Pharmacogenetics Flashcards
Define pharmacogenomics
The genomic approach to pharmacogenetics, concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy. Tests large sets of alleles across the genome to distinguish patients who have adverse affects to drugs.
Define pharmacogenetics
The study of the differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity. Typically involves the study of very few genes which are selected based on a priori knowledge of their roles in drug metabolism.
Define pharmacokinetics
The rate at which the body absorbs, distributes, metabolizes or excretes drugs or their metabolites (ADME). (ie, whether and how much of a drug reaches its target). Includes Cytochrome P450, glucoronyltransferase, thyopurine methyltransferase.
Define pharmacodynamics
The response of the drug binding to its target and downstream targets such as receptors, enzymes, or metabolic pathways. (ie, what happens when the drug successfully reaches its target). Includes glucose-6-phosphate dehydrogenase, vitamin K epoxide complex.
Name and describe the two phases of pharmacokinetics
Phase I: attach a polar group onto the compound to make it more soluble, usually hydroxylation
Phase II: attach a sugar/acetyl group to the drug to detoxify it and make it easier to excrete.
What are the primary families of CYP450 genes, where are they expressed, and what in phase do they function?
CYP1, CYP2, CYP3
Expressed mainly in the liver and intestinal epithelium.
Function in Phase I metabolism of drugs.
Name one drug and CYP enzyme that are involved in an activation pathway instead of a metabolizing pathway.
Codeine (inactive) is modified by CYP2D6 to produce morphine (active).
Three major phenotypes of drug sensitivity due to mutations of individual CYP genes.
Poor
Normal
Ultra fast/ultra rapid
Types of mutations that would result in poor drug processing phenotype.
Frame shift (no activity)
Nonsense (no activity)
Missense (typically reduced activity)
Type of mutation that would result in ultrarapid/ultrafast drug processing phenotype.
Copy number repeats (more than two copies of the gene)
What affect would drinking grapefruit juice have on a patient taking felodipine for hypertension and by what mechanism?
It could lead to severe hypotension. Grapefruit juice inhibits CYP3A activity in the intestinal epithelium for 24-48 hours. CYP3A is the principle metabolizer of felodipine, thus inhibiting its activity slows the metabolism and excretion of felodipine, allowing it to exhibit side effects.
In a renal transplant patient who develops a fungal infection, what changes must be made to cyclosporine levels due to administration of ketoconazole and why?
Cyclosporine, an immunosuppressant, must be reduced by 75% due to ketoconazole (an antifungal) inhibition of CYP3A. Reduced CYP3A metabolism leads to slowed clearing of cyclosporine, which can be nephrotoxic.
In a renal transplant patient who develops tuberculosis, what changes must be made to cyclosporine levels due to administration of rifampin and why?
Cyclosporine levels would need to be increased because rifampin is a CYP3A inducer. Higher rates of CYP3A metabolism would decrease cyclosporine levels which could lead to increased immune response and possible organ rejection.
What are adverse drug reactions and where do they rank as a national cause of death?
ADRs are negative reactions that occur in a patient who has received the proper amount of the correct drug for a condition the patient has. They are due to an individual response, and not to medical error. They are the 4th-6th leading cause of death in the US.
Name three broad categories of pharmacological effects of a drug.
Efficacy
No effect
Toxicity
