INTERAKSI OBAT
Drug interaction
 Drug interaction can be defined as the
modifications of the effects of one drug by the prior
or concomitant of another drug (poly-pharmacy)
 6.5% of adverse drug reactions in USA were
attributed to drug interactions (0.2% of these
patients may have life-treatening interactions)
 The potential drug interactions has been
observed to be 17% in surgical patients, 22% in
patients in medical wards, 23% in out patients
clinics.
Increasing risk of death
1 in 10
7
1 in 10
6
5
1 in 10
4
1 in 10
1 in 103
2
1 in 10
Lightning
Plane crash
Murder
Auto-cash
Fatal, unexpected
drug reaction
Drug-Drug interaction may alter drug effect by
Additive effect : 1 + 1 =2
Synergistic effect : 1 +1 > 2
Potentiation effect : 1 + 0 =2
Antagonism : 1-1 = 0
Mechanism of drug interaction
 Pharmacokinetic interactions
–
–
–
–
Absorption
Distribution
Biotransformation***
Excretion
 Pharmacodynamic interactions
–
–
–
–
Receptor interaction
Receptor sensitivity
Neurotransmitter release/Drug transportation
Electrolyte balance
 Physiological interactions
 Pharmaceutical interactions
Drug metabolism interaction
Enzyme inducers : increase metabolism of
concomitant drug therefor increase drug elimination
and decrease drug effect
Barbiturate, Rifampin, Phenytoin
Enzyme inhibitors : decresae metabolism
of concomitant drug therefor decrease drug
excretion and increase drug effect
Cimetidine, Ketoconazole, Erythromycin,
Clarithromycin, Chloramphenicol, Quinidine,
Sulphaphenazole
Pharmacodynamic interactions
 Receptor interaction
– Competitive
– Non-competitive
 Sensitivity of receptor
– Number of receptor
– Affinity of receptor
 Alter neurotransmitter release /drug transportation
 Alter water/electrolyte balance
Digoxin (0.25 mg) ½ tab od pc
Furosemide (20 mg) 1 tab po od pc
Answer
Increase digitalis effect due to diuretic induce
hypokalemia therefor increase sensitivity of
myocardium to digitalis
Physiological interactions
Drug A and Drug B bind to different receptors on
the same tissue but give opposite or similar
effect
Aspirin (anti-platelet)
+Warfarin/Coumarin (anticoagulant)
Increase bleeding
Pharmaceutical interactions
 Chemical or physiological interactions
– Vitamin C + amphotericin B
– Pennicilin + Vitamin C
Drug-Food interactions
 Grapefruit juice and Terfenadine
 Grapefruit juice and cyclosporin
 Grapefruit juice and felodipine
 Grapefruit contains : furanocoumarin compounds that can
selectively inhibit CYP3A4
Drug-Herb interactions
Ginko biloba
St. John’s wort: CYP3A4 inducer
Drug features associated with potential
interactions
Narrow therapeutic index :
– Phenytoin
– Cyclosporine
– Theophylline
Sharp response curve:
– Phenytoin
– Aminoglycoside
– Vancomycin
Dose dependent (Michaelis-Menten) kinetic
–Phenytoin
List of drug the most common
interacting drug
•Antacids
•Cimetidine
•Digoxin
•Warfarin
•Theophylline
•Ketoconazole
Problem in medical practice
same complaints
same finding
same diagnosis
same treatment
but differential effect ????
•Possible reasons
• Physiological factors
• Pathological factors
• Food
•Drug interaction
•Genetic
Pharmacogenetics
Pharmacogenomics
Pharmacology + Genetics/Genomics
• The study of how individual’s genetic
inheritance affects the body’s response to
drugs (efficacy & toxicity)
• The use of genetic content of humans for
drug discovery
Drug tablet
Sources of drug
variability
Release
Pharmacokinetics
Drug in gut
Absorption
Drug in blood
Distribution
Drug metabolites
Pharmacodynamics
Desired response
Drug in tissues
Drug in urine/bile
Drug at receptor
No response
Unwanted response
Genetic variations in drug response and
drug toxicity may result from
•Variation in drug
metabolizing enzymes
• Cytochromes P450
•Variation in drug
transporters
• P-glycoprotien
• Thiopurine S-methyltransferase
•Variation in drug targets
• Beta2-adrenergic receptor
• ACE
• Dopamine receptor
• Variation in disease
modifying genes
• Apolipoprotein (APOE)
DNA polymorphism
Changes in the DNA
sequence such as
– Nucleotide mutation
• The most frequent
DNA variation found in
the human genome is
single nucleotide
polymorphism (SNP)
– Nucleotide deletion
– Nucleotide insertion
– Gene deletion
– Gene duplication
Plasma drug concentration
Need to keep concentration of drug within
the therapeutic range
MTC
MEC
Time
Common genetic polymorphism of human
drug metabolizing enzymes
Enzyme
PM incidence
CYP2D6
Caucasians 5-10%
Asians 1%
CYP2C19
CYP2C9
Thiopurine Smethyltransferase
Caucasians 2-5%
Asians 7-23%
Caucasians < 1%
Caucasians & Asians 0.3%
Drug substrates
Dextromethrophan
beta-blockers
Antiarrythmics
Antidepressants
Neuroleptics
Mephenytoin
Mephobarbital
Hexobarbital
Diazepam
Omeprazole
Lansoprasole
Tolbutamide
(S)-Warfarin
Phenytoin
NSAIDs
Azathioprine
6-Mercaptopurine
6-Thioguanine
•A 9-yr old boy was prescribed Prozac (Fluoxetine) to help control emotional outbursts.
