Tricyclic antidepressants metabolic pathways

The 2D6 enzyme is the final common pathway for the metabolism of tricyclic antidepressants. May increase levels of substrates. 

Antacids reduce the absorption and enzyme-inducing drugs may decrease serum levels. Cimetidine and propranolol both increase serum levels. There can be competition for metabolic pathways by some tricyclic antidepressants (TCAs) and SSRIs (especially fluoxetine) which may increase serum levels. 

Differences in biotransformation capacities have been identified for at least two distinct groups poor metabolizers and extensive metabolizers. Poor metabolizers demonstrate a deficiency in one or more pathways of the cytochrome P/450 enzyme system. Since the metabolism of antidepressants and neuroleptics depends on this system (see appendix A), poor metabolizers may be at risk for complications of therapy. For certain tricyclic antidepressants and neuroleptics, it has been established that these individuals will demonstrate increased serum levels and exaggerated medication response. Additionally, they wiU be more susceptible to side effects. Although data is limited on the SSRIs, similar patterns are evident. 

Some drugs are competitive inhibitors of nonmicrosomal metabolic pathways. Serious reactions have been reported in patients treated with an MAO inhibitor, such as trancypromine or iproniazid, because they usually are sensitive to a subsequent dose of a sympathomimetic amine (e.g., amphetamine) or a tricyclic antidepressant (e.g., amitriptyline), which is metabolized by MAO. 

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