Anxiolytics Flashcards
GABA
principal inhibitory neurotransmitter in CNS, causes hyperpolarisation
GABAA receptor
ligand-gated ion channel, pentameric structure - Ionotropic receptor
principal inhibitory receptors in the CNS
permeable to chloride ions when GABA binds
Second GABA transmembrane domain provides selectivity for
chloride ions
Entry of Cl-
hyperpolarises the cell, making it more difficult to depolarise, and therefore reduces neural excitability
Agonists
activate the receptor
Antagonists
block effect of agonists, have no effect on receptor function on their own
Anxiety
activation of autonomic system = fight or flight
clinical issue when there is no reasonable cause and interferes with normal functioning
Generalised anxiety disorder (GAD)
- muscle tension
- restlessness
- autonomic effects: sweating, frequent urination, dizziness
- difficulty in concentrating
- insomnia
- irritability
Panic disorder
- palpitations
- nausea
- fear of dying
Sedatives
reduce alertness - they can relieve anxiety and, in higher doses, produce sleep.
Hypnotics
taken to induce sleep
Anxiolytics
taken to relieve anxiety and stress
Ideal anxiolytics
have no sedative effect
Belladonna alkaloids (historical)
atropine
scopolamine
both target ACh receptors, antimuscarinic
Opiates
opium
morphine
diamorphine (Heroin)
Anti-muscarinic: Still used as component of general anaesthesia, and in eye drops.
Atropine
now used in general anaesthesia
muscarinic ACh receptor antagonist
duration of action = 4 hours
Early 20th century anxiolytics
bromide
chloral hydrate (trichloroethanol)
urethane (ethyl carbamate). Still used for animal anaesthesia
thalidomide (teratogen)
barbituates
Barbituates
sedatives/hypnotics
e.g. amobarbital (sodium amytal)
phenobarbital
No longer used as sedatives because of harmful side effects (sedative properties).
(phenobarbital is used as an anti-convulsant, and thiopental as an i.v. anaesthetic).
Benzodiazepines
anxiolytics, sedatives, hypnotics, anticonvulsants
e.g. diazepam (Valium®)
temazepam
lorazepam
Now used as anxiolytics in acute cases only.
Some compounds therapeutically selective.
Azapirones
anxiolytics
e.g. buspirone
tandospirone
Effectiveness develops over 1-3 weeks.
Effective in GAD, but not panic attacks.
Barbituates - mechanism of action
sedative and anxiolytic actions are thought to arise from their binding to GABAA receptors, where they potentiate GABAergic signalling
Benzodiazepines
act at the benzodiazepine (BDZ) site of GABAA receptors to increase the receptor’s affinity for GABA (thereby increasing the size of responses)
Some benzodiazepines show selective activity
may be due to action at different GABAA receptor subtypes
e.g. zolpidem is an hypnotic
clonazepam is an anticonvulsant
Different drugs
bind at different sites on the GABA receptor
Allosteric potentiator
Increases affinity of receptors for another molecule
Diazepam
- long-acting “classical” benzodiazepine.
- Anxiolytics -> acute patients only
- Anxiolytic= antipanic or antianxiety agent
- Allosteric potentiator of GABAA receptor
Diazepam - mechanism of action
binds at benzodiazapene site on GABAA receptor, working as allosteric potentiator - does not activate receptor directly, increases affinity of receptor for GABA
more chloride movement into neurone
Phenobarbital
barbituate that acts as an allosteric potentiator of GABAA receptor, acting at a different site to the benzodiazapine site
Azapirones
These compounds are anxiolytics without sedative side effects.
act as agonists or partial agonists at 5HT1A receptors. - specific class of serotonin receptor, expressed at presynaptic membrane of synapse
activation by azapirones inhibits serotonin release
delayed therapeutic effect
Azapirones - mechanism of action
activate 5-HT1A receptors
decreases calcium due to second messenger signalling
decreased serotonin release from vesicles into synaptic cleft
smaller response at postsynaptic neurone
5-HT ligands
ligands acting as antagonists at other 5-HT receptors (e.g. ondansetron), also have anxiolytic properties - used to reduce illness from cancer chemotherapy, also reduces anxiety
-Activation of postsynaptic serotonin receptors (5HT2A, 5HT2C & 5HT3)
Increases anxiety
Antagonists of postsynaptic serotonin receptors act as anxiolytics
Activation of presynaptic serotonin receptors (5HT1A)
reduces 5HT release, and therefore reduces anxiety
agonists of presynaptic serotonin receptors will act as anxiolytics
Buspirone
azapirone
acts as anagonist of theserotonin5-HT1Areceptorwith highaffinity
leads to decrease in serotonin release so smaller response at postsynaptic neurone
short-term treatment
no immediate anxiolytic effects, and hence has a delayedonset of action - 2-4 weeks for full clinical efficacy
effective for GAD, not for phobias or social anxiety
Side effects of benzodiazepines and barbituates
sedation
respiratory depression, particularly with alcohol - has a wide therapeutic index but issues with alcohol
(can be treated with an antagonist; e.g. flumazenil)
tolerance and dependence (not addiction) - therefore not used for long term treatment, does not activate dopamine reward pathway so not classically addictive
increased anxiety, dizziness, nausea on cessation of treatment (withdrawal)
paradoxical effects of benzodiazepines:
e.g. aggression, depression, confusion
Interaction with alcohol and/or opioids
Benzodiazepine overdose
have a wide therapeutic index on their own and taken alone in overdose rarely cause severe complications or fatalities
taken in overdose in combination with alcohol, barbiturates or opioids, are particularly dangerous due to additive CNS and respiratory depressant effects
Diazepam and alcohol
alcohol is also an allosteric potentiator of the GABAA receptor, increasing receptor response to GABA - greater hyperpolarisation
side effects in combination
Azapirones - side effects
Relatively minor: Principally nausea, dizziness, headaches
Unlike benzodiazepines, azapirones lack abuse potential and are not addictive,
do not cause cognitive/memory impairment or sedation
do not appear to induce appreciable tolerance or physical dependence
However, azapirones are considered less effective with slow onset in controlling symptoms
Anti-depressants and anti-psychotics
calcium channel blocker pregabalin has been recently approved to treat GAD (also an anticonvulsant & analgesic). - does not interact with GABA system, binds to voltage gated Ca2+ channel
β-adrenoceptor antagonists (e.g. propranolol) are used in some cases to treat the symptoms of anxiety
