Pharmacogenetics Flashcards
Pharmacogenetics
Study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity. Typically involves the study of just a few genes and these genes are selected based on prior knowledge of their roles in drug metabolism.
Pharmacogenetics
Genomic approach to pharmacogenetics. Concerned with assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy. Analyzing sets of alleles at a large number of polymorphic loci rather than individual genes to distinguish patients who have responded adversely to what was considered a beneficial drug from those who had no adverse response.
What are the two major areas of drug response that involve variation?
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics
rate at which body absorbs, transports, metabolizes, or excretes drugs or their metabolites (ADME- absorbs, distributed, metabolize, excrete). Genetic example: cytochrome P450, glucuronyltransferase, thiopurine methyltransferase. “whether or how much drug reaches target”
Pharmacodynamics
the response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways. Genetic examples: glucose 6 phosphate dehydrogenase, vitamin K epozide complex. “concerned with what happens when drug sucessfully reaches its target”
Pharmacokinetics Phase I Metabolism
Attach a polar group onto the compund and make it more soluble; usually a hydoxylation step.
Pharmacokinetics Phase II Metabolism
attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
Genetic variation in pharmacokinetics/dynamics and/or Phase I/II metabolism causes _______ variation in drug response.
phenotypic; this becomes clinically important every time you write a prescription
The cytochrome P450 (CYP450) encodes for enzymes that are active where?
In the liver and to a lesser extent in the epithelium of small intestine.
The CYP families (CYP1, CYP2, CYP3) are particularly active including what six genes that are involved in the Phase I metabolism of ~90% of all commonly used medications?
CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. ** Note: there is a wide genetic polymorphic variation with phenotypic consequences in the CYP families of genes, which iswhy they are so important to prescribing physicians.
What is significant about CYP3A4 gene?
It itself takes part in metabolism of over 40% of all drugs used in clinical medicine.
Most CYP genes are important in the rate of inactivation of a drug, but what example gene shows that it is required to activate a drug?
CYP2D6; gene is necessary to convert codeine (inactive, almost no analgesic effect) to morphine (active with a potent analgesic effect)
Mutations on the CYP2D6 gene can effect function. Discuss result of frameshift, splicing, missense, and copy number alleles.
- Frameshift –> alter reading frame –> no activity. 2. Splicing –> skip exons and/ or alter reading frame –> no activity. 3. Missense –> alter protein function –> usually reduced activity, but can increase. 4. Copy Number Alleles –> increased gene copy alleles –> activity increased to ultra fast. 5. Nonsense –> alter protein translation –> no activity.
CYP variation can be present and important within the human secies as a whole, but differ where?
Ethnic populations. i.e. Patient that is Asians is more likely to complain that codeine you prescribed is not working because they are better metabolizers.
CYP3A gene
Substrate: Cyclosporine (Immunosupressant agents). Inhibitors: Ketoconazole (azole antifungal agents),and Grapefruit Juice. Inducer: Rifampin
