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Pharmacology Exam 5 > 72 - Pharmacogenomics II > Flashcards

72 - Pharmacogenomics II Flashcards

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?

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?

A

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

18
Q

What two polymorphisms affect cancer treatment?

A

5-Flurouracil (5-FU)

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

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

19
Q

Describe 5-FU

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?

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

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?

A

TPMT (Thiopurine methyltransferase)

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

23
Q

Moving onto statins…

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

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
Q

Describe the effect of SLCO1B1 and simvastatin drug in the body

A

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
Q

Moving onto estrogen…

A

Polymorphisms in estrogen receptor ERα

27
Q

Describe the Polymorphisms in estrogen receptor ERα

A

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
Q

Describe the SNP implicated in albuterol use

A

Genotype at the 16th amino acid residue of the ADRB2 affects response to albuterol use

29
Q

What happens in patients with this polymorphism

A

Effectiveness of albuterol is decreased

Less affinity for the drug to the beta adrenergic receptors

30
Q

How does smoking further alter the effect of albuterol?

A

Passive smoking appears to augment the downregulatory effect of arginine polymorphisms.

This is an example of an environmental factor affecting a gene

31
Q

Describe and example of the indirect pharmacogenetic phenotype

A

Indirect pharmacogenetic phenotype (oral contraceptives)

Polymorphisms in Factor V and prothrombin increase risk of venous thromboembolism (VTE) with oral contraceptives (OC)

32
Q

Describe the indirect pharmacogenetic phenotype of HIV patients taking reverse transcriptase inhibitors

A
  • 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
Q

Describe the phenotype of abacavir

A

Does NOT alter therapeutic effectiveness, but it DOES lead to an adverse effect

In individuals with the HLA-B57:01 variant allele (“HLA-B57:01-positive”), abacavir is not recommended and should be considered only under exceptional circumstances.”

Positive predictive value for hypersensitivity reaction is approx. 50%

34
Q

What is the adverse reaction in abacavir?

A

Stevens-Johnson syndrome

Can be very severe - skin peeling, red, errupting

35
Q

What polymorphism has been shown to increase the effectiveness of Alzheimer’s disease treatment?

A

APOE

36
Q

Describe the implication of APOE in AD treatmetn

A

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
Q

What is the genetic trait that makes hepatitis C patients to not respond to interferon alpha treatment

A
  • 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
Q

What is the polymorphism?

A

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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