Module 6 Drug Discovery Flashcards
(24 cards)
Abacavir (Ziagen)
- Should be avoided in patients with HLA-B* 5701 allele, unless benefits outweighs risks
- Clinical Effect : Increased risk of hypersensitivity reactions
Carbamazepine (Tegretol)
- Should be avoided in HLA-B*1502, unless potential benefit outweighs risks.
- The HLA-B*1502 allele increases the risk for serious and potentially fatal dermatologic reactions (e.g., Stevens- Johnson syndrome and toxic epidermal necrosis) with carbamazepine.
Irinotecan (Camptosar)
- The UGT1A1*28 allele is associated with increased risk for irinotecan-induced neutropenia, with homozygotes having the highest risk.
- Lower irinotecan starting doses are indicated in patients known to be homozygous for the UGT1A*28 allele.
- Patients with UGT1A1 deficiency are at an increased risk of developing severe toxicities including gastrointestinal toxicities and neutropenia
Celecoxib
Celecoxib clearance is reduced in carriers of the CYP2C9*3 allele. Celecoxib should be administered with caution and at lower doses in patients with the CYP2C9*3 allele.
Warfarin
- The CYP2C9*2 and *3 alleles are associated with reduced warfarin metabolism and increased bleeding risk, while the VKORC1-1639A allele is associated with increased warfarin sensitivity.
- Lower doses of warfarin should be started in patients known to have reduced function CYP2C9 or VKORC1 alleles. However, genetic testing is not mandated.
Trastuzumab (Herceptin)
- Decreased tumor progression in breast cancer with trastuzumab has only been demonstrated when HER2 is overexpressed.
- Overexpression of HER2 should be confirmed by protein overexpression or gene amplification prior to trastuzumab initiation.
Antidepressants
Antipsychotics
Antiarrhythmics
Atomoxetine
(Strattera)
- CYP2D6
- Greater likelihood of adverse reactions in people who are poor metabolizers; greater likelihood of treatment failure in people who are rapid metabolizers
Codeine
- CYP2D6
- Greater likelihood of adverse reactions in people who are rapid metabolizers; greater likelihood of treatment failure in people who are slow metabolizers
Beta-blockers (ends with -lol)
- CYP2D6
- Marked differences in plasma levels reported; clinical significance not currently known
Warfarin
Tolbutamide (Orinase)
Glipizide (Glucotrol)
Phenytoin (Dilantin)
- CYP2C9
- Poor metabolizers may exhibit toxic drug effects
Proton pump inhibitors (Omeprazole, Pantoprazole)
- CYP2C19
- Marked differences in plasma levels reported; increased gastric and duodenal ulcer healing rates documented in poor metabolizers and decreased rates in ultra-rapid metabolizers
Fluorouracil
Capecitabine
(Xeloda)
- Dihydropyridine dehydrogenase (DPD)
- Patients with DPD deficiency experience profound toxicity effects including lifethreatening gastrointestinal
toxicity, myelosuppression, and neurological toxicities
Mercaptopurine (Purinethol)
Thioguanine (Tabloid)
Azathioprine (Imuran)
- Thiopurine methyltransferase (TPMT)
- Patients with TPMT deficiency experience profound myelosuppression with normal doses
Oral Contraceptives
Tamoxifen (Nolvadex)
- Factor-V Leiden
- Increased incidence of deep vein and cerebral vein thrombosis (Tamoxifen included based on preliminary evidence)
Allopurinol (Xyloprim)
- HLA-B*5801
- Increased risk for hypersensitivity with this variant.
OATP & P-Glycoprotein transporters mediate the cellular uptake and excretion of ___
- Fexofenadine & Digoxin
- NSAID’s
- HIV-Protease inhibitors
- Beta-Lactam Antibiotics
The ACE inhibitor-induced cough has been linked to a polymorphism of which gene?
Bradykinin
Resources for Pharmacogenetic Info
- FDA
- PharmGKB
- Genetics/Genomics Competency Center
Pharmacogenomics can be used in drug discovery and development to
- Maximize the likelihood of high efficacy and low toxicity of the drug
- Increase the likelihood of a new drug making it to market quickly, safely , and with maximal benefits
Imatinib
(Gleevec)
- bcr-abl tyrosine kinase
- Administration to patients with chronic myeloid leukemia results in decreased proliferation and survival of leukemia cells
Imatinib mesylate
- CD117
- Gastrointestinal stromal tumor cells possessing the CD117 (or c-Kit) mutation have shown regression with imatinib, and imatinib is indicated for patients with the CD117 mutation and unresectable or metastatic gastrointestinal stromal tumors.
Hydralazine, Isoniazid, procainamide
- N-acetyltransferase 2 (NAT)
- Increased susceptibility to adverse effects of drugs that are acetylated. – fast acelylators may not respond to these drugs
- Slow acetylators experience toxicity
Phase 1 metabolizing enzymes
CYP families
DPD - (5FU, xeloda)
FMO
Phase 2 metabolizing enzymes
- N-acetyltransferase 2 (NAT 2) : Hydralazine, Isoniazid, procainamide
- Uridine diphosphateglucuronosyltransferase: (UGT) Irinotecan
- Thiopurine S-methyltransferase (TPMT) : Mercaptopurine, Azathioprine
- Catechol O-methyltransferase (COMT): Levodopa
