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Lassila Flashcards

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1
Q

What is CPIC?

A

Clinical Pharmacogenetics Implementation Consortium- guidelines designed to help clinicians understand how available genetic test results should be used to optimize drug therapy

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2
Q

What is PharmGKB?

A

Pharmacogenomics knowledgebase- collects, curates, and disseminates knowledge about PGx

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3
Q

What kind of data does PharmGKB publish?

A
  1. annotate genetic variants and gene-drug-disease relationships via lit review
  2. curate FDA labels containing PGx Information
  3. create clinical annotations for drug-gene pairs based on curated lit
  4. assign levels of evidence based on criteria such as replication, stat significance, and study size
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4
Q

What is pharmacogenetics?

A

study of the relationship between variations in a single gene and variability in drug disposition, response, and toxicity

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5
Q

What is pharmacogenomics?

A

study of the relationship between variations in a large collection of genes (up to the whole genome) and variability in drug disposition, response, and toxicity

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6
Q

What is a genome?

A

organism’s complete set of DNA including all its genes regulatory elements, and other nucleotide sequences

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7
Q

What is genomic organization?

A

Genome
Chromosome
Gene
Nucleotide

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8
Q

What is a genetic variant?

A

difference in DNA sequence compared with a reference sequence

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9
Q

What is a polymorphism?

A

common genetic variant, occurring 1% or more of the population

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10
Q

What is a mutation?

A

genetic variant, occurring in less than 1% of the population

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11
Q

What are single nucleotide variants?

A

the difference in 1 nucleotide of DNA account for most variations the human genome

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12
Q

What are insertion/ deletion variants?

A

insertion or deletion of one or more consecutive nucleotides from DNA sequence
Ex. insertion/ deletion of 287 consecutive bps in the ACE enzyme

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13
Q

What are variable number of tandem repeats?

A

Sequences of nucleotides repeated a variable number of times
Ex. Gilberrt’s Syndrome is caused by a variable number of TA repeats in the UGT1A1 gene

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14
Q

What is copy number variation?

A

gain (duplication) or loss (deletion) of a large region, usually >1000 bps
Ex. CYP2D6 drug metabolizing gene has CNVs, including deletions, duplications, and multiplications

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15
Q

What is an allele?

A

1 of 2 or more forms of DNA sequence that is located at a specific position on a specific chromosome

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16
Q

what is a genotype?

A

combination of alleles a person carries at a particular location in DNA (1 from other and 1 from father)

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17
Q

What is a phenotype?

A

measurable characteristic of an organism
(environmant and genetics)

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18
Q

What are pharmacologic phenotypes?

A
  1. ultrarapid, extensive, intermediate, poor metabolizers
  2. Pk- plasma drug concentration, AUC, clearance, Cmax
  3. Pd- responder, non-responder
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19
Q

What is a haplotype?

A

set of closely linked alleles that are located on one chromosome and inherited together as a unit or block

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20
Q

What is a diplotype?

A

combination of two haplotypes (1 haplotype from mom and 1 haplotype from dad) 2/3

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21
Q

What is the result of genetic variants in drug-metabolizing enzyme function?

A

Would affect:
1. clearance
2. AUC
3. half life

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22
Q

What does it mean if someone has decreased metabolism of an active parent drug?

A

increased plasma exposure of the active parent drug and decreased metabolism to inactive metabolites lead to increased risk of toxicity/ effect

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23
Q

What does it mean if someone has increased metabolism of an active parent drug?

A

decreased plasma exposure and decreased effect

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24
Q

What does it mean if someone has decreased metabolism of a prodrug?

