Pharmacology of Anxiolytics Flashcards
Drugs used to treat anxiety?
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)
Examples of benzodiazepines?
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
How is a specific benzodiazepine chosen?
Choice of drug determined by duration of action
Pharmacological effects of benzodiazepines?
- Reduced anxiety and agression
- Hypnosis / sedation
- Muscle relaxation
- Anti-convulsant effect
- Anterograde amnesia (undesired effect)
What is GABA?
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
Most important inhibitory NTs in the CNS?
GABA and glycine
Mechanism of action of benzodiazepines?
Act by increasing GABA-mediation inhibition
Benzodiazepines binds to a BDZ binding site, allowing +ve allosteric modulation; this potentiates the effects of GABA
Clinical uses of benzodiazepines?
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)
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Effects of BDZ agonists?
E.g: β-carbolines, have anxiogenic properties
NOTE - these are used in research to induce anxiety; other drugs are then used to correct
Safety of benzodiazepines?
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)
Other issues assoc. with benzodiazepines?
Paradoxical aggression
Anterograde amnesia and impaired coordination (beware Rohypnol)
Tolerance and dependance, leading to rebound anxiety on withdrawal and sometimes physical symptoms
Withdrawal symptoms from benzdiazepines?
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
Cause of withdrawal symptoms with benzodiazepines
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
How to withdraw benzodiazepines?
- Transfer patient to equivalent daily dose of diazepam / chlordiazepoxide (have a longer 1/2-life), preferably taken at night
- Reduce dose every 2-3 weeks in steps of 2 / 2.5mg; is withdrawal symptoms occur, maintain the dose until symptoms improve
- 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
Anti-depressants used for anxiety?
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
Acute effect of SSRIs in anxiety?
SSRIs increase extracellular 5-HT and have anxiogenic properties
Chronic effects of SSRIs in anxiety?
Anxiolytic properties appear
Mechanism of anxiolytic action of SSRIs?
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
- 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
Use of pregabalin in anxiety?
CCB and GABA enhancer
It is only considered if no response to other treatments
Use of β-blockers, e.g: propranolol, in anxiety?
Mainly used for somatic symptoms, e.g: palpitations and tremor
Use of buspirone in anxiety?
Prescribed with an SSRI, in order to modify effects on libido
Mechanism of action of buspirone?
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
