1. INTERAKSI OBAT

2. 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.

3. Increasing risk of death7 6 5 4 2 3
1 in 10
1 in 10
1 in 10
1 in 10
1 in 10
1 in 10
Lightning
Murder
Plane crash
Auto-cash
Fatal, unexpected
drug reaction

4. Drug-Drug interaction may alter drug effect by
Additive effect : =2
Synergistic effect : 1 +1 > 2
Potentiation effect : =2
Antagonism : 1-1 = 0

5. 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

6. 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

7. 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

8. 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

9. 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

10. Pharmaceutical interactions
Chemical or physiological interactions
Vitamin C + amphotericin B
Pennicilin + Vitamin C

11. Drug-Food interactions
Grapefruit juice and Terfenadine
Grapefruit juice and cyclosporin
Grapefruit juice and felodipine
Grapefruit contains : furanocoumarin compounds that can selectively inhibit CYP3A4

12. Drug-Herb interactions
Ginko biloba

13. St. John’s wort: CYP3A4 inducer

14. Drug features associated with potential interactions
Narrow therapeutic index :
Phenytoin
Cyclosporine
Theophylline
Sharp response curve:
Aminoglycoside
Vancomycin
Dose dependent (Michaelis-Menten) kinetic

15. List of drug the most common interacting drug
Antacids
Cimetidine
Digoxin
Warfarin
Theophylline
Ketoconazole

16. 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

17. 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

18. Sources of drug variability
Drug tablet
Drug in blood
Drug in tissues
Drug at receptor
Drug metabolites
Drug in urine/bile
Desired response
No response
Unwanted response
Sources of drug variability
excretion
metabolism
Release
Drug in gut
Absorption
Distribution
Pharmacokinetics
Pharmacodynamics

19. Genetic variations in drug response and drug toxicity may result from
Variation in drug transporters
P-glycoprotien
Variation in disease modifying genes
Apolipoprotein (APOE)
Variation in drug metabolizing enzymes
Cytochromes P450
Thiopurine S-methyltransferase
Variation in drug targets
Beta2-adrenergic receptor
ACE
Dopamine receptor

20. Changes in the DNA sequence such as
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

22. Thiopurine S-methyltransferase Caucasians & Asians 0.3%
Azathioprine
6-Mercaptopurine
6-Thioguanine
Caucasians & Asians 0.3%

23. 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."

24. CYP2D6 PM fail to generate active metabolite
Morphine
Codeine
O-demethylation
CYP2D6
CYP2D6 PM fail to generate active metabolite
No analgesic effect

25. 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:

26. Overactive metabolism can cause adverse events
“Normal” Activity
Morphine
Enzyme
Pro-Drug
(Codeine)
Morphine
Enzyme
“Ultra-rapid” Activity
Pro-Drug
(Codeine)

27. 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

28. Common TPMT alleles TPMT*1 TPMT*2 TPMT*3A TPMT*3B TPMT*3C wild type
Active enzyme
TPMT*2
Inactive enzyme
TPMT*3A
TPMT*3B
TPMT*3C
G238C
(Ala 80Pro)
G460A
(Ala154Thr)
A719G
(Tyr 240 Cys)

29. Inhibit DNA & RNA synthesis
6-Mercaptopurine
TPMT is the only detoxifying enzyme of 6-MP in hematopoietic cells
TPMT deficiency lead to hematopoietic toxicity
Thioguanine
nucleotides
(TGN)
Inhibit DNA & RNA synthesis
HGPRT
6-Thiouric acid
TPMT
Azathioprine
6-Methylmercaptopurine XO

31. Azathioprine treatment
Hematopoietic toxicity of azathioprine in a renal transplant patient carried heterozygous TPMT*3C
Azathioprine treatment
100 mg/day
GI hemorrhage
Opportunistic Infection
Tassaneeyakul et al. Transplantation; 76: , 2003

33. 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

34. 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

35. Fluorescence in situ hybridization chromogenic in situ hybridization
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

36. 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
6-Mercaptopurine Labeling
Information for Patients

37. Atomoxetine (Stratterra R) product information
Information for Patients

38. AmpliChip CYP450 Test Use for routine diagnosis of CYP2C9 and CYP2D6 gene

39. Today Future Targeted prescription of medicine: applied
pharmacogenomics
Today
empirical prescription
“One drug fit all”
Drug A
Drug B
Drug C
Drug D
Individual physician experience
Cost: time, money & well-being
Future
Rational prescription
“individualized”
Patient genetic’s profiles
Drug A
Drug B
Drug C
Drug D
Informed physician diagnosis
Saving : time, money & patient’s life

40. Base on your genetic profile you should take Drug A instead of Drug B