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Pharmacology Exam 5 > 72 - Pharmacogenomics II > Flashcards

72 - Pharmacogenomics II Flashcards

(38 cards)

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1
Q

What are the three types of pharmacogenetic phenotypes?

A
  • Pharmacokinetic
  • Pharmacodynamic
  • Indirect
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2
Q

Describe pharmacokinetics

A
  • The effect of a polymorphism in a gene or genes that regulate pharmacokinetics
  • Metabolic enzymes or drug transporters
  • Alters drug concentrations resulting in changes in therapeutic and adverse effects
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3
Q

Describe pharmacodynamics

A
  • The effect of a polymorphism in a gene that codes for drug targets such as receptors or enzymes
  • Can impair or enhance drug binding
  • Alters drug response
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4
Q

Describe indirect

A

The effects of polymorphisms in a gene that does not interact with the drug, not involved with disposition of the drug

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5
Q

What are the gene polymorphisms that affect pharmacokinetics that we will be discussing?

A

Metabolic enzymes

  • CYP2D6
  • CYP2C19
  • CYP2C9
  • DPD (Dihydropyrimidine dehydrogenase)
  • TPMT (Thiopurine methyltransferase)

Drug transporters
- Solute Carrier Organic Anion Transporter 1B1 (SLCO1B1)

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6
Q

Describe the drugs that CYP2D6 affects

A

Hepatic metabolism of 20% of commonly use drugs

  • Tamoxifen
  • Codeine
  • Paroxetine
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7
Q

Describe the interaction of CYP2D6 and tamoxifen

A
  • Tamoxifen metabolites competitively inhibit the estrogen receptor
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8
Q

Describe the interaction of CYP2D6 and codeine

A
  • Codeine is a prodrug
  • Normally, approx. 50-70% of codeine is glucuronidated and eliminated by kidney
  • 10-15% of codeine converted to norcodeine
  • 0-15% converted to morphine by CYP2D6
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9
Q

Do most codeine recipients have prior CYP2D56 genotyping?

A

No - Most patients receive codeine without prior CYP2D6 genotyping

Potential for adverse effects - you will have too much morphine in the body

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10
Q

Describe the interaction of CYP2D6 and paroxetine

A

This can account for why some patients are responsive to the antidepressant effect and some aren’t

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11
Q

Describe the drugs that CYP2D19 effects

A
  • Clopidogrel
  • Omeprazole
  • Lansoprazole
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12
Q

Describe the interaction of CYP2D19 and clopidogrel

A

If you don’t have functional CYP2C19, don’t use clopidogrl because it will not be effective

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13
Q

Describe the interaction of CYP2D19 and PPIs (omeprazole and lansoprazole)

A

The patients will not respond to PPIs (?)

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14
Q

What drug does CYP2C9 effect?

A

Warfarin

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15
Q

How does CYP2C9 affect warfarin metabolism?

A

Wild type allele: CYP2C9*1

Reduced function alleles: CYP2C92 and CYP2C93

  • Metabolize warfarin slowly
  • Greater risk for bleeding
  • Lower warfarin dose requirements
  • Longer duration to dose stabilization
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16
Q

How does VKORC1 polymorphism affect warfarin metabolism?

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A

SNPs associated with VKORC1 include:
- VKORC1-GA, VKORC1-GG, and VKORC1-AA

VKORC1-AA has the lowest activity

  • Less vitamin K dependent clotting factors produced
  • Lower warfarin dose necessary to achieve therapeutic effect
17
Q

What tool can you use to determine how your patient will respond to warfarin?

Study These Flashcards
A

You can use a gene-by-environment phenotype guide to warfarin dosing

18
Q

What two polymorphisms affect cancer treatment?

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A

5-Flurouracil (5-FU)

  • DPD (Dihydropyrimidine dehydrogenase)
  • TYMS (thymidylate synthetase)

6-mercaptopurine (6-MP)
- TPMT (Thiopurine methyltransferase)

19
Q

Describe 5-FU

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A

5-FU is metabolized into 5-fluorodeoxyuridine (FdUMP), which inhibits thymidylate synthase

Causes DNA damage by decreasing dTTP levels, leading to cell death

DPD reduces toxicity of 5-FU by inactivating it

Damages DNA by lowering dTTP levels and by being incorporated into DNA

20
Q

What are the adverse effects of 5-FU in a mutation?

