Anxiolytics and hypnotics Flashcards
what do anxiolytics and hypnotics treat?
anxiolytics treat anxiety
hypnotics treat sleep disorders
what is the fear response?
- defensive behaviours
- autonomic reflexes
- alertness
- negative emotion
- corticosteroid secretion
what is anxiety?
anticipatory fear response which is often independent of external events
what are anxiety disorders?
- panic disorder - overwhelming fear marked by somatic symptoms such as tachycardia chest pains, trembling
- social anxiety - fear of interacting with people
- phobias - strong fear response to specific objects/situations
- PTSD - triggered by recall of a stressful situation
- OCD - compulsive, ritualistic behaviour driven by irrational anxiety
- generalised anxiety - no clear reason or focus, an ongoing state of excessive anxiety
what are the treatment options for anxiety?
- anxiolytic/hypnotic agents - benziodiazepines (BZs) and barbiturates
- BZs have unwanted side effects such as amnesia
- BZs work instantly and are taken on a needed basis - antidepressants - can take several weeks to produce a response and must be taken continuously
- propranolol (beta antagonist) to block somatic symptoms
how are animals used to model anxiety?
- animal behaviours associated with fear can help study and evaluate anxiety drugs
- different models, experience and conditioning can give different results, reflecting the complexity of anxiety
- shows how anxiolytic drugs suppress behaviours associated with fear, leading to overcoming fear
what animal models can be used to study anxiety?
- elevated cross test/light and dark box test
- makes use of rodent’s fear of unfamiliar environment and desire to hide to avoid danger
- the time the animal spends in the less exposed environment is measured
- anxiolytic drugs reduce the fear response and hiding time of the animal - conflict tests - trained response to reward may be interjected with electric shock associated with specific sound
- in absense of anxiolytics, animal suppresses urge to get the reward when they hear the sound
- when treated, they ignore the sound and get the reward
what receptors are targets for anxiolytics and hypnotics?
GABAa receptors
what are GABAa receptors and their structure?
- chloride-sensitive ionotropic receptors - activation causes hyperpolarisation and reduction in excitability
- made up of 5 subunits - influences pharmacology
- in different parts of brain, different subunit combinations are expressed
- mediate fast inhibitory transmission
- has multiple binding sites for different ligands: BZs, barbiturates and ethanol can increase GABAa function to inhibit CNS
- 2 main binding sites - both must be occupied for GABAa to work
- pentametric stoichiometry: 2alpha, 2beta, 1gamma/delta/epsilon
what is the orthosteric site of a receptor?
agonist binding site which is responsible for switching on the signalling by a receptor
- competitive antagonists may bind here to block the action of the agonist
what are the agonists and antagonists of the orthosteric site of GABAa?
agonists: GABA, muscimol
antagonist: bicuculline, picrotoxin
what are allosteric sites of a receptor?
they do not switch on the signalling of a receptor themselves, but instead modify the function/signalling of the agonist-bound receptor
They only act if the orthosteric site is occupied by an agonist
If agonist is absent at orthosteric site, the allosteric site will not function
what are the agonists and antagonists of the allosteric site of GABAa?
agonist - benzodiazepoines e.g. diazepam (positive allosteric modulator)
antagonist - flumazenil (at BZ site)
- antagonist can be used to reverse BZ overdose
what is an allosteric modulator?
it does not activate the receptor on its own, but it does modify the behaviour of the receptor when an agonist is bound to the orthosteric site
what is a positive allosteric modulator (PAM)?
increases the signalling of an agonist-bound receptor
- BZs increase signalling of GABAa receptors
- only impact receptor if the orthosteric site is occupied by an agonist
what is a negative allosteric modulator?
decreases the signalling of an agonist-bound receptor
- beta-carboline decreases the signalling of GABAa receptors (opposite of BZ)
what are the physiological effects of BZ agonists?
- sedation/anxiolytic: decreased responsiveness to constant level of stimulation
- hypnosis: latency of sleep onset is decreased
- stage 2 sleep is increased and duration of rem is decreased
- duration of slow wave sleep (night terrors) is decreased - anterograde amnesia: prevent memory of events experienced while under influence
- anticonvulsant - inhibit development and spread of epileptiform activity
- reduction of muscle tone
what are benzodiazepines?
- used to treat anxiety and insomnia
- positive allosteric modulatior of GABAa
- activate midbrain dopamine neurons via GABAa to hijack mesolimbic reward system
- induce muscle relaxation, control epileptic seizures and can produce amnesia
- tolerance to the effects can be a sign of dependence - they can be abused after chronic clinical treatment for recreational purposes
what mediates the sedative actions of BZs?
alpha1-containing GABAa receptors
what mediates the anxiolytic actions of BZs?
alpha2-containing GABAa receptors
what kind of ligand is BZs for GABAa receptors?
positive allosteric modulators - BZs increase activity of GABAa
- increase Cl- current across membrane, only in the presence of GABA bound to the receptor
how do BZs and barbiturates modulate GABAa receptors?
BZs increase probability of GABAa opening
barbiturates increase the mean open time of GABAa
both result in more current flow and a bigger GABAa response
what action does beta-carboline have on GABAa?
it is a negative allosteric modulator
- decrease channel opening so less inhibition of excitatory neurons
- it is anxiogenic so can increase anxiety
- it is a proconvulsant - can lead to seizures
what action does flumazenil have on GABAa?
it is an antagonist at the BZ allosteric site
- it binds to an allosteric site so doesnt affect the receptor
- it can be used to reverse the effects of BZ overdose
