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April 2003April 2003
HIV and Psychiatric HIV and Psychiatric Medication InteractionsMedication Interactions
Karina K. Uldall, MD, MPHKarina K. Uldall, MD, MPH
April 2003April 2003
HIV/AIDS Research HIV/AIDS Research ProgramProgram
Department of PsychiatryDepartment of Psychiatry
UW School of MedicineUW School of Medicine
Seattle, WASeattle, WA
April 2003April 2003
ANTIRETROVIRALSANTIRETROVIRALS
• 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 2003April 2003
LIVERLIVER
• 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 2003April 2003
DRUG METABOLISMDRUG METABOLISM
• Cytochrome P450 system
• Affected by– age - hormones– nutrition - drug half life– stress - drug dosages– hepatic blood flow – liver disease
April 2003April 2003
CYTOCHROME P450CYTOCHROME 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 2003April 2003
CYTOCHROME P450CYTOCHROME 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 2003April 2003
P450 COMBINATIONSP450 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 2003April 2003
P450 VARIATIONSP450 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 2003April 2003
CYP 3ACYP 3A
• Substrates– alprazolam– midazolam– carbamazepine– sertraline– haloperidol– TCAs– thiothixene– zolpidem
– trazadone– heroin– morphine– triazolam– diazepam– ritonavir– Efavirenz– methadone
April 2003April 2003
CYP 3ACYP 3A
• Inhibitors– potent
• nefazadone• fluvoxamine• cannabis• grapefruit juice• ritonavir/saquinavir
– moderate• fluoxetine• paroxetine• sertraline• TCAs• indinavir/nelfinavir• efavirenz• amprenavir
– weak• venlafaxine• mirtazapine
April 2003April 2003
CYP 3ACYP 3A
• Inducers– phenobarbital– carbamazepine– alcohol– efavirenz
April 2003April 2003
CYP 2D6CYP 2D6
• Substrates– carbamazepine– mirtazapine– codeine– risperidone– fluoxetine– TCAs– trazadone– haloperidol
– morphine– amphetamine– ecstasy– meperidine– droperidol– phenothiazines– cannabis– paroxetine– venlafaxine– nicotine
April 2003April 2003
CYP 2D6CYP 2D6
• Inhibitors– potent
• fluoxetine• paroxetine• methadone• ritonavir
– moderate• desipramine• nortriptyline• bupropion• sertraline
– weak• efavirenz
• Inducers– phenobarbital– carbamazepine
April 2003April 2003
CYP 1A2CYP 1A2
• Substrates– caffeine– mirtazapine– clozapine– haloperidol– phenothiazines– imipramine– amitriptyline– clomipramine
– doxepin– benzodiazepines– olanzapine– thiothixene
April 2003April 2003
CYP 1A2CYP 1A2
• Inhibitors– potent
• fluvoxamine• ritonavir
– moderate• grapefruit juice• TCAs
– weak• nefazadone• mirtazapine• olanzapine• fluoxetine
• Inducers– cigarette smoke– cabbage– charcoal grilled foods
April 2003April 2003
CYP 2B6CYP 2B6
• Substrates– bupropion– diazepam– temazepam– nicotine
• Inducers– carbamazepine– phenobarbital
April 2003April 2003
CYP 2CCYP 2C
• Substrates– diazepam– amitriptyline– clomipramine– doxepin– imipramine– cannabis– PCP– efavirenz
• Inhibitors– potent
• fluvoxamine (9.19)• fluoxetine (9)• ritonavir
– moderate• paroxetine• sertraline (19)• fluoxetine (19)• efavirenz
April 2003April 2003
CYP 2CCYP 2C
• Inhibitors– weak
• venlafaxine• nefazodone
• Inducers– rifampin– rifabutin
April 2003April 2003
DRUG INTERACTIONSDRUG 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 2003April 2003
ANTIRETROVIRALSANTIRETROVIRALS
• P450 Substrates– all protease inhibitors– indinavir, squinavir, ritonavir, nelfinavir,
amprenavir
• P450 Inhibitors - reversible– strong - ritonavir– moderate - indinavir, nelfinavir– weak - saquinavir
April 2003April 2003
ANTIRETROVIRALSANTIRETROVIRALS
• P450 Inducers - lasts for several days– moderate - ritonavir, nelfinavir, nevirapine
April 2003April 2003
PSYCHIATRIC MEDICATIONSPSYCHIATRIC MEDICATIONS
• P450 Substrates– many psychiatric medications are metabolized
through the liver
• P450 Inhibitors– strong - fluoxetine, fluvoxamine– moderate - paroxetine, sertraline, TCAs– weak - venlafaxine, mirtazapine
April 2003April 2003
PSYCHIATRIC MEDICATIONSPSYCHIATRIC MEDICATIONS
• p450 Inducers– nicotine/cigarette smoke– carbamazepine– alcohol
April 2003April 2003
SUMMARYSUMMARY
• 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 2003April 2003
SUMMARYSUMMARY
• 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