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 - 6 gene April 2003

CYTOCHROME P450 Substrate Inhibitor Inducer 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 Inducer + 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 (ultra-rapid metabolizers) Some people have normal amounts (extensive metabolizers) Some people have less than normal amounts (poor metabolizers) April 2003

CYP 3A Substrates trazadone heroin alprazolam morphine midazolam carbamazepine sertraline haloperidol TCAs thiothixene zolpidem trazadone heroin morphine triazolam diazepam ritonavir Efavirenz methadone April 2003

CYP 3A Inhibitors moderate potent weak fluoxetine paroxetine nefazadone fluvoxamine cannabis grapefruit juice ritonavir/saquinavir moderate fluoxetine paroxetine sertraline TCAs indinavir/nelfinavir efavirenz amprenavir weak venlafaxine mirtazapine April 2003

CYP 3A Inducers phenobarbital carbamazepine alcohol efavirenz April 2003

CYP 2D6 Substrates morphine amphetamine carbamazepine ecstasy mirtazapine codeine risperidone fluoxetine TCAs trazadone haloperidol morphine amphetamine ecstasy meperidine droperidol phenothiazines cannabis paroxetine venlafaxine nicotine April 2003

CYP 2D6 Inhibitors Inducers weak efavirenz potent phenobarbital fluoxetine paroxetine methadone ritonavir moderate desipramine nortriptyline bupropion sertraline weak efavirenz Inducers phenobarbital carbamazepine April 2003

CYP 1A2 Substrates doxepin benzodiazepines caffeine olanzapine mirtazapine clozapine haloperidol phenothiazines imipramine amitriptyline clomipramine doxepin benzodiazepines olanzapine thiothixene April 2003

CYP 1A2 Inhibitors Inducers weak potent moderate cigarette smoke fluvoxamine ritonavir moderate grapefruit juice TCAs weak nefazadone mirtazapine olanzapine fluoxetine Inducers cigarette smoke cabbage charcoal grilled foods April 2003

CYP 2B6 Substrates Inducers bupropion diazepam temazepam nicotine carbamazepine phenobarbital April 2003

CYP 2C Substrates Inhibitors diazepam amitriptyline clomipramine doxepin imipramine cannabis PCP efavirenz Inhibitors potent fluvoxamine (9.19) fluoxetine (9) ritonavir moderate paroxetine sertraline (19) fluoxetine (19) efavirenz April 2003

CYP 2C Inhibitors Inducers weak rifampin rifabutin venlafaxine nefazodone Inducers rifampin rifabutin April 2003

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 P450 Inhibitors - reversible 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