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Pharmacogenetics

This was made by an MD Pharmacology post graduate student for a seminar.
References:
Goodman&Gillman,
Rang & Dale,
Bhattacharya,Sen,Ray

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Pharmacogenetics

  1. 1. Presented by: Dr.Adithi S Raghavan Moderated by: Dr.Anuradha H.V
  2. 2. Outline 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. 3. Introduction Pharmacogenetics is the study of the genetic basis for variation in drug response. Encompasses Pharmacogenomics which employs tools for surveying the entire genome to assess multigenic determinants in drug response.
  4. 4. Variation In drug response Interindividual variation in response to drugs – Serious problem Results in Lack of efficacy/Unexpected side effects Variation:  Pharmacokinetic  Pharmacodynamic  Idiosyncratic
  5. 5. Pharmacokinetic variation • Too much/not enough drug @site of action • Genes influence PK by altering expression of Proteins involved in ADME
  6. 6. Pharmacodynamic variation PD->/<effect of a drug @ a given conc @ site of action Interindividual variation in • Drug targets • G-proteins • Other downstream events
  7. 7. Idiosyncratic  Qualitatively abnormal reaction that occurs only in a few exposed individuals  Results from differences in enzymes or immune mechanisms
  8. 8. Importance of Pharmacogenetics to variability in Drug response
  9. 9. Pharmacogenetic variations May be due to : A.Single mutant gene-Genetic polymorphism B.Polygenic influences  Polygenic influences & environmental factors are responsible for normal biological variations.  Clinical practice-not significant
  10. 10.  Classical family studies provide information on drug response & genetics  Data limited  Twin studies show that drug metabolism is highly heritable, with genetic factors accounting for variation
  11. 11. Figure 7–2. Pharmacogenetic contribution to pharmacokinetic parameters. t1/2 of antipyrine is more concordant in identical in comparison to fraternal twin pairs. Bars show the t 1/2 of antipyrine in identical (monozygotic) and fraternal (dizygotic) twin pairs. (Redrawn from data in Vesell and Page, 1968.)
  12. 12. Genetic Fraternal twins-Wide Variation in Drug responses Environmental Identical Only Environmental
  13. 13.  Comparison of Intra twin vs. Inter pair variability 75-80% variability in PK t 1/2 s of drugs eliminated by metabolism is heritable  Heritability estimated by  Comparing intra-subject vs. inter subject variability in drug response  or disposition in unrelated individuals Assuming high intra subject reproducibility translates into high heritably.
  14. 14. Genes  Fundamental units of heredity  Consist of ordered sequence of nucleotides(Adenin e, Guanine ,Thymidine & Cytosine-A,G,T,C.
  15. 15.  Written in italics • CYP2D6-protein • CYP2D6-Gene  Most DNA-Chromosome  Small amountMitochondria.(Maternal Ovum)
  16. 16. DNA Transcribed Complementary mRNA Translated in Rough Endoplasmic reticulum Protein product Post translational modification Sequence of Amino Acids
  17. 17.  Rate of transcription Promoter region  RNA polymerase binds to initiate transcription
  18. 18. Mutations Heritable changes in base sequence of DNA Redundant Polymorphism Eliminated by natural selection Persist in several generations Silent mutation Confers advantage
  19. 19. Polymorphisms  Different alternative sequences at a locus within DNA strand(alleles) that persist in a population through several generations.  Arise due to mutation.  Stable-non functional.- Die out-disadvantageous  Increase in frequency over generations-selective advantage
  20. 20. Balanced polymorphism  Situation where several functionally distinct forms of a gene are common in a population  Ambiguity-preserves the gene Susceptibility to Hemolysis Linked gene for G6PD Deficiency Partial resistance to Malaria
  21. 21. Single Nucleotide Polymorphism 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
  22. 22. SNPs  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
  23. 23. Inherited Thrombophilia SNP in Factor V Leiden Prolonged immobility In Case of Hemorrhage than thrombosis Increased risk of Venous Thrombosis Advantage?
  24. 24. Combination of SNPs • In or near a gene Known as Haplotype • Inherited from each parent Predisposition to a Disease
  25. 25. Figure 7–10. Types of genetic variants that have been significantly associated with complex human traits and disease in 208 genome-wide association studies. See www.genome.gov/gwastudies/.
  26. 26. Mutation Disrupts Gene function ‘Single gene disorder’ Inherted;Mendelian fashion
  27. 27. Atypical Plasma cholinesterase Walter Kalow ;Suxamethonium sensitivity ;rate of metabolism Mendelian Autosomal Recessive trait Short acting NM blocker Plasma cholinesterase
  28. 28. 1:3000 fail to inactivate SXM rapidly Prolonged NM Block Recessive gene Abnormal plasma cholinesterase
  29. 29. Blood test Dibucaine Homozygoteswhen exposed HeterozygotesIntermediate Inhibits Abnormal enzyme less
  30. 30. Malignant hyperthermia  Autosomal dominant inherited.  Idiosyncratic ADR due to SXM on Ryanodine receptor  Also due to halogenated  Rapid rise of body temperature, inhalational agents (Halothane)  Incidence 1:20000  muscle rigidity,  tachycardia & cyanosis.
  31. 31.  Mechanism: Sudden rise in release Ca2+ from sarcoplasmic stores leading to muscle contraction & hyper metabolic rate.  Potentially fatal .  Important test family members of affected.  Impractical to screen routinely
  32. 32. 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
