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HIV and Psychiatric Medication Interactions Karina K. Uldall, MD, MPH April 2003 HIV/AIDS Research Program Department of Psychiatry UW School of Medicine Seattle, WA April 2003 ANTIRETROVIRALS • Non-Nucleoside Reverse Transcriptase Inhibitors – Nevirapine, Efavirenz, Delavirdine • Nucleoside Analogues – Tenofovir, Abacavir, Lamivudine, Zidovudine, Stavudine, Zalcitabine, Didanosine • Protease Inhibitors – Lopinavir, Ritonavir, Indinavir, Saquinavir, Nelfinavir, Amprenavir • Fusion Inhibitors – T-20, T-1249 April 2003 LIVER • weakens substances that could be harmful to the body via oxidation; substances are then excreted through the kidneys • attaches substances to proteins via conjugation; substances are then eliminated through the bowels or kidneys April 2003 DRUG METABOLISM • Cytochrome P450 system • Affected by – age - hormones – nutrition - drug half life – stress - drug dosages – hepatic blood flow – liver disease April 2003 CYTOCHROME P450 • Collection of liver enzymes • Classified into families (isoenzymes) • Further classified into subfamilies and genes • For example, P450 2D6 or CYP 2D6 – CYP root or super family – 2 family - D subfamily April 2003 - 6 gene CYTOCHROME P450 • Substrate – any drug metabolized by P450 enzymes • Inhibitor – any drug that inhibits the metabolism of a P450 substrate (strong, moderate, weak) • Inducer – anything that increases the amount of P450 enzymes (strong, moderate, weak) April 2003 P450 COMBINATIONS • Inhibitor + Substrate – higher levels of substrate • Inducer + Substrate – lower levels of substrate • Inhibitor + Inducer – normal, higher or lower levels of each • Inhibitor + Inhibitor – high levels of one or both April 2003 P450 VARIATIONS • Some people have more than normal amounts of certain P450 enzymes (ultrarapid metabolizers) • Some people have normal amounts (extensive metabolizers) • Some people have less than normal amounts (poor metabolizers) April 2003 CYP 3A • Substrates – – – – – – – – April 2003 alprazolam midazolam carbamazepine sertraline haloperidol TCAs thiothixene zolpidem – – – – – – – – trazadone heroin morphine triazolam diazepam ritonavir Efavirenz methadone CYP 3A • Inhibitors – potent • • • • • nefazadone fluvoxamine cannabis grapefruit juice ritonavir/saquinavir – moderate • • • • • • • fluoxetine paroxetine sertraline TCAs indinavir/nelfinavir efavirenz amprenavir – weak • venlafaxine • mirtazapine April 2003 CYP 3A • Inducers – – – – April 2003 phenobarbital carbamazepine alcohol efavirenz CYP 2D6 • Substrates – – – – – – – – April 2003 carbamazepine mirtazapine codeine risperidone fluoxetine TCAs trazadone haloperidol – – – – – – – – – – morphine amphetamine ecstasy meperidine droperidol phenothiazines cannabis paroxetine venlafaxine nicotine CYP 2D6 • Inhibitors – potent • • • • fluoxetine paroxetine methadone ritonavir – moderate • • • • April 2003 desipramine nortriptyline bupropion sertraline – weak • efavirenz • Inducers – phenobarbital – carbamazepine CYP 1A2 • Substrates – – – – – – – – April 2003 caffeine mirtazapine clozapine haloperidol phenothiazines imipramine amitriptyline clomipramine – – – – doxepin benzodiazepines olanzapine thiothixene CYP 1A2 • Inhibitors – weak – potent • • • • • fluvoxamine • ritonavir – moderate • grapefruit juice • TCAs nefazadone mirtazapine olanzapine fluoxetine • Inducers – cigarette smoke – cabbage – charcoal grilled foods April 2003 CYP 2B6 • Substrates – – – – April 2003 bupropion diazepam temazepam nicotine • Inducers – carbamazepine – phenobarbital CYP 2C • Substrates – – – – – – – – April 2003 diazepam amitriptyline clomipramine doxepin imipramine cannabis PCP efavirenz • Inhibitors – potent • fluvoxamine (9.19) • fluoxetine (9) • ritonavir – moderate • • • • paroxetine sertraline (19) fluoxetine (19) efavirenz CYP 2C • Inhibitors – weak • venlafaxine • nefazodone April 2003 • Inducers – rifampin – rifabutin DRUG INTERACTIONS • Many drug interactions with ARVs (especially with protease inhibitors) • Cytochrome P450 mechanism – metabolism through liver pathway – some drugs inhibit and some stimulate enzyme production – the effect of some drugs is increased, for others is decreased April 2003 ANTIRETROVIRALS • P450 Substrates – all protease inhibitors – indinavir, squinavir, ritonavir, nelfinavir, amprenavir • P450 Inhibitors - reversible – strong - ritonavir – moderate - indinavir, nelfinavir – weak - saquinavir April 2003 ANTIRETROVIRALS • P450 Inducers - lasts for several days – moderate - ritonavir, nelfinavir, nevirapine April 2003 PSYCHIATRIC MEDICATIONS • P450 Substrates – many psychiatric medications are metabolized through the liver • P450 Inhibitors – strong - fluoxetine, fluvoxamine – moderate - paroxetine, sertraline, TCAs – weak - venlafaxine, mirtazapine April 2003 PSYCHIATRIC MEDICATIONS • p450 Inducers – nicotine/cigarette smoke – carbamazepine – alcohol April 2003 SUMMARY • Fewer medications and lower doses are worthy goals • If someone has symptoms, always think of drug interactions • Keep up to date on each client’s med list (and substance use) • Consider diet/lifestyle and medication interactions April 2003 SUMMARY • Consult with a local pharmacist • Call the AETC/HRSA warmline: – (800) 933-3413 • Use the Internet: – www.aidsmeds.com – www.hivinsite.ucsf.edu/InSite.jsp?page=ar-00-00 – www.medscape.com/druginfo April 2003
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