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Pharmacogenetics 141110022651 Conversion Gate01
Pharmacogenetics 141110022651 Conversion Gate01
DR.SOURAV CHAKRABARTY
PGT(MD)
DEPT OF PHARMACOLOGY
B.S. MEDICAL COLLEGE.
INDEX
1. INTRODUCTION.
2. PHARMACOGENETICS,PHARMACOGENOMICS
&’PERSONALISED MEDICINE.’
3. REVIEW OF ELEMENTARY GENETICS.
4. HISTORY OF PHARMACOGENETICS.
5. EFFECTS ON DRUG RESPONSE BY GENES.
6. DRUG DEVELOPMENT & PHARMACOGENETICS.
7. USES OF GENETIC METHODS TO IDENTIFY VARIED
DRUG RESPONSE.
8. PHARMACOGENETICS IN CLINICAL PRACTICE
9. CONCLUSION
INTRODUCTION
• Drug Response :Environmental factors and genetic
factors.
• Pharmacogenetic disorders(plasma cholinesterase
deficiency, acute intermittent porphyria, drug
acetylation deficiency and aminoglycoside ototoxicity.
• Pharmacogenomic tests:Tests for variations in human
leukocyte antigen (HLA) genes.
• Genes influencing drug metabolism.
• Drug targets such as the epidermal growth factor
receptor HER2, tyrosine kinase inhibitors and the main
target for warfarin, vitamin K epoxide reductase
(VKOR).
Exogenous & Endogenous factors contribute to variation in drug response
CONTD…………..
• every year about 2 million people are hospitalized for drug
adverse reactions. And every year 100,000 people die
because of these reactions.
• This makes it the 6th leading cause of death worldwide
• 49% of adverse drug reactions associated with drugs that
are substrates for polymorphic drug metabolizing enzymes.
• Interindividual variation :can be
pharmacokinetic/pharmacodynamic/ idiosyncratic.
• If not taken into account, can result in lack of efficacy or
unexpected side effects
• Twin studies:very useful to explore genetic basis of drug
response variation.
• Pharmacogenetic contribution to pharmacokinetic
parameters. t1/2 of antipyrine is more concordant in identical
in comparison to fraternal twin pairs. Bars show the t1/2 of
antipyrine in identical (monozygotic) and fraternal (dizygotic)
twin pairs. (Redrawn from data in Vesell and Page, 1968.)
• PHARMACOGENETICS = Pharma and genetics
• Pharma the Greek word i.e. PHARMACON, related to
Drugs.
• Genetics related to genes / genome
• The study of the genetic basis for variation in drug
response.
Understanding human
genome
Simpler methods
identify genetic
information
Genetic information
specific to individual
No No trial Preselect
toxicity & error effective drug
REVIEW OF ELEMENTARY GENETICS
Definitions:
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. Referring to having
a gene for a disease for example, sickle-cell
disease is caused by a mutant allele of a haemoglobin
gene.
• An allele is an alternative form of
a gene (one member of a pair) that is
located at a specific position on a
specific chromosome
CONTD………..
• Mutations :Heritable changes in the base sequence of DNA.
• Occur during crossing over of DNA during Meiosis.
• Polymorphism :Variation in the DNA sequence that is present at an
allele frequency of 1% or greater in a population.
• Arise initially because of a mutation.
• If nonfunctional stable.
• If disadvantageous die out during subsequent generations .
• Two major types: single nucleotide polymorphisms (SNPs) and
insertions/deletions (indels)
• cosmopolitan or population (or race and ethnic) specific.
• 95% of the genome is intergenic, most polymorphisms are unlikely
to directly affect the encoded transcript or protein.
• Most pharmacogenetic traits are multigenic rather than monogenic.
MARKERS OF GENETIC
VARIATION
Types of Polymorphisms
• Single Nucleotide
Polymorphism (SNP): GAATTTAAG
GAATTCAAG
• Insertion/Deletion: GAAATTCCAAG
GAAA[ ]CCAAG
CONTD……………
• SNPs occur every 100–300 bases along
the 3 billion base human genome.
• The greatest number of DNA variations
associated with diseases or traits are
missense and nonsense mutations,
followed by deletions.
HISTORY
P4502C9
Other
P4502C8
P4501A2
P4503A4
P4502B6 P4502A6
MUTANT ALLELES OF PHASE I ENZYMES
CYP 450
Mutant Alleles Substrates
gene
Warfarin, losartan
CYP2C9*1 *2, *3, *4, *5, *6 phenytoin, tolbutamide
*2, *3, *4, *5, Proguanil, Imipramine,
CYP2C19*1 Ritonavir, nelfinavir,
*6, *7, *8 cyclophosphamide
Clonidine, codeine,
*1XN, *2XN, promethazine,
CYP2D6*1 *3,*4,*5, *6 propranolol, clozapine,
*9,*10,*17 fluoxetine, haloperidol,
amitriptyline
B.intermediate metabolizer heterozygous for the wild may require lower than
phenotype (IM) (10 - type allele average drug dose for
15%) optimal therapeutic
response.
CYP2C19 Omperazole
HLA-B5701 Abacavir
HLA-B1502 Carbamazepine
G6PD Deficiency Rasburicase; Dapsone; Primaquine; Chloroquine
SMART CARD
Person’s name
GENOME
(Confidential)
Personalized
medicine
BIBLIOGRAPHY
1. THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS ,GOODMAN & GILMAN,12TH
EDITION,2011,PAGE 145-165.
2. RANG & DALE’S PHARMACOLOGY,7TH
EDITION,2012,PAGE 132-137.
3. METHODS IN MOLECULAR BIOLOGY,VOL
448,PHARMACOGENOMICS IN DRUG
DISCOVERY & DEVELOPMENT,GARY
HARDIMAN,PAGE 21-29.
Thank You for
your Attention!