Genomic Medicine - Reed Flashcards
What are some variables that can affect drug concentration at locus of action, and thus affect drug response?
physiological variables, pathological factors, genetic factors, interaction with other drugs, and development of tolerance
*pharmacodynamics
What can affect the intensity of drug effect?
drug-receptor interaction, functional state of drug, and placebo effects
What are some variables that can affect drug response between the time the drug is ingested to the time it reaches the site of action?
rate and extent of absorption, body size and composition, distribution in body fluids, binding in plasma and tissues, and rate of elimination
*pharmacokinetics
what is the difference between pharmacokinetics and pharmacodynamics?
pharmacokinetics: what patient does to the drug - how?
pharmacodynamics: what drug does to the patient - why?
pharmacokinetics describes the processes that determine certain parameters that determine how effective a drug is. what are these parameters?
to be effective, a drug must reach its target, be in an active form, have a sufficient concentration, and be there for a sufficient period of time
What is “ADME” and what is it used for?
A: absorption
D: distribution
M: metabolism
E: excretion
getting the right form to the right place in the right amount
What is the dominant metabolizer enzyme? Describe the key enzymes and their characteristics.
cytochrome P450: CYP3A4, CYP2D6, CYP2C19 and CYP2C9
metabolizes nearly all drugs, found in liver and have broad substrate specificities
What is the difference between pharmacogenetics and pharmacogenomics?
pharmacogenetics: study of heritability in drug response
pharmacogenomics: development of new drugs based on increasing knowledge of all genes in the human genome
What was one of the first cases of pharmacogenetics?
increased frequency of hemolytic anemia in African-American soldiers treated with primaquine. African American-Americans have G6PDH
What role does CYP2D6 play in the pharmacokinetics and pharmacodynamics of Debrisoquine?
CYP2D6 is highly polymorphic (100 human variants) - most variants show diminished or no activity; can also be duplicated/amplified
Debrisoquine (anti-hypertensive) has an excessive effect in 5-10% of Caucasians; CYP2D6 is inversely proportional to debrisoquine: the more enzyme, the lower the concentration in the blood and the faster it is excreted
Most humans are extensive metabolizers, a small percentage are poor metabolizers and the smallest group are ultra rapid metabolizers (gene duplication); these distributions varies with race and ethnicity
Among groups of individuals with the same genetic background, how can you explain the variation in drug response?
- induction by changes in diet or other exposures increases enzyme expression levels (some foods have chemicals that increase the genetic expression of enzymes)
- increased expression of drug metabolizing enzymes results in lower concentrations and faster elimination of drugs
- following induction, dosing may need to be increased beyond what genotype alone predicts to achieve therapeutic concentrations of drug*
What is induction?
higher levels of expression of proteins that metabolize drugs due to environmental effects
increase expression of enzymes, increase metabolism, increase drug dosage/frequency
What is terfenadine and how does it work in our bodies? What can inhibit it and how does the inhibition work?
terfenadine is a pro-drug that is metabolized (oxidized) by CYP3A4 to its active form: fexofenadine. Fexofenadine is an active anti-histamine.
Erythromycin and many other drugs compete for/inhibit CYP3A4. inhibition of metabolism or excretion may require dosing alteration beyond what genotype alone predicts or choice of a different drug to achieve therapeutic concentrations
in this case, high concentrations of terfenadine will start targeting ion channels, like K, which negatively affect the heart
kinetics is predictable: more activity, less drug
what should you use to estimate genetics when looking for associations?
only use race/ethnicity in isolated populations
in most of society, race/ethnicity is a poor substitute for genetics
