We are all different..
This is why personalized medicine is important to everyone.
Why does someone need twice the standard dose to be effective?
Why does this drug work for you but not me?
Why do I have side-effects and you don’t?
Why do some people get cancer and others dont
Is Medicine a Science or an Art?
If it were not for the great variability among individuals,
medicine might well be a science, not an art.
Sir William Osler, Physician 1892
Father of modern medicine
The Goal of Personalized Medicine
The Right Dose of
The Right Drug for
The Right Indication for
The Right Patient at
The Right Time.
Pharmacogenetics & Pharmacogenomics
Pharmacogenetics is the study of the genetic basis for variation in drug
Pharmacogenetics: The role of genetics in drug responses.
F. Vogel. 1959
Pharmacogenomics: The science that allows us to predict a response to drugs
based on an individuals genetic makeup
Felix Frueh, Associate Director of Genomics, FDA
employs tools for surveying the entire genome &
Assess multigenic determinants of drug response.
Due to genetic polymorphism
Types of genetic polymorphism
Single nucleotide polymorphism (SNP)
more common, less serious
Insertion/ deletions (indels) less
Examples of Genetic Polymorphisms Influencing Drug Response
(GENE) DRUGSRESPONSES AFFECTED
Drug Metabolism and Transport
CYP2C9 Tolbutamide, warfarin,phenytoin, Anticoagulant effect of warfarin
CYP2C19 Mephenytoin, omeprazole, voriconazole, Peptic ulcer response to omeprazole;
hexobarbital, mephobarbital, propranolol, events after clopidogrel
proguanil, phenytoin, clopidogrel
CYP2D6 blockers, antidepressants, anti-psychotics, Tardive dyskinesia from antipsychotics,
codeine, debrisoquine, atomoxetine, side effects, codeine efficacy, imipramine dose
dextromethorphan, encainide, flecainide, requirement, blocker effect; breast cancer
fluoxetine, guanoxan, N-propylajmaline, recurrence after tamoxifen
perhexiline, phenacetin, phenformin,
propafenone, sparteine, tamoxifen
CYP3A4/3A5/3A7 Macrolides, cyclosporine, tacrolimus, Efficacy of immunosuppressive
Ca2+ channel blockers, midazolam, tacrolimus
terfenadine, lidocaine, dapsone, quinidine,
triazolam, etoposide, teniposide, lovastatin,
alfentanil, tamoxifen, steroids
Polymorphism of N-acetyl transferase
Acetylation of Isoniazid
Fast acetylators slow acetylators
hepatotoxicity peripheral neuropathy
Halothane induced hyperthermia
Abnormal rynodine receptor on
Excessive release of calcium
Precipitation of PORPHYRIA by
Haemolysis due to G6PD
Insulin resistance due to receptor
Genetically mediated abnormal reactivity to a
chemical in a small minority of individuals for
which no definite genotype has been
Not found in majority of population.
Aplastic aneamia due to chloramphenicol
Applications of pharmaco genetic
1. To enhance effectiveness
2. Decrease ADR
3. To make clinical trials faster &
Expensive and time consuming.
Influence of environmental factors
Greek “teras” meaning "malformation”
Teratogen: Any chemical, substance, or
exposure given to the pregnant mother that
may cause birth defects to the developing
Teratogenesis: The formation of an abnormal
It refers to capacity of a exogenous
agents to cause foetal abnormalities
when administered to the mother at
any stage of pregnancy.
The placenta - not strictly barrier -
drugs can cross effect n fetus.
Effects of Teratogens on the
Malformations (major or minor)
Intrauterine growth retardation
Mutagenesis (causing genetic mutation)
Factors That Determine the Effects
Dose reaching fetus
Time of pregnancy during which
drug exposure occurs
Duration of exposure
Effect of drugs on fetus during
Fertilization & implantation
conception to 17 days- Failure of pregnancy
18 to 55 days- Congenital malformations
Growth & development
56 days onwards-Developmental & functional abnormalities.
PHOCOMELIA : 'seal limbs'
Consists of an absence of development
of the long bones of the arms and legs
FETAL WARFARIN SYNDROME
• Saddle nose
• Retarded growth
• Defects of limbs,
eyes and central
Tetracycline- Teeth and bone damage
Caries and pigmentation
of permanent teeth
United States FDA
Pharmaceutical Pregnancy Categories
A Controlled human studies show no risk Inj MgSO4
No confirmatory evidence of risk in
C Risk cannot be ruled out
D Positive evidence of risk
X Contraindicated in pregnancy isotretinoin
Counseling women about teratogenic risk
The baseline teratogenic risk in
pregnancy (ie,even in the absence of
any known teratogenic exposure)
It is also critical to address the
maternal-fetal risks of the untreated
condition if a medication is avoided.
Pharmacogenetics is the study of variation in drug response due to genetic
Genetic variations can lead to decreased drug response or enhanced toxicity
So study of Pharmacogenetics is important
Teratogenicity- Fetal abnormalities caused by exogenous agents
Most vulnerable period- organogenesis
Patient education and Proper selection of drugs
Science concerned with providing medical care
based the genomic and molecular profile of the
Patient requires Treatment
Examination by the Physician
Genomic testing Traditional
Decision making by Physician, assisted by an Expert System
Prescribes individualized drug treatment
Here is my sequence
Doctors will be able to select the best drug to treat the disease and the appropriate
dose based on knowledge of patients specific genetic makeup!