Duloxpra Mechanism of Action

Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.
Pharmacology: Pharmacodynamics: Mechanism of action: Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake, with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. It was reported that duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas.
Pharmacokinetics: Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation.
Absorption: Duloxetine is well absorbed after oral administration, with a C_max occurring 6 hours post-dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80%. Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption.
Distribution: Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha1-acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.
Metabolism: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites, glucuronide conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy, 6-methoxy duloxetine. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of duloxetine are higher in these patients.
Elimination: The elimination half-life of duloxetine ranges from 8 to 17 hours. After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr.
Special Populations: Gender: Pharmacokinetic differences have been identified between males and females. However, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients.
Age: Pharmacokinetic differences have been identified between younger and elderly females (≥65 years), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly.
Renal impairment: Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment.
Hepatic impairment: Moderate liver disease (Child-Pugh Class B) affected the pharmacokinetics of duloxetine. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.
Breast-feeding mothers: Lactation did not influence duloxetine pharmacokinetics.
Paediatric population: The model-predicted duloxetine steady-state plasma concentrations in paediatric patients were mostly within the concentration range observed in adult patients.