Drug Interactions

DRUG INTERACTIONS BY LWASAMPIJJA BAKER ([email protected]) 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 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

Case Study: Lake (2) Oral Thrush

Case Study: Lake (3) His current ARV regimen is: Nevirapine 200 mg bid Zidovudine 300 mg bid Lamivudine 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

First Pass Effect  

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

Cytochrome P450 (CYP450) Substrate Medication depends on enzymatic pathway(s) for metabolism Object drug which is affected by inducer or inhibitor Inducer Speeds up metabolism Decreases substrate level (lack of efficacy is concern) Gradual onset/offset Inhibitor Slows metabolism Increases substrate level (toxicity is concern) Quick onset/offset

Cytochrome P450 Enzymes Patient Factors

Outcome of Drug Interaction

Drug Factors

•Genetics

•Dose

•Diseases

•Duration

•Diet/Nutrition

•Dosing Times

•Environment

•Sequence

•Smoking

•Route

•Alcohol

Variability

•Dosage Form

CYP 3A4 SubstratesCalcium channel blockers, Carbamazepine, Corticosteroids, Digoxin, Cyclosporine, Methadone, Protease inhibitors, Amitriptyline, Quinidine,Many, many more

InhibitorsInducersErythro-, > Carbamazepine, clarithromycin, phenytoin, phenobarbital Efavirenz,Grape Rifampin, rifabutin, fruit juice, St. John’s wort, Keto-, itra- > garlic fluconazole,PIs: Efavirenz, ritonavir >>> nevirapine amprenavir, atazanavir, indinavir, nelfinavir > saquinavir

CYP 2C9/19 Substrates       

Diazepam NSAIDs Phenobarbital Phenytoin Tolbutamide S-warfarin Sertaline

Inducers

Inhibitors        

Ritonavir Delavirdine Efavirenz Cimetidine Fluoxetine Fluvoxamine Omeprazole TMP/SMX

  

Rifampin Carbamazepine Phenobarbital

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

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

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

Red Flags for Potential Interactions 

PIs or NNRTIs and      



Benzodiazepines

Ergot alkaloids  Cardiac medicine Azole antifungals  Amiodarone, quinidine Antihistamines  Oral contraceptives Anticonvulsants Anti-tuberculars (rifamycins)  Containing estradiol  Macrolide antibiotics Warfarin  Methadone

PI/ NNRTI/ Antidepressant Drug Interactions Antidepressant

Potential for Interaction

Effects

Management

Amitriptyline

ritonavir, lopinavir/r, amprenavir,

Levels of Start with lower dose amitriptyline may (50%) of amitriptyline, be increased 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 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.

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: 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

Case Study: Endalk (2) His current medication regimen, which is: Nevirapine 200 mg bid Lamivudine 150mg bid Zidovudine 300 mg bid An 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. B. C. D.

Nevirapine and herbal medicine Zidovudine and ergotamine Ergotamine and nevirapine 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:   



2.

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

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 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

Case Study: Lake (2) Oral Thrush

Case Study: Lake (3) His current ARV regimen is: Nevirapine 200 mg bid Zidovudine 300 mg bid Lamivudine 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?