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Conference
"Interactions Among Drugs for HIV and Opportunistic Infections" Dr. Keith Gallicano (biography) English - 2002-04-15 - 30 minutes
Summary : Drug interactions are an important factor in the management and treatment of patients infected with HIV. In addition to their antiretroviral medications, patients may receive drugs for supportive care, opportunistic infections, and immunomodulation, as well as alternative medications obtained outside of their primary provider. Thus, interactions among these agents are often unavoidable. Most of these interactions are metabolic in nature as a result of alterations of cytochrome P450 (CYP) isoenzymes. All of the non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors are metabolized by CYP isoenzymes, and several are inhibitors and/or inducers of CYP. The nucleoside reverse transcriptase inhibitors (NRTI) are primarily eliminated by the kidneys and are not involved in CYP-mediated interactions. The role of membrane proteins that mediate the transcellular transport of drugs is now recognized in clinically significant interactions in infectious diseases. Inhibition and induction of membrane transporters such as P-glycoprotein (P-gp) and multiple-drug resistance-associated protein (MRP) that bind drugs can produce beneficial and detrimental interactions at sites where these transporters are located. For example, penetration of antiretroviral agents into HIV-1 reservoirs such as the central nervous system and male genital tract is important to control HIV penetration and evolution within these sites. Several protease inhibitors are substrates for and inhibitors or inducers of P-gp. Drugs such as ketoconazole increase exposure of ritonavir and saquinavir in cerebrospinal fluid by inhibiting CYP and P-gp at the blood-cerebrospinal fluid barrier. Both CYP and P-pg can present a barrier to the absorption of orally administered drugs and have a considerable effect on drug interactions. Drug interactions are often complex, time-dependent, and multidirectional. In HIV disease, interactions are complicated by their bi- or multi-directional nature, particularly when metabolic inhibitors, such as the protease inhibitors, and inducers, such as the rifamycins, are administered concurrently. Devising suitable dosing regimens for rifabutin in the presences of NNRTI and protease inhibitors has been challenging, especially for antiviral regimens that include ritonavir and lopinavir. Some agents such as ritonavir and some herbal products such as garlic are capable of acting as inhibitors during their initial dosing and as inducers during their extended therapy, which can question the relevance of single or acute dosing studies to multiple dosing conditions. This presentation will review clinically important beneficial and detrimental pharmacokinetic drug interactions in HIV therapy that occur between antiretroviral agents and other medications, and highlight the concerns that physicians have had from estimating the magnitude of drug interactions when inhibitors and inducers are given together, such as in the treatment and prevention of tuberculosis in HIV, or when the interacting drug has time dependent pharmacokinetics.
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