5. Pharmacogenetics And Pharmacogenomics Flashcards Preview

FMS: Pharmacology > 5. Pharmacogenetics And Pharmacogenomics > Flashcards

Flashcards in 5. Pharmacogenetics And Pharmacogenomics Deck (29):
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1. To understand the uses of pharmacogenomic information in drug choice, monitoring and dosing (objective)

Answer later

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2. To understand how genetic polymorphisms can affect the pharmacokinetic and pharmacodynamic properties of a drug (objective)

Answer later

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3. To understand specific examples of pharmacogenetic differences and how they impact therapeutic and adverse drug responses (objective, see list below)

Answer later:
-Common cytochrome P450 polymorphisms and their effects on drug metabolism
-Isoniazid fast and slow acetylators
-Thiopurine methyltransferase and the use of purine analogs as anti-cancer agents
-Roles for glucose-6-phosphate dehydrogenase variants in drug-induced hemolysis

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Pharmacogenetics (definition)

Influence of genetic variability on drug responses (both therapeutic and toxic drug responses)

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Pharmacogenomics (definition)

Use of genetic information to predict drug responses

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Genetic differences may influence:

Pharmacokinetics of a drug: effects on ADME
Pharmacodynamics of a drug: effects on mediators of a drug's action: both the direct target (receptor) with which the drug interacts and other processes (signal transduction pathways) that mediate a drug's action

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Percentage of drugs influenced by actionable pharmacogenes

7% of FDA-approved medications are affected by actionable inherited pharmacogenes

18% of US outpatient prescriptions are affected by actionable germline pharmacogenomics

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Pharmacokinetic examples: Phase 1 Enzymes

CYP2D6

Cytochrome P450 2D6 responsible for metabolism of 20-25% of all medications

Metabolizes several classes of drugs:
Antidepressants, antiarrhythmics, B-adrenergic receptor antagonists and analgesics

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CYP2D6 Polymorphisms

Four phenotypes:
1. Poor metabolizers (PM)
2. Intermediate metabolizers (IM)
3. Extensive metabolizers (EM)
4. Ultrarapid metabolizers (UM)

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Effect of CYP2D6 genetic polymorphisms on survival of women with ER(+) breast cancer treated with tamoxifen

Tamoxifen used in treatment of estrogen receptor ER(+) tumors
Tamoxifen is a prodrug

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CYP2D6: nortripyline metabolism

Later

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CYP2D6: codeine

Later

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Additional consideration: drug interactions

Multiple drugs are CYP2D6 inhibitors

Classified as strong (fluoxetine, paroxetine), moderate (sertraline, duloxetine), and weak (buprenorphine)

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Pharmacokinetic examples: Phase II reactions

Isoniazid metabolism by NAT2 enzyme

Thiopurines metabolism

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Isoniazid Metabolism

Used for treatment of tuberculosis

Metabolized by N-acetyltransferase 2 (NAT2), a phase II enzyme

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Slow acetylators and Fast acetylators

Later

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Clinical Significance of Isoniazid Acetylation Rate

Influence of acetylation rate on the anti-tuberculosis activity is uncertain.

It does appear that the rate of acetylation influences isoniazid toxicity: slow acetylators are more prone to suffer from isoniazid toxicity, including peripheral neuropathy

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Metabolism of Thiopurines

-Used to treat autoimmune conditions (Crohn's disease) and acute lymphoblastic leukemia and prevent organ transplant rejection
-Thiopurines include 6-mercaptopurine (6-MP) and azathioprine (AZA), have relatively low therapeutic index
-Neither 6-MP nor AZA has intrinsic activity, undergo biotransformations leading to formation of 6-thioguanine nucleotides (6-TGNs) that have cytotoxic effects and are incorporated into DNA
-Thiopurines inactivated by thiopurine S-methyltransferase (TPMT)

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Frequency distribution of red blood cell (RBC) thiopurine S-methyltransferase (TPMT) activity

20 variant alleles of TPMT

TPMT*2/3A/3C are defective alleles that encode for proteins with reduced catalytic activity

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Dosage Adjustment

Administration of standard doses of thiopurines to individuals with reduced or undetectable TPMT activity may produce life-threatening adverse events (myelosuppression, bleeding, severe infection). Need to reduce drug or use alternate drug.
Patients with high TPMT activity may display reduced response to standard doses of thiopurines and may require increased doses to get therapeutic response.

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Pharmacokinetic Examples: Other (not Phase I or II) Enzymes

Glucose 6-phosphate dehydrogenase

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Glucose 6-phosphate dehydrogenase

G6PD is rate-limiting step of PPP and role in maintaining NADPH and GSH levels
In RBC's, G6PD is exclusive source of NADPH and GSH
If G6PD deficiency, at increased risk for hemolysis when exposed to oxidative stress (infection, fava beans, certain drugs) due to reduced antioxidant capacity

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G6PD

Deficiency, can develop haemolytic anaemia after eating broad beans or taking drug rasburicase.

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G6PD Deficiency

Defined as less than 60% activity

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G6PD Variants

Gene on X chromosome
180 genetic variants (90% single-base substitutions) for reduced catalytic activity
Hemizygous-deficient males and homozygous-deficient females express reduced activity phenotypes
Due to X-chromosome mosaicism, G6PD activity in cells from heterozygous females may range from fully functional to severly deficient

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Pharmacodynamic Examples

B2-adrenergic receptor polymorphisms

Gefitinib and EGFR mutations

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B2-adrenergic receptor polymorphisms influence bronchodilator response in asthma

B2AR agonists (albuterol) treat asthma
Two polymorphic loci in the coding region of receptor: Gly-16/Arg-16 and Glu-27/Gln-27
Children study:
Mutation in first loci children more likely to respond to albuterol
No association in second loci in response to albuterol

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Gefitinib and EGFR Mutations

Gefitinib is a tyrosine kinase (TK) inhibitor that targets the epidermal growth factor (EGF) receptor (used to treat non-small-cell lung cancer)

Most patients don't respond to gefitinib, but 10% display rapid therapeutic response
High sensitivity due to somatic mutations clustered around ATP-binding pocket of EGFR TK domain.
Mutations associated with increased EGF-stimulated TK catalytic activity and increased sensitivity to gefitinib inhibition.

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Challenges in implementing pharmacogenomics

Need for means to compare adverse reactions associated with a drug across multiple studies

Imaging and biomarkers may help