DRUG INTERACTIONS

BY
LWASAMPIJJA BAKER
(bubakes2000@gmail.com)

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
Outcome of
Patient Factors Drug Drug Factors
Interaction

•Genetics •Dose
•Diseases •Duration
•Diet/Nutrition •Dosing Times
•Environment •Sequence
•Smoking •Route
•Alcohol •Dosage Form
Variability
 CYP 3A4
Substrates- Inhibitors- Inducers-
Calcium channel Erythro-, > Carbamazepine,
blockers, clarithromycin, phenytoin,
Carbamazepine, Efavirenz,Grape phenobarbital
Corticosteroids, Rifampin, rifabutin,
fruit juice,
Digoxin, St. John’s wort,
Cyclosporine, Keto-, itra- > garlic
Methadone, fluconazole,PIs: Efavirenz,
Protease inhibitors, ritonavir >>> nevirapine
Amitriptyline, amprenavir,
Quinidine,Many, atazanavir,
many more indinavir,
nelfinavir >
saquinavir
 CYP 2C9/19
Substrates Inhibitors Inducers
 Diazepam  Rifampin
 Ritonavir
 NSAIDs  Carbamazepine
 Delavirdine
 Phenobarbital
 Efavirenz
 Phenobarbital
 Phenytoin
 Tolbutamide  Cimetidine
 S-warfarin  Fluoxetine
 Sertaline  Fluvoxamine
 Omeprazole
 TMP/SMX
 CYP 2D6:
Substrates Inhibitors
Amphetamines Ritonavir
Codeine-to-morphine Cimetidine
Fluoxetine
Haloperidol
Haloperidol
Hydrocodone-to-morphine. Paroxetine
Metoprolol, propranolol Quinidine
Phenothiazines Methadone
Risperidone
TCAs(amitriptyline)
 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
 Azole antifungals  Cardiac medicine

 Antihistamines  Amiodarone, quinidine

 Anticonvulsants  Oral contraceptives

 Anti-tuberculars (rifamycins)  Containing estradiol

 Warfarin  Macrolide antibiotics

 Methadone
 PI/ NNRTI/ Antidepressant
Drug Interactions
Antidepressant Potential for Effects Management
Interaction
Amitriptyline ritonavir, Levels of Start with lower dose
lopinavir/r, amitriptyline may (50%) of amitriptyline,
amprenavir, be increased adjust dose when
addIng ritonavir.
Monitor for side
effects
Fluoxetine ritonavir, Levels of both As above
lopinavir/r, all fluoxetine and
other PIs, ARVs may be
efavirenz increased
Sertraline ritonavir, Levels of As above
lopinavir/r, all sertraline may
other Pis, be increased.
efavirenz ARV levels
not likely to
change.
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: Avoid food:
 ddI: 47% ↓ with meal
 Lopinavir (capsules or  Efavirenz: ↑ 79% high fat meal
solution): ↑ 50-130% increases toxicity
 Rifampin: food may ↑ levels
 Isoniazid
Avoid Antacids
 PIs  Fluoroquinolones
 Indinavir
 Isoniazid
 (fos)amprenavir
 Amprenavir  Dapsone
 Atazanavir  Zalcitabine
 Ketoconazole
 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. 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
2. 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?