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Drug Interaction
Kannikar Kongbunkiat,MD
30 March 2007
Drug Interaction
• Measurable modification of the action of one
drug by prior or concomitant administration of
another substance.
• Substance → prescription and nonprescription
drugs, food or alcohol
• Mechanism
- Pharmacokinetic
- Pharmacodynamic
Pharmacodynamic Mechanisms
• Receptor Interactions
- β- adrenergic blocking+ β2- adrenergic agonists
- antiparkinsonian (levodopa) + dopamine blocking drugs
(haloperidol, metoclopramide)
Pharmacodynamic Mechanisms (cont’n)
• Additive and antagonistic interactions
- Alcohol+ BDZ→ sedative effect
- Warfarin+ ASA→  risk of bleeding
- Hydrocortisone+ HCTZ→ hyperglycemia, hypo K
- K-sparing diuretic+ ACEI → hyper K
Pharmacokinetic Mechanisms
• Chemical interactions
• Interaction affection oral bioavailability
- Interactions affecting absorption
- Interactions affecting presystemic elimination
• Protein- binding interactions
• Interaction due to altered biotransformation:
inducer, inhibitor
• Interaction due to altered renal excretion
Interaction affecting oral bioavailability
1. Interaction affecting gastric emptying
rate of gastric
emptying
Rate of
absorption
Not extent of
drug
bioavailability
Rapid onset of
effect of drug
Interaction affecting oral bioavailability
2. Interactions affecting drug absorption
• absorbed in small intestine by process of
passive diffusion
• drug damage intestinal absorptive surface:
antineoplastic
• Food, acid- base intestine
• Transporter: P- glycoprotein (P-gp)
• Cytochrome P450 (CYPs): CYP3A4
P- glycoprotein
 ATP binding cassette transporter (ABCB1)
 known as multidrug resistance 1 (MDR1)
gene.
 first described in tumor cells: resistant to
various anticancer agents
 normal tissues with excretory function→ efflux
 transporter limits the absorption of orally
administered drugs, promotes drug elimination into
bile and urine
Gut lumen
Gut wall
Portal vein
absorption
metabolism
Liver
metabolism
CYP3A4
p-glycoprotein
To Feces
Urine
การคาบเกี่ยวกันระหว่าง substrate ของ P- gp และ CYP3A4
Protein- Binding Interactions
What is protein binding
Reversible interaction of drugs with proteins in
plasma
free drug + free protein = drug- protein complex
- albumin
- 1- acid glycoprotein
- lipoproteins
Are protein binding drug interaction important?
Fraction unbound (fu) =
Unbound drug concentration
Total drug concentration
in vitro
Warfarin  99% bound , 1% unbound
fu = 1/ 100 = 0.01
Warfarin  98% bound , 2% unbound
fu = 2/100 = 0.02
Increase two- fold in active unbound concentration
in vivo
High hepatic clearance drugs given intravenous: morphine, propranolol
-A superfamily of heme protein.
- Responsible for metabolism of
endogenous and exogenous compounds
- Drugs, environmental chemical
- CYPs responsible for ~50% of drugs
that metabolized in the liver
Human CYPs Involved in Drug Metabolism
5%
3%
1%
10%
50%
30%
CYP3 A4
CYP2 D6
CYP2 C9
CYP2 C19
CYP1 A2
CYP2 E1 &CYP2 A6
Inhibitor and inducer
substrate
inducer
Metabolism
Metabolites
(active/inactive)
substrate
inhibitor
Metabolism
Metabolites
(active/inactive)
Substrate of CYPs
1A2
2B6
2E1
-theophylline
-caffeine
-clozapine
-phenacetin
- methadone
-enfluran
-cyclophosphamide -halothane
-acetaminophen
-benzene
-ethanol
inhibitor
cimetidine
fluoroquinolone
inhibitor
ticlopidine
inhibitor
inducer
broccoli
tobacco
inducer
inducer
phenobarbital
rifampin
ethanol
isoniazid
disulfiram
2C19
H+ inibitor
omeprazole
lanzoprazole
pantoprazole
antiepileptics
phenytoin
phenobarbital
2C9
antiepileptics
phenytoin
phenobarbital
NSAIDs
diclofenac
ibuprofen
piroxicam
oral hypoglycemic
tolbutamide
glipizide
ACEII inh
losartan
irbesartan
2D6
Beta blockers
carvediol
metoprolol
timolol
propranolol
antidepressants
amitrityline
clomipramine
imipramine
nortriptyline
3A4
Macroline
clarithromycin
erythromycin
roxithromycin
Benzodiazepine
alprazolam
diazepam
midazolam
triazolam
Immune
Modulator
cyclosporine
tacrolimus
HIV antiviral
indinavir
ritonavir
nelfinavir
saquinavir
2C19
2C9
2D6
3A4
Prokinetic
cisapride
Antihistamine
astemizole
terfenidine
Ca++ blockers
amlodipine
diltiazem
felodipine
nifedipine
verapamil
HMGCoA
reductase
atorvastatin
cerivastatin
lovastatin
not pravastatin
simvastatin
2C19
2C9
2D6
3A4
Azole drugs
Ketoconazole
itraconazole
Steroid 6-beta-OH
estradiol
Inhibitors
cimetidine
indomethacineaa
Inhibitors
isoniazid
Inhibitors
celecloxib
cimetidine
Inhibitors
cimetidine
ciprofloxacin
Inducer
corbamazepine
rifampin
Inducer
rifampin
Inducer
rifampin
dexamethasone
Inducer
rifampin
barbiturate
phenytoin
glucocorticoids
Interaction due to altered
renal excretion
• Water soluble drugs eliminated largely
unchanged by kidneys
• Glomerular filtration unlikely to be
affected by other drugs
• Tubular secretion can affected by other
drugs: penicillin+ probenecid
High- risk clinical settings
• Index drugs with a narrow therapeutic
index
• Patient taking large numbers of drugs
• Critically ill patients
• Patients with HIV infections
• The passive patients
• Drug abusers
Phenytoin
 Dilantin; capsule 100 mg/cap, tablet 50 mg/tab
 Partial seizures and generalized tonic-clonic
seizures
 Absorption of phenytoin is highly dependent on
the formulation of the dosage form
 More than 90% blinding to albumin
 Metabolized in the liver, zero order elimination
 Narrow therapeutic range (10-20 mg/L)
Case 1
A 23-year-old female patient received phenytoin
suspension 300 milligrams/day via nasogastric
tube with the nutritional enteral product.
Although phenytoin doses were increased (400
milligrams /day) phenytoin trough concentrations
remained low (2.9 to 4.5 mcg/mL).
Phenytoin
NG tube feeding
suspension formula
Antacid
Enteral formula
decrease absorption
of phenytoin
depend on type
of formula
Recommendation - feeding 2hr after antacid and
enteral formula
- delay feeding antacid and
enteral formula about 2 hr
after phenytoin feeding
When oral therapy was replaced with intravenous
doses of 400 milligrams/day, phenytoin serum
concentrations increased to 16.2 mcg /mL
(Hatton, 1984).
Case 2
Generalize seizure with nephrotic syndrome
Cr 0.9 mg/dl, serum albumin 1.3 g/dl
Phenytoin level 8.23 mg/L
PH 
observed
concentrat

