Benzodiazepines

Question 1

Mechanisms of action

Answer 1

The target of benzodiazepines is the γ-aminobutyric acid type A (GABAA) receptor. The GABAA 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 GABAA receptor. This has a widespread depressant effect on synaptic transmission. The clinical manifestations of this include reduced anxiety, sleepiness, sedation and anticonvulsive effects.

Question 2

Adverse effects

Answer 2

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.

Question 3

Warnings

Answer 3

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.

Question 4

Interactions

Answer 4

The effects of benzodiazepines are additive to those of other sedating drugs, including alcohol and opioids. Most 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.

Question 5

Prescribing

Answer 5

Choose duration of action depending on use eg:

Alcohol withdrawal or seizures = long-acting

Anxiety/insomnia = medium-acting

Sedation = short-acting

Question 6

Administration

Answer 6

Diazepam is available as a water-based solution and an oil-in-water emulsion. The solution is more irritant to veins. Intravenous administration of benzodiazepines, whether for seizures or sedation, should be undertaken only where facilities and expertise exist to deal with over-sedation (including capabilities for airway management). They should be injected slowly.

Question 7

Communication

Answer 7

When treating insomnia and anxiety, advise your patient that pharmacological therapy is only a short-term measure. Discuss the risks of dependence, advising that this can be minimised by avoiding daily use if possible and taking them for no longer than 4 weeks. Advise patients that they should not drive or operate complex or heavy machinery after taking the drug, and caution them that sometimes sleepiness may persist the following day.

Question 8

Monitoring

Answer 8

Close monitoring of the patient’s clinical status and vital signs are essential following IV or high-dose oral administration of a benzodiazepine, including the settings of seizures, alcohol withdrawal and sedation. In insomnia and anxiety, enquiry about symptoms and side effects is the best form of monitoring.