Benzodiazepines

Key examples

• Diazepam
• Temazepam
• Lorazepam
• Chlordiazepoxide
• Midazolam

 

Common indications

1. In the first-line management of seizures and status epilepticus.
2. In the first-line management of alcohol withdrawal reactions.
3. As a common choice for sedation for interventional procedures, if general anaesthesia is unnecessary or undesirable.
4. For short-term treatment of severe, disabling or distressing anxiety.
5. For short-term treatment of severe, disabling or distressing insomnia.

 

Mechanisms of action

• The γ-aminobutyric acid type A (GABA-A) receptor is a chloride channel that opens in response to binding by GABA, the main inhibitory neurotransmitter in the brain. 
• Opening the channel allows chloride to flow into the cell, making the cell more resistant to depolarisation. 
• Benzodiazepines facilitate and enhance binding of GABA to the GABA-A receptor. 
• This has a widespread depressant effect on synaptic transmission. 
• The clinical manifestations of this include reduced anxiety, sleepiness, sedation and anticonvulsive effects. 
• Ethanol (‘alcohol’) also acts on the GABA-A receptor, and in chronic excessive use the patient becomes tolerant to its presence. Abrupt cessation then provokes the excitatory state of alcohol withdrawal. This can be treated by introducing a benzodiazepine, which can then be withdrawn in a gradual and more controlled way.

 

Important adverse effects

• Predictably, benzodiazepines cause dose-dependent drowsiness, sedation and coma. There is relatively little cardiorespiratory depression in benzodiazepine overdose (in contrast to opioid overdose), but loss of airway reflexes can lead to airway obstruction and death. If used repeatedly for more than a few weeks, a state of dependence can develop. Abrupt cessation then produces a withdrawal reaction similar to that seen with alcohol.

 

Warnings

• The elderly are more susceptible to the effects of benzodiazepines so should receive a lower dose. Benzodiazepines are best avoided in patients with significant respiratory impairment or neuromuscular disease (e.g. myasthenia gravis). They should also be avoided in liver failure as they may precipitate hepatic encephalopathy; if their use is essential (e.g. for alcohol withdrawal), lorazepam may be the best choice, as it depends less on the liver for its elimination.

 

Important interactions

• The effects of benzodiazepines are additive to those of other sedating drugs, including alcohol and opioids. 
• Most benzodiazepines depend on cytochrome P450 enzymes for elimination, so concurrent use with cytochrome P450 inhibitors (e.g. amiodarone, diltiazem, macrolides, fluconazole, protease inhibitors) may increase their effects.