Pharmacology
Anaesthesia
Which of the following is NOT a typical feature of benzodiazepine toxicity:
Answer:
Features of benzodiazepine toxicity include:- drowsiness
- ataxia
- dysarthria
- nystagmus
- occasionally respiratory depression and coma
Benzodiazepines
Pharmacology / Anaesthesia / Central Nervous System
Last Updated: 4th April 2019
Mechanism of action
Benzodiazepines are gamma-aminobutyric acid (GABA) receptor agonists which enhance inhibitory synaptic transmission throughout the central nervous system, with sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties.
Indications
Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or causing the patient unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness. The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate. Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or causing the patient extreme distress.
Prescribing of these drugs is widespread but dependence (both physical and psychological) and tolerance may occur. Therefore hypnotics and anxiolytics should be reserved for short courses to alleviate acute conditions. Withdrawal of a benzodiazepine should be gradual because abrupt withdrawal may produce confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens.
Benzodiazepines possess useful properties for premedication including relief of anxiety, sedation, and amnesia; short-acting benzodiazepines taken by mouth are the most common premedicants. Benzodiazepines are also used in intensive care units for sedation, particularly in those receiving assisted ventilation.
Contraindications
Benzodiazepines are contraindicated in:
- Respiratory depression
- Marked neuromuscular respiratory weakness, such as unstable myasthenia gravis
- Obstructive sleep apnoea syndrome (symptoms may be aggravated)
- Severe hepatic impairment (the elimination half-life of diazepam may be prolonged; increased risk of coma)
- Phobic or obsessional states, chronic psychosis or hyperkinesis (paradoxical reactions may occur)
Cautions
Benzodiazepines should be used with caution in:
- Respiratory disease
- Muscle weakness and myasthenia gravis (symptoms may be aggravated)
- Organic brain disease
- Severe renal impairment (increased cerebral sensitivity to diazepam; a reduced dose may be appropriate)
- Dependent, obsessive-compulsive, or avoidant-type personality disorders (may increase the risk of dependency)
- Frailty and the elderly (increased falls risk; a reduced dose may be appropriate)
- A history of drug and/or alcohol misuse or dependency (increased risk of dependency)
- Patients taking other central depressants concomitantly e.g. alcohol, barbiturates
Side Effects
Adverse effects include:
- Drowsiness and lightheadedness
- Confusion and ataxia (especially in the elderly), amnesia, muscle weakness
- Headache, vertigo, tremor, dysarthria, hypotension, decreased libido, erectile dysfunction, gynaecomastia, urinary retention
- Paradoxical effects such as talkativeness, excitement, irritability, aggression, anti-social behaviour, and suicidal ideation
- Withdrawal symptoms, for example anxiety, depression, anorexia, impaired concentration, insomnia, abdominal cramps, palpitations, tremor, tinnitus and perceptual disturbances
- Tolerance and dependence (people who use benzodiazepines longer term can develop tolerance and eventual dependence)
Toxicity
Features of benzodiazepine toxicity include:
- drowsiness
- ataxia
- dysarthria
- nystagmus
- occasionally respiratory depression and coma
Flumazenil is used to antagonise the effects of benzodiazepines. It can be used to reduce the sedative effects of benzodiazepines in anaesthesia, intensive care, diagnostic procedures and in overdose.
Type Examples
Midazolam has a short duration of action (< 6 hours), lorazepam and temazepam have an intermediate duration of action (12 - 18 hours) and diazepam and chlordiazepoxide have a long duration of action (24 - 48 hours). Shorter-acting compounds may be preferred in patients with hepatic impairment but they carry a greater risk of withdrawal symptoms.
Chlordiazepoxide is routinely used for symptoms associated with acute alcohol withdrawal.
Diazepam is used to produce mild sedation with amnesia. It is a long-acting drug with active metabolites and a second period of drowsiness can occur several hours after its administration.
Temazepam is given by mouth for premedication and has a shorter duration of action and a more rapid onset than oral diazepam; anxiolytic and sedative effects last about 90 minutes although there may be residual drowsiness.
Lorazepam produces more prolonged sedation than temazepam and it has marked amnesic effects.
Midazolam is a water-soluble benzodiazepine that is often used in preference to intravenous diazepam; recovery is faster than from diazepam, but may be significantly longer in the elderly, in patients with a low cardiac output, or after repeated dosing. Midazolam is associated with profound sedation when high doses are given intravenously or when it is used with certain other drugs.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
