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pharmacogenetics and teratogenecity

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  1. 1. PHARMACO GENETICS Dr. Anu Chandran Department of pharmacology Trivandrum medical college
  2. 2. Personalized Medicine
  3. 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. 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. 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. 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. 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. 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. 9. Single Nucleotide Polymorphism(SNP)
  10. 10. Pharmacokinetic Variations ( involving drug metabolism ) Pharmacodynamic Variations (involving drug-receptor interactions) Phase I Phase II Consequences of polymorphism
  11. 11. Pharmacokinetic Variations Succinyl choline PsuedocholinesteraseAtypical Psuedocholinesterase
  12. 12. Pharmacokinetic Variations Atypical pseudocholinesterase Slow hydrolysis of Succinyl choline  prolonged apnea
  13. 13. Pharmacokinetic Variations Isoniazid N Acetyl transferase Fast Acetylators Slow Acetylators
  14. 14. Pharmacokinetic Variations Acetylation Polymorphism of N-acetyl transferase Acetylation of Isoniazid Fast acetylators slow acetylators hepatotoxicity peripheral neuropathy
  15. 15. Pharmacodynamic variations Halothane induced hyperthermia Abnormal rynodine receptor on sarcoplasmic reticulum Genetic polymorphism Excessive release of calcium
  16. 16. Other examples  Precipitation of PORPHYRIA by barbiturates Haemolysis due to G6PD deficiency. Insulin resistance due to receptor mutations
  17. 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. 18. Applications of pharmaco genetic knowledge Personalise medicine 1. To enhance effectiveness 2. Decrease ADR 3. To make clinical trials faster & cost effective
  19. 19. LIMITATIONS  Expensive and time consuming.  Influence of environmental factors  Ethical issues
  20. 20. Dr. Anu Chandran
  21. 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. 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.
  24. 24. Effects of Teratogens on the Fetus Spontaneous abortion Malformations (major or minor) Intrauterine growth retardation Mental retardation Carcinogenesis Mutagenesis (causing genetic mutation)
  25. 25. Factors That Determine the Effects of Teratogens Dose reaching fetus Time of pregnancy during which drug exposure occurs Duration of exposure
  26. 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. 27. THALIDOMIDE PHOCOMELIA : 'seal limbs' Consists of an absence of development of the long bones of the arms and legs
  28. 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. 29. PHENYTOIN Cleft lip/palate Microcephaly Mental retardation
  31. 31. ISOTRETINOIN Mental retardation and learning disabilities Eye & ear deformities Cleft lip, cleft palate & other facial abnormalities Heart defects Microcephaly & Hydrocephaly
  33. 33. FETAL WARFARIN SYNDROME • Saddle nose • Retarded growth • Defects of limbs, eyes and central nervous system
  34. 34. Tetracycline- Teeth and bone damage Yellow staining Enamel hypoplasia Caries and pigmentation  of permanent teeth
  35. 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. 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. 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. 38. Personalized Medicine (Individualized therapy) Science concerned with providing medical care based the genomic and molecular profile of the individual patient
  39. 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. 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. 41. Is personalized medicine finally arriving?
  42. 42. Economic impact on patients… Genotyping cost Treatment failure cost