Pharmacogenetics & Teratogenicity

CLASS FOR BDS STUDENTS

1. PHARMACOGENETICS Dr. RENJU.S.RAVI

2. DEFINITION “ The science that deals with the study of variation in drug response due to variation in genes “

3. PHARMACOGENOMICS The use of genetic information to guide the choice of drug & Dose on an individual basis

4. Types of genetic variation Single nucleotide polymorphism (SNP)  more common, less serious Insertion/ deletions ( indels )  less common, serious

5. Single Nucleotide Polymorphism

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

7. Pharmacokinetic Variations PHASE I Atypical pseudo cholinesterase Slow hydrolysis of Succinyl choline  prolonged apnea

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

9. Pharmacodynamic variations Halothane induced hyperthermia Abnormal ryanodine receptor on sarcoplasmic reticulum Genetic polymorphism Excessive release of calcium

10. Other examples Precipitation of PORPHYRIA by barbiturates Hemolysis due to G6PD deficiency. Insulin resistance due to receptor mutations

11. 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 anemia due to chloramphenicol

12. Applications of p. genetic knowledge Personalise medicine To enhance effectiveness Decrease ADR To make clinical trials faster & cost effective

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

14. TERATOGENICITY

15. 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.

16. 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 does not strictly constitute a barrier and any drug can cross it to a greater or lesser extent.

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

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

19. COMMON TERATOGENS

20. 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

21. United States FDA Pharmaceutical Pregnancy Categories A Controlled human studies show no risk Inj MgSO 4 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

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

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

24. PHENYTOIN - Fetal Hydantoin syndrome Cleft lip/palate Microcephaly Mental retardation

25. VALPROATE- NEURAL TUBE DEFECTS

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

27. FETAL ALCOHOL SYNDROME

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

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

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

31. 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

32. Thank you