Flashcards in genetic stuff Deck (25):
What is pharmacogenetics?
study of heritable variability in drug response. genetic influences on pharmacokinetic and phramacodynamic variability, as well as many charateristics of an individual that are directly or indirectly determined by genetics
What is pharmacogenomics?
study of new drug development based on incr. knowledge of genes in the genome
What does a monophasic distribution of drug conc. in a population indicate from a genetic standpoint?
drug conc. influenced by polygenic set of complex traits- combination of many genetic influences acting in conjunction w the environment
What does a bi or triphasic distribution of drug conc. indicate? What is an example of a drug where a biphasic distribution is noted?
this indicates mendelian inheritance.
dominant/recessive trait for biphasic
codominence for triphasic.
isoniazid is an example drug (for TB)
A patient has a variant form of a drug-metabolizing enzyme. what might I expect?
differences in metabolism of many different drugs, since these enzymes play a role in the metab of several compounds.
differences in the metab of some drugs handled by the enzyme may be more pronounced than in other drugs- effects of the variation may be selective.
What is one metab-related explanation for drug-drug interactions?
drug-metabolizing enzymes may act on many different drugs. if two drugs share the same enzyme, you may need to adjust- admin of one drug leads to upreg of the metab enzyme, which will also incr. the metab of the second drug, for example.
Why does grapefruit juice often affect drug effects?
grapefruit juice inhibits intestinal CYP3A4. CYP3A4 involved in metab of 50% of drugs.
What enzyme hydrolyzes midazolam and tacrolimus? What happens in people with a variant of this enzyme?
People with a truncation can't metabolize midazolam and tacrolimus. incr. active drug levels are observed.
What is the story with proton pump inhibitors and the CYP2C19 polymorphism
CYP2C19 variants don't metabolize proton pump inhibitors well- better cure rate for overproduction of gastric acid.
What is the story with irinotecan and UGT1A1?
this is a topoisomerase inhibitor that must be transformed to its active form SN28. SN28 is glucuronidated by UGT1A1. too much drug can be dangerous and is seen in some pts with UGT1A1 polymorphism.
What is the story with thiopurines and TPMT polymorphisms?
TPMT metabolizes anti-leukemic drugs (thiopurines) and is polymorphic. if on the lower end of TPMT activity, you must reduce dosage to prevent toxicity.
How might transporter polymorphisms influence drug concentrations?
genetic variability in transporters changes effective concentration of drugs in intracellular compartments. also changes their excretion patterns. also important with irinotecan (topoisomerase inhibitor for cancer)
When looking at the pharmacodynamic variability in a population (variability in the response to a drug at a given conc), what kind of a curve do we usually see?
describe the cumulative frequency distribution in a graph of pharmacodynamic variability.
sigmoidal. slope reflects variability- steep slope indicates greater population homogeneity.
What kinds of factors influence pharmacodynamic variations in the population?
quantitative number/concentrations of drug receptors
genetic differences the quality of the drug receptor.
What is the story SNPs in the gene for the beta 2 adrendergic receptor ADRB2?
Gln to glu changes at codon 27 make these receptors more responsive to vasodilation by isoproterenol
Arg to gly changes associated by less airway response to albuterol.but doesn't desensitize like gly/gly or arg/gly genotypes.
What is an example of a somatic genetic variation that has an effecto on pharmacodynamics?
epidermal growth factor receptor (EGFR) and cancer
in some forms of small cell lung carcinoma there is an activating muation in epidermal growth factor receptors. these cancers are sensitivity to certain EGFR inhibitors like gelfitinib or erlotinib.
In breast cancer, overexpression of EGFR gene makes tumors responsive to trastuxumab
What is the MOA of warfarin?
purpose: serves as an anti-coagulant
warfarin inhibts vitamin K reductase (C1 subunit). reduced forms of vitamin k serve as cofactors for Y-glutamyl carboxylase, which activates clotting factors. without reduced vitamin K, Y-glutamyl carboxylase can't activate the clotting factors --> anticoagulant!
How is warfarin metabolized?
warfarin is a racemic mixture: S warfarin 5X more potent than R warfarin. S warfary metabolized by CYP2C9; R warfarin by other cyp proteins
What factors influence pharmacokinetics of warfarin?
three polymorphysims in the CYP2C9 gene (WT, intermediate, low activity levels)
What factors influence pharmacodynamics of warfarin?
VKORC1 (vitamin K reductase subunit C1), the drug target of warfarin, also polymorphic- one variant much more responsive to warfarin than others
What is the traditional model of drug discovery?
1. basic science research into the disease yields a drug target
2. a compound is designed and synthesized- the compound that first shows any potential is a lead compound
3. Analogues of the lead compound are made that improve on it.
4. testing, clincal trials, etc. etc. --> process takes 10+ yrs
Describe the pharmacogenomic approach to drug development?
1. Identify genes and variants that contribute to disease phenotype.
2. Virtual screening is used to identify structures/compounds like to interact well with a relevant variant
pre-synthesized library of compounds are screened ("high throughput screening")
3. preclinical/toxicology testing
4. clinical trials with genetic profiles of test
What are the two main methods of develping a library of chemical compounds that can be screened in a high throughput fashion for drug development?
What is common to both of these methods?
1. successive building blocks added to a structure- compound grows in one direction
2. many directions allowed from a n initial template building block that allows for addition of many different building blocks
Both typically performed in an automated fashion with template conjugated to solid phase well.