drug interactions

BYLWASAMPIJJA BAKER

([email protected])

DRUG INTERACTIONS

17/09/2009

Learning Objectives Identify primary drug interaction concepts Describe types and mechanisms of

interactions Identify drug interactions commonly

encountered with antiretroviral drugs Describe how to manage known

interactions

Definition: The pharmacological result, either desirable

or undesirable, of drugs interacting with themselves or with other endogenous chemical agents, components of the diet, or with chemicals used in or resulting from diagnostic tests.

Case Study: Lake

Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on therapy, presents to the clinic to get more medication to treat his thrushHe has been taking his brother’s medication, which seemed to help at first and then stopped working. He would like to get some more to clear the white plaques on his tongue

Case Study: Lake (2)Oral Thrush

Case Study: Lake (3)

His current ARV regimen is:Nevirapine 200 mg bidZidovudine 300 mg bidLamivudine 150 mg bid

He has one pill of his brother’s medication left. The physician brings it to the pharmacy to determine what medication it is. The tablet is identified as ketoconazole 200 mg

Case Study: Lake (4)

Is this an appropriate medication to use with his current ARV regimen?

What are some counseling points for this patient?

Beware A drug interaction can occur whenever a:

New medication is started Medication is discontinued Dose is changed Drug is changed

Remember: Inducing interactions

Gradual onset/offset Inhibiting interactions

Quick onset/offset

Mechanisms for Drug Interactions Pharmacokinetic Interactions

Altered drug absorption and tissue distribution Chelation, pH, efflux proteins or drug transporters)

Altered drug metabolism Induction/inhibition

Reduced renal excretion Altered intracellular activation

Impairment of phosphorylation (D4T, ZDV) The outcome of these interactions could be

additive/synergistic, antagonistic/opposing or potentiation

Mechanisms for Drug Interactions (2) Pharmacodynamic interactions

Additive or synergistic interactions Antagonistic or opposing interactions

Recognize that metabolism can occur in the intestines, liver or blood

Route of orally administered drugs: Absorbed in the gastrointestinal tract Then pass through the portal venous system to the

liver where they are exposed to first pass effect, which may limit systemic circulation

Once in the systemic circulation, drugs interact with receptors in target tissues

First Pass Effect

Cytochrome P450 (CYP450)Substrate

Medication depends on enzymatic pathway(s) for metabolismObject drug which is affected by inducer or inhibitor

InducerSpeeds up metabolismDecreases substrate level (lack of efficacy is concern)Gradual onset/offset

InhibitorSlows metabolismIncreases substrate level (toxicity is concern)Quick onset/offset

Cytochrome P450 Enzymes

Outcome of Drug

Interaction

Variability

Patient Factors Drug Factors

•Genetics

•Diseases

•Diet/Nutrition

•Environment

•Smoking

•Alcohol

•Dose

•Duration

•Dosing Times

•Sequence

•Route

•Dosage Form

CYP 3A4Substrates-Calcium channel blockers, Carbamazepine, Corticosteroids,Digoxin,Cyclosporine,Methadone, Protease inhibitors, Amitriptyline, Quinidine,Many, many more

Inhibitors-Erythro-, > clarithromycin,

Efavirenz,Grape

fruit juice,

Keto-, itra- > fluconazole,PIs: ritonavir >>> amprenavir, atazanavir, indinavir, nelfinavir > saquinavir

Inducers-Carbamazepine, phenytoin, phenobarbitalRifampin, rifabutin, St. John’s wort, garlicEfavirenz, nevirapine

CYP 2C9/19 Substrates

Diazepam NSAIDs Phenobarbital Phenytoin Tolbutamide S-warfarin Sertaline

Inhibitors Ritonavir Delavirdine Efavirenz Cimetidine Fluoxetine Fluvoxamine Omeprazole TMP/SMX

Inducers Rifampin Carbamazepine Phenobarbital

CYP 2D6:SubstratesAmphetaminesCodeine-to-morphine Haloperidol Hydrocodone-to-morphine.Metoprolol, propranololPhenothiazines RisperidoneTCAs(amitriptyline)

InhibitorsRitonavirCimetidineFluoxetineHaloperidolParoxetineQuinidineMethadone

Interactions among HIV drugsitself: NRTIs

Most important are 2 types of interactions:• Do not combine 2 NRTIs that require sameenzymes for intracellular phosphorylation:– d4T + AZT– ddC, FTC, 3TC• Do not combine TDF with ddI– Increased ddI toxicity– Loss of immunological response

NNRTIs are inducers of CYP3A• PIs are substrates of CYP3A• When combining NNRTIs with PIs, usuallythe dose of the PI is increased, forexample:– LPV/r 533/133 (4 caps) BID + EFV, or– LPV/r 600/150 (3 tabs) BID + EFV

