The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceCYP2D6 inhibition by SSRIs when coadministered with opiate drugs such as codeine andhydrocodone results in lack of conversion to active form and a significant decrease in narcoticefficacy, and should be avoided. 426 picasAs a general rule, two underlying mechanisms cause clinically significant drug interactions amongthese groups. One involves the alteration of the hepatic metabolism of some psychotropic agents,leading to an increase or decrease of their therapeutic effect or causing an increase in theiradverse effects. The other involves psychotropic agents that increase the adverse effects or limitthe efficacy of protease inhibitors. Most of the currently available, newer antidepressant agentsare substrates for cytochrome P450 enzyme system isoenzymes.Substrates can simply be described as substances that are amenable to the action of enzymes inthis cytochrome P450 enzyme system of the liver. A drug or chemical substance can have any oneof three relationships to the CYP450 enzyme system; it can be a substrate, an inducer, or aninhibitor. Inhibitors of the CYP system are medications or chemical substances, including herbalremedies, which may cause a decrease in the volume of enzymes produced by this system reducingthe metabolism of such drugs and thereby increasing their levels.This is the basis for the use of ritonavir as a PI enhancer in dual protease regimens. The SSRIs,for instance, and nefazodone are inhibitors of many CYP450 isoenzymes. When such agents areadministered concomitantly with other agents—such as the PIs, the NNRTIs, or othernonantiretroviral agents which may also be substrates, inducers or inhibitors of these enzymes—drug accumulation can occur, leading to potentially dangerous and sometimes unpredictabletoxicities. Inhibitors of the CYP450 enzymes such as the azole antifungals, namely ketoconazole,itraconazole and to a much lesser extent fluconazole (hence making it the most desirable in HIVdisease) and erythromycin will cause a decrease in the clearance of such drugs as citalopram(Celexa), terfenadine, midazolam (Versed), and triazolam (Halcion) (specifically mentioned inthe February 2001 DHHS Guidelines for Treatment of HIV in Adults and Adolescents), leading tocardiac arrhythmias and sudden and unexplained deaths.XXVIIU.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau 559