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 1 in 10 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 Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance

Pharmacodynamic interactions

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) 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 Grapefruit Grapefruit Grapefruit selectively

juice and Terfenadine juice and cyclosporin juice and felodipine contains : furanocoumarin compounds that can inhibit CYP3A4

Drug-Herb interactions
Ginko biloba

St. Johns 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 individuals genetic inheritance affects the bodys response to drugs (efficacy & toxicity) The use of genetic content of humans for drug discovery

Drug tablet
Release
Pharmacokinetics

Sources of drug variability

Drug in gut
Absorp tion

Drug in blood

Distribution

Drug metabolites

Drug in tissues

Drug in urine/bile

Pharmacodynamics

Drug at receptor

Desired response

No response

Unwanted response

Genetic variations in drug response and drug toxicity may result from

Variation in drug metabolizing enzymes

Cytochromes P450 Thiopurine Smethyltransferase

Variation in drug transporters

P-glycoprotien

Variation in drug targets

Variation in disease modifying genes

Apolipoprotein

DNA polymorphism Changes in the DNA sequence such as

Nucleotide mutation
The most frequent DNA variation found in the human genome is single nucleotide

Need to keep concentration of drug within the therapeutic range

P s adu c n e taio la m r g o c nr t n

MTC

MEC

T e im

C om m on eneti ol m or is m o f d r g m e t a b o liz in g e n z y m e s li Enz inci nce r

m an

CY

Caucasians - % Asians %

CY C 9

Caucasians - % Asians - %

tr tes extr et r n bet -bl ckers Anti rr t ics Anti epressants Neur leptics ephenyt in Mephobarbital exobarbital iazepam Omeprazole ansoprasole olbutami e ( )- arfarin Phenytoin NSAI s
Azathioprine 6-Mercaptopurine 6-Thioguanine

CY C9
Thiopurine Smethyltransferase

Caucasians < %

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

Codeine
CYP2D6

Morphine

O-demethylation

CYP2D6 PM fail to generate active metabolite

No analgesic effect

LifeLife-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 g/L (normal 1-4 g/L) morphine-3-glucuronide was 580 g/L (normal 8-70 g/L) morphine-6-glucuronide was 136 g/L (normal 1-13 g/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
Enzyme

Morphine Morphine Morphine

Pro-Drug (Codeine)

Enzyme Enzyme

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 TPMT*2
wild type Active enzyme Inactive enzyme
G238C (Ala 80Pro)

TPMT*3A TPMT*3B

Inactive enzyme
G460A (Ala154Thr) A71 G (Tyr 240 Cys)

Inactive enzyme

TPMT*3C

G460A (Ala154Thr)

Inactive enzyme

A71 G (Tyr 240 Cys)

Azathioprine
XO

6-Thiouric aci

6-Mercaptopurine
HGPRT TPMT

Thiogua nine nucleoti des (TGN) Inhibit DNA & RNA synthesis

6-Methylmercap
TPMT is the only detoxifying enzyme of 6-MP in hematopoietic cells TPMT deficiency lead to hematopoietic

14 12

Hematopoietic toxicity of azathioprine in a renal transplant patient carried heterozygous TPMT*3C TPMT*3
White blood count Platelet count

400

300 /L)

/L) White blood count (10

10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24

GI hemorrhage 200 Opportunistic Infection

100 Platelet count (10

Azathioprine treatment 100 mg/day

Days after transplantation

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

Herceptin
- Anti-HER2 antibody

TM

- 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

USUS-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

Future

empirical prescription Rational prescrip individualized One drug fit all Patient genetic s Drug A Drug B Drug A Drug D Drug C
Individual physician experience Cost: time, money & well-being

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