Interactions among HIV drugsitself: NRTIs…

Red Flags for Potential Interactions PIs or NNRTIs and

Ergot alkaloids Azole antifungals Antihistamines Anticonvulsants Anti-tuberculars (rifamycins) Warfarin

Benzodiazepines

Cardiac medicine Amiodarone, quinidine

Oral contraceptives Containing estradiol

Macrolide antibiotics Methadone

PI/ NNRTI/ Antidepressant Drug Interactions

Antidepressant Potential for Interaction

Effects Management

Amitriptyline ritonavir, lopinavir/r,

amprenavir,

Levels of amitriptyline may be increased

Start with lower dose (50%) of amitriptyline, adjust dose when addIng ritonavir. Monitor for side effects

Fluoxetine

ritonavir, lopinavir/r, all other PIs, efavirenz

Levels of both fluoxetine and

ARVs may be increased

As above

Sertraline ritonavir, lopinavir/r, all other Pis, efavirenz

Levels of sertraline may be increased. ARV levels

not likely to change.

As above

Metabolic Characteristics of ARVs

NNRTIs: Do NOT Co-administer Ergot derivatives (ergotamine) Benzodiazepine: midazolam, triazolam Rifampicin (Nevirapine) – unless there is NO

alternative Terfenadine (Efavirenz) Herbal – St. Johns wort

Food-Drug InteractionsA food-drug interaction can occur when the food you eat affects the ingredients in a medication you are taking, preventing the medicine from working the way it should. Food-drug interactions can happen with both prescription and over-the-counter medications, including antacids, vitamins, and iron pills.

Food-Drug Interactions…Points to note-Advise patients to take medication with a full glass of water.-Not stir medication into food or take capsules apart (unless directed by your physician). -Do not take vitamin pills at the same time you take medication (i.e, take medication 1 hour after taking vitamins).-Not mix medication into hot drinks, because the heat from the drink may destroy the effectiveness of the drug.-Never take medication with alcoholic drinks.-Ask the patient about all medications they are taking, both prescription and non-prescription.

Antiretroviral/Food Interactions Take with food: Lopinavir (capsules or

solution): 50-130%

Avoid food: ddI: 47% with meal Efavirenz: 79% high fat meal

increases toxicity Rifampin: food may levels Isoniazid

Avoid Antacids PIs

Indinavir (fos)amprenavir Amprenavir Atazanavir

Ketoconazole

Fluoroquinolones Isoniazid Dapsone Zalcitabine Delavirdine

Drug Interaction Case Studies

Case I

Case Study: EndalkEndalk is 45 year-old HIV+ male presenting for routine follow-up. He has been on HAART for two years. CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL. He comes into the pharmacy after seeing a physician for his migraines. He is glad to try a new medication as his headaches have been a problem for years. He is so distraught about them that he has begun to take an herbal product to help with his mood

Case Study: Endalk (2)

His current medication regimen, which is:Nevirapine 200 mg bidLamivudine 150mg bidZidovudine 300 mg bidAn herbal medicine when he feels “down”

New medications prescribed today: Ergotamine + caffeine

Case Study: Endalk (3)

Which of the following combinations represents a potential drug-drug interaction?

A. Nevirapine and herbal medicine

B. Zidovudine and ergotamine

C. Ergotamine and nevirapine

D. Caffeine and zidovudine

Case Study II: Sara

Sara is a 41 year-old female with esophageal candida and has just completed a 10 day course of fluconazole. She has lost weight because symptoms of thrush made it difficult to swallow. She weighs 62 kg. She is to begin ARV therapy today.

Case Study: Sara (2) She presents with the following

prescription: Zidovudine 300 mg bid Stavudine 40 mg bid Nevirapine 200 mg once daily for the first 2

weeks, then increase to 200 mg bid Cotrimoxazole DS, 1 tablet daily

1. Is this an appropriate regimen for her? Can you identify any possible drug interactions

Case Study: Lake

Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on therapy, presents to the clinic to get more medication to treat his thrushHe has been taking his brother’s medication, which seemed to help at first and then stopped working. He would like to get some more to clear the white plaques on his tongue

Case Study: Lake (2)Oral Thrush

Case Study: Lake (3)

His current ARV regimen is:Nevirapine 200 mg bidZidovudine 300 mg bidLamivudine 150 mg bid

He has one pill of his brother’s medication left. The physician brings it to the pharmacy to determine what medication it is. The tablet is identified as ketoconazole 200 mg

Case Study: Lake (4)

Is this an appropriate medication to use with his current ARV regimen?

What are some counseling points for this patient?