Drugdrug Interactions Pharmacodynamic Interactions

Pharmacodynamic interactions are those in which the action of one drug affects the action of the other. More commonly, the effects of the two drugs are additive and result in an adverse event. Perhaps the best example is the interaction of the tricyclics with MAOI drugs. The most dangerous sequence is to give a large dose of a tricyclic to a patient who is already taking an MAOI. This can result in a sudden increase in catecholamines and a potentially fatal hypertensive reaction. These two compounds have been used together to treat patients with refractory depression (Goldberg and Thornton 1978; Schuckit et al. 1971). Treatment is begun with lower doses, and either the two compounds are started together or the tricyclic is started first. Once begun, coadministration may actually reduce the risk of tyramine reactions (Pare et al. 1985); however, because the protective effect is variable and unpredictable, the usual MAOI diet is maintained.

Perhaps the most common pharmacodynamic interaction is when two psychotropic drugs are added together, resulting in increased sedation. This interaction might occur when tricyclics are combined with antipsychotic agents or with benzodiazepines. Other pharmacodynamic interactions can occur. By blocking the transporters, the tricyclics block the uptake and thus interfere with the action of guanethidine. Desipramine and the other tricyclics reduce the effect of clonidine.

Quinidine is an example of a drug with a potential dynamic and kinetic interaction with tricyclics. Because the tricyclics have quinidine-like effects, the effects of tricyclics and quinidine on cardiac conduction are potentially additive. In addition, quinidine is a potent CYP2D6 isoenzyme inhibitor that can raise tricyclic levels, further adding to the problem.

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