pharmacogenetics dds.ppt
- 2. 1. Definition – Pharmacogenetics 2. Variation in drug response 3. Pharmacogenetic importance 4. Elementary genetics 5. Single gene PK disorders 6. Therapeutic drugs & clinically available PG tests 7. Conclusion
- 3. .PHARMACOGENTICS : Pharma & Genetics Pharma – The greek word i,.e Pharmacon, related to Drugs. Genetics – related to genes / genome. The study of the genetics basis for variation in drug response. PHARMACOGENOMICS : It employs the tools for surveying the entie genome to assess mutigenic determinants of drug response. PERSONALISED MEDICINES : Individualising drug therapy in light of genomic information.
- 4. To use genetic information specific to an individual patient to preselect a drug that will be effective and not cause toxicity. Better than relying on trials and error supported by physical clues. USFDA : Addition of pharmacogenomics labelling information to the package inserts of over 50 drugs.
- 5. Inter individual variation in response to drugs – Serious problem Results in Lack of efficacy/Unexpected side effects Variation: Pharmacokinetic Pharmacodynamic Idiosyncratic
- 6. Too much/not enough drug at site of action. Metabolism Transporters Plasma protein binding
- 7. Thiopurine drugs ( tioguanine, Mercaptopurine and its prodrug Azathioprine) and TPMT(Thiopurine-S-methyltransferase) activity : Bone marrow and liver toxicity. About 1 in 300 Caucasians and African-Americans are TPMT- deficient . 5-Fluorouracil (5-FU) and DPYD(dihydropyrimidine dehydrogenase ) activity: Decreased metabolism leukocytopenia, stomatitis, diarrhea, nausea and vomiting
- 9. PD->/<effect of a drug at a given concentration at site of action Interindividual variation in •Drug targets G-proteins •Immune Molecules •Receptors •Ion channel and enzymes
- 10. Qualitatively abnormal reaction that occurs only in a few exposed individuals Results from differences in enzymes or immune mechanisms.
- 13. Defination : A gene is the basic instruction –a sequence of nucleic acids ( DNA or, in the case of certain viruses RNA ), while an allele is one variant of that gene. Referreing to having a gene for disease for eg. Sickle cell disease is caused by a mutant allele of a haemoglobin gene. An allele is an alt. form of a gene ( one member of a pair ) that is located at a specific position on a specific chromosomes.
- 15. ‘ DNA Transcribed Complementary mRNA Translated in Rough Endoplasmic reticulum Sequence of Amino Acids Post translational modification Protein product
- 16. Redundant Polymorphism Confers advantage Persist in several generations Silent mutation Eliminated by natural selection
- 17. Different alternative sequences at a locus within DNA strand(alleles) that persist in a population through several generations. A rise due to mutation. Increase in frequency over generations-selective advantage
- 18. SNPs are DNA sequence variations that occur when a single nucleotide in the genome sequence is altered. May entail substitution of one nucleotide to another(C for T). Result in ‘frame shift’ in translation
- 19. Result can be loss of protein synthesis, abnormal protein synthesis or an abnormal rate of protein synthesis. Individuals differ from each other approx. every 300- 1000 nucleotides with an estimated total of 30 million SNP. Can occur in coding & non coding regions Important determinant of disease-e.g. Inherited Thrombophilia
- 20. Mutation in (F5) gene causes V Leiden F5 instruct for making protein coagulation controled by several protein including APC. Increased risk of Venous Thrombosis In Case of Hemorrhage than thrombosis
- 23. Suxamethonium or succinylcholine sensitivity ;rate of metabolism Mendelian Autosomal Recessive trait Short acting NM blocker Plasma cholinesterase
- 24. Genetic abnormality of calcium channels with skeleton muscle. Autosomal dominant inherited. Idiosyncratic ADR due to SXM on Ryanodine receptor Also due to halogenated inhalational agents ( induced anaesthesia by blocking CNS neurotransmission teRapid rise of body perature, muscle rigidity, Rapid heart beat
- 25. Mechanism: Sudden rise in release Ca2+ from sarcoplasmic stores leading to muscle contraction & hyper metabolic rate. Potentially fatal
- 26. Treatment: Dantrolene 1 mg/kg i.v repeated up to 10mg/kg. (prevents release of Ca2+ from sarcoplasmic reticulum) Symptomatic Rx of Hyperthermia Rx of Cardiac arrhythmias
- 27. • Inherited hepatic disorder, Autosomal dominant • Deficiency of HBMS (hydroxymethylbilane synthase) • Mutation in gene coding Porphobilinogen deaminase(PBGD)
