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 patient
s may have life-treatening interactions)
✔ The potential drug interactions has been
observed to be 17% in surgical patients, 22% in pati
ents in medical wards, 23% in out patients clinics.
Increasing risk of death

7 6 5 4 2
1 in 10 1 in 10 1 in 10 1 in 10 1 in 103 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 my
ocardium to digitalis
Physiological interactions

Drug A and Drug B bind to different receptors on

the same tissue but give opposite or similar effec
t
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 dru
gs (efficacy & toxicity)
• The use of genetic content of humans for
drug discovery
 Sources of drug
Drug tablet variability
Release
Drug in gut
Pharmacokinetics
Absorpti
on
Drug in blood
Distribution

b oli sm excreti
me ta Drug in tissues o
Drug metabolites n Drug in urine/bile

Drug at receptor
Pharmacodynamics

Desired response No response Unwanted response

Genetic variations in drug response and
drug toxicity may result from

•Variation in drug
•Variation in drug
metabolizing enzym
transporters
es • P-glycoprotien
• Cytochromes P450
• Thiopurine S-
methyltransferase
• Variation in
•Variation in drug
disease modifying
targets
genes
• Beta2-adrenergic • 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
 Need to keep concentration of drug within
the therapeutic range
Plasmadrug concentration

MTC

MEC

Time
 Common genetic polymorphism of human
drug metabolizing enzymes
Enzyme PMincidence Drugsubstrates
Dextromethrophan
CYP2
D6 Caucasians5
-10
% beta-blockers
Asians1% Antiarrythmics
Antidepressants
Neuroleptics
Mephenytoin
Mephobarbital
CYP2
C19 Caucasians2-5
% Hexobarbital
Asians7 -2
3% Diazepam
Omeprazole
Lansoprasole
Tolbutamide
CYP2
C9 Caucasians<1
% (S)-W arfarin
Phenytoin
NSAIDs

Thiopurine S- Azathioprine
methyltransferase Caucasians & Asians 0.3% 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
Codeine Morphine
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
 Overactive metabolism can
cause adverse events

“Normal” Activity
Morphine

Pro-Drug
(Codeine) Enzyme
Morphine

Morphine

Enzyme Morphine
Pro-Drug
Enzyme
(Codeine) 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
nactive enzyme
G460A A719G
(Ala154Thr) (Tyr 240 Cys)
TPMT*3B
nactive enzyme
G460A
(Ala154Thr)
TPMT*3C
nactive enzyme
A719G
(Tyr 240 Cys)
Azathioprine 6-Thiouric acid
XO

6-Mercaptopurine
HGPRT TPMT

Thioguani 6-Methylmercaptopurin
ne • TPMT is the only
nucleotide detoxifying enzyme of 6-
s MP in hematopoietic cells
(TGN)
Inhibit DNA • TPMT deficiency lead to
& RNA hematopoietic toxicity
synthesis
Hematopoietic toxicity of azathioprine
in a renal transplant patient carried
heterozygous TPMT*3C
14 400

12
White blood count
300
White blood count (10 /L)

Platelet count (109/L)

Platelet count
10
9

GI hemorrhage
8 200

6
Opportunistic Infection
100

Azathioprine treatment 0
2
100 mg/day
0
0 2 4 6 8 10 12 14 16 18 20 22 24

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 normal
 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 Immunohistochemical chromogenic in situ

hybridization 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 Future
empirical prescription Rational prescription
“One drug fit all” “individualized”
Drug A Patient genetic’s profiles
Drug B
Drug A
Drug D Drug B
Drug C
Drug C Drug D
Individual physician experienceInformed physician diagnosis
Saving : time, money & patient’s lif
Cost: time, money & well-being
 Base on your genetic profile you
should take Drug A instead of Drug B