Antidepressants
Modern antidepressants can be divided into several chemical classes. The traditional tri cyclic antidepressants include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin and imipramine. The newer generation of antidepressants include the selective serotonin reup take inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Other antidepressants include the monoamine oxidase inhibitor moclobemide, and other mixed-uptake inhibitors (mirtazapine, nefazodone and venlafaxine).
The tricyclic antidepressants are metabolised by three major pathways: N-oxidation, hydroxyl ation of the alicyclic ring and of the aromatic ring, and N-dealkylation of the dialkylamino group. The last route gives rise to the most important metabolites, since the N-demethylated metabolites are themselves pharmacologic ally active. Amitriptyline is metabolised to nortriptyline, and imipramine to desipramine; both metabolites are also available as therapeutic agents (Fig. 1). When monitoring concentrations of tricyclic antidepressants for their therapeutic effect, it is important to determine both the parent drug and the desalkyl metabolites, as the latter may be present in a significant quantity. These can be summed to provide an estimate of therapeutic activity. The hydroxy metabolites predominate in the urine, and usually occur as glucuronide conjugates. The other classes of antidepressants have varied chemical structures, and hence their fate is very much dependent on the drug concerned (Fig. 2).
Figure 1 Major pathways of dosulepin (dothiepin) metabolism.
Figure 2 Key metabolic pathways for selective serotonin reuptake inhibitors.
