DRUG INTERACTIONS

Transcript

1. BY LWASAMPIJJA BAKER (bubakes2000@gmail.com) DRUG INTERACTIONS 17/09/2009

2. Learning Objectives o Identify primary drug interaction concepts o Describe types and mechanisms of interactions

o Identify drug interactions commonly encountered with antiretroviral drugs o Describe how to manage known interactions

3. Definition: o 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. 4. 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 thrush He 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

5. Case Study: Lake (2) Oral Thrush 6. Case Study: Lake (3)

o His current ARV regimen is: Nevirapine 200 mg bid Zidovudine 300 mg bid

Lamivudine 150 mg bid o 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

7. Case Study: Lake (4) Is this an appropriate medication to use with his current ARV

regimen? What are some counseling points for this patient? 8. Beware

o A drug interaction can occur whenever a: New medication is started Medication is discontinued

Dose is changed Drug is changed

o Remember: Inducing interactions

Gradual onset/offset

Inhibiting interactions Quick onset/offset

9. 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 10. Mechanisms for Drug Interactions (2)

Pharmacodynamic interactions Additive or synergistic interactions Antagonistic or opposing interactions

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

o 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

12. Cytochrome P450 (CYP450) o Substrate

Medication depends on enzymatic pathway(s) for metabolism

Object drug which is affected by inducer or inhibitor o Inducer

Speeds up metabolism Decreases substrate level (lack of efficacy is concern) Gradual onset/offset

o Inhibitor Slows metabolism

Increases substrate level (toxicity is concern) Quick onset/offset

13. Cytochrome P450 Enzymes Outcome of Drug Interaction Variability Patient Factors

Drug Factors o Genetics

o Diseases o Diet/Nutrition o Environment

o Smoking o Alcohol

o Dose o Duration o Dosing Times

o Sequence o Route

o Dosage Form 14. CYP 3A4 Substrates -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 o Inducers-

Carbamazepine, phenytoin, phenobarbital Rifampin, rifabutin, St. John’s wort, garlic

Efavirenz, nevirapine 15. CYP 2C9/19

o Substrates Diazepam NSAIDs

Phenobarbital Phenytoin

Tolbutamide S-warfarin Sertaline

o Inhibitors Ritonavir

Delavirdine Efavirenz Cimetidine

Fluoxetine Fluvoxamine

Omeprazole TMP/SMX

o Inducers

Rifampin Carbamazepine

Phenobarbital 16. CYP 2D6: Substrates Amphetamines Codeine-to-morphine Haloperidol

Hydrocodone-to-morphine. Metoprolol, propranolol Phenothiazines Risperidone

TCAs(amitriptyline) Inhibitors Ritonavir Cimetidine Fluoxetine Haloperidol Paroxetine Quinidine Methadone

17. Interactions among HIV drugs itself: NRTIs Most important are 2 types of interactions: • Do not combine 2 NRTIs that require same enzymes for intracellular phosphorylation: – d4T + AZT – ddC, FTC, 3TC • Do not combine TDF with ddI –

Increased ddI toxicity – Loss of immunological response 18. Interactions among HIV drugs itself: NRTIs… NNRTIs are inducers of CYP3A • PIs

are substrates of CYP3A • When combining NNRTIs with PIs, usually the dose of the PI

is increased, for example: – LPV/r 533/133 (4 caps) BID + EFV, or – LPV/r 600/150 (3 tabs) BID + EFV

19. Red Flags for Potential Interactions o 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

20. PI/ NNRTI/ Antidepressant Drug Interactions As above Levels of sertraline may be increased. ARV levels not likely to change. ritonavir, lopinavir/r, all other Pis, efavirenz

Sertraline As above Levels of both fluoxetine and ARVs may be increased ritonavir, lopinavir/r, all other PIs, efavirenz Fluoxetine Start with lower dose (50%) of amitriptyline, adjust dose when addIng ritonavir . Monitor for side effects Levels of

amitriptyline may be increased ritonavir, lopinavir/r, amprenavir, Amitriptyline Management Effects Potential for Interaction Antidepressant

21. Metabolic Characteristics of ARVs 22. NNRTIs: Do NOT Co-administer

o Ergot derivatives (ergotamine)

o Benzodiazepine: midazolam, triazolam o Rifampicin (Nevirapine) – unless there is NO alternative

o Terfenadine (Efavirenz) o Herbal – St. Johns wort

23. Food-Drug Interactions A 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. 24. 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.

25. Antiretroviral/Food Interactions o Take with food:

o Lopinavir (capsules or solution): 50-130% o Avoid food :

o ddI: 47% with meal

o Efavirenz: 79% high fat meal increases toxicity

o Rifampin: food may levels

o Isoniazid 26. Avoid Antacids

o PIs Indinavir (fos)amprenavir

Amprenavir Atazanavir

o Ketoconazole o Fluoroquinolones o Isoniazid

o Dapsone o Zalcitabine

o Delavirdine 27. Drug Interaction Case Studies Case I 28. Case Study: Endalk Endalk 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

29. Case Study: Endalk (2)

o His current medication regimen, which is: Nevirapine 200 mg bid

Lamivudine 150mg bid Zidovudine 300 mg bid An herbal medicine when he feels “down”

o New medications prescribed today: Ergotamine + caffeine 30. Case Study: Endalk (3)

o Which of the following combinations represents a potential drug-drug interaction? Nevirapine and herbal medicine Zidovudine and ergotamine

Ergotamine and nevirapine Caffeine and zidovudine

31. 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. 32. Case Study: Sara (2)

o 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

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

33. 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 thrush He 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

34. Case Study: Lake (2) Oral Thrush

35. Case Study: Lake (3) o His current ARV regimen is:

Nevirapine 200 mg bid Zidovudine 300 mg bid Lamivudine 150 mg bid

o 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 36. Case Study: Lake (4) Is this an appropriate medication to use with his current ARV

regimen? What are some counseling points for this patient?

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