Protease Inhibitors
Antiretroviral drugs are classified by the viral life cycle they inhibit and, in some cases, by their chemical structure. There are currently five classes of antiretroviral drugs: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse
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Antiretroviral drugs are classified by the viral life cycle they inhibit and, in some cases, by their chemical structure. There are currently five classes of antiretroviral drugs: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), integrase inhibitors, and entry inhibitors. Although grouped in classes, these medications have unique side effect profiles, drug–drug interactions, and potency. All currently recommended treatment regiments consist of a backbone of two NRTIs and a third antiretroviral drug, typically a NNRTI, a ritonavir-boosted protease inhibitor, or an integrase inhibitor. It is important for care providers of HIV-infected patients with psychiatric or substance abuse disorders to recognize the potential interactions between psychotropic and antiretroviral medications, especially with respect to protease inhibitors. All protease inhibitors are metabolized by the cytochrome P450 (CYP) system and possess enzyme-inhibiting or enzyme-inducing properties. Cytochrome P450 enzymes are responsible for drug metabolism and bioactivation of various substrates, including many psychotropic medications. Drugs that interact with the CYP system usually do so in one of three ways—by acting as a substrate, through inhibition, or through induction. A drug can at the same time be a substrate for and induce or inhibit one or more CYP enzymes. Enzyme inhibition usually involves competition with another drug for the enzyme binding site. Enzyme induction occurs when a drug stimulates the synthesis of more enzyme protein, enhancing the enzyme’s metabolizing capacity. Individuals may also exhibit genetic polymorphisms which result in varying levels of activity for specific enzymes, and therefore altered levels of drug metabolism. Inhibition of CYP metabolic pathways by ritonavir, a protease inhibitor, forms the basis for its use with other “boosted” protease inhibitors. Ritonavir is a potent inhibitor of CYP3A4, the enzyme primarily involved in the metabolism of most T. Wagner (*) University Hospitals Case Medical Center, Cleveland, OH, USA e-mail: [email protected] S. Loue (ed.), Mental Health Practitioner’s Guide to HIV/AIDS, 337 DOI 10.1007/978-1-4614-5283-6_69, # Springer Science+Business Media New York 2013
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protease inhibitors. Ritonavir’s inhibition of the CYP3A4 enzyme reduces the metabolism of a concomitantly administered protease inhibitor, resulting in increased bioavailability and penetration of the boosted-protease inhibitor, despite reduced doses and less frequent administration. Although the drug interaction involving ritonavir has proven beneficial in antiretroviral therapy regiments with respect to boosted-protease inhibitors, other potential CYP interactions may lead to toxicity or failure. Numerous medications used to treat individuals with psychiatric and substance abuse disorders interact with the CYP system and are at risk for drug interaction. Although the clinical significance of such interactions is no
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