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Dr. Raghu MN PHARMACOGENOMICS
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PROTOCOL Introduction History Polymorphisms Transporter Metabolic Receptor Enzymatic Ion channel Pharmacogenetics of ADR Pharmacogenetics and drug discovery. Conclusion Referrences
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INTRODUCTION Pharmagenomics- deals with influence of genetic variation on drug response in patients by correlating gene expression with drug’s efficacy or toxicity. Pharmagenomics Vs Pharmacogenetics Pharmagenetics – single gene interaction with drugs. Pharmacogenomics-whole genomic interaction.
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What is DNA??? DNA A, T, G, C Codon Gene Chromosome Genome ENGLISH Abcdefg….xyz Word Sentence Chapter Book
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Importance Of Pharmacogenomics “One-size-fits-all drugs” only work for about 60 percent of the population at best. But the other 40 percent of the population increase their risks of adverse drug reaction because their genes do not do what is intended of them.
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In today's world, only 30-60% of drugs work effectively to rid of a patient's illness. However, with the application of pharmacogenomics, the success rate of drugs will increase to 100%, curing all patients.
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HISTORY 510 B.C - PYTHAGORAS 1866 - MENDEL 1906 - GARROD 1956 - CARSON 1957 - VOGEL 1957 - KALOW 1960 - PRICE EVANS 1988 - GONZALEZ
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KEY CONCEPTS AND TERMS Monogenic variation Polygenic variation Somatic mutations Polymorphisms Single Nucleotide Polymorphisms(SNP’s)
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SINGLE NUCLEOTIDE POLYMORPHISMS Single nucleotide polymorphisms is DNA sequence variation occurring when a single nucleotide A,T,C or G in a genome.
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TRANSPORTER POLYMORPHISMS ABC transporters- resistance of malignant cells to anticancer agents. ABC transporters include ABCB1(P-glycoprotein) ABCC1(MRP1) ABCC2(MRP2) ABCG2(BCRP, ABCP)
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OTHER TRANSPORTER POLYMORPHISMS Serotonin transporter polymorphisms Solute carrier transporters Dopamine transporter polymorphisms Norepinephrine transporter polymorphisms
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POLYMORPHISMS RELATED TO METABOLISMS Cytochrome P450 (CYP450) are involved in various metabolic and biosynthetic process Account for biotransformation of 60% of most commonly prescribed drugs
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Warfarin and VKORC1
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Vitamin K epoxide reductase, complex 1 (VKORC1) Mutations in VKORC1 Cause Warfarin Resistance and Multiple Coagulation Factor Deficiency Type 2 VKORC1 synthesizes vitamin K epoxide reductase (VKOR), which resides in the endoplasmic reticulum of the hepatocyte and other cells VKOR is inhibited by warfarin, especially S-warfarin S-warfarin is metabolized by CYP2C9 VKOR activity is required for post-translational modification (?-glutamyl carboxylation) of Glu residues on clotting factors II, VII, IX, X and proteins C, S, and Z
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Genotyped 200 warfarin-treated patients for common SNPs in VKORC1. found VKORC1 C1173T, which explained 29% of the variability in warfarin dose Combined VKORC1 SNP, the CYP2C9*2 and CYP2C9*3 SNPs, and clinical factors, to derive a regression model that accounted for 56% of the variability in the warfarin dose.
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VKORC1 Distributions Stratified by Race Group B haplotypes had larger doses, more mRNA transcript for VKORC1, and were more frequent in white and African-American pts. Group A haplotypes had smaller doses and were more frequent in Asian pts.
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Receptor polymorphisms Receptors are basically proteins present in cytoplasm or plasma membrane or nucleus. Receive specific signals from surrounding cells or wider environment within organisms which signals the cell to do some specific work.
