if stopped (nightmares) – reduce slow-wave sleep – best used for acute stress or jet-lag, not chronic insomnia Benzodiazepines - uses • Alcohol withdrawal – – – – reduce withdrawal symptoms prevent seizures long half-life better e.g. chlordiazepoxide reducing dose over 5-10 days Benzodiazepines - uses • Psychosis – high doses in acute psychotic states can reduce severe agitation – tolerance can develop, therefore limit to a few days – antipsychotics better in agitated depression – Note: risk of paradoxical increase in agitation possible (triazolam withdrawn due to this). Probably part of withdrawal syndrome in shortacting benzodiazepines Benzodiazepines - uses • Other uses: – muscle relaxation – anticonvulsant – anterograde anmesia (minor surgical procedures) Benzodiazepines - tolerance • “the need for larger doses to achieve the same effect with repeated administration” • Less marked than barbiturates (induction of drugmetabolising enzymes) • Relatively quickly (days-weeks): – sedative, hypnotic, anticonvulsant and muscle relaxant effects • Slowly (months): – anxiolytic effects • Rarely: – amnesic effects Benzodiazepines - tolerance • Mechanisms of tolerance: 1. Pharmacokinetic factors (body’s effect on drug) • not important in benzodiazepine tolerance 2. Pharmacodynamic factors (drug’s effect on body) • most important mechanism, affects sensitivity to drug: 1. reduction in BDZ receptors 2. uncoupling of links between BDZ and GABA receptors 3. Cognitive factors Benzodiazepines - dependence • Occurs secondary to tolerance • Adaptive changes left unopposed in absence of drug • Rebound hyperexcitability causes a withdrawal syndrome • Suppressed by recommencing drug, hence chronic use and dependence • REM sleep rebound on cessation of hypnotics is particularly prominent Benzodiazepines – withdrawal symptoms Anxiety symptoms Perceptual disturbances Severe (but rare,<5%) Anxiety Dysphoria Tremor Muscle pains Sleep disturbance Headache Nausea Anorexia Sweating Fatigue Hypersensitivity to stimuli Abnormal bodily sensations Abnormal sense of movement Depersonalisation Visual disturbances Paranoid psychosis Depressive episode Seizures Confusion Hallucinations Benzodiazepines - withdrawal • Occurs in approximately 45% of patients using benzodiazepines for >6 months • Symptoms in first week, last 7-10 days • Short-acting benzodiazepines cause more acute withdrawal effects (rapid drop in plasma concentrations) • Triazolam: – very short-acting – no longer in use due to withdrawal effect within hours of single dose – early morning insomnia and daytime anxiety if used as a hypnotic Benzodiazepines – managing withdrawal • Usually can be done as outpatient (unless previous seizures on withdrawal) • Short half-life drugs changed to long halflife drugs • Gradual reduction (approx 2mg diazepam or 25% daily dose), every 1-2 weeks over 4-16 week period • β-blockers can reduce severity of symptoms but not outcome • Education and support are important • Anxiety management, relaxation therapy Benzodiazepines - antagonists • Competitive antagonists useful to reverse effects of benzodiazepines • Flumazenil often used in benzodiazepine overdose or for treatment of comatose patient suspected of overdose • 200µg IV over 15 seconds • Further 100µg IV over 10 seconds after one minute if no response. Max 1mg. • t1/2 1-2 hours, so drowsiness may return • Side effects: anxiety, agitation, nausea, convulsions Buspirone • 5-HT1A partial receptor agonist • Also binds to dopamine receptors but this action less important in anxiety • 5-HT1A receptors are inhibitory autoreceptors that reduce release of 5-HT and other mediators • Also inhibit NA in locus coeruleus neurons so reduce arousal • Buspirone takes days-weeks to have an effect (?more complex action) • Ineffective in panic attacks or severe anxiety states Buspirone • • • • Non-sedating Does not cause motor incoordination No withdrawal effects Main side-effects: – – – – nausea dizziness