drug elimination Flashcards
define drug elimination
irreversible removal of drug from the body by all routes
2 things that elimination includes
metabolism
excretion
define drug excretion
removal of the intact drug
excretion method for nonvolatile drugs
renal excretion
excretion method for volatile drugs
lungs -> expired into air
6 routes of drug excretion
biliary (liver)
lungs
saliva
breast milk
feces
kidney
salivary excretion is for drugs with _____
high saliva to plasma ratio
what is the most important characteristic that drugs need to possess to cross biological membranes
lipophilicity
excretion method for most drugs that are not absorbed
feces
where do drugs excreted via biliary route go to next
feces
what is the most important route of elimination
renal excretion
3 processes that renal excretion involves (& location)
glomerular filtration (bowman’s capsule)
tubular reabsorption (distal tubule)
tubular secretion (proximal tubule)
characteristics of a drug that determine its excretion via biliary route
chemical structure
polarity
molecular size
clearance measures _____ without identifying _____
drug elimination from body without identifying individual process
clearance technical definition
volume of plasma/body fluid that is cleared of all drug per unit time
ml/min or L/hr
clearance has nothing to do with _____
the amount of the drug
what 2 organs are able to clear drug out of the plasma
liver
kidney
equation for total clearance
= rate of elimination / [drug in plasma]
(ml/min)
renal excretion equation
= filtration + secretion - reabsorption
3 factors of a molecule that determine glomerular filtration
molecular size
molecular shape
charge
what is the “restrictive filtration” size range for glomerular filtration
will filter all drugs < 20 kDa
will selectively filter drugs 20 - 60 kDa
will NOT filter drugs > 60 kDa
drugs are ONLY filtered across glomerulus if _____
they are unbound (free)
gold standard to measure renal clearance & why
inulin
bc it is ONLY filtered (no reabsorption or secretion)
active tubular secretion mechanism
translocation of drug from plasma -> urine
mediated by OAT, OCT, or P-gp efflux transporters
why is tubular secretion considered an “active” process, & what is the consequence of this
bc it uses carrier molecules & requires a supply of energy
can be competitively inhibited
penicillin tubular secretion can be competitively inhibited by _____, which _____
probenecid
decreases penicillin’s renal clearance
handling of drugs bound to plasma proteins in glomerular filtration vs tubular secretion
GF: drug bound to plasma protein is not filtered due to size
TS: drug is stripped off of protein so it can be excreted
2 reasons a drug in glomerular filtrate is reabsorbed from tubules into peritubular capillaries
drug has lipophilic characteristics
there is a positive concentration gradient between the tubule & peritubular capillary
acidic urine favors reabsorption of _____
weak acids
alkaline urine favors reabsorption of _____
weak bases
hepatobiliary excretion mechanism
drug absorbed across GI tract into portal circulation
->
drug uptake by hepatocytes
->
excretion of drug/metabolite into bile
->
bacterial deconjugation & reabsorption of drug
mechanism of drug uptake by hepatocytes
uptake by transporters
->
drug transformed into metabolite
->
metabolite transported into bile canaliculi
OR
effluxed out of hepatocyte into blood by ATP
what are the 2 primary determinants for drug/metabolite excretion into bile
molecular weight (needs to be pretty high)
drug needs to have a strong polar group
what is the size threshold for biliary excretion in humans
> 500 Da
examples of drugs that undergo enterohepatic recycling (excretion into bile)
hormones (estrogen)
morphine 6-glucuronide
estradiol glucuronide
abx (doxycycline)
where do glucuronide metabolites excreted into bile go next, and what happens there
duodenum
microbes that produce beta-glucuronidase enzyme deconjugate the metabolite ->
frees the parent compound that is then reabsorbed
what can affect biliary drug elimination
-liver disease / injury
-age (neonate or geriatric)
-drug competition for same carrier protein
example of drug whose chronic administration can affect biliary elimination
phenobarbital
example of drugs whose co-administration can speed up enterohepatic recycling
ion exchange resins
&
drugs like abx & estrogens
factors that affect pulmonary elimination of drugs
-respiration rate
-pulm blood flow
-water (aqueous) solubility
-cardiac output
-volatility
factors that INCREASE rate of drug loss via pulmonary elimination
-increased RR
-increased pulm blood flow
-low aqueous (water) solubility
-increased CO (cardiac output)
-increased volatility
characteristics of a drug that easily passes into breast milk
-high [drug in maternal blood]
-low plasma protein binding
-high lipid solubility (lipophilicity)
what types of drug get trapped in breast milk, & why
weak bases/alkaline drugs (such as barbiturates)
bc breast milk pH is acidic, so an alkaline drug will ionize in the breast milk & be unable to return to system
factors of drug that affect breast milk elimination of drugs
-[drug in maternal blood]
-plasma protein binding
-lipid solubility (lipophilicity)
-pKa (ionization constant) of drug in maternal blood
excretion of drugs via sweat & saliva depends on _____
(minor route)
diffusion of non-ionized drug species
some drugs partitioned in saliva can be _____
tasted in mouth even after IV administration
presence of ion-exchange resin will _____ clearance of an estradiol
increase
avg molecular weight of a drug w strong polar group
350 Da
molecular weight of glucuronic acid (which is added to MW of a drug that undergoes glucuronidation)
200 Da
total body clearance equation
total body clearance =
plasma clearance x body weight
renal clearance equation
renal clearance =
total body clearance x % drug excreted in urine (in decimal form)
if renal clearance = GFR, what is true about the drug behavior in the nephron
the drug is only filtered
if renal clearance > GFR, what is true about the drug behavior in the nephron
the drug is filtered and actively secreted
if renal clearance < GFR, what is true about the drug behavior in the nephron
the drug is filtered and reabsorbed systemically
what promotes fecal elimination of a drug undergoing enterohepatic recirculation
administering an ion-exchange resin
the enzyme produced by the bacteria in the gut has the ability to do what to a drug, & what is the name of this enzyme
regenerate the drug from conjugated metabolite
beta-glucuronidase
