Pharmacogenomics: Pharmacology

Front 1

Pharmacogenomics

Back 1

studies the individual differences in response to drug therapy due to inheritance

Front 2

Factors that influence drug response phenotype:

Back 2

age
gender
underlying disease
genetic variation

Front 3

What do gene differences between individuals affect?

Back 3

drug targets
drug transporters
enzymes that catalyze drug metabolism

Front 4

Genetic Variation General

Back 4

Any two people differ on average at about 1 nucleotide in every 1,000 their genome totaling around 3 million base pairs throughout the genome.

Front 5

SNPs

Back 5

single nucleotide polymorphisms

one nucleotide is exchanged for another at a given position

Front 6

Nonsynonymous Coding SNP

Back 6

if an SNP changes the encoded amino acid

Front 7

Other Differences in DNA due to ?

Back 7

insertions
deletions
duplications
reshufflings

Front 8

Where do functionally sig. DNA difference tend to fall?

Back 8

within genes: within their coding sequences or in promoter, enchancer, splice sites, or other sequences that control gene transcription or mRNA stability

Front 9

Promise of Pharmacogenomics

Back 9

maximize drug efficacy by targeting drugs only to those patients who are most likely to benefit while, at the same time, reducing the incidence of adverse drug reactions

Front 10

Types of Genetic Variation

Back 10

1. variation in drug metabolism (pk)
2. variation in drug targets (PD)
3. idiosyncratic drug effects

Front 11

What is the most common factor responsible for pharmacogenetic variation in drug responses?

Back 11

Genetic variation in enzymes that catalyze drug metabolism: polymorphisms

Front 12

Examples of Enzymes

Back 12

Butyrylcholinesterase

N-acetyltransferase 2

CYP2D6

Thiopurine S-methyltransferase

Front 13

Butyrylcholinesterase Polymorphism

Back 13

BChE hydrolyses acetylcholine and it's analogues

patietns with variations have decreased rate of metabolism of the muscle relaxant succinylcholine: which results in prolonged paralysis

Front 14

N-acetyltransferase 2 Polymorphism

Back 14

phase II enzyme

catalyzes acetylation of isoniazid and other drugs

inherited functionality

Front 15

Slow Acetylators vs. Fast Acetylators

Back 15

slow: metabolize isoniazid slowly and have high blood drug levels: associated with drug toxicities

fast: metabolize isoniazid rapidly and have low blood druge levels

Front 16

Examples of Drug Toxicities due to Slow Acetylators

Back 16

Hydralazine and Procainamide induced Lupus

Isoniazid induced neurotoxicity

Front 17

CYP2D6 Polymorphism

Back 17

member of cytochrome P450 family, phase I drug -metabolizing enzymes

Antidepressants
Antiarrhythmics
analgesics

Front 18

Examples of CYP2D6 Differences

Back 18

Debrisoquine: Antihypertensive

Sparteine: Oxytotic

Front 19

Poor Metabolizers
Extensive Metabolizers
Ultrarapid Metabolizers

Back 19

poor: homozygous for recessive alleles, low activity
5-10% Caucasions

extensive: heterozygous or homozygous for wild-type allele
3% in Spaniards
13% in Ethiopians

Ultrarapid: have 13 copies of the gene

Front 20

what drugs does the CYP2D6 metabolize?

Back 20

Metoprolol: B-adrenergic blocker

Haloperidol: Neuroleptic

Codeine and Dextromethrophan: Opiods

Fluoxetine, Imipramine, and Desipramine: Antidepressants

Front 21

Thiopurine S-methyltranferase Polymorphism (TPMT)

Back 21

catalyzes the S-methylation of the anticancer thiopurines 6-mercatopurine and azathioprine

thiopurines have a narrow therapeutic index and some patients suffer from life threatening myelosuppression

Front 22

Example

Back 22

TMPT*3A associated with low TPMT activity

5% of caucassions

Homozygotes are at risk for myelosuppression when treated with thiopurine drugs: treat these patients with 1/10 or 1/15 normal dose

Front 23

Variation in Drug Targets: Pharmacodynamics

Back 23

5-lypoxygenase

EGFR

Front 24

5-Lipoxygenase Polymorphism

Back 24

metabolism of arachidonate by lipoxygenases results in production of leukotrienes

leukotrienes implicated in asthma

encoded by ALOX5 gene

promoter region contains 5 repeat allele (VNTRs) 77%

patients homozygous for repeat numbers other than the wild type version express less 5-lipoxygenase and respond less with inhibitor treatment

Front 25

Does a polymorphism need to cause a disease in order to influence the treatment of a disease?

Back 25

NO

Front 26

Mutations in the Gene encoding EGFR

Back 26

epidermal growth factor receptor

drug target in somatic (tumor) DNA involving gain of function mutation in the gene encoding EGFR

over expressed in nonsmall cell lung cancer

Front 27

Gefitinib

Back 27

inhibitor of tyrosine kinase of EGFR

approved for treatment of NSCLC

patients of Asian orign respond better than Caucasion

patients with mutations in ATP-biding site of the tyrosine kinase domain receptor respond better to gefitinib

frequency of mutations was 26% in japan and only 2% in US

Front 28

Multiple Genes: Pharmacokinetics + Pharmacodynamics example

Back 28

Warfarin

racemic mixture: S is 3-5 times more potent than R-warfarin

the stereoisomers are metabolized by different enzymes

S via CYP2C9

R via CYP2C9, CYP3A4, 1A1, 1A2, ETC.

Front 29

Variant Alleles of CYP2C9

Back 29

C9*2
C9*3
C9*1 wild type

variants have a lower activity than the wild type allele

Front 30

What do patients require with the variant alleles of CYP2C9?

Back 30

decreased doses of warfarin to achieve an anticoagulant effect otherwise they will have increased risk of bleeding

Front 31

Pharmacodynamic component of Warfarin therapy:

Back 31

the molecular target for warfarin is vitamin K epoxide reductase

gene encoding the enzyme is vitamin K epoxide reductase complex 1, VKORC1

Front 32

Importance of VKORC1

Back 32

shows a number of polymorphisms which affect warfarin dose requirement

responsible for approximately 25 to 30% of differences in warfarin dose. 5% to 15% is due to variations in CYP2C9