Why are benzodiazapenes sometimes used?
They are CNS depressant drugs that act as anxiolytics or hypnotics immediately. When the dose is increased they have a sedative/hypnotic effect.
What other class of drugs can be used as anxiolytics?
Antiepileptic drugs such as pregabalin and gabapentin Beta blockers can reduce sweating, tachycardia and tremors Barbiturates Buspirone (delayed action of 1 - 3 weeks and can be used if someone has generalized anxiety disorder) Antidepressant drugs
What classes of drugs beside benzodiazapenes can be used to induce sleep?
Sedating antihistamines such as diphenyhydramines can be used to induce sleep. Newer sedatives used
How do benzodiazapenes work?
They affect the GABAergic system. Benzodiazapenes, zolpidem, and barbiturates act on GABAa receptor. (they do not affect GABAb)
What kind of receptor is GABAa?
What kind of receptor is GABAb?
What kind of structure does GABAa have? What protein subunits make it up?
They are pentameric ion channel proteins and most are composed of α, β, and γ2 subunits.
Where do benzodiazapenes act on the GABAa protein?
Between the γ2 and α subunits
Where do barbiturates act on the GABAa protein?
They bind to the β subunit and increase the time of channel being open thus making cell more hyperpolarized.
Where does GABA bind on the GABAa protein?
On the 2 interfaces between α and β subunits
What does the GABAa receptor do?
When both GABAa receptors are bound by the GABA molecules the channel opens up and allows chloride ions into the cell making it hyperpolarized and harder to stimulate.
What kinds of situations are barbiturates dangerous in?
Large doses due to large inhibitory effect.
What kind of effect do benzodiazapenes have on GABAa channels?
Benzodiazapenes are positive allosteric modulators thus increasing the frequency of opening of the GABAa channels.and increasing inhibitory effect.
What kinds of protein targets are benzodiazapenes reactive to?
α1, α2, α3, and α5 subunits
What is the advantage of using benzodiazapenes over barbiturates?
Benzodiazapenes are reversible more easily via
How is zalpoden different to other benzodiazapenes?
zalpoden are selective for α1 unlike diazapenes which act on all receptors equally.
Which receptor is responsible for addictive properties of benzodiazapenes?
α1 is the receptor responsible for addictive properties of benzodiazapenes so zalpoden still has addictive effects.
How is the response different between using benzodiazapenes and barbiturates?
Less probability of overdose problems with benzodiazapenes
Additional disadvantage of barbiturates relative to benzodiazapens:
They induce hepatic cytochrome P450 which doesn’t happen with benzodiazapenes
What are the therapeutic benefits of using benzodiazapenes?
Reduction in anxiety (diazepam, oxazepam, alprazolam)
Induction of sleep (temazepam)
Skeletal muscle relaxation (diazepam, clonazepam) [note: may not be a good idea for elderly with muscular weakness]
Anticonvulsant effects (clonzepam, clobazam)
Intravenous sedation (midazolam) [anterograde amnesia may be caused by this but that brings about a positive effect when administered intravenously]
How are benzodiazapenes metabolised?
Initial demethylation of diazepam at the 1 position -> desmethyldiazepam -> temazepam (minor portion) + oxazepam (major portion)
What is the difference between the onset of action in temazepam/oxazepam and diazepam?
When you compare the onset of action of temazepam and oxazepam it is faster than diazepam due to hydroxyl group making them more water soluble and so there is a faster onset of action in the brain after taking temazepam/oxazepam compared to diazepam.
How long do benzodiazapenes act for?
Ultra short acting benzodiazapenes (act <5 hours) [triazolam, alprazolam, midazolam, clonazepam]
Short acting benzodiazapenes (act 5 - 10 hours) [temazepam/oxazepam]
Medium (10 - 24 hours)
Long (>24 hours) [diazepam]
Why is diazepam such a long acting benzodiazapene?
Not only is diazepam long acting due to its long half life, it also forms active metabolites such as temazepam and nordazepam
What kind of action are benzodiazapenes used for?
They may be used for short-term in severe situational anxiety by poteniating GABA activity in the amygdala and other limbic regions of the brain.
How are anxiety disorders treated in the long term?
Most anxiety disorders are treated using psychological therapies.
