Pharmacokinetic aspects of TCAs

All TCAs are fairly well absorbed following oral administration. Although it is recommended that TCAs are administered in divided doses initially, their relatively long half-lives (12-20 hours) and relatively wide dose range (50-300 mg) mean that a once daily dose at night is often preferred. However, it must be remembered that, due to the structure of the drugs, the higher therapeutic doses have potent anticholinergic effects which lead to a reduction in gastrointestinal tract activity and gastric emptying. As a consequence, the absorption of the antidepressant is impeded, as is that of any drug given concurrently. The plasma concentration of most TCAs reaches a peak 2-8 hours after oral administration and once absorbed the drugs are widely distributed. As these drugs are highly protein bound, and also bind to tissue proteins, they have a high apparent volume of distribution. This implies that plasma drug monitoring to ensure optimal therapeutic response is of questionable value, even though it is often recommended that the most satisfactory antidepressant response occurs in the plasma concentration range of 50-300 ng/ml, toxic effects becoming apparent when the drug concentration reaches 0.5-1.0 mg/ml.

The metabolism and elimination of TCAs takes several days to occur, the elimination half-life ranging from 20 hours for amitriptyline to 80 hours for protriptyline. The half-life values for the desmethylated metabolites such as desmethylimipramine and nortriptyline are approximately twice those of the parent compounds imipramine and amitriptyline. It is also well established that the half-life values of the TCAs are considerably greater in the elderly, which predisposes such patients to a greater possibility of severe side effects.

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