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Pharmacology: Pharmacodynamics: Mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that Mirtazapine acts as an antagonist at central presynaptic α 2 adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity.
Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors and has no significant affinity for the 5-HT1A & 5-HT1B receptors. Mirtazapine is a potent antagonist of histamine (H1) receptors (prominent sedative effects), moderate peripheral α1 adrenergic antagonist (occasional orthostatic hypotension reported in association with its use) and as a moderate antagonist at muscarinic receptors (relatively low incidence of anticholinergic side effects associated with its use).
Pharmacokinetics: Mirtazapine is rapidly and completely absorbed following oral administration and has a half-life of about 20 to 40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL and is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro, data from human liver microsomes indicate the cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of Mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. Elimination is predominantly via urine (75%) with 15% in feces. Several unconjugated metabolite possess pharmacological activity but are present in the plasma at very low levels. The (-) enantiomer has an elimination half life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times high as that of the (+) enantiomer.
