- Drug Interactions- June2012
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Drug Interactions
UY1/FMBS/L2S4/PHCL/Drug Interactions
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Lecture plan Definition Types of drug interactions Mechanisms of drug interactions
Drug interactions before administration Drug interactions at site of absorption Drug interactions at site of distribution Drug interactions at the level of metabolism Drug interactions at the level of excretion
Consequences of drug interactions Effects on efficacy/toxicity Example of Harmful drug interactions Example of Beneficial drug interactions
factors affecting Drug interactions drug-related factors drug-related factors
drug interaction website
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Drug interactions (DI): Definition
Definition:Alteration of the effect and/or potency of one
drug (Victim drug) by the prior or theconcurrent administration of another drug(s)
(Perpetrator drug) If the interaction results in diminished
efficacy or increased toxicity, then a
therapeutic drug interactionhas occurred Multiple drug therapy can give rise to drug-DI
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Types of Drug Interactions
1. Drug Drug interactions2. Drug Nutrients interactions
3. Drug Herbal interactions
4. Drug Environment interactions5. Drug Disease interactions
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Drug interactions before drugadministration
Phenytoin precipitates in dextrosesolution
Intra-vesicular amphotericin precipitates
in saline.bladder wall necrosis Gentamicin covalently binds piperacillin,
azlocillin, cefoxitin..loss of antibiotic
effect
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Drug interaction at absorptionsites
Most absorption changes are observed inGI and may be due to changes in
Chelation/complexation/adsorption
Gastric pH
Motility
Flora/Gut metabolism
Effect of food
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Changes in Drug Absorption Alterations of gastric pH
If a drug changes the gastric pH, it can affect theabsorption and thus concentration of other drugs thathave specific pH requirements for absorption
Presence or absence of food Food can enhance or decrease the bioavailability of a
drug--often because of gastric acidity Some drugs must be administered one hour before or
two hours after eating
Chelation Binding of two drugs/compounds to form insoluble
complexes that cannot be absorbedthis changesabsorption of a drug
i i h
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Drug interactions at thedistribution site
Altered plasma protein binding (PPB)A drug is displaced from its PPB, increases
unbound concentration and effect
Altered drug transport
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Metabolism-based drug interactions(Liver and GI tract)
CYP inhibition: enzyme activity and metabolism (Cl,AUC)
drug effect (efficacy/or toxicity)
Induction: enzyme activity, metabolism (Cl,AUC
Drug effect (efficacy and/or toxicity)
Note:
For prodrugs, inhibition may result in loss ofefficacy/toxicity and induction in enhanced
efficacy/toxicity
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Substrate of CYPs1A2 2B6 2E1
-theophylline-caffeine
-clozapine
-phenacetin
- methadone-cyclophosphamide
-enfluran-halothane
-acetaminophen
-benzene
-ethanolinhibitor
cimetidine
fluoroquinolone
inhibitor
ticlopidineinhibitor
disulfiram
inducer
broccoli
tobaccoinducer
phenobarbital
rifampininducer
ethanol
isoniazid
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2C19 2C9 2D6 3A4H+inibitor
omeprazole
lanzoprazolepantoprazole
antiepileptics
phenytoin
phenobarbital
antiepileptics
phenytoin
phenobarbitalNSAIDs
diclofenacibuprofen
piroxicam
oral hypoglycemic
tolbutamide
glipizide
ACEII inh
losartan
irbesartan
Beta blockers
carvediol
metoprololtimolol
propranolol
antidepressants
amitrityline
clomipramine
imipramine
nortriptyline
Macroline
clarithromycin
erythromycinroxithromycin
Benzodiazepine
alprazolam
diazepam
midazolam
triazolam
ImmuneModulator
cyclosporine
tacrolimus
HIV antiviralindinavir
ritonavir
nelfinavir
saquinavir
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2C19 2C9 2D6 3A4Prokinetic
cisapride
Antihistamineastemizole
terfenidine
Ca++blockers
amlodipine
diltiazem
felodipine
nifedipine
verapamil
HMGCoAreductase
atorvastatincerivastatin
lovastatin
not pravastatin
simvastatin
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2C19 2C9 2D6 3A4Azole drugs
Ketoconazole
itraconazole
Steroid 6-beta-OH
estradiol
Inhibitors
cimetidine
indomethacineaaInhibitors
isoniazid
Inhibitors
