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DRUG INTERACTIONS
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1. BY LWASAMPIJJA BAKER ([email protected]) 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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