Therapeutic Options in the Treatment of Clozapine-Induced Sialorrhea

Donald P. Rogers, Pharm.D., and Jennifer K. Shramko, Pharm.D.

Pharmacotherapy. 2000;20(9) 

In This Article

Pathophysiology of Clozapine-Induced Sialorrhea

Clozapine has affinity for many receptors including those belonging to the adrenergic and muscarinic families. Stimulation of the alpha1-receptor at postjunctional sites causes peripheral vasoconstriction, and antagonism results in relaxation.[6] The a2-receptors, on the other hand, are located both presynaptically and postsynaptically. Stimulation of these receptors causes a reduction in release of norepinephrine (NE) and acetylcholine. Clozapine has antagonistic effects at both a1- and a2-receptors. It was suggested that both subtypes of receptors are on the salivary glands, where blockade causes an increase in blood flow, resulting in increases in salivary flow and composition.[7]

Muscarinic receptors are classified into five subtypes. The M1 and M4 receptor subtypes predominate in various secretory glands. Clozapine is antagonistic at M1, M2, M3, and M5 receptor subtypes, but in vitro findings indicate that it is a full agonist at the M4 receptor.[8,9] In lieu of its potent anticholinergic effects at other receptor subtypes, clozapine's stimulation of the M4 receptors in salivary glands leads to an increase in secretions.[9] Agonism at the M4 receptor may determine in part why sialorrhea does not occur with other atypical anti-psychotics, especially those with a-blockade.

Other theories suggest that the excessive salivation experienced by patients taking clozapine may be due to problems with deglutition or other nocturnal disturbances. Although the drug does not objectively increase saliva flow rates compared with controls, patients subjectively complain of an increase in the amount of saliva they produce, especially during the night, as well as of choking sensations.[3,10]

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