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A SEMINOR ON DOSAGE ADJUSTMENT IN GENETIC VARIABILITY
PRESENTED TO
KUMARA SWAMY
SENIOR LECTURER
PRESENTED BY
JYOTHI.K
PHARM.D (PB) 2 ND YEAR
Pharmacogenetics Pharmacogenetics involves the search for
genetic variations that lead to interindividual difference in drug response
or
The study of variation in drug responses under hereditary control is known as Pharmacogenetics.
Introduction
Gene is a series of codons that specifies a particular protein.
Gene contain several regions
exons – that encodes for the final protein
introns-that consists of intervening non coding regions.
promoter regions that regulate gene transcriptions.
Cont…At each gene locus an individual carries 2
alleles one from each parent.
Allelle is defined as the sequence of nucleic acid bases at a given gene chromosomal locus.
Two identical allelles make up a homozygous genotype.
Two different allelles make up a heterozygous genotype.
A phenotype refers to the outward expression of the genotype.
Introduction
- Variability in drug response between individuals is due to genetic and environmental effects on drug absorption, distribution, metabolism or excretion( pharmacokinetics) and on target protein (receptor) or downstream protein signalling ( pharmacodynamics)
-several idiosyncrcally determined atic adverse drug reactions have been explaned in terms of genetically determined variation in the activity of the enzymes involved in metabolism or of other proteins (eg-variants of haemoglobin and haemolysis).
Cont…
Mutation results in a change in the nucleotide sequence of DNA,
Single nucleotide polymorphismGENETIC INFLUENCE ON DRUG METABOLISM
Abnormal sensitivity to a drug may be the result of a genetic variation of the enzymes involved in the metabolism.
PHASE I DRUG METABOLISM
CYP2D6
The CYP2D6 gene is found on chromosome 22 and over 50 polymorphic variants.
The function of this enzyme(4- hydroxylation of debrisoquine, an adrenergic neuron blocking drug previously used to treat HTN ) is deficient in about 7-10 % of the UK population.
Cont….The many genotypic variants yield 4 main
phenotypes of CYP2D6
- poor metabolizers(7-10% of caucasians)
- intermediate metabolizers and extensive metabolizers ( 85-90% 0f caucasians)
- ultra rapid metabolizers ( 1-2 % of caucasians, but upto 30% in egyptians)
UM patients require higher doses of CYP2D6 drug substrates for efficacy
CYP2C9 polymorphism The CYP2C9 gene is found on chromosome 10
and 6 polymorphic variants have been found
The rate of oxidation of a sulphonylurea drug, TOLBUTAMIDE .
CYP2C9 polymorphisms cause reduced enzyme activity, with 1-3% of caucasians being poor metabolizers(slow)
Drug metabolized by CYP2C9 are eliminated slowly in poor metabolizers, who are therefore susceptible to dose related ADRS.
Eg: warfarin
losartan
celecoxib
CYP2C19 polymorphism CYP2C19 is found on chromosome 10 and 4
polymorphic variants have been found.
These polymorphism produce reduced enzyme activity and 3-5% of caucasians and 15-20% of asians have genotype which yield a poor(slow) metabolizer phenotype.
Such patients require lower doses of drugs metabolized by CYP2C19 enzyme.
Eg: PPI’S ( omeprazole, pantaprazole, lansoprazole)
Some anticonvulsants(phenypoin, phenobarbitone)
Variation in drug metabolism/pharmacodynamics due to genetic polymorphism
Pharmacogenetic variation
Mechanism occurence Drugs involved
PHASE I DRUG METABOLISM:Defective CYP2D6
Functionally defective
7-10% caucasians,1%saudi arabians,30% chinese
Originally defined by reduced CYP2D6 debrisoquine hydroxylation; beta blockers; metoprololTCA: nortriptylinreSSRI: fluoxetineOpiods: morphineAnti-dysrhythmics: encainide
ULTRA RAPID METABOLISM: CYP2D6
Duplication 2D6
1-2% caucasians, 30% egyptians
Pharmacogenetic variation
Mechanism occurence Drugs involved
PHASE II DRUG METABOLISM:Rapid acetylator status
Increased hepatic N-acetyl transferase
45% caucasians isoniazid; hydralazine; some sulphonamides;phaenelzine;dapsone;procainamide
Abnormal pharmacodynamic responses:Malignant hyperthermia with muscular rigidity
Polymorphism in ryanodine receptor
1: 20 000 of population
Some anesthetics , especially inhalational eg- isoflurane, suxamethonium
Other:Ethanol sensitivity
Relatively low rate of ethanol metabolism by aldehyde dehydrogenase
orientals ethanol
Variation in drug metabolism/pharmacodynamics due to genetic mutations
Pharmacogenetic variation
Mechanism occurence Drugs involved
G6PD deficiency, drug induced haemolytic anaemia
80 distinct forms of G6PD
10 000 000 affected world wide
8- aminoquinolines, antimicrobials and minor analgesics
Methaemoglobinaemia:Drug induced haemolysis
Methaemoglobin reductase deficiency
1: 100 are heterozygotes
Same drugs as for G6PD deficiency
Acute intermittent porphyria:Exacerbation induced by drugs
Increased activity of D-amino levulinic synthetase secondary to defective porphyrin synthesis
Aute intermittent type 15: 1000 000 in sweden : porphyria cutanea tarda 1:100 in afrikaaners
Barbiturates, cloral, chloroquine, ethanol, griseofulvin, sulphonamides, phenytoin,