pharmacogenetics and teratogenecity

1. PHARMACO GENETICS
Dr. Anu Chandran
Department of pharmacology
Trivandrum medical college

2. Personalized Medicine

3. Personalized Medicine
 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

4. 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

5. The Goal of Personalized Medicine
The Right Dose of
The Right Drug for
The Right Indication for
The Right Patient at
The Right Time.

6. Pharmacogenetics & Pharmacogenomics
 Pharmacogenetics is the study of the genetic basis for variation in drug
response.
 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
 Pharmacogenomics 
 employs tools for surveying the entire genome &
 Assess multigenic determinants of drug response.

7. Pharmacogenetics
Due to genetic polymorphism
Types of genetic polymorphism
Single nucleotide polymorphism (SNP) 
more common, less serious
Insertion/ deletions (indels)  less
common, serious

8. Examples of Genetic Polymorphisms Influencing Drug Response
GENE PRODUCT
(GENE) DRUGSRESPONSES AFFECTED
Drug Metabolism and Transport
CYP2C9 Tolbutamide, warfarin,phenytoin, Anticoagulant effect of warfarin
nonsteroidal anti-inflammatory
CYP2C19 Mephenytoin, omeprazole, voriconazole, Peptic ulcer response to omeprazole;
cardiovascular
hexobarbital, mephobarbital, propranolol, events after clopidogrel
proguanil, phenytoin, clopidogrel
CYP2D6 blockers, antidepressants, anti-psychotics, Tardive dyskinesia from antipsychotics,
narcotic
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
effects of
Ca2+ channel blockers, midazolam, tacrolimus
terfenadine, lidocaine, dapsone, quinidine,
triazolam, etoposide, teniposide, lovastatin,
alfentanil, tamoxifen, steroids

9. Single Nucleotide Polymorphism(SNP)

10. Pharmacokinetic
Variations
( involving drug
metabolism )
Pharmacodynamic
Variations
(involving drug-receptor
interactions)
Phase I Phase II
Consequences of polymorphism

11. Pharmacokinetic Variations
Succinyl choline
PsuedocholinesteraseAtypical Psuedocholinesterase

12. Pharmacokinetic Variations
Atypical pseudocholinesterase
Slow hydrolysis of Succinyl choline 
prolonged apnea

13. Pharmacokinetic Variations
Isoniazid
N Acetyl
transferase
Fast Acetylators
Slow Acetylators

14. Pharmacokinetic Variations
Acetylation
Polymorphism of N-acetyl transferase
Acetylation of Isoniazid
Fast acetylators slow acetylators
hepatotoxicity peripheral neuropathy

15. Pharmacodynamic variations
Halothane induced hyperthermia
Abnormal rynodine receptor on
sarcoplasmic reticulum
Genetic polymorphism
Excessive release of calcium

16. Other examples
 Precipitation of PORPHYRIA by
barbiturates
Haemolysis due to G6PD
deficiency.
Insulin resistance due to receptor
mutations

17. IDIOSYNCRACY
 Genetically mediated abnormal reactivity to a
chemical in a small minority of individuals for
which no definite genotype has been
described.
 Cause unknown.
 Not found in majority of population.
 Aplastic aneamia due to chloramphenicol

18. Applications of pharmaco genetic
knowledge
Personalise medicine
1. To enhance effectiveness
2. Decrease ADR
3. To make clinical trials faster &
cost effective

19. LIMITATIONS
 Expensive and time consuming.
 Influence of environmental factors
 Ethical issues

20. Dr. Anu Chandran

21. TERMS
Greek “teras” meaning "malformation”
 Teratogen: Any chemical, substance, or
exposure given to the pregnant mother that
may cause birth defects to the developing
fetus.
 Teratogenesis: The formation of an abnormal
embryo.

22. Teratogenicity
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.

23. COMMON TERATOGENS

24. Effects of Teratogens on the
Fetus
Spontaneous abortion
Malformations (major or minor)
Intrauterine growth retardation
Mental retardation
Carcinogenesis
Mutagenesis (causing genetic mutation)

25. Factors That Determine the Effects
of Teratogens
Dose reaching fetus
Time of pregnancy during which
drug exposure occurs
Duration of exposure

26. Effect of drugs on fetus during
pregnancy
 Fertilization & implantation
conception to 17 days- Failure of pregnancy
 Organogenesis
18 to 55 days- Congenital malformations
 Growth & development
56 days onwards-Developmental & functional abnormalities.
Most
vulnerable
period

27. THALIDOMIDE
PHOCOMELIA : 'seal limbs'
Consists of an absence of development
of the long bones of the arms and legs

28.  Tetracyclines  staining of teeth
 Androgens  musculaniasation of female
fetus
 Lithium  Ebstein’s anomaly
 Phenytoin  Fetal Hydantoin syndrome
 Alcohol  Fetal Alchohol syndrome
 Valproate  Neural tube defects

29. PHENYTOIN
Cleft lip/palate
Microcephaly
Mental retardation

30. VALPROATE- NEURAL TUBE DEFECTS

31. ISOTRETINOIN
Mental retardation and
learning disabilities
Eye & ear deformities
Cleft lip, cleft palate & other
facial abnormalities
Heart defects
Microcephaly & Hydrocephaly

32. FETAL ALCOHOL SYNDROME

33. FETAL WARFARIN SYNDROME
• Saddle nose
• Retarded growth
• Defects of limbs,
eyes and central
nervous system

34. Tetracycline- Teeth and bone damage
Yellow staining
Enamel hypoplasia
Caries and pigmentation
 of permanent teeth

35. United States FDA
Pharmaceutical Pregnancy Categories
A Controlled human studies show no risk Inj MgSO4
Thyroxine
B
No confirmatory evidence of risk in
humans
Penicillin
Paracetamol
C Risk cannot be ruled out
Morphine
codiene
D Positive evidence of risk
Phenytoin
valproate
X Contraindicated in pregnancy isotretinoin

36. Counseling women about teratogenic risk
The baseline teratogenic risk in
pregnancy (ie,even in the absence of
any known teratogenic exposure)
about 3%.
It is also critical to address the
maternal-fetal risks of the untreated
condition if a medication is avoided.

37. Summary
 Pharmacogenetics is the study of variation in drug response due to genetic
variation
 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

38. Personalized Medicine
(Individualized therapy)
Science concerned with providing medical care
based the genomic and molecular profile of the
individual patient

39. Patient requires Treatment
Examination by the Physician
Genomic testing Traditional
investigations
EXPERT SYSTEM
Decision making by Physician, assisted by an Expert System
(interactive interpretation)
Prescribes individualized drug treatment

40. 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!

41. Is personalized medicine
finally arriving?

42. Economic impact on patients…
Genotyping
cost
Treatment failure
cost