Variability among Patients in Drug Response

Lecture given 2/5/2026

what are some phenotypic and genotypic factors that affect drug response?

body size and composition, age, gender, genetics, adherence to drug regimen, drug tolerance/resistance, drug interactions, drug allergic reactions

how doe Vd change with body weight?

increases proportionally

dose is often normalized for body weight

may be affect by body composition- % fat, % fluid compartments

what effect does obesity have on Vd?

depends on drug type, lipophillic drugs like diazempam will have a much large Vd than drugs like theophylline

elimination half life is _____ proportional to Vd and _______ proportional to ClT

directly, inversely

t/f both Vd and ClT are related to body weight

true

elimination half life _____ with increase in body weight

increases only slightly

why might older individuals respond to drugs differently?

decline in renal function to 50% by 90 years

greater risk of falls from sedating drugs

increased risk of disease- disease induced changes in pharmacokinetics and pharmacodynamics or drug interactions due to polypharmacy

t/f some drug side effects are more problematic in one gender

true- impotence in males from antihypertensive agents, some drugs of greater risk in person of child-bearing age due to potential adverse effects on fetus

what are potential sites of action of drugs on reproductive function and the fetus?

ovulation, blastocyst development and implantation, fetal differentiation and growth, fetal drug targets as in the adult (opioids), placental function, uterine contractility (NSAIDS)

teratogen

greek for monster

agent which causes an anatomic abnormality in the fetus

congenital defect referred to as malformation

thalidomide induced phocomelia

occurred in 1960s in pregnant individuals using drug for treatment of morning sickness

outbreak lead to FDA regulations requiring demonstrations of safety for all drugs

FDA classification A

no fetal risk, based on human studies

FDA classification B

fetal risk in animals, not in humans

FDA classification C

fetal risk in animals, humans unknown

FDA classification D

fetal risk, but acceptable benefit/risk

FDA classification X

fetal risk outweighs benefit

what does the FDA require for prediction of risk from animal studies?

data from 2 species (usually rat or mouse and rabbit)

mating behavior, embryolethality, fetal growth rates, anatomical malformations

study outcomes are provided in drug label (as of 2015)

is sensitivity high or low in predictive animal studies?

high- most human teratogens are teratogenic in one animal species

is specificity high or low in predictive animal studies?

low- many nonteratogens in human are teratogenic in one animal species

what are some factors affecting fetal risk?

exposure time in gestation- highest risk in 1st trimester bc of organ formation and tissue differentiation

dose and access to fetus- depends on physiochemical properties of the drug

what drug properties increase access to the fetus?

low MW (<1000 Da) and high lipophilicity

high MW mAbs access fetus via IgG transport mechanisms

what mechanisms allow high MW mAbs to access fetus?

FcRn endocytotic mechanism begins in first trimester and increases during gestation

some mAbs increase teratogenic risk such as epidermal growth factor receptor inhibitors (HER2 antagonists used in cancer)

fetal alcohol syndrome

teratogenic effect of ethyl alcohol

low birth weight, small head size, characteristic facial abnormalities (widespread eyes), intellectual development disorder (cognitive dysfunction)

t/f the teratogenic effects of ethanol are dose dependent

true-

0 drinks per day is <1% risk of FAS, and birth weight of 3300 g

>5 drinks per day is 11-19% risk of FAS, and birth weight of 2000g

what are the effects of maternal smoking?

increased risk of preterm delivery, increased risk of fetal growth retardation especially during 3rd trimester (adverse effects on placental function and nutrient delivery to the fetus, effects are not congenital but smoking causes low birth weight)

dose dependent relationship

antiseizure agent valproic acid

increases in neural tube defects from exposure during first trimester (1-2% incidence of spina bifida)

risk of maternal seizures with adverse effect on fetus may warrant risk of drug use (pregnancy D category)

what effects do tetracyclines have on a fetus during pregnancy?

tooth and bone abnormalities

what effects do NSAIDs have on a fetus during pregnancy?

effect on uterus to delay onset and prolong labor

what effects do opioids have on a fetus during pregnancy?

fetus can experience drug effects like those produced in the mother

what are some genetic polymorphisms that can affect drug response?

enzymes on biotransformation (effecient v poor metabolizers), drug transporters, drug receptors

*CYP450 2D6

deficiency decreases biotransformation and therefore analgesic efficacy of prodrug codeine

n-acetyltransferase (NAT2)

important in biotransformation of anti-TB agent (isoniazid)

plasma cholinesterase

deficiency leads to prolonged paralysis by neuromusclular blocker succinylcholine

what diseases are important to pay attention to as they may cause pharmacokinetic changes?

renal and liver disease

what pharmacokinetic changes may be seen with renal disease?

may decrease drug renal Cl

renal clearance predicted by creatinine Cl, patient with renal dysfunction and reduced GFR must have reduced dosage rate for drugs eliminated by renal route

what pharmacokinetic changes may be seen with liver disease?

may reduce albumin synthesis and change Vd

may decrease drug hepatic clearance due to reduction in hepatic blood flow or decreased enzyme activity

what are some common reasons for poor adherence?

symptom free indication (like pt don’t feel hypertension), side effects, misunderstanding of therapeutic goal, complexity of regimen, polypharmacy, cost

tolerance

increased clearance due to enzyme induction

receptor downregulation or desensitization can be either