Anxiolytics

Question 1

GABA

Answer 1

principal inhibitory neurotransmitter in CNS, causes hyperpolarisation

Question 2

GABAA receptor

Answer 2

ligand-gated ion channel, pentameric structure - Ionotropic receptor

principal inhibitory receptors in the CNS

permeable to chloride ions when GABA binds

Question 3

Second GABA transmembrane domain provides selectivity for

Answer 3

chloride ions

Question 4

Entry of Cl-

Answer 4

hyperpolarises the cell, making it more difficult to depolarise, and therefore reduces neural excitability

Question 5

Agonists

Answer 5

activate the receptor

Question 6

Antagonists

Answer 6

block effect of agonists, have no effect on receptor function on their own

Question 7

Anxiety

Answer 7

activation of autonomic system = fight or flight

clinical issue when there is no reasonable cause and interferes with normal functioning

Question 8

Generalised anxiety disorder (GAD)

Answer 8

• muscle tension
• restlessness
• autonomic effects: sweating, frequent urination, dizziness
• difficulty in concentrating
• insomnia
• irritability

Question 9

Panic disorder

Answer 9

• palpitations
• nausea
• fear of dying

Question 10

Sedatives

Answer 10

reduce alertness - they can relieve anxiety and, in higher doses, produce sleep.

Question 11

Hypnotics

Answer 11

taken to induce sleep

Question 12

Anxiolytics

Answer 12

taken to relieve anxiety and stress

Question 13

Ideal anxiolytics

Answer 13

have no sedative effect

Question 14

Belladonna alkaloids (historical)

Answer 14

atropine
scopolamine

both target ACh receptors, antimuscarinic

Question 15

Opiates

Answer 15

opium
morphine
diamorphine (Heroin)

Anti-muscarinic: Still used as component of general anaesthesia, and in eye drops.

Question 16

Atropine

Answer 16

now used in general anaesthesia

muscarinic ACh receptor antagonist

duration of action = 4 hours

Question 17

Early 20th century anxiolytics

Answer 17

bromide

chloral hydrate (trichloroethanol)

urethane (ethyl carbamate). Still used for animal anaesthesia

thalidomide (teratogen)

barbituates

Question 18

Barbituates

Answer 18

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).

Question 19

Benzodiazepines

Answer 19

anxiolytics, sedatives, hypnotics, anticonvulsants

e.g. diazepam (Valium®)

temazepam

lorazepam

Now used as anxiolytics in acute cases only.
Some compounds therapeutically selective.

Question 20

Azapirones

Answer 20

anxiolytics

e.g. buspirone

tandospirone

Effectiveness develops over 1-3 weeks.
Effective in GAD, but not panic attacks.

Question 21

Barbituates - mechanism of action

Answer 21

sedative and anxiolytic actions are thought to arise from their binding to GABAA receptors, where they potentiate GABAergic signalling

Question 22

Benzodiazepines

Answer 22

act at the benzodiazepine (BDZ) site of GABAA receptors to increase the receptor’s affinity for GABA (thereby increasing the size of responses)

Question 23

Some benzodiazepines show selective activity

Answer 23

may be due to action at different GABAA receptor subtypes

e.g. zolpidem is an hypnotic

clonazepam is an anticonvulsant

Question 24

Different drugs

Answer 24

bind at different sites on the GABA receptor

Question 25

Allosteric potentiator

Answer 25

Increases affinity of receptors for another molecule

Question 26

Diazepam

Answer 26

- long-acting "classical" benzodiazepine. - Anxiolytics -> acute patients only - Anxiolytic = antipanic or antianxiety agent - Allosteric potentiator of *GABAA* receptor

Question 27

Diazepam - mechanism of action

Answer 27

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

Question 28

Phenobarbital

Answer 28

barbituate that acts as an allosteric potentiator of GABAA receptor, acting at a different site to the benzodiazapine site

Question 29

Azapirones

Answer 29

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

Question 30

Azapirones - mechanism of action

Answer 30

activate 5-HT1A receptors decreases calcium due to second messenger signalling decreased serotonin release from vesicles into synaptic cleft smaller response at postsynaptic neurone

Question 31

5-HT ligands

Answer 31

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

Question 32

-Activation of postsynaptic serotonin receptors (5HT2A, 5HT2C & 5HT3)

Answer 32

Increases anxiety Antagonists of postsynaptic serotonin receptors act as anxiolytics

Question 33

Activation of presynaptic serotonin receptors (5HT1A)

Answer 33

reduces 5HT release, and therefore reduces anxiety agonists of presynaptic serotonin receptors will act as anxiolytics

Question 34

Buspirone

Answer 34

azapirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity leads to decrease in serotonin release so smaller response at postsynaptic neurone short-term treatment no immediate anxiolytic effects, and hence has a delayed onset of action - 2-4 weeks for full clinical efficacy effective for GAD, not for phobias or social anxiety

Question 35

Side effects of benzodiazepines and barbituates

Answer 35

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

Question 36

Benzodiazepine overdose

Answer 36

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

Question 37

Diazepam and alcohol

Answer 37

alcohol is also an allosteric potentiator of the GABAA receptor, increasing receptor response to GABA - greater hyperpolarisation side effects in combination

Question 38

Azapirones - side effects

Answer 38

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

Question 39

Anti-depressants and anti-psychotics

Answer 39

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