Variability in Drug Response Flashcards
list the factors that contribute to variability in drug response btw patients
Compliance Disease Genetics Age Drug interactions
describe significance of adverse drug reactions, how to reduce
more patients are taking more drugs (2/3 doc visit = Rx)
frequency of interactions increases with # of drugs
patient history is key (drug, herb, diet, conditions etc)
list variety of substances with which drugs may interact
other drugs (with similar or opposite effects), foods etc.
how genetics affects drug response
most genetic variation due to single nucleotide polymorphisms (SNPs)
i.e. CYP450 gene. Most people are extensive metabolizers. some ppl are poor metabolizers-reduced enzyme activity bc a SNP made protein that was not functional. Some ppl are ulta-rapid metabolizers because of SNPs that result in gene duplication, metabolize much faster.
Each subgroup would require diff dose of some drug for same effect
CYP2D6
enzyme that metabolizes codeine (prodrug) to produce morphine
case report: mother is ultra rapid metabolizer of 2D6 enzyme, much more codeine being metabolized into morphine. transmitted to baby, baby dies
how age affects absorption
oral delivery:
young & old have increased stomach pH. acid labile drugs will have higher relative plasma conc.
infant has decreased absorption of weak acid drug from stomach
(increased pH, so less H+, less Ha and more A- which cannot be absorbed)
how age affects drug distribution and plasma concentration
Paediatrics: higher TBW (hydrophilic drugs have decreased plasma concentration), lower fat, so lipophilic drugs have increased concentration
Geriatrics: lower TBW, so increased hydrophilic drug concentration, higher fat so lower lipophilic drug concentration
Both: lower plasma proteins which increases [free drug]
how age affects metabolism
Phase 1 enzymes (i.e. P450): pediatrics have some at birth, but others take 3 months to develop. geriatrics have overall decrease
phase 2: pediatrics take several months to be fully expressed, no change in elderly
liver function: decreased mass and BF in both
HL will increase, so must decrease the dose or increase the dosing interval
effect of age on plasma [propranolol] which is eliminated by phase 1 enzymes
much higher Cmax in elderly
area under curve (represents body’s cumulative drug exposure) in young people is half that of elderly
due to different metabolism rates and increased HL in elderly
effect of age on excretion
elimination of renally excreted drugs is decreased in young & old
infants: immature kidney function (only 20% that of adult for 1st yr)
geriatrics: decline kidney function
- reduced size, glomeruli, nephrons, BF
HL increases, must decrease dose or increase dosing interval
PD interactions-additive or synergistic
combining 2 drugs with similar pharm. effects
- can be advantage if intentional
- can be harm if unintentional
i.e. anti-coagulant+anti-platelet = hemorrhage
PD interactions-antagonistic
combine 2 drugs with opposite pharm effects
i.e. antihypertensive + decongestant = opposing effects on BP
drug interactions affecting absorption
gastric pH:
increased pH with PPI, H2 antagonist, or antacids can affect absorption of weak acid and weak base drugs
drug interactions affecting drug distribution
drug transport pumps: drug that increases/decreases expression of transporter pumps can alter distribution
least likely
how drug interactions affect metabolism
plus example with CYP3A4
phase 1 cytochrome P450 enzymes can be induced or inhibited by other drugs/food
ex: drug A is a substrate for CYP3A4 (it is metabolized by it). normally drug A would give therapeutic effect/. person takes A alongside a CYP3A4 inhibitor (drug b) results in increased [A] in blood and toxicity.
if took A alonside a cyp inducer, would have reduced [A] and therapeutic failure
