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 7 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

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: Aminoglycoside Vancomycin Dose dependent (Michaelis-Menten) kinetic

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

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

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

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

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

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."

CYP2D6 PM fail to generate active metabolite 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 Enzyme Pro-Drug (Codeine) Morphine Enzyme “Ultra-rapid” Activity Pro-Drug (Codeine)

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 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)

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

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: 265-266, 2003

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

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

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

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

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