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Beta-2 Adrenergic Receptor Polymorphisms and Response to Albuterol in Asthma Hyperreactivity of the airways is the hallmark of asthma Airway smooth muscle contains beta-2 receptors that produce broncodilation Albuterol is a beta-2 agonist that is used in the treatment of asthma Produces smooth muscle cell relaxation and bronchodilation Forced expiratory volume in 1 second (FEV1) Phenotypic measure of response
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Beta-2 Polymorphisms and Response to Albuterol Single 8 mg albuterol dose Albuterol-evoked increases in FEV1 were higher and more rapid in Arg16 homozyotes compared with Gly carriers Codon 16 polymorphism is a determinant of bronchodilator response to albuterol Lima JJ et al. Clin Pharmacol Ther 1999; 65: 519-25
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Beta-blockers and Hypertension (HTN) HTN is the most prevalent chronic disease in the US and a contributor to morbidity and mortality Beta-blockers are one of the drugs used in the treatment of HTN Marked variability in response to beta-blockers 30-60% of patients fail to achieve adequate blood pressure lowering with beta-blockers Common beta-blockers used in HTN: Metoprolol Atenolol
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Podlowski, et al. J Mol Med 2000;78:90. Beta-1 Adrenergic Receptor Codon 49 Ser?Gly Codon 389 Arg?Gly
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Some receptor polymorphisms
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Enzymatic polymorphisms Glucose 6-phosphate dehydrogenase deficiency Atypical plasma cholinesterase enzyme polymorphisms
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33 Glucose-6-phosphate dehydrogenase activity Effects >100 million worldwide R-NH2 CYP MPO PGH Synthase R-NOH ERYTHROCYTE R-NOH O2 HgbFe+2 R-NO HgbFe+3 Reactive Oxygen NADH NAD+ MetHgb Reductase NADPH or GSH(?) NADP+ or GSSG(?) HMP Shunt G-6-PD Dependent SOD Catalase GSH Peroxidase Detoxification Splenic Sequestration Hemolytic Anemia GSH Semi-mercaptal sulfinamide R-NH2
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34 Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency Acetanilide Nitrofurantoin Primaquine Methylene Blue Sulfacetamide Nalidixic Acid Sulfanilamide Sulfapyridine Sulfamethoxazole
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35 INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic Group Incidence(%) Ashkenazic Jews 0.4 Sephardic Jews Kurds 53 Iraq 24 North Africa <4 India 5.7- 29%
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36 A. Atypical Plasma Cholinesterase a rapid acting, rapid recovery muscle relaxant - 1951 usual paralysis lasted 2 to 6 min in patients occasional pt exhibited paralysis lasting hrs cause identified as an “atypical” plasma cholinesterase Hydrolysis by pseudocholinesterase choline succinylmonocholine
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37 Atypical plasma cholinesterase has 1/100 the affinity for succinylcholine as normal enzyme occurs in 1:2500 individuals tested clinically via the abilityof dibucaine to inhibit esterase hydrolysis of benzoylcholine Adapted from: Pharmac Ther 47:35-60, 1990. normal enzyme inhibited > 70% abnormal inhibited < 30%
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38 NAT1*4 NAT2*4 NAT2*5A NAT2*6A NAT2*7A PABA PAS SMX PA DDS N- Acetyl transferase
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39 ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE Population % Slow % Hetero Fast % Homo Fast South Indians 59 35.6 5.4 Caucasians 58.6 35.9 5.5 Blacks 54.6 38.6 6.8 Eskimos 10.5 43.8 45.7 Japanese 12 45.3 42.7 Chinese 22 49.8 28.2
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40 XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN Hydrazines isoniazid hydralazine phenylzine acetylhydrazine hydrazine Arylamines dapsone procainamide sulfamethazine sulfapyridine aminoglutethimide Carcinogenic Arylamines benzidine ?-naphthylamine 4-aminobiphenyl Drugs metabolized to amines Sulfasalazine nitrazepam clonazepam caffeine
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Other Enzymatic polymorphisms
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Ion channel polymorphisms Pain is a complex phenomenon, mediated by transductive processes in the periphery, conduction to the spinal cord via first-order spinal sensory (dorsal root ganglion) neurons and processing at multiple higher levels that include the dorsal horn, thalamus and cortex . Nav1.7 sodium channels TRPA1 Kv9.1
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Pharmacogenomics and ADR Primary benefit of pharmacogenomics- helpful in reduction of adverse drug effects. By identifying which receptor/enzyme/ transporter/ metabolic defect is responsible to disease we can avoid many unnecessary drugs and related adverse effects.
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Role of pharmacogenomics in drug discovery Although several pharmacogenetic studies but its application for drug discovery has to be started on a larger scale. CYP2C9*2 and CYP2C9*3 are poor metabolizers compared to CYO2C9*1 ß2 adrenergic polymorphisms in asthma.
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New chemical entity(NCE)? Market(1960) (7.9 years) (9-12 years) New chemical entity(NCE)? Market(1990) Other important factor is cost Most important factor for termination of clinical trial is lack of efficacy Before the advent of pharmacogenomics the efficacy and safety was poorly predictable in clinical trial ? increased failure rates.
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Benefits of pharmacogenomics: More Powerful Medicines Better, Safer Drugs the First Time Improvements in the Drug Discovery and Approval Process Advanced Screening for Disease More Accurate Methods of Determining Appropriate Drug Dosages Decrease in the Overall Cost of Health Care
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Complexity of finding gene variations that affect drug response Limited drug alternatives No incentives for drug companies to make multiple Pharmacogenomics products Barriers to pharmacogenomics progress:
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The Future NUTRIGENOMICS TOXICOGENOMICS PROTEONOMICS BIOINFORMATICS and many more
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AmpliChip CYP450: CYP2D6 & CYP2C19
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S M A R T C A R D Raghu 9738081772 GENOME (Confidential) Personalized Medicine: Opinion: This sort of card would initially (~2025?) include mostly information related to drug metabolizing enzymes. Around ~2050 it might include an entire individual genome (or at least, few millions SNPs..) In your wallet May be by 2050?
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REFERENCES Brunton LL, Chabner BA, Knollmann BC; Goodman & Gilman's The Pharmacological Basis of Therapeutics - 12th Ed. Hall IP, Munir Pirmohamed; Pharmacogenetics – 1st Ed Liewei Wang, Mcleod HL, Weinshilboum RM; Genomics and Drug Response. N Engl J Med 2011;364:1144-53 . Lima JJ, Blake KV, Tantisira KG; Pharmacogenetics of asthma. Curr Opin Pulm Med. 2009 Jan ; 15(1): 57–62. Alex Sparreboom, Romano Danesi, Yuichi Ando; Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resis Updates 6 (2003) 71–84. Daly AK; Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundamental & Clinical Pharmacology 17 (2003) 27–41.
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