Polymorphism affecting drug metabolism.pptx

Genetic Polymorphism
Types of genetic Polymorphism
Single neucleotide Polymorphism
Insertion/Deletion Polymorphism
Polymorphic Repetetive Sequences
Copy Number Variations
Pharmacogenetics
Extensive Metabolizers
Intermediate Metabolizers
Poor Metabolizers
Ultra Rapid Metabolizers
Drug Metabolism
Genetic Polymorphism in Drug Metabolism
P450 enzymes in Drug Metabolism
Cytochrome P4502C Subfamily
CYP2C19 and Diazepam
Phase 1 Enzymes
Phase 2 Enzymes

1. POLYMORPHISM AFFECTING DRUG METABOLISM NAME: SABITRI PRADHAN DEPT . OF PHARMACOLOGY

2. GENETIC POLYMORPHISM POLYMORPHISM : P olymorphism is the occurrence of two or more clearly different forms among the members of a population or colony or the life cycle of an individual organism. A lso referred to as alternative phenotypes, in the population of a species.  GENETIC POLYMORPHISM: The existence of many forms of DNA sequences at a locus within the population. It is the variation in DNA sequences. Genetic polymorphism of a drug metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphism are generated by mutations in the genes for these enzymes, which caused decreased , increased, or absent enzyme expression or activity by multiple molecular mechanisms.

3. TYPES OF GENETIC POLYMORPHISM Genetic polymorphism are of four types : SINGLE NEUCLEOTIDE POLYMORPHISMS (SNPs) INSERTION/DELETION POLYMORPHISM POLYMORPHIC REPETETIVE SEQUENCES COPY NUMBER VARIATIONS

4. SINGLE NEUCLEOTIDE POLYMORPHISMS(SNPs) SNPs are single base pair alterations and its most prominent source of variation in human genome. A DNA sequence variation that occurs when a single nucleotide (adenine, thymine,cytosine,or guanine) in the genome sequence is altered. SNPs holds the key role in defining the risk of an individual’s susceptibility to various illnesses and response to drugs. SNPs in the coding region are of two types: Synonymous: Do not affect the protein sequence. Nonsynonymous : Change the amino acid sequence of protein.

5. INSERTION/DELETION POLYMOPHISM An insertion/deletion polymorphism, commonly abbreviated ‘ indel ’ is a type of genetic variation in which a specific nucleotide sequence is present (insertion) or absent (deletion) . An Insertion changes the DNA sequence by adding one or more nucleotides to the gene. As, a result, the protein made from the gene may not function properly . A deletion changes the DNA sequence by removing at least one nucleotide in a gene. Specific nucleotide sequence of various lengths (1-several 100bps) is inserted or deleted . Widely spread across the genome.

6. POLYMORPHIC REPETETIVE SEQUENCES Variable number tandem repeats comprise over two thirds of the human genome. Can involve as few as 2 copies or many thousands copies. Based on the size of repeat unit it can be classified as followed :- MACROSATELLITES (repeats longer than 100 bps) MINISATELLITES (repeats usually less than 50 bps long) MICROSATELLETIES (repeat unit less than 10 bps)

7. COPY NUMBER VARIATIONS It is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. It is a type of duplication or deletion event that affects a considerable number of base pairs. Another frequent source of genome variation . It involves repetition of complete gene sequence. It occurs due to duplication or deletion events.

8. PHARMACOGENETICS It is the study of how a person’s genes affect the way he or she responds to drugs. It is being used to learn ahead of time what the best drug or the best dose of a drug will be for a person. genotype analysis can be used to identify DNA changes in specific metabolic pathways that produce abberant phenotypes. Hence, patients can be classified according to their ability to metabolize certain drugs as: Extensive metabolizers Intermediate metabolizers Poor metabolizers Ultra rapid metabolizers

9. EXTENSIVE METABOLIZERS Normal metabolism. Expected response at standard dose. INTERMEDIATE METABOLIZERS Slower than the normal metabolism. May experience some or lesser degree of the consequences of poor metabolizers.

10. POOR METABOLIZER Too slow or no metabolism. No response at standard dose. High risk for adverse reactions and side effects. ULTRA RAPID METABOLIZER Faster than normal metabolism. No response at standard dosage (non-responder). High risk for adverse reactions and side effects.

11. DRUG METABOLISM The metabolism of drugs into more hydrophilic metabolites is essential for their elimination from the body, as well as for termination of their biological and pharmacological activity. Drug metabolism or biotransformation reactions are classified as either phase I functionalization reactions or phase II biosynthetic (conjugation reactions). The enzyme systems involved in the biotransformation of drugs are localized primarily in the liver. These biotransformation reactions are carried out by CYPs (cytochrome CYP450 isoforms) and by variety of transferases.

12. GENETIC POLYMORPHISM IN DRUG METABOLISM

13. P450 ENZYMES IN DRUG METABOLISM The polymorphic form P450(CYP) enzymes superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins and carcinogens. Genotyping of CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism , the most important polymorphisms are those of the genes coding for CYP2C9,CYP2C19,CYP2D6 and CYP3A4/5,which can result in the therapeutic failure or serve adverse reactions.

14. CYTOCHROME P4502C SUBFAMILY It accounts for approximately 18% of the CYP content in the liver. CYP2C19 It catalyzes the metabolism of several proton pump inhibitors (e.g omeprazole), diazepam,thalidomide and some barbiturates. It is also responsible for inactivation of propanalol and metabolic activation of anti malarial drug Proquanil. There are 6 different types of polymorphism – CYP2C9*1 ,*2,*3,*4,*5,*6

15. CYP2C19 AND DIAZEPAM Diazepam is demethylated by CYP2C19. Plasma diazepam half-life is longer in individuals who are homozygous for the defective CYP2C19 *2 allele compared to those who are homozygous for the wild type allele. Half life of the desmethyldiazepam metabolite is also longer in CYP2C19 poor metabolizers. High frequency in Asian population. Diazepam induced toxicity may occur as a result of slower metabolism hence careful dosing in Asian population should be done.

16. REFERENCES David B.Troy., Paul Beringer. Remington; The Science and Practice of Pharmacy; 21 st Edition; pages:1230-1239. Shargel Leon; Comprehensive Pharmacy Review; 7 th edition; 2010. H.L. Sharma; K.K. Sharma; Principles of Pharmacology,3 rd edition;2017. http://www.biology-online.org/dictionary/Genetic_polymorphism .

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