Merasal Mechanism of Action

Pharmacotherapeutic group: Antidepressants. ATC code: N06AX11.
Pharmacology: Pharmacodynamics: Mirtazapine is a presynaptic alpha₂-antagonist, which increases noradrenergic and serotonergic neurotransmission in the central nervous system. The serotonergic effect is a result of a specific action on the 5-HT₁-receptors, since mirtazapine blocks both the 5-HT₂- and the 5-HT₃-receptors. Both enantiomers of mirtazapine are active agents.
The S(+) enantiomer blocks alpha₂- and 5-HT₂-receptors, whereas the R(-) enantiomer blocks 5-HT₃-receptors. The H₁-antagonistic effect is considered to the cause of the sedative effect of mirtazapine. The anticholinergic effect of mirtazapine is minimal and within therapeutic doses there are seldom clinically significant cardiovascular adverse events.
Mirtazapine is an antidepressant, which can be used to treat the episodes of major depression. The presence of symptoms such as anhedonia, psychomotor inhibition, sleep disturbances (early wakening) and weight loss, increase the chance of a positive response. Other symptoms are: loss of interest, suicidal thoughts and changes in mood (better in the evening than in the morning). Mirtazapine begins to exert its effect in general after 1 to 2 weeks of treatment.
Paediatric population: Two randomised, double-blind, placebo-controlled trials in children aged between 7 and 18 years with major depressive disorder (n=259) using a flexible dose for the first 4 weeks (15-45mg mirtazapine) followed by a fixed dose (15, 30 or 45 mg mirtazapine) for another 4 weeks failed to demonstrate significant differences between mirtazapine and placebo on the primary and all secondary endpoints. Significant weight gain (≥7%) was observed in 48.8% of the Remeron treated subjects compared to 5.7% in the placebo arm. Urticaria (11.8% vs 6.8%) and hypertriglyceridaemia (2.9% vs 0%) were also commonly observed.
Pharmacokinetics: Absorption: After oral administration of mirtazapine tablets, the active substance mirtazapine is rapidly and well absorbed (bioavailability about 50%), reaching peak plasma levels after about 2 hours. Food intake has no influence on the pharmacokinetics of mirtazapine.
Distribution: About 85% of mirtazapine is bound to plasma proteins. Steady state concentrations are reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range.
Metabolism and elimination: The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded but in young men the half-lives have been shorter.
Mirtazapine is metabolized effectively and eliminated in urine and faeces over a few days. Biotransformation mainly occurs through demethylation and oxidation and subsequent conjugation. In vitro studies of human liver microsomes show that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the mirtazapine 8-hydroxy metabolite, whereas the CYP3A4 enzyme is assumed to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active, and its pharmacokinetic profile is similar to that of non-metabolized drug.
Special patient populations: The clearance of mirtazapine may be decreased in patients with renal or hepatic insufficiency.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity, genotoxicity or reproductive toxicity.
Mirtazapine induced no effects of clinical relevance in chronic safety studies in rats or dogs and reproductive toxicity studies in rats or rabbits. In reproductive toxicity studies in rats and rabbits at high dose levels, 20 and 17 times the maximum human dose at mg/m² basis, respectively, no teratogenic effects were observed. There were, however, increase in post-implantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation. Mirtazapine was not genotoxic in a series of tests for gene mutation and chromosomal and DNA damage. Thyroid gland tumours found in a rat carcinogenicity study and hepatocellular neoplasms found in a mouse carcinogenicity study are considered to be species-specific, non-genotoxic responses associated with long-term treatment with high doses of hepatic enzyme inducers.