Sleep regulation is influenced by a wide range of neurotransmitters. Those promoting wakefulness include noradrenalin, serotonin (5-hydroxytryptamine/5-HT), acetylcholine, dopamine, histamine and orexins. Orexins, also known as hypocretins, are hypothalamic neuropeptides associated with maintaining normal wakefulness among other functions, and activate several downstream signal pathways.4,17,18

Drugs inhibiting histamine H1 receptors will reduce levels of arousal. Antihistamines used for their sedative activity need to cross the blood-brain barrier, but are not particularly selective histamine receptor antagonists. In addition, they can also affect choline, noradrenaline and dopamine receptors, contributing further to side effects and adverse events.4

The principle neurotransmitter promoting sleep is gamma-aminobutyric acid (GABA) which inhibits a wide range of brain cells (and particularly in the hypothalamus) via several pathways.4

GABA-A receptors are stimulated by benzodiazepines, ‘Z drugs’ and barbiturates, but individual drugs have different specificities for the different GABA-A-receptor subtypes, affecting different aspects of the sleep regulatory pathways. Traditional benzodiazepines are the least selective.

Melatonin secretion from the pineal gland is triggered by activation of what is regarded as the ‘circadian pacemaker’, namely the suprachiasmatic nucleus (SCN) of the hypothalamus. In normal circumstances, melatonin secretion increases with darkness and drowsiness follows activation of melatonin receptors. Beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit melatonin secretion.4,19