Lecture 5: Variations in Drug Responses in Special Populations Flashcards
what are the characteristics of the typical subject in a phase 1 clinical trial?
young (usually male) adult with no underlying disease conditions
changes in doses populations of different ages, weight, and organ function are typically made by ___
estimates
what is pharmacogenetics?
alteration of a single gene results in modified drug response
what is pharmacogenomics?
combination of multiple genetic differences across the genome resulting in varied responses to drugs
the largest source of variation in response to drugs in the adult population is due to ____ differences
genetic
there are genetic variations in many of the drug ___ enzymes
metabolizing
CYP2d^ is an example of an enzyme with ____ that result in cliniycallysignificant variations in response. This enzyme is responsible for the conversion of ___ to ___
genetic polymorphisms; codeine to morphine
t/f many genetic polymorphisms have beeb identified, but most don’t have clinically relevant results
true
____ metabolizers are most people and get the predicted effects of the drug
extensive (EM)
___metabolizers have less than the predicted effects in the case of a pro-drug such as codeine
poor (pm)
____ metabolizers have a greater than predicted effect in the case of pro-drugs such as codeine
ultra rapid (URM)
how can the issue of ultra-rapid metabolizers be corrected for mother’s breastfeeding?
choosing a different drug that does not have active metabolites
what is the function the OATP1B1 hepatic transporter?
facilitates entry on organic anions into hepatocytes for metabolism
what 2 genetic variations have been found in the OATP1b1 hepatic transporters?
- single amino acid changes that alter the function
2. reduced function phenotypes
how might a reduced OATP1B1 result in adverse reaction to simvastatin?
simvastatin has potential to cause muscle toxicity, and if the OATP1B1 has reduced function, there will be higher simvastatin concentration and more risk
the normal function of the OATP1B1 transporters are required for drug ___
metabolism and clearance
if a patient has reduced OATP1B1 function, should they be prescribed a lower or higher dose of statin?
lower
alteractions in the protein structure of the B2–AR influence ____ responses to regular ___ treatment
airway; bronchodilator
what is the single genetic change on the B2–AR receptor that influences the response to bronchodilators?
switch of Arg vs Glycolysis on codon 16
patients with the homozygous arginine on codon 16 of the B2–AR receptors experience what change in responsiveness to bronchodilators?
greater receptor desensitization and diminished responsiveness
patients with the homozygous glycine codon 16 of the B2–AR receptor experience what change in responsiveness to brocnhodilators?
less receptor desensitization and no change in responsiveness
neonates and infants have have ___ body water %
higher
premature babies have ___ body fat %
lower
elderly have ___ body water %
lower
elderly have ___ body fat %
higher
bioavailability of drugs ___ in class 3 obesity
increases
obesity
multifactorial disease that impacts many body systems, not simply a higher percentage of body fat
highly lipophilic drugs are expected to ___ Vd with higher adipose tissue in the body
increase
Obese patients often have ___ metabolism
unpredictable
many obese patients also suffer from hypertension, causing a ___ in renal excretion of drugs
decrease
it is important to consider drugs that cross the ___ in pregnant women
placenta
drugs that cause birth defects are called
teratogen
systems in what phase are most susceptible to teratogens?
developing
early in embryo development, teratogen exposure poses the highest overall risk to the development of ______ that may result in ___
anatomic abnormalities ; miscarriage
what is an example of early embryo anatomic abnormality that results in miscarriage
neural tube detects in the CNS
in later phases of fetal development, most of the major organs are formed, but teratogen exposure may impact ____ or ___
physiological function or final development of structures
what are the 5 FDA pregnancy categories for teratogens?