alb
 1 - 0.1  
4 . 4 gm / dl

ion

  0 . 1

8.23
PH 
0.2 1.3  0.1
Collected phenytoin level 22.86 mg/L
Saturation of Phenytoin metabolism
(zero order metabolism)
Constant amount of drug is
eliminated per unit time on
matter how much drug is in
the body
40
30
20
Therapeutic range
10
0
200 300 400 500 600
Dose/day (mg/day)
Phenytoin serum concentration and symptoms of toxicity
Phenytoin serum
conc (mg/L)
Sign and symptoms
20
Horizontal nystagmus
30
Vertical nystagmus, ataxia,
slurred speech, drowsiness
Confusion, disorientation,
lethargy, hyperactivity, mania,
coma, respiratory depression
40
50
Paradoxical seizure
Phenytoin
Inhibitor
(cimetidine, INH,
CYP2C9
omeprazole, wafarin)
Inducer
(rifampin, CBZ)
HPPH
glucuronide
urine
phenytoin
inducer
inhibitor
TDM
phenobarbital
Digoxin
•
•
•
•
•
Inc contractility ,slow HR in AF
Absorp from GI 60-80%
Enterohepatic circulation
Elimination half life= 30-50 hrs
Pgp subsrtate
Drug interaction
• Decrease digoxin absorption
•
•
•
•
•
Antacid
Metoclopramide
Kaolin-pectin
Anticholinergic
Clarithomycin and Erythomycin inhibit
Eubacterium lentum
Drug interaction
• Increase digoxin level ( renal clearance)
•
•
•
•
•
Verapamil
Diltiazem
Amiodarone
Spironolactone
Quinidine
Cyclosporin A,Tacolimus
• CYP3A4 substrate
• Increase CSA,TCM level (CYP3A4 inb)
• Diltiazem,verapamil
• Ketoconazole itraconazole fluconazole voriconazole
• Nefazodone fluvoxamine,fluoxetine
• Atorvastatin,simvastatin,lovastatin: myopathy
(CYP3A4 substrate)
CYP2C9
S isomer
Warfarin
R isomer
CYP3A4
CYP 1A2
CYP3A4
CYP2C19
Very similar to Dilantin
Warfarin
• Warfarin coadministration with NSAIDs, or
even COX 2 inhibitor =more bleeding
• NSAIDs also CYP2C9 substrate
• Omeprazole affect CYP2C19 = mild effect
• Oral Vitamin K Intake should not exceed
500 mg
Vitamin K is found in leafy green vegetables such as spinach and
lettuce, cabbage, cauliflower, broccoli, and; wheat bran; organ meats;
cereals; some fruits; meats; cow milk and other dairy products; eggs;
soybeans; and other soy products.
Antiretroviral (Protease Inhibitor)
• CYP 3A4
• Increase PI level (CYP 3A4 inhibitor)
• Ritonavir (so PI + low dose ritonavir = Boosted PI
eg. Lopinavir / Ritonavir (Kaletra)
• Ketoconazole + other –AZOLE
• decrease PI level (CYP 3A4 inducer)
• Rifampicin
Antiretroviral (Protease Inhibitor)
• CYP 3A4 substrate
• Statin ; (except. Pravastatin, Fluvastatin,
Rosuvastatin<Crestor>)
• PI are absorbed best in lower pH so
PPI / H2RA decrease PI absorption
drug interaction website
www.drug-interactions.com
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