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PCTH 325 > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

1
Q

What type of resource is PharmGKB?

A

Takes available evidence (ex. journal articles) outlining relationships between genetic variation and variable drug responses

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2
Q

What type of resource is PharmVar?

A

Repository for allelic variation (and haplotype structure) for genes important for pharmacogenomics

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3
Q

What type of resource is Clinical Pharmacogenetics Implementation Consortium (CPIC)? Also, name 2 other guideline groups

A

Translates available genetic information into therapeutic decisions through production of clinical practice guidelines

  1. Dutch Pharmacogenetics Working Group (DPWG)
  2. Canadian Pharmacogenomics Network for Drug Safety (CPNDS)
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4
Q

5 examples of drugs with genetic variation influencing pharmacokinetics

A
  1. CYP2C9 (drug-metabolizing enzyme) - warfarin
  2. CYP2D6 (drug-metabolizing enzyme) - codeine
  3. TPMT/NUDT15 (drug-metabolizing enzyme) - azathioprine (aka 6-mercaptopurine)
  4. SLCO1B1 (drug transporters) - Simvastatin
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5
Q

What are prodrugs?

A

Poor metabolizers that have a dec. risk of adverse drug rxns but an incd. risk of treatment failure (ie. nonreponse)

Ex. codeine, bioactivated by CYP2D6

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6
Q

What are active drugs?

A

Poor metabolizers that have an incd. risk of adverse drug rxns that’s typically accompanied by incd. (or excessive) response to treatment

Ex. azathioprine and 6-mercaptopurine, inactivated by TPMT

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7
Q

What are 3 characteristics of codeine and CYP2D6?
(gene, phenotype, therapeutic change)

A
  1. Gene: CPY2D6; involved in codeine metabolism/bioactivation
  2. Phenotype: different levels of morphine (pain relief) in different metabolizers
  3. Therapeutic change: personalized dosing
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8
Q

How does codeine impact pharmacokinetics?

A

It is a prodrug that requires drug metabolism for therapeutic effect (bioactivated by CYP2D6). The codeine therapeutic recommendation can be made based on metabolizer status (ie. CYP2D6 phenotype)

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9
Q

What are 3 characteristics of azathioprine (6-mercaptopurine) and TPMT?

(gene, indication, and variation)

A
  1. Gene: TPMT; involved in drug metabolism/inactivation
  2. Indication: used to treat nonmalignant immunologic disorders and lymphoid malignancies
  3. Variation: TPMT loss-of-function single nucleotide variants are relatively common (ex. *2, *3A, *3B, *3C)
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10
Q

How is azathioprine (6-mercaptopurine) pharmacokinetics influenced by genetic variation in TPMT?

A

Azathioprine (6-mercaptopurine) is an example of an active drug requiring drug metabolism to stop therapeutic effect (inactivated by TPMT)

TPMT is required for drug inactivation -> TMPT LOF alleled leads to reduced inactivation -> incd. 6-thioguanine nucleotide exposure -> incd. risk of toxicity

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11
Q

How is azathioprine (6-mercaptopurine) pharmacokinetics influenced by genetic variation in NUDT15?

A

NUDT15 is involved in metabolizing toxic 6-thioguanine (6-TGN) nucleotides -> NUDT15 LOF alleles results in reduced metabolism -> incd. 6-TGN exposure -> incd. risk of toxicity

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12
Q

What are 3 characteristics of azathioprine (6-mercaptopurine) and TPMT/NUDT15?

(phenotype, implications, and therapeutic change)

A
  1. Phenotype: different levels of the active drug for different metabolizers
  2. Implications: patients with LOF alleles only tolerate lower doses and are at highest risk of bone marrow toxicity
  3. Therapeutic change: personalized dosing with lower doses recommended for carriers of LOF variation
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13
Q

What are 6 characteristics of simvastatin and SLCO1B1?

