Pharmacology of Anxiolytics

Question 1

Drugs used to treat anxiety?

Answer 1

Barbiturates (historical use; no longer recommended as they are toxic in OD)

Benzodiazepines (ONLY USED ACUTELY AND SHORT-TERM, for 2-4 weeks, due to risk of dependency)

Anti-depressant drugs (SSRIs are the 1st line drug treatment for anxiety)

Buspirone (2nd line)

Pregabalin (3rd line)

β-blocker, e.g: propranolol (used to treat physical symptoms of anxiety)

Question 2

Examples of benzodiazepines?

Answer 2

Midazolam (can be administered orally, IV, IM)

Lorazepam, oxazepam, temazepam, alprazolam, nitrazepam, diazepam
NOTE - diazepam is often used for anxiety or alcohol withdrawal in out-patients, as it is relatively safe

Chlordiazepoxide (used for inpatients with alcohol withdrawal)

Flurazepam

Clonzaepam

Question 3

How is a specific benzodiazepine chosen?

Answer 3

Choice of drug determined by duration of action

Question 4

Pharmacological effects of benzodiazepines?

Answer 4

1. Reduced anxiety and agression
2. Hypnosis / sedation
3. Muscle relaxation
4. Anti-convulsant effect
5. Anterograde amnesia (undesired effect)

Question 5

What is GABA?

Answer 5

Gamma Amine Butyric Acid - the main inhibitory NT in the brain; it has widespread distribution

Glycine is another very important inhibitory NT; it is restricted to the spinal cord and brainstem

They both cause hyperpolarisation of target cells; GABA binds to the GABA binding site

Question 6

Most important inhibitory NTs in the CNS?

Answer 6

GABA and glycine

Question 7

Mechanism of action of benzodiazepines?

Answer 7

Act by increasing GABA-mediation inhibition

Benzodiazepines binds to a BDZ binding site, allowing +ve allosteric modulation; this potentiates the effects of GABA

Question 8

Clinical uses of benzodiazepines?

Answer 8

Acute treatment of extreme anxiety

Hypnosis

Alcohol withdrawal

Mania (only used short-term for mania)

Delirium (usually used 2nd line, after anti-psychotics)

Rapid tranquilisation

Pre-medication before surgery or during minor procedures (usually midazolam)

Status epilepticus (no more than 2 doses of 10mg)

Question 9

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Answer 9

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Question 10

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Answer 10

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Question 11

Effects of BDZ agonists?

Answer 11

E.g: β-carbolines, have anxiogenic properties

NOTE - these are used in research to induce anxiety; other drugs are then used to correct

Question 12

Safety of benzodiazepines?

Answer 12

Fairly safe in OD, as they are unlikely to cause respiratory depression alone; can cause issues if combined with an antagonist, such as Flumazenil (increases anxiety)

Question 13

Other issues assoc. with benzodiazepines?

Answer 13

Paradoxical aggression

Anterograde amnesia and impaired coordination (beware Rohypnol)

Tolerance and dependance, leading to rebound anxiety on withdrawal and sometimes physical symptoms

Question 14

Withdrawal symptoms from benzdiazepines?

Answer 14

Rapid withdrawal can cause confusion, toxic psychosis and convulsions

Other symptoms:
• Insomnia
• Subjective anxiety
• Loss of appetite and weight loss
• Tremor
• Perspiration
• Tinnitus
• Perceptual disturbances

Question 15

Cause of withdrawal symptoms with benzodiazepines

Answer 15

Neuroadaptation of the GABA response

Chronic treatment causes decreased response to GABA and so withdrawal results in anxiety / convulsions, potentially due to decreased density of BZ receptors

Question 16

How to withdraw benzodiazepines?

Answer 16

1. Transfer patient to equivalent daily dose of diazepam / chlordiazepoxide (have a longer 1/2-life), preferably taken at night
2. Reduce dose every 2-3 weeks in steps of 2 / 2.5mg; is withdrawal symptoms occur, maintain the dose until symptoms improve
3. Reduce dose further, if necessary, in even smaller steps

NOTE - reduce the dose slowly before stopping completely; the time required for withdrawal can vary from 4 weeks (typically) to a year

Question 17

Anti-depressants used for anxiety?

Answer 17

SSRIs are used 1st line for:
• Panic disorder, OCD, PTSD, phobias
• GAD (paroxetine, escitalopram)

TCAs, e.g: clomipramine, imipramine:
• 2nd line for panic disorder (unlicensed indication) and OCD

Venlafaxine:
• GAD

Moclobemide:
• Social anxiety disorder

Question 18

Acute effect of SSRIs in anxiety?

Answer 18

SSRIs increase extracellular 5-HT and have anxiogenic properties

Question 19

Chronic effects of SSRIs in anxiety?

Answer 19

Anxiolytic properties appear

Question 20

Mechanism of anxiolytic action of SSRIs?

Answer 20

Unclear:
1. Neuroadaptive changes, e.g: in expression of 5-HT and / or glucocorticoids, that depend upon sustained exposure to higher EC conc. of 5-HT

2. Enhanced corticosteroid synthesis - neuroactive steroids (synthesised form cholesterol) and have a wide range of actions, inc. action on GABA receptor; may play a role in neuronal plasticity, learning and emotional homeostasis

Question 21

Use of pregabalin in anxiety?

Answer 21

CCB and GABA enhancer

It is only considered if no response to other treatments

Question 22

Use of β-blockers, e.g: propranolol, in anxiety?

Answer 22

Mainly used for somatic symptoms, e.g: palpitations and tremor

Question 23

Use of buspirone in anxiety?

Answer 23

Prescribed with an SSRI, in order to modify effects on libido

Question 24

Mechanism of action of buspirone?

Answer 24

5-HT1A receptor partial agonist

Pre-synaptic dopamine antagonist at certain receptors

Partial α1 receptor agonist

OVERALL EFFECT - suppressed serotonergic activity and enhances noradrenergic and dopaminergic cell firing

Question 25

Long-term strategies for anxiety treatment?

Answer 25

Usually inc. psychological therapies (CBT)