A

decreased plasma exposure and effect

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25
What does it mean if someone has increased metabolism of a prodrug?
increased plasma exposure of the active parent drug and decreased metabolism to inactive metabolites lead to increased risk of toxicity/ effect
26
What is a HLA?
Human Leukocyte Antigens- present intracellular antigens (drugs) to the immune system to determine if they are self or non-self; highly polymorphic
27
What HLA variation is associated with Abacavir-gene-related immune response?
HLA-B *57:01
28
What HLA variation is associated with Allopurinol-gene-related immune response?
HLA-B *58:01
29
What HLA variation is associated with aromatic anticonvulsants (carbamazepine) -gene-related immune response?
HLA-B *15:02 HLA-A *31:01
30
When do patients experience an Abacavir HSR?
within the first 6 weeks (median onset, 10 days)
31
What are the symptoms of Abacavir HSR?
1. fever 2. rash 3. GI symptoms 4. fatigue 5. cough 6. dyspnea
32
What should be done if Abacavir HSR occurs? When can the med be restarted?
1. immediate discontinuation and supportive care 2. re-challenge is CI
33
What did the PREDICT-1 study find?
Presence of HLA-B *57:01 is predictive of clinically- diagnosed and immunologically confirmed Abacavir HSR
34
What is analytical validity?
ability of a genetic test to measure accurately and reliably the genotype of interest
35
What is clinical validity?
accuracy with which a test can predict the presence or absence of the clinical outcome (phenotype) or disease of interest
36
What is clinical utility?
likelihood that the test will lead to an improved outcome
37
What are the types of Carbamazepine cutaneous HSRs?
1. Mild maculopapular eruptions (MPE) 2. drug reaction with eosinophilia and systemic symptoms (DRESS) 3. SJS 4. TENs
38
What is MPE?
Mild Maculopapular Eruptions- mild skin rash
39
What is DRESS?
Drug reaction with eosinophilia and systemic symptoms- skin rash plus fever, angioedema, lymphadenopathy, hepatitis
40
What gene is associated with an increased risk of Carbamazepine- induced SJS and TENs?
HLA-B *15:02
41
What gene is associated with MPE, DRESS, SJS, TENS, and is a driver of Carbamazepine HSRs in populations where HLA-B*15:02 is lower (Europeans, Africans, Japanese)?
HLA-A *31:01
42
What BBW does Carbamazepine have?
patients with ancestry in genetically at-risk populations should be tested for the presence of HLAB*15:02
43
What populations are at-risk for the presence of HLAB*15:02?
1. Chineese (han, hong kong) 2. Malaysia 3. Thailand 4. Philippines 5. India 6. Vietnam 7. Cambodia
44
If someone is HLA-B*15:02 positive what other anticonvulsants be avoided?
1. Oxcarbazepine 2. Phenytoin 3. Fosphenytoin
45
If someone is HLA-B*15:02 positive what other anticonvulsants be used with caution?
1. Lamotrigine 2. Eslicarbazepine 3. Phenobarbital
46
What other HLA-B alleles are associated with Carbamazepine SJS/TEN in Southeast Asians?
1. HLA-B *15:08 2. HLA-B *15:11 3. HLA-B *15:21
47
What gene is associated with allopurinol-induced HSR, SJS, and TEN?
HLA-B58:01
48
When should genetic testing for allopurinol be done?
testing for HLA-B*58:01 is conditionally recommended for patients of Southeast Asian descent
49
What gene is associated with Phenytoin SJS/ TEN?
HLA-B*15:02
50
What should be done if someone already taking Phenytoin test positive for the HLA-B*15:02 gene?
if used continuously for longer than 3 months without incidence of HSR, cautiously consider use in the future
51
What enzyme is responsible for the conversion of Amitryptiline to Nortriptyline?
CYP2C19
52
What enzyme is responsible for converting Amitryptiline and Nortriptyline to their active metabolites?
CYP2D6
53
How are CYP2D6 poor metabolizers affected by Amitryptiline and Nortriptyline?
increased plasma concentration and higher risk of adverse effects
54
How are CYP2C19 poor metabolizers affected by Amitryptiline and Nortriptyline?
increased plasma concentration and higher risk of adverse effects
55
When is CYP2D6 active and fully mature?
early childhood
56
When is CYP2C19 active and fully mature?
increased activity in children; activity decreased with age
57
What are common SEs with CYP2D6 and CYP2C19 metabolites of Amitryptiline and Nortriptyline?
1. arrhythmias 2. heart block 3. tachycardia
58
What SSRIs are metabolized by CYP2D6?
1. Paroxetine 2. Fluvoxamine
59
What SSRIs are metabolized by CYP2C19?
1. Citalorpam 2. Escitalopram 3. Sertraline
60

Personalized Theraputics (6 decks)

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