Surajit-Pharmacogenetics

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Slide 1: 

WELCOME YOU ALL

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PHARMACOGENETICS Surajit Saha M.Pharm 1st sem Dept. of Pharmaceutics

INTRODUCTION : 

INTRODUCTION The term pharmacogenetics comes from the combination of two words: Pharmacology and Genetics Pharmacogenetics is the study of genetic factors that influence how a drug responses.

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Exogenous & Endogenous factors contribute to variation in drug response

AIM OF PHARMACOGENETIC STUDIES : 

AIM OF PHARMACOGENETIC STUDIES Identify and categorize the genetic factors that underlie the differences and apply this in clinical practice Rational, individual therapy Screening for those patients who carry the genes which place them at risk in case of certain therapies Discovering which drugs are potentially dangerous for carriers of a given polymorphism Establishing the frequency of pharmacogenetic phenotypes

DNA IS INFORMATION : 

DNA IS INFORMATION DNA A, T, G, C Codon Gene Chromosome Genome ENGLISH Abcdefg….xyz Word Sentence Chapter Book

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The differences in the response to a given drug can be attributed to two major factors that are under genetic influence: Pharmacokinetic: genetically based differences in the processes influencing bioavailability Pharmacodynamic: genetically based differences in the proteins at which the drug acts

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EXAMPLES OF GENETIC POLYMORPHISMS INFLUENCING DRUG RESPONSE

MOLECULAR MECHANISM OF GENETIC POLYMORPHISM : 

MOLECULAR MECHANISM OF GENETIC POLYMORPHISM Genetic variation occuring with a frequency of 1% or more in the population 1. SNP (single nucleotide polymorphism): most frequent type difference in a single base of the genomic sequence usually 1/1000 base most does not influence the structure or function of proteins SNP can occur In exons (may alter the structure of proteins and may lead to functional consequences) In introns (may influence splicing) In the regulatory regions (may influence expression of the gene)

Promoter , Intronic , Intergenic etc MECHANISM OF SNPs

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2. Insertion/deletion( Indels) polymorphism: insertion or deletion of a few nucleotides 3. Variable number tandem repeats: variation in the number of times a sequence of several hundred base pairs is repeated 4. Simple tandem repeats (microsatellites): 2-4 nucleotides repeated a variable number of times

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Monogenic (influence by single gene) Polygenic (influenced by several genes, the effect may be additive or interactive) Multifactorial (both genetic and environmental factors contribute) GENE POLYMORPHISM----PHARMACOGENETIC TRAITS

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Genotype: gene structure encoding for the given characteristics Phenotype: the manifestation of the genotype, which can be observed and can be influenced by other factors: Other gene products Environment Acquired characteristics Frequency of genetic polymorphisms differs greatly among ethnic groups The functional relevance of a given polymorphism can vary across ethnic groups

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Determination of genotype: PCR,Gel electrophorosis Determination of phenotype: determination of metabolic rate (level of original drug/metabolit in urine) after administration of a given dose of the drug, pharmacokinetic parameters are measured (halflife, clearance, plasma levels) Distribution of phenotypes in the population: Multimodal (usually bi- or trimodal) distribution indicates determination by a single gene having polymorphic variants Unimodal distribution indicates polygenic multifactorial inharitance, or monogeic inheritance but no polymorphism

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The function is usually bi- or trimodal indicating two or three phenotypes: Enhanced/extensive metaboliser: intensive metabolisation, resulting in low plasma concentration of the drug usually heteozygote or homozygote dominant Intermedier metaboliser Poor metaboliser or nonmetaboliser: Slow or no metabolisation of the drug resulting in high plasma concentration for an extended time Usually homozygote recessive

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Rx +  =  Rx +  =  Rx +  =  ? ? ? ?

PERSONALISED MEDICINE : 

PERSONALISED MEDICINE Personalised medicine is the therapy that will directly affect the genomic structure of a patient rather than any kind of “Trial & Error” method prescribed by a therapist or by a doctor. Example: Hypertension Antihypertensive drug

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Neuromuscular blocking agent: Example: Suxamethonium Category : Anaesthetics MoA: Blocks neuromuscular junction (Hydrolyzed by plasma cholinesterase) Availability: 1 in 3000 individuals fails to inactivate suxamethonium rapidly Results: Permanent paralysis due to lack of cholinesterase

IDIOSYNCRATIC REACTION : 

IDIOSYNCRATIC REACTION An idiosyncratic reaction is a qualitatively abnormal & extra-ordinary response to a drug which is different from its charesteristic pharmacological action. Harmful,sometime fatal reaction-occurs in small minority of individuals Reaction may occur with low dose. Genetic factor Immunological factors

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More powerful medicines: Safer drugs the first time: More accurate methods of determining dosages: Better vaccines: POTENTIAL BENEFITS OF PHARMACOGENETIC STUDY

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Drug response Drug targets -- Psychiatry Drug metabolism Drug development PHARMACOGENETICS IN PRACTICE

REFERENCES : 

REFERENCES Brunton L, Parker K, Gillman G A, Blumenthal D, Buxton I, Pharmacogenetics, “Manual Of Pharmacology & Therapeutics”11th edition, The McGraw-Hill companies, International edition, New Delhi, pp-57-71. Rang P H, Dale M M, Ritter M J, Flower J H, Individual variation & drug interaction, “Pharmacology” 6th Edition, Churchill Livingstone, Elsevier Limited, London, pp-739-749. Berg.M.J, Tymoczko.L.J, Stryer.L,DNA,RNA,Fiow of Genetic information, “Biochemistry”,5th edition, W.H.Freeman & Company.

Contd…. : 

Contd…. 4.www.slideworld.org/slidestag.aspx/pharmacogenetics 5.www.clinicalresearch.pitt.edu/docs/Pharmacogenomics.pdf 6.www.sciag.ukzn.ac.za/.../PHARMACOGENETICS%20GENE%20360.ppt 7.www.cop.ufl.edu/.../Cattaneo%20pharmacogenetics%20Stresa.pdf 8.www.uiowa.edu/~c046138/genet.ppt

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THANK YOU