•Child died suddenly ; toxicology tests show massive overdose of fluoxetine
•Adoptive parents investigated for homicide.
•Psychiatrist notices unusually high levels of Prozac indicatiing CYP2D6 deficiency.
•Subsequent genetic testing showed that child had CYP2D6 gene defect
“After Michael died, we found out that there were tests to spot enzyme
deficiencies that can cause adverse drug reactions. I felt devastated when I heard
that. It should be the norm that the tests are used whenever there are concerns
about possible side effects."
Morphine
Codeine
O-demethylation
CYP2D6
CYP2D6 PM fail to generate
active metabolite
No analgesic effect
Life-threatening complication after
cough suppression therapy with codeine
•62 yr man with pneumonia treated with codeine (25 mg
tid) for cough
•4 days after drug administration , the pt’s consciousness
rapidly deteriorated, and he became unresponsive.
•At the time of the pt’s coma,
• plasma morphine was 80 μg/L (normal 1-4 μg/L)
• morphine-3-glucuronide was 580 μg/L (normal 8-70 μg/L)
• morphine-6-glucuronide was 136 μg/L (normal 1-13 μg/L )
• CYP2D6 genotyping : ultra rapid metabolism
N Engl J Med 2004;351:2827-31
Overactive metabolism can
cause adverse events
“Normal” Activity
Morphine
Pro-Drug
(Codeine)
Enzyme
Morphine
Morphine
Pro-Drug
(Codeine)
Enzyme
Morphine
Enzyme
Morphine
Enzyme
Morphine
“Ultra-rapid” Activity
Thiopurine S-methyltransferase (TPMT)
polymorphism
Cytosolic phase II enzyme involved in the
metabolism of thiopurine and thioguanine
anticancer drugs
Azathioprine
6-Mercaptopurine
6-Thioguanine
exhibits genetic polymorphism
Common TPMT alleles
TPMT*1
wild type
Active enzyme
TPMT*2
Inactive enzyme
G238C
(Ala 80Pro)
TPMT*3A
Inactive enzyme
TPMT*3B
G460A
(Ala154Thr)
A719G
(Tyr 240 Cys)
Inactive enzyme
TPMT*3C
Inactive enzyme
G460A
(Ala154Thr)
A719G
(Tyr 240 Cys)
Azathioprine
6-Thiouric acid
XO
6-Mercaptopurine
HGPRT
Thioguanine
nucleotides
(TGN)
Inhibit DNA &
RNA synthesis
TPMT
6-Methylmercaptopurine
• TPMT is the only detoxifying
enzyme of 6-MP in hematopoietic
cells
• TPMT deficiency lead to
hematopoietic toxicity
Hematopoietic toxicity of azathioprine in a renal
transplant patient carried heterozygous TPMT*3C
14
400
White blood count
Platelet count
300
10
GI hemorrhage
Opportunistic Infection
8
6
200
100
4
Azathioprine treatment
100 mg/day
2
0
0
0
2
4
6
8
10
12
14
16
18
Days after transplantation
Tassaneeyakul et al. Transplantation; 76: 265-266, 2003
20
22
24
Platelet count (109/L)
9
White blood count (10 /L)
12
Discovery of Herceptin for treatment of
breast cancer
•Beast tumors that are Her2 over expressing
•Metastasis faster
•Poorly response to chemotherapy and poor prognosis
•Approximately 30% of breast cancer are Her2 positive
•Her2 receptor plays important role in normal cell growth by signaling
the cell to divide and multiply
Herceptin
TM
- Anti-HER2 antibody
- Breast cancer patients with poor
prognosis : over expression of HER2
- Anti-HER2 antibody bind to HER2 and
inhibit HER2 function : slowing tumor
growth
Prior to prescription of Herceptin, the patient need to be
diagnosed whether there is an over expression of HER2
Cost : About 28,000 bths/wk, In clinical trials, the median time
on Herceptin was 36 wks, total cost 1,000,000 bths
Fluorescence in situ
hybridization
Immunohistochemical
chromogenic in situ
hybridization
US-FDA Labeling Regulations
If evidence is available to support the safety and
effectiveness of the drug only in selected subgroup of the
larger population with a disease, the labeling shall describe
the evidence and identify specific tests needed for
selection and monitoring of patients who need the drug
-21 CFR 201.57
6-Mercaptopurine Labeling
Information for Patients
Atomoxetine (Stratterra R) product information
Information for Patients
AmpliChip CYP450 Test
Use for routine diagnosis of CYP2C9 and
CYP2D6 gene
Targeted prescription of medicine: applied
pharmacogenomics
Today
empirical prescription
“One drug fit all”
Drug A
Drug B
Drug D
Future
Rational prescription
“individualized”
Patient genetic’s profiles
Drug A
Drug B
Drug C
Drug C
Individual physician experience
Cost: time, money & well-being
Drug D
Informed physician diagnosis
Saving : time, money & patient’s life
Base on your genetic profile you
should take Drug A instead of Drug B