april 2003 hiv and psychiatric medication interactions karina k. uldall, md, mph

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