Pharmacogenetics Flashcards
Pharmacogenetics
The study of differences in drug response due to allelic variation in genes. Affects drug metabolism; efficacy;; and toxicity. Typically involves study of just a few genes selected by their known role in drug metabolism
Pharmacogenomics
Concerned with assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy. Large numbers of polymorphic loci being identified in Pts who have responded adversely vs. those who had no adverse response
Pharmacokinetics
Describes absorption; distribution; metabolism and excretion of drugs (ADME). IE whether or how much drug reaches targets. Drug removal. EX Cytochrom P450; thiopurine methyltransferase; etc.
Pharmacodynamics
Describes the relationship between the concentration of a drug at its site of action and the observed biological effects. IE what happens when the drug successfully reaches its target. Drug effect. EX G-6-P dehydrogenase; vit. K epozide complex
How can you further breakdown pharmacokinetics?
2 basic ways that drugs are metabolized: Phase I and Phase II
Phase I
Attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
Phase II
Attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
What does the cytochrome P450 gene encode for? What do they do? Where are they active?
CYP450 genes encode enzymes that metabolize (through Phase I) a large number of drugs (90% of all common meds). Very active in the liver and a bit in epithelium of the small intestine.
What is the most active gene in the CYP family?
CYP3A4 - take part in metabolism of >40% of all drugs
What does CYP2D6 activity do in regard to codeine?
Activates codeine by converting it to morphine. (Note:this is different than most CYP genes that inactivate drugs)
What are the 3 different phenotypes when it comes to drug metabolism?
Normal; poor; Ultrarapid/ultrafast
What is an important CYP3A substrate?
Cyclosporine (an immunosuppressant)
Name 2 CYP3A inhibitors
Ketoconazole (antifungal agent); Grapefruit juice
Name 2 CYP2D6 substrates
Tricyclic antidepressants; Opioids (codeine-activates)
Name 3 CYP2D6 inhibitors
Quinidine (antiarrhythmic); Fluoxetine (Prozac); Paroxetine (Paxil - SSRI)
Name 1 substrate of CYP2C9
warfarin
What is a substrate of the NAT gene?
Isoniazid for tuberculosis
What 2 substrates are there for the TMPT gene?
6-mercaptopurine; 6-thioguanine
What do 6-mercaptopurine; 6-thioguanine treat? What must you remember about these drugs?
Immunosuppresant. Used to treat ALL et al. Must remember that if you give children with ALL standard doses you will KILL the child due to immunosuppression
Name 2 substrates of G6PD gene
Sulfonamide antibiotics; dapsone (antibiotic)
What is important to remember about the mechanism of G6PD enzymes?
X-linked enzyme
If a Pt is G6PD deficient; what are they susceptible to after drug exposure?
hemolytic anemia
What is a substrate of VKORC1 gene?
warfarin (blood thinner)
Most major drugs are effective in what percentage of Pts?
25% - 60%
What are the expected mutations on poor drug metabolizers?
Frameshift; splicing; nonsense; missense (some)
What happens if poor metabolizers are given normal doses?
Since most CYP genes are inactivators; Pts will usually be overdosed
What are the expected mutations on ultrafast drug metabolizers?
Increased copy number; missense (some)
What happens if ultrafast metabolizers are given normal doses?
Since most CYP genes are inactivators; Pts will usually be underdosed
