Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
45 Cards in this Set
- Front
- Back
|
When a protein is important in a drug action or disposition, then genetic differences between individuals in that drug's action or disposition are expected. Why?
|
Proteins are gene products and many of those products exhibit genetic polymorphism. SNPs, gene deletions, gene amplifications determine protein structure, configuration and/or concentration.
|
|
|
Kids present a pharmacogenetic challenge because they have complex (blank) that impact their drug response.
|
Kids present a pharmacogenetic challenge because they have complex ONTOLOGICAL PHENOTYPES that impact their drug response.
|
|
|
Name the 4 examples of drugs given in class that have explicit FDA recommendations for using pharmacogenetic info to improve drug efficacy/safety.
|
1. 6-mercaptopurine (TPMT)
2. irinotecan (UGT1A1) 3. tamoxifen (CYP2D6) 4. abacavir (assoc w/ HLA-B variant) |
|
|
Making phenotype determinations in the context of pharmacogenetic testing is difficult for many reasons. Name 'em (page 112).
|
1. require probe drug
2. confounded by diet, disease, other genetic and environmental factors 3. dependent on specificity of the probe drug |
|
|
Phenotype determinations in the context of pharmacogenetic testing is difficult. What about genotype determination? Is that easier?
|
1. can amplify gene of interest by PCR
2. can distinguish variant alleles by RFLP analysis or allele-specific gene amplification |
|
|
Name the isozyme responsible for acetylation polymorphism.
|
N-acetyltransferase (NAT2) isozyme (it metabolizes aromatic amine & hydrazine drugs)
|
|
|
The slow acetylator differs from the rapid acetylator due to (blank).
|
The slow acetylator differs from the rapid acetylator due to SNPs in one or both of the NAT2 alleles.
|
|
|
Are there more slow acetylators in the Asian population? Middle Eastern? European and and American?
|
Asia: low % of slow
Mid Eastern: very high % of slow European & American: 50/50 |
|
|
(blank) is more common in slow acetylators treated with isoniazid and hydralazine.
|
PERIPHERAL NEUROPATHY is more common in slow acetylators treated with isoniazid and hydralazine.
|
|
|
Peripheral neuropathy is more common in slow acetylators treated with (blank) and (blank).
|
Peripheral neuropathy is more common in slow acetylators treated with ISONIAZID and HYDRALAZINE.
|
|
|
This unwanted reaction is more common in slow acetylators treated with procainamide and hydralazine.
|
Drug-induced lupus is more common in slow acetylators treated with procainamide and hydralazine.
|
|
|
Hypersensitivity reactions are more common in slow acetylators treated with (blank).
|
Hypersensitivity reactions are more common in slow acetylators (reduced NAT2) treated with SULFONAMIDES.
|
|
|
(blank) is more common in rapid acetylators treated with amonafide.
|
MYELOSUPPRESSION is more common in rapid acetylators treated with amonafide.
|
|
|
Myelosuppression is more common in (blank) acetylators treated with amonafide.
|
Myelosuppression is more common in FAST acetylators treated with amonafide.
|
|
|
(blank) cancer is more common in smokers who are slow acetylators.
|
URINARY BLADDER cancer is more common in smokers who are slow acetylators.
|
|
|
Slow acetylators are at risk of developing toxic levels after taking various drugs. These toxic levels produce adverse effects. Name a few.
|
1. Peripheral neuropathy (isonazid & hydralazine)
2. drug-induced lupus (procainamide & hydralazine) 3. hypersensitivity (sulfonamides) 4. urinary bladder cancer |
|
|
People who are homozygous for reduced thiopurine-S-methyltransferase enzyme develop (blank) when treated with thiopurines - which is used to treat ALL.
|
People who are homozygous for reduced thiopurine-S-methyltransferase enzyme develop HEMATOPOIETIC TOXICITY when treated with thiopurines - which is used to treat ALL.
|
|
|
What drug mentioned is used as part of chemotherapy for remission induction and maintenance therapy of ALL? What enzyme deactivates this drug?
|
Mercaptopurine is deactivated by thiopurine-S-methyltransferases.
|
|
|
Mercaptopurine is used in the management/treatment of ALL. What else is mercaptopurine used to treat?
|
1. IBD
2. Crohn's |
|
|
The most commone allele in white folk who have reduced thiopurine-S-methyltransferase activity is (blank).
|
The most commone allele in white folk who have reduced thiopurine-S-methyltransferase activity is TPMT*3A.
|
|
|
NAT2 and TPMT genotypes are due to SNPs. What about the UGT1A family of enzymes - do SNPs cause decreased UGT1A levels?
|
Nope. A series of TA repeats in the proximal promoter affect UGT1A levels.
|
|
|
UGT1A1 is primarily responsible for bilirubin glucuronidation. However, a lower than normal UGT1A1 concentration is associated with Gilbert's syndrome. What is the allele associted with the syndrome and how many repeats does it have?
|
UGT1A1*28 allele has 7 TA repeats and is assoc with Gilberts
|
|
|
(blank) is effective against several cancers. Its active metabolite is inactivated by UGT1A1.