  33. 33. Acute intermittent porphyria  Commonest & most severe form of hepatic porphyria  Autosomal dominant  Mutation in gene coding Porphobilinogen deaminase(PBGD)
  34. 34. Haem Biosynthesis PBGD key enzyme Red cell precursors Hepatocytes & other cells
  35. 35. Mutation Reduces activity Haem precursors (incl.Porphyrin) PBGD Build up
  36. 36.  Strong interplay with environment through exposure to drugs ,hormones& other chemicals  Use of sedative, anticonvulsant or other drugs in patients undiagnosed-can be Lethal  Most drugs(not just CYP inducers) can precipitate acute attacks in susceptible individuals
  37. 37. ALA synthase in liver Induced by drugs like Barbiturates ALA(delta amino laevulanic acid) Porphyrins Increased ALA production Acute Attack
  38. 38. Frank disease 5 times more common in Women Hormonal Fluctuations Precipitate Acute Attacks
  39. 39. Drug acetylation status
  40. 40. Acetyltransferase • Single recessive gene associated with low enzyme activity Acetylation Elimination of Isoniazid
  41. 41.  American population; equal no's ‘fast’ &’slow’ acetylators  Other ethnic groups ;different proportions  Slow>Egyptians,british swedish  Rapid> Canadians,Asians,Latin americans
  42. 42. Isoniazid;2 different forms toxicity Peripheral Neuropathy Isoniazid Slow acetylators Hepatotoxicity Acetylhydrazine Fast acetylators
  43. 43. Hydralazine Acetyltransferase Metabolism of Procainamide Dapsone Other sulfonamides
  44. 44. Acetylator status Influences Drug induced lupus Skin, joints & Autoimmune kidneys Idiopathic ADR Caused By many agents
  45. 45. Aminoglycoside ototoxicity • Mitochondrial gene • Most common predisposing mutation m.1555A>G,mitochondrial DNA mutation • 30-60% ototoxicity in china(Aminoglycosides-cheap)
  46. 46. Bind to Bacterial ribosomes Mutation of human mitochondrial ribosomes is similar Aminoglycosides 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
  47. 47. Defect in Ethanol metabolism • 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
  48. 48.  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,
  49. 49. Personalized Medicine Understanding human genome Simpler methods identify genetic information Genetic information specific to individual No toxicity No trial & error Preselect effective drug
  50. 50. US FDA has approved PG labeling info to package inserts of over 50 drugs Use patchy
  51. 51. Clinical Pharmacogenetic tests  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 a test is less convincing than the ideal of an RCT of PG informed prescribing strategy versus current best practice
  52. 52. Tests increasingly used 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
  53. 53. Methodology Mutations in Germline All cells of the Next generation Venous blood samples(Chromosomal & Mitochondrial DNA in WBCs
  54. 54. Somatic cell mutations • Genomic tests done on DNA from samples of tumor Presence or absence guides drug selection obtained surgically. • Tests involve amplification of relevant sequences and Tumours Pathogenesis molecular biological methods often utilizing chip technology to identify various polymorphisms
  55. 55. ABACAVIR & HLA-B*5701  Abacavir-Reverse transcriptase inhibitor  Highly effective - HIV Infection  Severe Rashes  Susceptibility linked to HLA variant HLAB*5701
  56. 56. Anticonvulsants & HLAB*1502 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
  57. 57. Clozapine and HLA-DQB1*0201  Effective antipsychotic drug  Agranulocytosis 1% of patients  Studies-small  Specificity and sensitivity yet to be established
  58. 58. Thiopurines and TPMT  Thioguanine,Mercaptopurine & its prodrug Azathioprine Low TPMT activity High TPMT High Conc of active TGN in blood Lower conc TGN  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 Bone marrow Toxicity Reduced efficacy
  59. 59. Before treatment  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)
  60. 60. 5-FLUOROURACIL(5-FU) &DPYD 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
  61. 61. TAMOXIFEN & CYP2D6 TAMOXIFEN CYP2D6 Polymorphic variation Estrogen antagonist ENDOXIFEN  Suggested link between CYP2D6 genotype& efficacy.  Genotyping tests available.  Tetrabenzaine used to Huntington's disease may also be influenced by cyp2d6
  62. 62. IRINOTECAN & UGTA1*28  Topoisomerase I inhibitor.  Marked activity against colorectal & lung cancers(minority)  Toxicity(Diarrhoea & BM suppression very severe  Active metabolite SN-38  UDP glucuronyltransferase  Reduced activity syndrome Hyberbilirubinemia Gilberts
  63. 63. TRASTUZUMAB & HER2 • Herceptin is mAB that antagonizes epidermal growth factor(EGF) by binding to one of its receptors(human epidermal growth factor receptor 2-HER2) • Somatic mutation tissue HER2 in tumour
  64. 64. DASATINIB,IMATINIB & BCR-ABL1 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.
  65. 65. o IMATINIB-TYROSINE kinase inhibitor o CML & other myelodysplastic disorders.
  66. 66. WARFARIN & CYP2C9 +VKORC1 GENOTYPING  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
  67. 67. Conclusion Pharmacogenetics  proves that concept of susceptibility to ADR can be genetically determined  Offers possibility of a more precise ‘Personalised ‘ Medicine for several drugs & disorders.  Field of intense research, rapid progress. Challenge remains about its feasibility in Clinical setup

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This was made by an MD Pharmacology post graduate student for a seminar. References: Goodman&Gillman, Rang & Dale, Bhattacharya,Sen,Ray

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