- 28. • mitochondrial DNA mutation • Mitochondrial 12S ribosone RNA gene. • Most common predisposing mutation • 30-60% ototoxicity in china(Aminoglycosides-cheap)
- 29. Bind to Bacterial ribosomes For a single dose in susceptible individuals. Screening for this variant appropriate in children Increased affinity to ribosomes in hair cells in ear for several months Aminoglycosides
- 30. • Rate of Metabolism differs with race • Oriental races- accumulation of acetaldehyde. • Due to slower rate of oxidation of acetaldehyde as a result of genetic polymorphism Especially in Japanese
- 31. Around 80% of Asians have a variant gene ADH1B Almost all Chinese and Koreans- ADH1C Coding alcohol dehydrogenase -toxic acetaldehyde at a much higher efficiency 50% of Asians, the increased acetaldehyde accumulation, the mitochondrial ALDH2 allele, less functional acetaldehyde dehydrogenase enzyme,
- 33. Understanding human genome Simpler methods identify genetic information Genetic information specific to . individual Preselect effective drug No toxicity No trial & error
- 34. Anticipated to be one of the first applications of human genome sequencing. Development slowed by various scientific , commercial, political and educational barriers. Cost effectiveness Evidence in support of atest is less convincing than the ideal of an RCT of PG informed prescribing strategy versus current best practice
- 35. 1.Variants of different HLA strongly linked to susceptibility to severe idiosyncratic reactions 2.Genes controlling aspects of drug metabolism 3.Genes encoding drug targets
- 37. Abacavir-Reverse transcriptase inhibitor Highly effective - HIV Infection Severe Rashes Susceptibility linked to HLA variant HLAB*5701
- 38. Carbamazepine Severe life threatening rashes Stevens Johnson Syndrome Toxic epidermal Necrolysis Almost only in Asians FDA recommends Chinese patients to be screened for this allele Similar problem with Phenytoin for same allele
- 40. prodrug Azathioprine Treat Leukemia's(ALL),Inflammatory Bowel disease & Immunosuppression Cause Bone marrow & Liver toxicity Detoxified by Thiopurine S methyltransferase(TPMT) present in blood cells & by Xanthine oxidase Thioguanine,Mercaptopurine & its Low TPMT activity High TPMT Reduced efficacy Lower conc TGN Bone marrow Toxicity High Conc of active TGN in blood
- 41. Phenotyping (by a blood test for TPMT activity) Genotyping TPMT Alleles TPMT*3A,TPMT*3C,TPMT*2 is recommended. Careful monitoring of WBC count & drug interaction with allopurinol(due its effect on Xanthine Oxidase)
- 42. Effective antipsychotic drug Agranulocytosis 1% of patients Studies-small Specificity and sensitivity yet to be established
- 43. Extensively used to treat solid Tumours. Unpredictable mucocutaneous toxicity. Detoxified by dihydropyrimidine dehydrogenase(DPYD)-clinically identifiable multiple genetic variants FDA recommends no to be given to those with DPYD deficiency
- 44. TAMOXIFEN variation Suggested link between CYP2D6 genotype& efficacy. Genotyping tests available. Tetrabenzaine used to Huntington's disease may also be influenced by cyp2d6 Estrogen antagonist ENDOXIFEN CYP2D6 Polymorphic
- 45. Topoisomerase I inhibitor. Marked activity against colorectal & lung cancers(minority) Toxicity(Diarrhoea & BM suppression very severe Active metabolite SN-38 Gilberts UDP glucuronyltransferase Reduced activity Hyberbilirubinemia syndrome
- 47. • Herceptin is mAB that antagonizes epidermal growth factor(EGF) by binding to one of its receptors(human epidermal growth factor receptor 2-HER2) HER2 in tumour • Somatic mutation tissue
- 48. o DASATINIB –dual BCR/ABL & Src tyrosine kinase inhibitor o Used in hematological malignancies(Philadelphia chromosome) o CML ALL o Mutation (T3151) in BCR/ABL confers resistance to inhibitory effect of dasatinib.
- 49. o IMATINIB-TYROSINE kinase inhibitor o CML & other myelodysplastic disorders.
- 51. WARFARIN Dosing individualized by measuring INR(International normalized ratio) Thrombotic effects(lack of efficacy) Adverse effects(bleeding) common PG testing proposed based on polymorphism in its key target, vitamin K epoxide reductase(VKOR) &CYP2C9 GENOTYPE involved in its metabolism
- 52. Ph proves that concept of susceptibility to ADR can be genetically determined Offers possibility of a more armacogenetics Precise ‘Personalised ‘ Medicine for several drugs & disorders. Field of intense research, rapid progress. Challenge remains about its feasibility in Clinical setup