Is it possible that mirtazapine antagonizes the effect of paracetamol the same way as the setrons (

Fråga: Is it possible that mirtazapine antagonizes the effect of paracetamol the same way as the setrons (granisetron and topisetron)?

This is a general question.

Sammanfattning: It is still unclear if the inhibitory effect of granisetron and topisetron on paracetamol effect in healthy subjects was due to 5HT3-antagonism or if there is any other mechanism responsible for this effect. The inhibitory effect of mirtazapine of 5-HT3 is probably lower than the setrons. Hence, it is unclear if mirtazapine would have the same effect on the analgesic effect of paracetamol as topisetron and granisetron.

Svar: Mirtazapine is an adrenergic alpa-2-antagonist used for treatment of depression. It increases the release of norepinephrine by blocking presynaptic alpha-2-adrenoreceptors (1). Mirtazapine may also increase serotonin release (1) but the evidence for this has been questioned (2). Mirtazapine is also a 5-HT2a-, and 5-HT3-antagonist (1).

Paracetamol is an analgesic drug with an unknown mechanism of action. It has been speculated that paracetamol inhibits cyclooxygenase in the central nervous system (3). Several animal studies have implicated that the effect of paracetamol is mediated by serotonin (3,4,5,6,7).

No literature reports of a pharmacokinetic and pharmacodynamic interaction between paracetamol and mirtazapine has been found. There is no theoretical background for any pharmacokinetic interaction.

The effect of the selective 5-HT3-antagonists topisetron and granisetron on the pharmacodynamics and pharmacokinetics of paracetamol have been studied in a randomised, double-blind crossover trial. Twenty-six healthy volunteers were pretreated with intravenous topisetron, granisetron or placebo. A single dose of 1 gram paracetamol was given and the pain severity was measured by using a method based on electric stimulation. The analgesic effect of paracetamol was almost completely inhibited by administration of granisetron and topisetron. No change in the pharmacokinetics of paracetamol was observed (8).

Animal studies investigating the effect of paracetamol on different 5-HT-receptor subtypes have given conflicting results. One thing that has been shown is that paracetamol has no affinity for the 5-HT3 receptor (9). Several animal studies have implicated that the effect of paracetamol may be influenced by 5-HT1-receptors (4,6), other 5-HT2-receptors (5,7), and some suggests an indirect involvement of 5-HT3-receptors (3,4). One animal study suggests that the inhibitory effect of topisetron on paracetamol effect is mediated by another mechanism than inhibition of 5-HT3 (10).

Granisetron and topisetron are both selective for the 5-HT3-receptor and granisetron has Ki (affinity constant for inhibitors) of 0.26 nM (11,12). Mirtazapine is a less potent inhibitor with a Ki of 79 nM (13). Based on the pharmacokinetic profile of the substances, mirtazapine is assumed to inhibit 5-HT3-receptors to a lower extent than granisetron when given at recommended dosage. de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996;57(suppl 4):19-25 Gillman PK. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Hum Psychopharmacol Clin Exp 2006;21:117-25. Pelissier T, Alloui A, Caussade F, Dubray C, Cloarex A, Lavarenne J, Eschalier A. Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytryptamine3 receptors: in vivo and in vitro evidence. J Pharmacol Exp Ther 1996;278:8-14 Sandrini M, Pini LA, Vitale G. Differential involvement of central 5-HT1B and d5-HT3 receptor subtypes in the antinociceptive effect of paracetamol. Inflamm Res 2003;52:347:52. Srikiatkhachorn A, Tarasub N, Govitrapong P. Acetaminophen-induced antinociception via central 5-HT(2A) receptors. Neurochem Int 1999;34:491-8. Roca-Vinardell A, Ortega-Alvaro A, Gibert-Rahola J, Mico JA. The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen. Anesthesiology 2003;98:741-7. Pini LA, Sandrini M, Vitale G. The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol 1996;308:31-40 Pickering G, Loriot M-A, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: First evidence of a central serotonergic mechanism. Clin Pharmacol Ther 2006;79:371-8 Raffa RB, Codd EE. Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays). Life Sci 1996;59:PL37-40 Libert F, Bonnefont J, Bourinet E, Doucet E, Alloui A, Hamon M, Nargeot J, Eschalier A. Acetaminophen: a central analgesic drug that involves a spinal tropisetron-sensitive, non-5-HT3 receptor-mediated effect. Mol Pharmacol 2004;66:728-34 Gan TJ. Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting. CNS Drugs 2005;19:225-38. Blower PR. The role of specific 5-HT3 antagonism in the control of cytostatic drug-induced emesis. Eur J Cancer 1990;26 suppl 1:S8-11 Kooyman AR, Zwart R, Vanderheijden PM, Van Hooft JA, Vijverberg HP. Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells. Neuropharmacology 1994;33:501-7.