Flashcards in Pharmacogenics Deck (57)
1
Pharmacogenetics
the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
variable response to individual gene
2
Pharamacogenomics
the genomic approach to the pharmacogenetics, is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.
Variable response due to multiple loci across the genome
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pharamcogenetics is the study or
clinical testing of genetic variation that gives rise to differing response to drugs
4
codeine metabolism
require CYP2D6 gene to activate.
More copies makes you metabolize more
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normally metabolize ____% of codeine to morphine
10%
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once a drug is taken, the drug must:
1. reach its target
2. exert its effect
3. do the above before being inactivated/eliminated
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pharmacokinestics
describes absorption, distribution, metabolism and excretion of drugs (commonly referred to as ADME)
cytochrom p450, glyconyltransferase, thiopureine methyltransferase
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pharmacodynamics
describes the relationship between the concentration of a drug at its site of action and observed biological effects
9
most major drugs are only effective in ___% of patients
25-60
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the CYP450 complex is
1. the gene products active in liver and intestinal epithelium
2. 3 main families: (CYP1, CYP2, CYP3)
3. CYP3A4
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the CYP1, CYP2, CYP3 have 6 main genes:
and phase I for ___% of common drugs
CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4
90%
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what gene accounts for 40% of all common drugs
CYP3A4
There is less genetic variation on CYP3A4 than other CYPs
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Most CYP's function to _____ drugs
inactivate.
But rarely they are needed to activate
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example of gene needed to activate a drug
CYP2D6
which converts codeine to morphine
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gene: CYP3A:
1. cyclosporine
2. ketoconanazole
2. rifampin
4. grapefruit juice
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CYP2D6 gene
codeine, this is needed to activate
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CYP2c9 + VKORC1
warfarin
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NAT
isoniazid
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TPMT
6-mercaptopurine/6-thiguanine and childhood
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G6PD
hemolytic anemia after sulfa drugs
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Pharmacokinetics:
• Genetic Examples:
Cytochrome P450, glucuronyltransferase, thiopurine methyltransferase
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Pharmacodynamics:
• Genetic Examples:
Glucose-6-phosphate dehydrogenase, vitamin K epoxide complex
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Pharmacokinestics is broken down farther into
two basic ways that drugs are metabolized through biotransformers
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pharmacokinestics phases
phase 1
phase 2
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phase 1 metabolism
attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
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phase 2 metabolism
attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
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Frameshift -->
alter reading frame --> NO ACTIVITY
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splicing-->
skip exons and/or alter reading frame--> no activity
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missense -->
alter protein function--> usually REDUCED ACTIVITY
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copy number alleles -->
increased gene copy alleles --> INCREASED (ULTRAFAST)
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based on the combinations (since individuals have 2 alleles in their genotypes), have 3 major phenotypes
1. normal
2. poor (includes null alleles)
3. ultrarapid/ultrafast
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A single 8 oz glass of grapefruit juice can inhibit _______ activity for 24-48 hours.
CYP3A
(largely through intestinal inhibition of CYP3A).
33
drinking grapefruit juice while taking felodipine for hypertension can lead to ________
significant hypotension due to potentiation of the felodipine effect since CYP3A activity is reduced and metabolism/elimination of felodipine is similarly slowed.
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Dosage of the immunosuppressive drug _______ (used in kidney transplants for instance) must be reduced by _____% to avoid toxicity when the _________ is added to treat a fungal infection.
cyclosporine
75%
antifungal ketoconazole
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Mechanism- ketoconazole temporarily inhibits _____ metabolism which leads to raised levels of _______ which can be neprotoxic.
CYP3A
cyclosporine
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Renal transplant patient who is exposed to tuberculosis and requires________:
rifampin prophylaxis:
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the dose of cyclosporine must be ______ since rifampin is a _____ inducer and leads to more ______.
increased
CYP3
rapid metabolism and elimination of cyclosporine.
If you fail to take this into account, the cyclosporine levels will decrease and organ rejection will become a problem.
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gene: CYP3A
drugs:
cyclocsporin
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CYP3A inhibitors
1. ketocoazole
2. grapefruit juice
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CYP3A inducer
rifampin
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what gene effects cyclosporin?
CYP3A
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gene: CYP2D6
drugs:
1. tricyclic antidepressants
2. codeine
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CYP2D6 inhibitors
1. qinidine
2. fluoxetine
3. paroxetine
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what gene is involved with tricyclic antidepressants?
CYP2D6
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gene: NAT
drug:
isoniazid for tuberculosis
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isoniazid for tuberculosis gene involved is?
NAT
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gene: TMPT
drugs:
1. 6-mercaptopurine
2. 6-thioguanine
leukemia
-Often presented as the classic example of a pharmacogenetic mechanism that can be fatal if ignored
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what gene is involved in 6-mercaptopurine?
TMPT
49
G6PD
drug?
1. sulfonamide
2. dapsone
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mechanism of G6PD drugs
X-linked enzymes
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G6PD deficient individuals are susceptible ______
to hemolytic anemia after drug exposures
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gene affected by sulfonamide
G6PD
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gene for dapsone?
G6PD
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gene for warfarin
VKORC1
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Warfarin is a
blood thinner that is most commonly prescribed medicines, given to >200,000 patients/yr
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one of the most commonly prescribed drugs
warfarin
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