(indication, gene, variation, phenotype, implication, therapeutic change)

A
  1. Indication: used for cholesterol reduction
  2. Gene: SLCO1B1 (drug transporter responsible for the hepatic uptake, and subsequent elimination, of statins)
  3. Variation: the most common LOF variant is SLCO1B1*5 that reduces transporter activity
  4. Phenotype: differences in drug exposure between patients
  5. Implications: patients with LOF variants (SLCO1B1*5) have incd myopathy b/c of incd drug exposure
  6. Therapeutic change: SLCO1B1*5 carriers should consdier lower doses, alternative statins, or incd monitoring
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14
Q

How is simvastatin pharmacokinetics influenced by genetic variation in SLCO1B1?

A

SLCO1B1 is required for drug elimination -> SLCO1B1*5 reduces transport/elimination -> incd. statin exposure -> incd. myopathy risk

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15
Q

3 examples of drugs with genetic variation influencing pharmacodynamics

A
  1. HLA-B (off-target effects) - carbamazepine
  2. IFNL3/IL18B; IFNL4 (part of disease mechanism) - interferon/hepatitis C drugs
  3. VKORC1 (drug target) - warfarin
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16
Q

3 characteristics of VKORC1 and warfarin

(indication, gene, variation)

A
  1. Indication: used as an anticoagulant (treatment of blood clots)
  2. Gene: VKORC1 (the target enzyme of warfarin that participates in vitamin K recycling)
  3. Variation: a common reduction-of-function variant that exists that leads to decreased dose requirements
17
Q

3 characteristics of IFNL4 and hepatitis C drugs

(indication, gene, variation)

A
  1. Indication: used for viral eradication
  2. Gene: IFNL4 plays a role in the immune response to the virus
  3. Variation: leads to activation of the IFNL4 that leads to an overactive immune response and increased risk of treatment failure
18
Q

MOA of IFNL4 variant and hepatitis C drugs - why is an overactive immune system response to the virus bad?

A

rs1297860 is linked to an insertion variant that activates the IFNL4 pseudogene -> overactive immune response to the virus -> promotes the generation of viral genetic variants more resistant to antiviral treatment

19
Q

How does IFNL4 and hepatitis C drugs affect phenotype, implications, and therapeutic change?

A

Phenotype: variability in antiviral drug effectiveness on different patients

Implications: patients with the IFNL4 variant have a higher risk of treatment failure (and need for a re-treatment)

Therapeutic change: more effective antivirals could be considered in patients carrying IFNL variants

20
Q

3 characteristics of HLA variants and carbamazepine

(indication, genes, and variation)

A
  1. Indication: used as an anticonvulsant
  2. Genes: HLA-A and HLA-B are genes that present intracellular antigens to the immune system
  3. Variation: indivs. carrying HLA-B15:02 and HLA31:01 variation are at increased risk of severe skin reactions
21
Q

What are the notations for the HLA gene variants?

A

Carriers are denoted as positive for the risk alleles, and non-carriers are negative for the risk alleles

22
Q

How does HLA variants and carbamazepine affect phenotype, implications, and therapeutic change?

A

Phenotype: the variants are necessary, but not sufficient for the development of severe skin reactions

Implications: patients positive for the risk alleles are at incd. risk for severe skin reactions

Therapeutic change: patients positive for the risk alleles are recommended to use a different drug if possible

22
Q

What are 2 possible ways to incorporate pharmacogenetic information into clinical decisions?

A
  1. Pharmacogenetic testing performed only when a specific drug is being considered
  2. Comprehensive pharmacogenomic information collected and made readily available for the future
23
Q

What is the strength and weakness of pharmacogenetic testing performed only when a specific drug is being considered?

A

Strength: assessing only variants with clinical relevance allows for rapid evidence-informed treatment decisions

Weakness: requires quick turnaround time, integration of pharmacogenetics testing into clinic flow, and pharmacogenomics training for care providers

24
Q

What is the strength and weakness of comprehensive pharmacogenomic information collected and made readily available for the future?

A

Strength: care providers can receive notifications for safety and effectiveness concerns for any drug considered over a patient’s lifetime (where genetic info is embedded in electronic health records)

Weakness: required curated and regularly-updated pharmacogenomic info to guide treatment decisions

PCTH 325 (19 decks)

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