Histamine receptor antagonists sedative effects

Atopic Dermatitis. The mechanism of itching associated with atopic dermatitis remains unknown, but histamine is almost certainly involved to some extent as histamine concentrations are increased in the skin and in the plasma of patients with this disorder (39,42). Second-generation H receptor antagonists, unlike first-generation H receptor antagonists, have not been uniformly found to be effective in relieving itching in atopic dermatitis, which may be related to the absence of a sedative effect (43). 

From time to time it has been suggested that histamine has some role in a number of behaviours and motor activity while the established and marked sedative effect of Hi receptor antagonists, mentioned at the start of this section, has consistently been considered to indicate a role for histamine in arousal and the sleep-waking cycle (see Chapter 22). 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Histamine-1 receptor antagonists (e.g., diphenhydramine) and antidepressants with high histamine-1 blockade (e.g., doxepin and amitriptyline) have been used for acute sleep disturbances but may cause anticholinergic side effects, daytime sedation, and weight gain. Trazodone, a serotonin-2A and ai -adrenergic antagonist, has sedative properties at lower doses and may be useful to promote sleep. The chronic use of benzodiazepines is not recommended for insomnia... 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Indeed, on the basis of the cyclase assay, amitriptyline is one of the most potent H2-antagonists presently available (KD 0.05 /iM) [ 181, 193]. The dissociation constants for many of the antidepressants are sufficiently low to suggest that the activation of adenylate cyclase by histamine may be inhibited by therapeutically effective concentrations of these compounds [81, 193]. This biochemical action of the tricyclic and tetracyclic antidepressants may thus represent part of the molecular basis of clinical antidepressant activity [193]. It should also be noted that most tricyclic and tetracyclic antidepressants are much more potent inhibitors of H,-receptor responses [67, 120] than they are of the H2-cyclase response, and this property of these compounds may mediate the sedative actions of these drugs [71, 73, 75]. 

---