- A
- B
- C
- D
- X
category A of drugs in pregnancy
shown to be safe for use in pregnancy
categories B/C of drugs in pregnancy
may cause harm or pose risk to fetus
category D of drugs in pregnancy
drug likely to cause harm, use caution
category X of drugs in pregnancy
will cause harm DO NOT USE
category X drugs are typically those that interfere with pathways involved in fetal ___
developemtb
give 4 examples of category X drugs for pregnancy
ACE inhibitors, warfarin, anti seizure drugs, valproic acid
ACE inhibitors in pregnancy can result in ___ and ___
fetal renal and cardiovascular damage
warfarin in pregnancy can result in ___, ____, and ___
anatomical malformations, CNS and CV damage, high rate of miscarriages
antiseizure drugs in pregnancy can result in ___ and ___
neural tube defects and cardiovascular damage
valproic acid in pregnancy can result in ___ , ____ and ___
neural tube defects, anatomical malformations and CNS & CV damage
neural tube defects result in malformations of the ___ and ___
spinal cord and CNS
list 5 examples of drugs safe for use in pregnancy (category A)
- penicillin
- heparin
- diphenhydramine
- short acting benzodiazepines such as lorazepam in the 3rd trimester
- topically applied drugs like inhaled corticosteroids for asthma
t/f it is impossible to know if a drug will be 100% safe for use in pregnancy
true
the new FDA requirements for drug use in pregnancy are more ____ and provide much more information regarding ___ and ___
descriptive; risks and evidence
the teratogenic risk of ibuprofen depends on the
trimester
ibuprofen can be listed as what class teratogen?
B, C, D
what is the preferred analgesic for mild pain relief during pregnancy
acetaminophen
there are major birth defects in ___% of the population and of this population, ___% are thought to be caused by drug use
1-3; 2-3
t/f it is possible that a mother’s uncontrolled medical condition may cause more harm to the fetus than the medication used to control the condition
treu
even if a drug doesn’t have teratogenic effects, a neonate constantly exposed to a drug, such as opioids, can develop ___ and suffer from ___ after birth
dependence; withdrawal
drugs that interfere with development of healthy bones and teeth should not be used in ___ unless absolutely necessary
children
why are tetracycline antibiotics not recommended for children?
tetracycline binds to calcium in teeth and becomes permanently embedded, resulting in yellow/drown discolouration that cannot be removed
what is something to consider when thinking of adverse effects in children?
many drugs are net studied in children, so they may have unexpected effects and may not be able to articulate the exact effects as well as an adult may be able to
how are absorption and distribution different in children?
children have constant body composition and organ function as they develop and grow
___, ___ and ___ can significantly impact the bioavailability of drugs in very young children
blood flow, muscle mass, GI function
drug metabolizing enzymes are expressed at varying levels throughout development, which results in variations in ___ compared to adults
drug clearance
neonates have ____ clearance compared to adults
slower
clearance may be much ___ in children than adults
faster
t/f phenobarbital, a barbiturate has a shorter half life in toddlers than adults
true
when paediatric dosing hasnt been determined by the drug manufacturer, dosing is typically considered to be more accurately determined based on ___ rather than weight
body surface area
why is body surface area a more accurate measurement for dosing in children than weight?
due to variations in body compositions of children compared to adults
absorption processes are not known to change in healthy aging, however there are some effects of ____ that are more common in older adults
lifestyle modification
t/f inconsistent diet and irregular eating patterns can have significant impact on drug absorption
true
what are 2 ways in which metabolism changes with old age?
- decreased hepatic metabolsim
2, reduced capacity of some CYP enzymes
how is excretion of drugs impacted by aging?
reduced renal function, therefore decreased clearance
what is the greatest effect on altered pharmacokinetics in older adults?
the decrease in glomerular function to excrete drugs
what is glomerular filtration?
process in which molecules are removed from the blood in the nephrons and transferred to the urine
a decrease in glomerular filtration results in
drugs circulating for longer period of time
how does the cardiac index in old age affect renal and hepatic function?
decreased blood flow, which slows filtration
rate of removal of drug may be reduced if renal function is __
impaired
if there is renal impairment, active or toxic metabolites may accumulate to ___
unsafe levels
what is creatinine?
metabolic waste product removed by the kidneys
serum levels of creatinine in a healthy adult should be very ___, which makes this protein a good surrogate measure for ___ and ___
low; glomerular filtration rate and kidney function
in old age there is greater sensitivity to respiratory ___
depression
in old age there is a ___ in delivery of inhaled drug, why is that?
decrease; because it is more common to experience respiratory drepression, preventing the optimal delivery
patient with diabetes have an increased risk of ___ diseases and may have other organ system impairments such as ____, ___ and ___
retinopathies; neuropathies and nephropathies
polypharmacy increases the risk for ___ and ____
drug interactions and serious adverse effects
it has been estimated that there is a nearly 100% chance of an adverse reaction when a patient is taking ___ or more medications
10