If they don’t work SSRIs and SNRIs are useful.
Benzodiazapenes are good for use as required.
How is oxazepam different to diazepam in action?
Diazepam is long acting and causes lots of drowsiness due to its half life and production of active metabolites.
Oxazepam is more slowly absorbed and so it doesn’t produce the same level of drowsiness. It also has a short half life and duration of action.
Oxazepam is a better anxiolytic to use for elderly patients due to less likely chance to reduce alertness and metaboism.
How are benzodiazapenes inactivated?
Why is oxazepam metabolism more elderly friendly than diazepam?
Demethylation and hydroxylation reaction of the liver are impaired in elderly but conjugation reactions are fine.
What receptor is important for sedative effect of benzodiazapenes?
Alpha1 type receptors
Which receptors influence the type of sleep that predominates as a result of benzodiazapene usage?
Alpha2 type receptors.
Why is temazepam used?
It helps with insomnia but it should not be used nightly for more than 1 - 2 weeks.
It is slowly absorbed.
It has a short duration of action (15 hours half-life)
It is relatively slowly absorbed.
What are the side effects of benzodiazapenes?
Side-effects are mainly related to CNS depression: Drowsiness, lethargy, impaired coordination, muscle weakness, vertigo, nausea, and memory loss.
Tolerance can develop to anxiolytic and hypnotic effects.
Tolerance develops to most of the side-effects.
Disinhibition in some individuals may lead to rage, violence, and antisocial acts.
What are withdrawal symptoms of benzodiazapenes?
Is the dependence on benzodiazapenes psychological or physical?
It is both
What are contraindications for benzodiazepines?
History of drug use
Severe respiratory disease or sleep apnoea
Severe hepatic impairment
Elderly with cognitive problems
Pregnant and breastfeeding women should not take benzodiazapines
What happens as a result of barbiturate overdose?
Deep coma and respiratory arrest can result
What happens as a result of benzodiazapine overdose?
Much less serious and not fatal, hwever, compounds effects of alcohol and heroin and can result in problems of potentiation.
How are benzodiazapene overdoses treated?
Competitive receptor antagonist flumazenil
Note with using flumazinil:
Flumazinil has a short half life of approximately 1 hour so it is important to monitor for long time.
What does zolpidem do?
It is a non-benzodiazapene sedative used as a hypnotic that binds selectively to alpha1 benzodiazapene receptors to produce sleep with minimal anxiolytic and muscle relaxant effects.
How does zolpidem effect sleep?
It has less efects on REM sleep and stages III and IV nREM than benzodiazapenes.
How long is zolpidem (z-drug) action?
4 - 6 hours because it is rapidly eliminated by hepatic enzymes.
What kind of treatment is zolpidem intended for?
Short-term treatment of insomnia. (Should not be used for more than 1 - 2 weeks)
What side effects have been found to cause concern in people taking zolpidem?
Sleepwalking and bizarre behaviour
Can tolerance and dependence develop to zolpidem?
What drug is used to treat zolpidem overdose?
Flumazenil can be used to reverse excessive respiratory depression produced by zolpidem.
What is buspirone?
Partial agonist on 5-HT1a receptors. It has some affinity for dopamine receptors where it can act as an antagonist.
What is the use of buspirone?
Unsuitable for acute anxiety because its anxiolytic effect requires 1 - 3 weeks to develp.
Buspirone is effective for generalised anxiety disorder, but it is ineffective for panic disorder. It may also have some antidepressant activity.
What are the advantages of using buspirone?
It does not produce excessive drowsiness, does not impair coordination and does not produce significant dependence and withdrawal.
What are the main side effects of buspirone?
Tachycardia, palpitations, nausea, dizziness, headaches, restlessness.
Is buspirone safe in overdose?
Why does buspirone create a delayed effect?
It acts on 5-HT1A receptors as an agonist. It has less efficacy than normal 5-HT so it competes with the higher efficacy molecules creating less firing of the postsynaptic neuron initially. In response to this, the cell upregulates more receptors and now the larger number of agonists can act on 5-HT1a receptors and thus create more action potentials. During the delayed time the synapse content doesn’t change much in concentration of neurotransmitter.
What should be the first line drug therapy for anxiety disorders?