|
IRINOTECAN is effective against several cancers. Its active metabolite is inactivated by UGT1A1.
|
|
|
Normally, UGT1A1 inactivates the Irinotecan metabolite in patients who are taking the drug as cancer treatment. From what 2 things might the patient suffer if he is homozygous for UGT1A1*28?
|
1. myelosuppression
2. diarrhea |
|
|
A whole lotta drugs are metabolized by CYP2D6. If the isozyme is absent or deficient, a person is considered a (blank).
|
A whole lotta drugs are metabolized by CYP2D6. If the isozyme is absent or deficient, a person is considered a POOR METABOLIZER.
|
|
|
A whole lotta drugs are metabolized by CYP2D6. If the isozyme is amplified due to gene duplication, a person is considered an (blank).
|
A whole lotta drugs are metabolized by CYP2D6. If the isozyme is amplified due to gene duplication, a person is considered an EXTENSIVE METABOLIZER.
|
|
|
What % of white folk are CYP2D6 deficient, and, therefore, poor metabolizers?
|
5-10%
|
|
|
CYP2D6 is important in the oxidation of many drugs. Name 4 general drug categories that are oxidized by CYP2D6.
|
1. beta-blockers
2. anti-arrhythmics 3. antidepressants 4. neuroleptics (anti-psychotics) |
|
|
A CYP2D6 extensive metabolizer is at risk of (blank) and (blank).
|
A CYP2D6 extensive metabolizer is at risk of therapeutic failures and adverse effects.
|
|
|
Tamoxifen is transformed to the potent anti-estrogen, endoxifen, by (blank).
|
Tamoxifen is transformed to the potent anti-estrogen, endoxifen, by CYP2D6.
|
|
|
What will happen to endoxifen concentrations in a patient who is taking tamoxifen and she is a poor metabolizer?
|
Endoxifen concentrations will be markedly reduced.
|
|
|
How is a patient's outcome changed if she is a poor metabolizer and taking tamoxifen?
|
She has deficient CYP2D6 and cannot transform tamoxifen to endoxifen. Thus...
1. shorter time to recurrence of breast cancer 2. worse relapse-free survival relative to those who are extensive metabolizers |
|
|
Being a poor metabolizer is an independent predictor of breast cancer outcome in post-menopausal women taking (blank) for early breast cancer.
|
Being a poor metabolizer is an independent predictor of breast cancer outcome in post-menopausal women taking TAMOXIFEN for early breast cancer.
|
|
|
Let's say a drug that you want to give to your patient is dependent on CYP2D6 to produce active metabolites. If your patient is a poor metabolizer, will he be more or less sensitive to the drugs? What can this lead to?
|
less sensitive; can lead to therapeutic failure
|
|
|
2 examples of drugs that require CYP2D6 to produce an active metabolite
|
2 examples of drugs that require CYP2D6 to produce an active metabolite are TAMOXIFEN and CODEINE.
|
|
|
Your patient started to take codeine for treatment of pain. However, he doesn't seem to be feeling any relief. Hmm...wonder what's going on?
|
He's probably a CYP2D6 poor metabolizer.
|
|
|
You have a patient who is homozygous for variant CYP2C9 alleles. You are thinking about prescribing him warfarin. Is this a good idea?
|
CYP2C9 inactivates warfarin. Without warfarin inactivation - due to decreased CYP2C9 activity - the patient is at risk of bleeding complications.
|
|
|
Your patient is given succinylcholine and develops prolonged apnea and requires a longer period of mechanical ventilation. What polymorphism does your patient probably have?
|
variant allele encoding atypical serum cholinesterase
|
|
|
What antiretroviral drug could elicit a severe hypersensitivity in patients with a HLA-B variant?
|
Abacavir
|
|
|
Abacavir given to an HIV patient who has the HLA-B5701 variant could cause (blank).
|
Abacavir given to an HIV patient who has the HLA-B5701 variant could cause severe hypersensitivity.
|
|
|
P-glycoprotein transporter is important in the cellular efflux of substrates. SNPs in the transporter gene could be associated with altered (blank) and (blank).
|
P-glycoprotein transporter is important in the cellular efflux of substrates. SNPs in the transporter gene could be associated with altered drug disposition and response.
|
|
|
Albuterol is a beta-2 agonist and used for the treatment of asthma. What is the gene that encodes the beta-2 receptors?
|
ADRB2 is the gene, and 13 polymorphisms have been identified in it.
|
|
|
Two ways that myelosuppression can occur (as discussed in the notes)
|
(1) NAT2 rapid acetylators taking amonafide are at risk of suffering from myelosuppression
(2) people with deficient UGT enzymes (due to UGT1A1*28 polymorphism) who are taking irinotecan are risk of suffering from myelosuppression |
|
|
Thoridazine is contraindicated in patients with this particular metabolic phenotype
|
Thoridazine is contraindicated in those are are poor metabolizers (CYP2D6 deficient)
|
|
|
Phenytoin is oxidized by this CYP ezyme
|
CYP2C9
(so is warfarin and sulfonylureas) |
