Benzodiazepines
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Mechanism of action
Benzodiazepines are gamma-aminobutyric acid (GABA) receptor agonists which bind to GABAA receptors and enhance GABA binding to the receptor. GABA is an inhibitory neurotransmitter that inhibits synaptic transmission throughout the central nervous system (CNS).Indications
Benzodiazepines have sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties which make them suitable for the following:- Anxiolytics (short term only)
- Anticonvulsants
- Sedation (procedural sedation, premedication or short term treatment of insomnia)
- Muscle relaxant (pain relief for certain musculoskeletal conditions e.g. muscle spasm)
- Alcohol withdrawal
Addiction and withdrawal
Physical and psychological dependence is a well known issue with benzodiazepines. Tolerance may also occur requiring escalation of dosing for the same effects. Short course are advised to prevent these issues developing.
Note that those who have taken benzodiazepines long term may suffer from a benzodiazepine withdrawal syndrome (sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, difficulty in concentration, dry wretching, nausea, weight loss, palpitations, headache, muscular pain, stiffness, perceptual changes and in severe cases seizures and psychotic reactions) if withdrawn suddenly. Withdrawal should be gradual to avoid this developing.
Physical and psychological dependence is a well known issue with benzodiazepines. Tolerance may also occur requiring escalation of dosing for the same effects. Short course are advised to prevent these issues developing.
Note that those who have taken benzodiazepines long term may suffer from a benzodiazepine withdrawal syndrome (sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, difficulty in concentration, dry wretching, nausea, weight loss, palpitations, headache, muscular pain, stiffness, perceptual changes and in severe cases seizures and psychotic reactions) if withdrawn suddenly. Withdrawal should be gradual to avoid this developing.
Side Effects
Common:
- Alertness decreased
- Anxiety
- Ataxia (more common in elderly)
- Confusion (more common in elderly)
- Depression
- Dizziness
- Drowsiness (which may be desirable in some instances e.g. painful procedures)
- Dysarthria
- Fatigue
- Headache
- Hypotension
- Mood altered
- Muscle weakness
- Nausea
- Respiratory depression (particularly with high dose and IV use—facilities for its treatment are essential)
- Sleep disorders
- Tremor
- Vision disorders
- Dependance and withdrawal syndrome
- Agitation
- Amnesia (which may be desirable in some instances e.g. painful procedures)
- Aggression behaviour
- Delusions or hallucination
- Drug reaction
- Overdose
Toxicity (overdose)
Benzodiazepines overdose may cause drowsiness, ataxia, dysarthria, nystagmus, and occasionally respiratory depression and coma.
Flumazenil is a treatment option for benzodiazepine toxicity but it is not without its risks.
Flumazenil is a benzodiazepine antagonist. It can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients. Flumazenil may prevent the need for ventilation, particularly in patients with severe respiratory disorders; it should be used on expert advice only and not as a diagnostic test in patients with a reduced level of consciousness.
Benzodiazepines overdose may cause drowsiness, ataxia, dysarthria, nystagmus, and occasionally respiratory depression and coma.
Flumazenil is a treatment option for benzodiazepine toxicity but it is not without its risks.
Flumazenil is a benzodiazepine antagonist. It can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients. Flumazenil may prevent the need for ventilation, particularly in patients with severe respiratory disorders; it should be used on expert advice only and not as a diagnostic test in patients with a reduced level of consciousness.
Contraindications
- Acute pulmonary insufficiency
- Marked neuromuscular respiratory weakness e.g. post stroke or myasthenia
- Not for use alone to treat chronic psychosis or depression or anxiety associated with depression in adults
- Obsessional states
- Phobic states
- Sleep apnoea syndrome
- Severe hepatic impairment
- Breast feeding
Cautious use is also advised in the following:
- Debilitated patients (reduce dose)
- Elderly or frail patients (consider dose reduction and falls risk)
- History of alcohol dependence or abuse
- History of drug dependence or abuse
- Myasthenia gravis
- Personality disorder (within the fearful group—dependent, avoidant, obsessive-compulsive) may increase risk of dependence)
- Chronic respiratory disease
- Renal failure
- Mild to moderate hepatic impairment
- Pregnancy
Benzodiazepine profiles
The college expects candidates to have specific knowledge of diazepam, chlordiazepoxide, temazepam, lorazepam and midazolam.
| Drug | Peak Plasma Levels | Mean Plasma Half-Life |
|---|---|---|
| Diazepam | 30-90 minutes | 20-42 hours (active metabolites 36-200 hours) |
| Chlordiazepoxide | 1-2 hours | 5-30 hours (active metabolites 36-200 hours) |
| Lorazepam | 2 hours | 8-25 hours |
| Temazepam | 1.5 hours | 8-9 hours |
| Midazolam | <30 minutes | 1-6 hours |
Source: MHRA & Ashton benzodiazepine equivalence table
| Drug | Duration of action | notes |
|---|---|---|
| Midazolam | <6 hours (short) | Fast acting Causes profound sedation |
| Lorazepam | 6-8 hours (short to intermediate) | Preferred in ALD due to short half life More prolonged sedation than temazepam |
| Temazepam | 6-8 hours (short to intermediate) | Anxiolytic and sedative effects last approximately 90 minutes |
| Diazepam | 24-48 hours (long) | Active metabolites may cause secondary period of drowsiness hours after administration |
| Chlordiazepoxide | 24-48 hours (long) | Used for alcohol withdrawal |