celecloxib
cimetidine
Inhibitors
cimetidine
ciprofloxacin
Inducer
corbamazepine
rifampinInducerrifampin
Inducer
rifampindexamethasone
Inducerrifampin
barbiturate
phenytoin
glucocorticoids
I t ti d t lt d
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Interaction due to alteredrenal excretion
Tubular secretion can be affected by otherdrugs with have the same mechanism of
secretion:
Example: penicillin+ probenecid
Water soluble drugs eliminated by glomerular
filtration and largely unchanged by kidneys
Glomerular filtration unlikely to be affected by other
drugs
C f D
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Consequences of DrugInteractions
Clinically unimportant (occasional) Many process and pathways of drug
elimination are minor to be of concern; noneed to change dose, regimen or schedule
Clinically important (many are avoidablewith proper knowledge of PK, PD andmechanisms of interaction)
Mild - require dosage monitoring/adjustment(unusual)
Severe (life threatening)contraindicated
(rare)
C f D
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Consequences of DrugInteractions
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Beneficial Drug Interactions
The antiretroviral agent saquinavir (ProteaseInhibitors-PI) Drug interactions:
Problems:
Limited efficacy even when combined with NRTIs because ofvery unfavorable PK:
low and variable oral bioavailability
high systemic clearance (short half-life).
Consequences: Administration of high doses of the drug to enhance antiretroviral activity:
High pill burden Increased cost of antiretroviral therapy
Solution:
PK Interaction: saquinavir/ritonavir results in increasedbioavailability of saquinavir
PK I t ti
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PK Interaction:saquinavir/ritonavir (Kaletra)
Mechanism:
Ritonavir is very potentinhibitor of intestinaland hepatic CYP3A
Enhance bioavailabilityand prolong half-life ofsaquinavir
Improve antiretroviraleffect of saquinavir(Pharmacoenchancement)
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PHARMACOENHANCMENT
Principle:
Administer a low, non-therapeutic dose of a drug toinhibit the metabolism and / or transport of a seconddrug and thereby reduce first-pass elimination andsystemic clearance.
Result:
Increase the bioavailability, AUC and half-life oftarget drug.
Utility: Plasma concentrations maintained above viral IC95
for entire dosing interval.
Dosing interval extended to 12 hours.
Some drug related factors
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Some drug-related factorsaffecting Drug interactions
Drug dosage/concentration
Narrow therapeutic index
Low bioavailability
Duration of treatment
Timing and sequence of administration
Number of drugs prescribed*
Route of administration
Fraction metabolized
Problematic PK (nonlinear)
Compliance
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Relationship between DrugInteraction and Number of
drugs prescribed*
D i t ti d d ff t
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Drug interaction and adverse effects
increase with the number of drugs used
Absolute number of drugs concurrentlyreceived by a patient is the best predictorof adverse effects:
3-5% in patients taking a few drugs may
experience drug interaction
Up to 20% in patients who receive 10-20drugs may experience interaction
Patient population with poly-pharmacyinclude:
HIV infected patients, elderly patients, patients onchemotherapy
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A patient may receive multiple
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A patient may receive multiplemedications for various reasons:
Intentional: Drug combinations are beneficial in the
management of some diseases (e.g. infection,cancer, hypertension and diabetes)
To treat coexisting diseases (e.g. diabetesand hypertension, HIV and opportunisticinfections)
Unintentional: Unexpected Prescription of different drugs by differentphysicians
Over-thecounter, herbal and nutrients
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Some patient related factors
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Some patient-related factorsaffecting Drug interactions
Body weight Genetic polymorphism
Age, gender
Alcohol use Race
Tobacco use
Alcohol use
Diet
Disease state
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drug interaction
websitewww.drug-interactions.com
www.epocrates.com
http://www.drug-interactions.com/http://www.epocrates.com/http://www.epocrates.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/ -
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