Topic 7 Part 1 Pharmacogenomics Flashcards
What pharmacogenomics will allow
- Individualized medication use based on genetically determined variation in effects and side effects.
- Use of medications otherwise rejected because of side effects.
- More accurate methods of determining appropriate dosage.
How pharmacogenomics works
- Identifying gene sequence variations (SNPs) that affect drug response.
- Identifying disease susceptibility genes which represent potential new drug targets.
- Identifying gene sequence variations that can cause adverse drug reactions.
Hereditary variations in drug responses include _
Variations in absorption rates, drug metabolism, drug inactivation and elimination, and target receptors.
Variations in drug metabolism
- If a gene codes for an enzyme, it converts a prodrug into the active form.
- Variant of a gene leads to mutation of an enzyme, causing the drug to be metabolized too quickly, insufficiently, or not at all.
- Example: Clopidrogel (Plavix) - 15% of the population lacks the enzyme that converts Plavix into the active form, so the drug has no effect in these individuals.
Variations in target receptors
- If a gene codes for a target receptor, it enables a drug to bind to a protein and cause a cascade of cellular events.
- Variant of a gene leads to an aberrant receptor to which the drug cannot attach. Can also lead to over- or under-abundance of the particular receptor.
- Example: Warfarin (Coumadin) - mutations in two genes can cause an increased or decreased response, leading to bleeding or thrombosis, respectively. For this reason, there is a wide range of doses of this drug.
Variations in the CYP2C9 or VKORC1 genes require a person to be prescribed a lower dose of _
Warfarin.
Patients with VKORC1 polymorphisms are at risk for exaggerated _ response.
Anticoagulant.
Low CYP2C9 activity results in higher plasma levels of warfarin so the patient is at risk for _
Bleeding.
CYP2C9 is involved in _ metabolism.
Warfarin.
VKORC1 influences warfarin’s anticoagulation effect through _
Vitamin K.
Thiopurine methyltransferase
- An enzyme that transfers methyl groups onto purines, which is involved in chemotherapy drug metabolism.
- About 1 in 300 people have a mutation that prevents them from metabolizing chemo drugs, and should be treated with 10-15 times less chemo than is commonly prescribed, due to increased toxicity.
- Genotyping or functional enzyme assay is now the standard practice in cancer centers.
Slow acetylator phenotype
- “Slow drug metabolizers” - a mutation causes slow clearance of the drug and associated toxicity.
- This phenotype is found in 40-60% of Caucasians, 80% of the Middle Eastern population, but only 20% of Japanese.
- Example: Isoniazid - an anti-tuberculosis drug; causes peripheral neuropathy in slow drug metabolizers.
Imatinib (Gleevec)
- Drug used to treat chronic myelogenous leukemia (CML) by blocking the activity of a fusion protein that is mutated in people with this type of leukemia.
- Gleevec was found to be 98% effective in treating CML, but the person has to be on the drug for their entire lives, due to the possibility of resistance.
Which processes of drug response are most subject to genetic variation?
Drug activation or deactivation and duration of drug actions.
An Asian American man and his Caucasian wife are both taking warfarin (Coumadin) daily because of atrial fibrillation. The husband asks why he is prescribed a much smaller than average dose of the drug to keep his international normalized ratio (INR) at 2.0 and his wife takes the average dose even though he is taller and heavier than she is. What is the nurse’s best response?
“Many Asian Americans do not break down warfarin as fast as Caucasians, so the drug is more effective at lower dosages.”