Study These Flashcards
A

Just know that you can have too much myelosuppression and you can

Adverse effects include oral and GI ulcers and bone marrow suppression

21
Q

DPD mutation

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A

Polymorphism that leads to higher toxicity of 5-FU

5-FU kills cells by inhibiting thymidylate synthetase

Insertion polymorphism in enhancer region can cause increases or decreases in TS activity

Pharmacodynamic phenotype ***

KNOW THAT IT IS PHARMACODYNAMIC - not pharmacokinetic ***

22
Q

What polymorphism affects response to 6-MP?

Study These Flashcards
A

TPMT (Thiopurine methyltransferase)

TPMT inactivate 6-MP, a drug used to treat acute lymphoblastic leukemia

23
Q

Moving onto statins…

Study These Flashcards
A

They did a Genome-wide association study (GWAS) of statin-induced myopathy

24
Q

Describe the Genome-wide association study (GWAS) of statin-induced myopathy

Study These Flashcards
A
  • Statistical association of myopathy with each SNP and the chromosomal location of each SNP
  • Strong probability of specific SNP on gene in chromosome 12 associated with Simvastatin-induced myopathy
25
Describe the effect of SLCO1B1 and simvastatin drug in the body
Solute Carrier Organic Anion Transporter 1B1 (SLCO1B1) Liver uptake of simvastatin - T/T genotype (valine/valine): Normal transport - T/C genotype (valine/alanine): Decreased transport - C/C genotype (alanine/alanine): Low transport
26
Moving onto estrogen...
Polymorphisms in estrogen receptor ERα
27
Describe the Polymorphisms in estrogen receptor ERα
Polymorphism in the intron between the 1st and 2nd exon of the ERα gene Homozygotes for the less common allele (C/C) had a greater increase in HDL levels following hormone replacement therapy (HRT) (estrogen/progesterone) Example of a pharmacodynamic*** pharmacogenetic phenotype They get BETTER results, so that's good
28
Describe the SNP implicated in albuterol use
Genotype at the 16th amino acid residue of the ADRB2 affects response to albuterol use
29
What happens in patients with this polymorphism
Effectiveness of albuterol is decreased Less affinity for the drug to the beta adrenergic receptors
30
How does smoking further alter the effect of albuterol?
Passive smoking appears to augment the downregulatory effect of arginine polymorphisms. This is an example of an environmental factor affecting a gene
31
Describe and example of the indirect pharmacogenetic phenotype
Indirect pharmacogenetic phenotype (oral contraceptives) Polymorphisms in Factor V and prothrombin increase risk of venous thromboembolism (VTE) with oral contraceptives (OC)
32
Describe the indirect pharmacogenetic phenotype of HIV patients taking reverse transcriptase inhibitors
- Reverse transcriptase inhibitor used to treat HIV - ABC hypersensitivity (ABC-HSR) reaction in 5-8% of ABC-treated patients - Individuals with the HLA-B*57:01 allele have a high risk of have hypersensitivity reaction to ABC - HLA-B is the human leukocyte antigen B which presents peptides to immune cells - Has no effect on pharmacokinetics or pharmacodynamics of abacavir
33
Describe the phenotype of abacavir
Does NOT alter therapeutic effectiveness, but it DOES lead to an adverse effect In individuals with the HLA-B*57:01 variant allele ("HLA-B*57:01-positive"), abacavir is not recommended and should be considered only under exceptional circumstances.” Positive predictive value for hypersensitivity reaction is approx. 50%
34
What is the adverse reaction in abacavir?
Stevens-Johnson syndrome Can be very severe - skin peeling, red, errupting
35
What polymorphism has been shown to increase the effectiveness of Alzheimer's disease treatment?
APOE
36
Describe the implication of APOE in AD treatmetn
Indirect pharmacogenetic phenotype APOE (Apolipoprotein E): - Lipoprotein found in chylomicrons, VLDL, IDL, and HDL - Absence of certain alleles in the APOE gene correlate with better therapeutic success for Alzheimer’s disease therapy with tacrine
37
What is the genetic trait that makes hepatitis C patients to not respond to interferon alpha treatment
- HBV and HCV globally account for 60% of cirrhosis and 80% of hepatocellular carcinoma (HCC) and cause 1 million deaths each year - Interferon-α common treatment - Known for decades that 30%-45% did not receive benefit - Also known that African-American patients were more refractory to treatment - Genome-wide association studies (GWAS)
38
What is the polymorphism?
SNP polymorphism in IL-28 gene predicted response to interferon-α treatment Patients with the polymorphism will NOT have a good response to the drug - it will not rid them of hep C

Pharmacology Exam 5 (5 decks)

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