PHAR: Anxiolytics & Hypnotic Drugs Flashcards
Why are benzodiazepines rather than barbiturates are used as anxiolytics and hypnotics?
- barbituates are stronger CNS depressants, OD can cause severe respiratory depression and coma, benzodiazepines won’t. - there is a direct antidote for benzos (IV flumazenil) but not for barbituates - Barbituates are also stronger inducers of CYP450 causing tolerance of them (along with faster metabolism of other drugs).
What are the therapeutic effects of benzodiazepines?
Different benzos have different main therapeutic effects:
Anxiolytic: Diazepam, oxazepam, alprazolam
Hypnotic: Tempazepam
Muscle Relaxant: Diazepam, clonazepam
Anticonvulsant: Clonazepam, clobazam IV
Sedation + some anterograde amnesia: Midazolam
Describe the metabolism of diazepam, oxazepam and temazepam
Diazepam is metabolised to Nordazepam (and to temazepam to a small extent). Nordazepam is metabolised to oxazepam, as is temazepam. Temazepam and Oxazepam are metabolised by glucoronidation to inactive metabolites.
Give a comparison of oxazepam with diazepam for absorption, metabolism, duration of action and withdrawal symptoms, difference in effects.
ABSORPTION: Diazepam is more quickly absorbed and metabolised than Oxazepam meaning that you get more initial drowsiness
METABOLISM: Diazepam is mainly metabolised to Nordazepam and Oxazepam (both active metabolites) whereas Oxazepam is immediately inactivated by metabolism.
DURATION OF ACTION: Because diazepam is metabolised to Oxazepam it has a longer half-life (30hrs vs 10). This longer half-life means you may get accumulation & residual drowsiness
WITHDRAWAL: Longer half-life means that diazepam has less severe withdrawal.
OTHER DIFFERENCES: Diazepam has muscle relaxant & anticonvulsant properties, oxazepam doesn’t.
Why is oxazepam a better anxiolytic than diazepam for elderly patients?
Less drowsiness & confusion (shorter half life, slower absorption) No skeletal muscle relaxation effects (reduced chance of causing falls). Oxazepam’s metabolism is also less impaired by age-related decline of hepatic oxidative metabolism.
Explain the use of temazepam as a hypnotic
Temazepam is good as a hypnotic because it has a short half life (~15 hours) so there is minimal residual drowsiness in morning. Slowly absorbed so better for maintaining sleep than initiating.
Side-effects for benzodiazepines
The side effects for benzos are all those associated with CNS depression: - Drowsiness - Lethargy - Coordination - Muscle weakness - Vertigo - Nausea - Memory loss Can cause disinhibition leading to antisocial behaviour. Tolerance generally develops to both anxiolytic/hypnotic effects and side effects.
Dependence & withdrawal for benzodiazepines
Dependence is both physical & psychological, begins developing ~1/2 weeks. Physical withdrawal ~3/4 weeks: - Tremors - anxiety - insomnia - occasional convulsion/delirium Much more serious when high doses for months/years, can cause seizures and can be life threatening. Diazepam withdrawal less severe than shorter acting ones ie oxazepam, because of its long half-life.
Contraindications for benzodiazepines
- history of drug abuse - severe respiratory disease or sleep apnoea - severe hepatic impairment (mild = try oxazepam?) - myasthenia gravis - elderly with cognitive problems - pregnant/breastfeeding (can use sparingly but avoid repeated doses)
Explain the use of flumazenil
Because of its max-effect profile it’s hard to fatally overdose on benzodiazepines. Generally observation, possibly respiration is the only treatment needed. OD can be dangerous if combined with other CNS depressants like alcohol as they have additive effects. In this case you treat the respiratory depression with IV flumazenil, a competitive benzodiazepine receptor antagonist. Note however only has half-life of 1 hour so re-sedation may occur if a long-acting benzo was used. May need to readminister. Not often necessary, more commonly used to reverse benzos used for medical procedures.
Explain the use of zolpidem as a hypnotic
Alpha1 selective, non-benzodiazepine, hypnotic sedative. Not anxiolytic or muscle relaxing. Fast but short half life (4-6 hours, rapidly inactivated by hepatic enzymes). 1-2 weeks nightly because of addiction/dependence. Overdose dangerous if combined with other CNS depressants. Reports of sleepwalking & bizarre patients, particularly when abused, combined with alcohol, not actually asleep but amnesic because dependence has developed, taking very high doses. NOTE z-drugs can temporarily bring some people out of locked-in syndrome/coma for unknown reason
Explain the use of buspirone as an anxiolytic
Takes 1-3 weeks for work, only for GAD, not panic disorder. No drowsiness or coordination effects, not addictive or dependence building. Minor side effects: tachycardia, palpitations, headache, nausea, dizziness, restlessness. No serious OD risk. Works through binding 5HT1a receptors which are inhibitory and located post-synaptically and on the serotonin axons, creating inhibition of firing. When they are stimulated post-synaptically in the limbic system there is anxiolytic action. The delay is because although they stimulate the post-synaptic receptors they also inhibit the serotonin neurons from firing so there is less serotonin available in the cleft, countering its agonist effects. When there is return to normal serotonin levels you get the anxiolytic effects.
Explain the use of SSRIs and SNRIs for anxiety disorders
SSRI’s & SNRI’S are first line for anxiety disorders as they can be used long term without risk of dependence/addiction: SSRIs = citalopram SNRIs = venfalaxine Sleep = mirtazapine
Mechanism of action for benzodiazepines, barbituates & Z-drugs
The main anxiolytics (bezos, Z-drugs and barbituates) are all CNS depressants which work through perpetuating the GABAergic inhibitory system in the brain. Act through the inhibitory, ionotropic (chloride channel) GABAa receptors on the post-synaptic membrane. GABAa = pantamers made from alpha (a), beta (b) & gamma (y) subunits. Barbituates bind at b subunit. Benzodiazepines: a subunit (1, 2, 3, 5) Z-drugs: a subunit (only alpha 1) Barbituates bind and increase duration of opening of the chloride channels, or at high doses directly open them. Benzodiazepines change conformation of receptor, increase affinity for GABA binding = increase frequency of opening of the channel.
