Anxiolytics (Block 4)

Question 1

Ionotropic receptors (ligand-gated ion channels)

Answer 1

Contains integral ion channel (cationic or anionic)
Multiple protein subunits (4 or 5)
Fast activation

Question 2

What is GABA?

Answer 2

An amino acid
Principle inhibitory neurotransmitter in mammalian CNS

Question 3

How is GABA produced?

Answer 3

By the decarboxylation of glutamate

Question 4

Where is GABA found?

Answer 4

Almost exclusively in the brain
In high concentrations

Question 5

What does the release of GABA cause?

Answer 5

Hyperpolarisation of target neurones through activation of 2 receptor subtypes (GABA-alpha and GABA-beta)
Entry of Cl- hyperpolarises the cell, making it more difficult to depolarise, and therefore reduces neural excitability

Question 6

Types of metabotropic receptors - G-protein coupled

Answer 6

Intracellular effects via action of the G protein
Slower activation

Question 7

Other than the brain, where is 5-hydroxytrptamine (5-HT) found?

Answer 7

Many non-neuronal cells (eg platelets and mast cells)
The peripheral nervous system

Question 8

5-HT’s actions are principally (but not exclusively)

Answer 8

inhibitory

Question 9

Effects of 5-HT

Answer 9

Impacts wide range of physiological and behavioural processes, including sleep, mood, sensory transmission, and feeding.
Also mediates hallucinogenic properties of many psychoactive drugs

Question 10

Agonists and antagonists

Answer 10

Agonists activate the receptor; antagonists block the effect of agonists. Antagonists have no effect on receptor function on their own.

Question 11

Anxiety

Answer 11

Normal & essential response to perceived/impending danger (different to fear, which is of a known threat)
Becomes a clinical issue when there’s no reasonable cause and it interferes with normal functioning

Question 12

Examples of anxiety disorders

Answer 12

Generalised anxiety disorder (GAD)
Post-Traumatic Stress Disorder (PTSD)
Panic disorder, with or without agoraphobia

Question 13

Symptoms of GAD

Answer 13

Muscle tension
Restlessness
Autonomic effects - sweating, frequent urination, dizziness
Difficulty in concentrating
Insomnia
Irritability

Question 14

Symptoms of panic disorder

Answer 14

Palpitations
Nausea
Fear of dying

Question 15

Sedative

Answer 15

Reduce alertness
Relieve anxiety & in high doses induce sleep

Question 16

Hypnotics

Answer 16

Induce sleep

Question 17

Anxiolytics

Answer 17

Drugs taken to relieve anxiety and stress.
Ideal anxiolytics have no sedative effect. Anxiolytic drugs, whether sedative or not, may sometimes be referred to as minor tranquillisers.

Question 18

Historical anxiolytic agents

Answer 18

Belladonna alkaloids (atropine, scopolamine)
Opiates (opium, morphine, diamorphine (heroine))

Question 19

Historical agents - Atropine

Answer 19

Historically used as an anxiolytic agent
General anaesthesia
Atropine is a muscarinic receptor antagonist (GPCR)
So prevents acetylcholine binding
Duration of action= 4 hours

Question 20

Historical agents - Barbiturates

Answer 20

Used a lot in WW1
Sedatives
Harmful side effects
A big step forward for the time

Question 21

Current agents - Benzodiazepines

Answer 21

Commercially - Valium
Only used in acute cases now but was used very widely before
Tolerance issue, hence decrease in reduction despite success

Question 22

Current agents - Azapirones

Answer 22

Effectiveness develops over 1-3 weeks
Effective in GAD but not in panic attacks
Licensed for short term treatment in the UK

Question 23

Mechanisms of action - barbiturates

Answer 23

Bind to GABAA receptors
Potentiate GABAergic signalling
Sedative and anxiolytic actions

Question 24

Mechanisms of action - Benzodiazepines

Answer 24

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

Question 25

The GABA-A receptor - ligand gated ion channel

Answer 25

Ionotropic receptor, permeable to chloride ions Action therefore inhibitory Endogenous agonist is GABA (-aminobutyric acid) Similar to nicotinic acetylcholine receptors, with five subunits per channel

Question 26

Therapeutic selectivity

Answer 26

Some benzodiazepines show therapeutic selectivity. Action at different GABAA receptor subtypes may underlie this. Eg -> zolpidem is an hypnotic; clonazepam is an anticonvulsant

Question 27

Allosteric potentiator

Answer 27

Allosteric potentiators act by increasing the affinity of the receptor for GABA. They therefore increase receptor responses to GABA without activating the receptor directly.

Question 28

Examples of allosteric potentiators

Answer 28

Diazepam Barbiturate

Question 29

Serotonin and anxiety - Azapirones

Answer 29

Anxiolytics without sedative side effects Agonists or partial agonists agonists at 5-HT-1A receptors -> activation inhibits serotonin release via inhibition of of adenylate cyclase Therapeutic effects are delayed, suggesting complex mechanism of action Some also bind to other sites, but anxiolytic effect is probably from action at 5-HT

Question 30

Post-synaptic serotonin receptors and anxiety

Answer 30

Activation of post-synaptic serotonin receptors increases anxiety

Question 31

Pre-synaptic serotonin receptors and anxiety

Answer 31

Activation of pre-synaptic serotonin receptors reduces 5HT release, this reducing anxiety

Question 32

Azapirones - Buspirone

Answer 32

Agonist of the serotonin 5HT1A receptor with high affinity No immediate anxiolytic effects; delayed onset of action - may take 2-4 weeks to manifest Similar in GAD treatment to benzodiazepines Ineffective in treating phobias or social anxiety disorder

Question 33

Buspirone in the UK

Answer 33

Only indicated for short-term anxiety treatment

Question 34

Side effects of benzodiazepines and barbiturates

Answer 34

Sedation Respiratory depression, particularly with alcohol Tolerance and dependence (NOT addiction) Increased anxiety Dizziness Nausea on cessation of treatment

Question 35

Benzodiazepines and overdose

Answer 35

Wide therapeutic index -> taken alone in overdose rarely cause sever complications or fatalities Taken in overdose in combination with alcohol, barbiturates, or opioids -> particular dangerous due to additive CNS and respiratory depressant effects

Question 36

Side effects of azapirones

Answer 36

Relatively minor, primarily nausea, dizziness, and headaches

Question 37

Pros of azapirones over other treatments

Answer 37

Relatively minor side effects Lack abuse potential and are not addictive No cognitive/memory impairment No sedation Do not appear to induce appreciable tolerance or physical dependence

Question 38

Cons of azapirones compared to other treatments

Answer 38

Less effective Slow onset in controlling symptoms

Question 39

Other anxiolytics

Answer 39

Pregabalin -> calcium channel blocker Beta-adrenoreceptor antagonists -> can be used to treat SYMPTOMS of anxiety

Question 40

Current UK clinical guidelines for anxiolytics

Answer 40

Recommended that psychological therapy be tried before drugs prescription SSRI or SNRI to be tried first Benzodiazepines for short-term acute treatment only Buspirone also limited to short-term use where SSRI/SNRI is poorly tolerated