headache restlessness Barbiturates • Diethylbarbituric acid (1903), phenobarbital (1912) • t1/2 : 30-90 hours • Hepatic metabolism • Induce cytochrome P450 and conjugating enzymes…drug interactions • Enhance action of GABA at its receptors and produce depressant activity on CNS: – – – – hypnotic sedative anxiolytic anticonvulsant Barbiturates • Adverse effects: – impairment of psychomotor function – chronic cognitive impairment and paradoxical hyperactivity in children – vertigo – nausea – vomiting – diarrhoea • Tolerance and dependence • Overdose: – respiratory and cardiovascular depression – cross-potentiation with alcohol Rapid tranquillisation • Nice guidelines on management of violence and aggression: http://www.nice.org.uk/nicemedia/pdf/cg02 5_SPC_chart_for_press.pdf • Lecture in MRCPsych Paper III course Rapid tranquillisation Medication Time to peak plasma concentration Half-life Haloperidol IM 15-60 mins 10-36 hours Haloperidol liquid 2-6 hours 10-36 hours Haloperidol tablet 2-6 hours 10-36 hours Lorazepam IM 60-90 mins 12-16 hours Lorazepam tablet 2 hours 12 hours Olanzapine disp 5-8 hours 32-50 hours Olanzapine IM 15-45 mins 32-50 hours Risperidone disp 1-2 hours 24 hours Risperidone liquid 1-2 hours 24 hours Risperidone tablet 1-2 hours 24 hours Rapid tranquillisation (Maudsley) 1. De-escalation, time out, placement 2. Offer oral treatment • • • • • haloperidol 5mg or olanzapine 10mg or risperidone 1-2mg with or without lorazepam 1-2mg repeat every 45-60 minutes 3. Consider IM treatment • • • • lorazepam 1-2mg haloperidol 5mg olanzapine 5-10mg (NB not with BDZ) repeat up to two times at 30-60 minutes Rapid tranquillisation 4. Consider IV treatment (very very rare!) • • diazepam 10mg over >5 minutes repeat after 5-10 minutes if needed up to three times 5. Seek expert advice (if not already done…) • • • • amylobarbital 250mg IM paraldehyde 5-10 ml IM very, very rare! Please read full NICE/Trust guidelines Accuphase (zuclopenthixol acetate) • Not used for rapid tranquillisation • Considered if repeated injections of antipsychotics/benzodiazepines required in acutely psychotic patient • 50-150mg (max 400mg in 2 weeks) • Sedative effects after 2 hours, peak at 12 hours • Effects up to 72 hours Accuphase (zuclopenthixol acetate) • Should not be used if patient is: – – – – – – – accepting oral medication neuroleptic naïve sensitive to EPSE unconscious pregnant suffering renal/hepatic impairment suffering from cardiac disease • It is not a ‘chemical straightjacket’ • Best used in those with previous good response Exam questions A 24-year old with anxiety and depression presents following an overdose of 30 diazepam tablets. She is drowsy and poorly compliant with examination. Which of the following is true regarding diazepam? A. Blood levels are useful in deciding if ventilation is required B. The half-life of its sedative effects is 2-3 hours C. Only active after metabolic activation D. Is water-soluble and predominantly renally excreted E. Its sedative effects are exaggerated by alcohol Exam questions A man is admitted for alcohol detoxification. He has tender hepatomegaly but refuses transfer to a medical ward. The treatment choice for detox would be: A. Diazepam B. Clobazam C. Alprazolam D. Chlordiazepoxide E. Nitrazepam Exam questions Which of the following is not a common symptom of benzodiazepine withdrawal syndrome? A. Stiffness B. Tinnitus C. Blurred vision D. Hypertension E. Headache Exam questions Which of the following regarding buspirone is false? A. It is a 5-HT1A partial agonist B. Effects are usually evident after 8-10 hours C. It can cause galactorrhoea D. Dysphoria has been reported E. It has no significant withdrawal syndrome Exam questions Which of the following regarding benzodiazepines is false? A. Oxazepam and lorazepam are shortacting B. Diazepam is 95% protein-bound C. They are ineffective in phobic states D. They initially increase REM sleep E. Withdrawal can cause rebound insomnia