Z-drugs

Key examples

• Zopiclone
• Zolpidem

 

Common indications

• Short-term treatment of insomnia which is debilitating or distressing.

 

Mechanisms of action

• The ‘Z-drugs’ have a similar mechanism of action to benzodiazepines, although they are chemically quite distinct. Their target 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. 
• Like benzodiazepines, Z-drugs 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, and sedation. 
• Note that they are not useful anticonvulsants, as they can only be taken orally. 
• In general, Z-drugs have a shorter duration of action than benzodiazepines.

 

Important adverse effects

• All Z-drugs can cause daytime sleepiness, which may affect ability to drive or perform complex tasks the day after taking the medication. Rebound insomnia may occur when the drugs are stopped. Other central nervous system effects include headache, confusion, nightmares and (rarely) amnesia. As Z-drugs are chemically distinct from each other, their adverse effects differ. 
• Zopiclone can cause taste disturbance, whereas zolpidem more commonly causes gastrointestinal upset. Prolonged used of Z-drugs beyond 4 weeks can lead to dependence, with withdrawal symptoms on stopping, including headaches, muscle pains and anxiety.
• In overdose, Z-drugs cause drowsiness, coma and respiratory depression.

 

Warnings

• Z-drugs should be used with caution in the elderly, who are often more sensitive to drugs with central nervous system effects. 
• They should not be prescribed for patients with obstructive sleep apnoea or those with respiratory muscle weakness or respiratory depression, in whom they may worsen respiratory failure during sleep.

 

Important interactions

• Z-drugs enhance the sedative effects of alcohol, antihistamines and benzodiazepines. They enhance the hypotensive effect of antihypertensive medications. 
• As Z-drugs are metabolised by cytochrome P450 enzymes, P450 inhibitors (e.g. macrolides) can enhance sedation, whereas P450 inducers (e.g. phenytoin, rifampicin) can impair sedation.