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)

Phase II drug metabolism

Acetylator status ( N-acetyltransferase)

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,