Decreased tyramine sensitivity after discontinuation of amitriptyline therapy. An index of pharmacodynamic half-life.

A combined pharmacodynamic and pharmacokinetic approach was made to study the pharmacodynamic half-life (Pd1/2) of amitriptyline (AT). Six depressed patients were treated with 150 mg of amitriptyline as a single oral dose at night for six or more weeks. Decreased tyramine sensitivity (DTS), an index of this drug's pharmacological activity, was determined serially at various intervals after the last dose. Plasma concentrations of AT and nortriptyline (NT) were also estimated at above intervals. It was possible to detect DTS for 228-300 h after the last oral dose and the mean Pd1/2 of this decline of pharmacodynamic effect was observed to be 135 h. However, no measurable amount of AT or NT was present after 84 h and the mean elimination plasma half-life (t1/2) of AT and NT were 37.7 and 38.9 h, respectively. (In this study, pharmacokinetic parameters of NT were directly related with those of AT.) Prolonged pharmacodynamic effect of this drug after discontinuation should be borne in mind in order to avoid drug interactions and autonomic complications, especially after overdosage. Pd1/2, as assessed by DTS, correlated directly with the t1/2 (r = 0.91) and inversely with the plasma clearance rate (r = 0.60) of NT. DTS test can be used as an alternative technique to assess the biological activity of a drug which inhibits noradrenaline reuptake mechanism and/or blocks alpha-adrenoceptors at the peripheral neuronal sites, especially, where facilities to measure plasma concentrations of such drugs are limited.