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Pharmacogenetics & Teratogenicity

CLASS FOR BDS STUDENTS

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Pharmacogenetics & Teratogenicity

  1. 1. Dr. RENJU.S.RAVI
  2. 2. DEFINITION “The science that deals with the study of variation in drug response due to variation in genes “
  3. 3. PHARMACOGENOMICS • The use of genetic information to – guide the choice of drug & –Dose on an individual basis
  4. 4. Types of genetic variation • Single nucleotide polymorphism (SNP)  more common, less serious • Insertion/ deletions (indels)  less common, serious
  5. 5. Single Nucleotide Polymorphism
  6. 6. Consequences of polymorphisms Pharmacokinetic Variations ( involving drug metabolism ) Pharmacodynamic Variations (involving drug-receptor interactions) Phase I Phase II
  7. 7. Pharmacokinetic Variations PHASE I Atypical pseudo cholinesterase Slow hydrolysis of Succinyl choline  prolonged apnea
  8. 8. Pharmacokinetic Variations PHASE II • Acetylation • Polymorphism of N-acetyl transferase Acetylation of Isoniazid Fast acetylators slow acetylators hepatotoxicity peripheral neuropathy
  9. 9. Pharmacodynamic variations • Halothane induced hyperthermia Abnormal ryanodine receptor on sarcoplasmic reticulum Genetic polymorphism Excessive release of calcium
  10. 10. Other examples • Precipitation of PORPHYRIA by barbiturates • Hemolysis due to G6PD deficiency. • Insulin resistance due to receptor mutations
  11. 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. 12. Applications of p. genetic knowledge •Personalise medicine 1. To enhance effectiveness 2. Decrease ADR 3. To make clinical trials faster & cost effective
  13. 13. LIMITATIONS  Expensive and time consuming.  Influence of environmental factors  Ethical issues
  14. 14. 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.
  15. 15. 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.
  16. 16. Factors That Determine the Effects of Teratogens • Dose reaching fetus • Time of pregnancy during which drug exposure occurs • Duration of exposure
  17. 17. Effects of Teratogens on the Fetus Spontaneous abortion Malformations (major or minor) Intrauterine growth retardation Mental retardation Carcinogenesis Mutagenesis (causing genetic mutation)
  18. 18. COMMON TERATOGENS
  19. 19. 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 vulner able period
  20. 20. 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
  21. 21. THALIDOMIDE PHOCOMELIA : 'seal limbs' Consists of an absence of development of the long bones of the arms and legs
  22. 22. • 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
  23. 23. PHENYTOIN - Fetal Hydantoin syndrome • Cleft lip/palate • Microcephaly • Mental retardation
  24. 24. VALPROATE- NEURAL TUBE DEFECTS
  25. 25. ISOTRETINOIN Mental retardation and learning disabilities Eye & ear deformities Cleft lip, cleft palate & other facial abnormalities Heart defects Microcephaly & Hydrocephaly
  26. 26. FETAL ALCOHOL SYNDROME
  27. 27. FETAL WARFARIN SYNDROME • Saddle nose • Retarded growth • Defects of limbs, eyes and central nervous system
  28. 28. Tetracycline- Teeth and bone damage • Yellow staining • Enamel hypoplasia • Caries and pigmentation of permanent teeth
  29. 29. 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.
  30. 30. 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

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