Genetic polymorphism was formerly applied to variants occurring at a frequency greater than 1%.
Types: SNPs,Insertions or deletions
Pharmacokinetic variations and pharmacodynamics variations
Application on G6PD deficiency
2. Introduction
• Different individual exhibits different response to a same dose of drug.
• Mainly genetic built of individuals is responsible for the variations of
drug responses.
• Genetic variability of drug responses could be due to single gene
mutation or polygenic mutation ( majority being single nucleotide
polymorphisms).
• The term Genetic Polymorphism was formerly applied to variants
occurring at a frequency greater than 1%.
3. Pharmacogenetics
• Pharmacogenetics: Study of genetic variation in drug response in an
individual and often implies large effects of a small number of DNA
variants.
• Pharmacogenomics : Study of larger numbers of variants, in an
individual or across a population, to explain the genetic component of
variable drug responses.
• Aim of pharmacogenetics:
To identify which of these variants or combination of variants have
functional consequence for the drug effects.
4. Importance of Pharmacogenetics to
Variability in Drug Response
• Depends on the environmental factors and genetic factors.
• Result in altered protein sequence and function or in altered protein
levels through regulatory variation.
• Key genes for variable drug actions are those which encoding:
1. Drug-metabolizing enzymes
2. Drug transport molecules
3. Targets with which drugs interact
4. Host of other genes that modulate the context in which drugs act.
5. Types of Genetic Variants
1. Single-nucleotide polymorphisms (SNPs)
2. Insertions or deletions :
Range in size from a single nucleotide to an entire chromosome;
smaller ones are generally termed indels, and larger ones are designated
CNVs (Copy Number Variations).
Indels :- e.g. TA repeat in UGT1A1 [TATATAA TATATATAA]
CNVs :- Gene Duplications e.g., CYP2D6, up to 13 copies
6. Pharmacogenetic Traits
• A pharmacogenetic trait is any measurable trait associated with a drug.
Some traits reflect the beneficial or adverse effect of a drug in a
patient.
• Disadvantage : They reflect many genetic and nongenetic influences,
• Advantage : They indicate a drug’s clinical effects.
• Examples : Enzyme activity, drug or metabolite levels in plasma or
urine, or drug-induced changes in gene expression patterns.
10. Application on G6PD deficiency
• First pharmacogenetic examples to be discovered (X-linked
monogenic trait)
• Results in severe hemolytic anemia in individuals after ingestion of
fava beans or various drugs, including many antimalarial agents.
• Normally present in red blood cells, regulates levels of the antioxidant
glutathione.
• Antimalarials such as primaquine increase red blood cell fragility in
individuals with G6PD deficiency, leading to profound hemolytic
anemia;
11. Continue….
• More common in African Americans.
• Severity of the deficiency syndrome varies among individuals and is
related to the amino acid variant in G6PD.
• Severe form is associated with changes at residues that are highly
conserved across evolutionary history.
12. Pharmacokinetic Alterations
• Determinants : Particular metabolizing enzymes and transporters,
affect drug concentrations and therefore they are major determinants
of therapeutic and adverse drug response.
• Acording to drug metabolizing enzymes individuals are categorized
into :
1. Poor metabolizer having a reduced enzyme efficacy which leads
to increase risk of adverse drug reactions or toxicity.
2. Ultra-rapid metabolizers having significantly increased enzyme
efficacy, which may increase chance of therapeutic failure.
13. Drug metabolism :
Gene Product (Gene) Drugs Responses Affected
CYP2C9 Warfarin, phenytoin,
NSAIDS
• Anticoagulant effect
of Warfarin.
CYP2C19 Omeprazole,
voriconazole,
propranolol,
clopidogrel
• Peptic ulcer
Response to
Omeprazole.
• Cardiovascular
events after
clopidogrel.
14. Drug metabolism
Gene product (Gene) Drug Responses Affected
CYP2D6 B blockers,
antidepressant, codeine,
tamoxifen
• B blocker effect
• Tardive dyskinesia
from antipsychotics
• Codeine efficacy
• Breast cancer
recurrence after
tamoxifen
CYP3A4/3A5/3A7 Tacrolimus, midazolam,
quinidine
• Efficacy of
immunosuppressive
effects of tacrolimus
15. Drug transport :
Gene product (gene) Drugs Responses Affected
N-acetyltransferase (NAT2) Isoniazide, hydralazine,
sulfonamides,
procainamide, dapsone
• Isoniazide neurotoxicity
• Hydralazine-induced
lupus
• Hypersensitivity to
sulfonamides
Glutathione transferases
(GSTM1,GSTT1,GSTP1)
Several anticancer agents • Decreased response in
breast cancer,
• more toxicity and worse
response in acute
myelogenous leukemia.
16. Drug transport
Gene product (Gene) Drugs Responses affected
Organic cation transporter
(SLC22A2, OTC2)
Metformin • Renal clearance
Thiopurine
methyltransferase (TPMT)
Mercaptopurine,
azathioprine
• Thiopurine toxicity and
efficacy,
• risk of second cancers
Catechol-o-
methyltransferase
Levodopa • Enhanced drug effects
UDP-glucuronosyl-
transferase
Irinotecan,bilirubin • Irinotecan toxicity
18. Modifiers
Gene product (Gene) Drugs Responses affected
G6PD deficiency Primaquine and other
oxidizing drugs
Haemolytic anemia
Iron channels (HERG,
KvLQT1, Mink, MiRP1)
Erythromycin, cisapride,
clarithromycin, quinidine
• Increase risk of drug-
induced torsades de
points
• Increased QT interval
MTHFR Methotrexate • GI Toxicity
Prothrombin, factor V Oral contraceptives • Venous thrombosis risk
19. Clinical Pharmacogenomics
• Used to predict the safety, toxicity and efficacy of the drugs either as
part of drug development or as part of an individual’s optimum
treatment regimen.
• Techniques for gene specific drug development:
1. Recombinant DNA technology
2. Polymerase chain reaction
3. High-throughput DNA sequencing and related molecular biology
techniques.
20. Step towards Personalized Medicine
• Focuses on individualized drug treatment according to each Patient’s
molecular diagnosis and genetic makeup.
• Appropriate drug selection and rational dosage adjustment.
• Have clinical significance mostly for prodrugs and drugs with narrow
therapeutic index.
• Drug safety is always the area of primary concern.
• Targeted cancer therapy is a promising individualized drug therapy.
21. Challenges
Implementation of personalized medicine as routine care till not
possible due to many issues like:
• Particular drug is effected by multiple factors (Multiple genes are
responsible for same adverse effect).
• Lack of suitable test to detect the genetic variation (If available then
it’s cost-effectiveness may be a burden).
• Exploring sensitive information (someone’s genetic makeup) may rise
privacy, security and ethical issues.
• Clinicians not always aware of tests availability.
22. Conclusion
• Deal with the interactions between genetics and drug response.
• Have a great application in drug development and therapeutics
• Step towards personalized medicine and a critical approach to solve
the problem of variations in drug response due to genetic
polymorphism.
• Rational drug therapy on the basis of Patient’s genotype to maximize
benefit and minimize harm.
• To foresee the safety, toxicity and efficacy of drugs as part of drug
discovery and development.
