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How to explain the Clozapine-induced sialorrhea?

Paper i proceeding
Författare Jörgen Ekström
Tania Godoy
Riva A
Publicerad i International Symposium on Morphological Sciences;Taotmina-Messina;18-22 september 2010
Sidor 24
Publiceringsår 2010
Publicerad vid Institutionen för neurovetenskap och fysiologi
Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi
Sidor 24
Språk en
Ämnesord amisulpride;clozapine;N-desmethylclozapine;sialorrhoea
Ämneskategorier Fysiologi, Fysiologi

Sammanfattning

About one-third of the schizophrenic patients receiving clozapine-therapy complain of hypersalivation, which is particularly troublesome during the night, and which may lead to discontinuation of the treatment. Objective measurements of the salivary flow are few, and data are, in fact inconsistent. The reported hypersalivation has, by some authors, even been attributed to a dysfunctional swallowing reflex. Animal experiments on the in vivo salivary effect of clozapine have been lacking until recently. We have established, using the anaesthetized rat as model, that clozapine, indeed, causes secretion from parotid and submandibular glands. The effect is small and "direct", indepentent of central nervous mechanisms, pre-synaptic intraglandular events and circulating catecholamines. It is exerted via muscarinic-M1-receptors, since it is abolished by pirenzepine. Clozapine exerts dual effects, since it inhibits secretion mediated via muscarinic-M3-receptors and α-adrenergic receptors and consequently, reduces both parasympathetic and sympathetic nerve evoked secretion. A main metabolite of clozapine is N-desmethylclozapine. Compared to its parent compound, we found this drug to exert stronger agonistic action via muscarinic M1-receptors and weaker antagonistic actions via M3-receptors and α-adrenergic receptors. Theoretically, N-desmethylclozapine adds its excitatory effect to that of clozapine. Moreover, the secretory response to the two drugs are gradually enhanced in surgically denervated glands. Thus theoretically, chronic blockade of M3- and α-receptors sensitizes the muscarinic-M1-receptors to clozapine and its metabolite as consequence of the prolonged pharmacological denervation. To conclude, during sleep the excitatory action of clozapine and N-desmethylclozapine will dominate, while during a meal, under reflex secretion, their inhibitory action is likely to dominate.

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