3b. Elimination - ADME II: elimination of drugs Flashcards
what is elimination
processes involved in removing a drug from the body
what are the 2 parts of drug elimination
metabolism = biotransformation of a drug excretion = mechanism or pathway a drug leaves the body
what does excretion result in
result in irreversible loss of drug from the body
what are the 4 main paths of drug excretion
biliary excretion
kidney
respiration via lungs
tears/sweat/milk/saliva
what are the 2 ways drugs can be eliminated
a fraction can be excreted as unchanged drug and other fraction can be subjected to metabolism before excretion
biliary excretion involves what organ and what happens
liver
active secretion of drug or metabolites from hepatocyte in liver to bile. bile is conc in gall bladder and transport drug to gut for excretion in faeces so is an alternative to kidneys
drugs excreted in bile can also be reabsorbed into plasma via enterohepatic circulation
what is enterohepatic circualtion
begins with drug absorption across GI tract into portal circulation followed by uptake into liver
some drug will reach systemic circulation but some will be excreted in bile, some may be conjugated in liver and conjugated metabolites may be secreted in bile and returned to intestine via biliary duct
Conjugated metabolites are poorly absorbed in gut due to high polarity so excreted in faeces
Gut microbiota produce enzymes that can deconjugate drugs so some of parent frug molecule will be released from conjugate in intestine and reabsorbed, cross intestinal wall and taken into liver again, restarting cycle
Result in reservoir of recirculating free drug in our body. Drugs that undergo extensive enterohepatic circulation have a longer duration of action as they are recycled
what is the effect of enterohepatic circulation on plasma conc after single oral dose of drug
what will you see on graph plasma conc over time
instead of seeing decrease in plasma conc following absorption phase, will have more than one absorption phase and this prolongs drugs elimination
multiple peaks on graph
what does the kidney do
regulate volume and composition of body fluids and conserves essential compounds and removes waste products
what does the kidney do to water soluble drugs and metabolites
remove water soluble drugs and metabolites
what does the kidney do to lipophilic drugs and metabolites
usually retained as they undergo reabsorption
what are the 3 processes of renal excretion
glomerular filtration
active secretion
passive reabsorption
what is the nephron
functional unit of kidney to filter blood
what does a nephron consist of
blood supply and ducts called tubules
what happens to the blood filtered by glomerulus
blood filtered by glomerulus is caught by nephron tubule and bowmans tubule is proximal tubule that surrounds glomerulus and catches filtrate
what is the path that a filtrate travels through the tubules
Filtrate travels through the rest of the tubules such as the proximal convoluted tubule, loop of henle and distal conv tubule before exiting nephron into common collecting duct that are shared by many nephrons
what is the glomerular filtration rate
volume of filtrate formed by both kidneys per min
what is the normal plasma flow
600mL/min
what does it mean when people say that the renal blood flow and GFR change in parallel
any increases in blood flow will cause increase in GFR
what effect does molecular size have on GFR
harder to pass through if molecule is larger
the plasma proteins will do what to molecules being filtered
plasma proteins will restrict molecules being filtered as they are v large molecules
describe how the GFR is a passive process
Passive process depends on molecular size and ionization and conc of drug in plasma as movement will go down conc gradient
filtered drug will pass down to where in the nephron
proximal tubule
what is the path of parts of nephrons
proximal tubules -> loop of henle -> distal tubule -> collecting duct
what happens to drugs not filtered in the glomerular
leave through efferent arteriole that runs closely to renal tubule
renal tubule cells have transporters that allows active transport of drug from plasma into tubule lumen
what transporters transport anions
OAT - organic anion transporter
what transporters transport cations
OCTs - organic cation transporter
tubular transporters exhibit what feature and what is its substrate specificities
saturability = reach max rate of excretion
has overlapping substrate specificities
what does overlapping substrate specificities of transporters lead to regarding excretion
leads to competition and inhibition so leads to decrease excretion and therefore plasma conc of drug
what does the nephron water reabsorption do to conc gradient
what kinds of molecules are relevant to the conc gradient
Water reabsorbed as it passes through tubules so water leave tubule leaving drug behind increasing drug conc in renal tubule
Can create favourable conc grad for passive diffusion from high to low conc
Non-ionised/lipid soluble drugs are only relevant drugs as are only type that can cross membrane easily polar dugs will stay in tubule for excretion
what can passive reabsorption be manipulated by
what does active secretion and reabsorption do to it
Can be manipulated by altering pH of tubular fluid or urine. Active secretion contributes to renal excretion whereas reabsorption conspires against it
how does body size influence renal drug excretion
GFR is proportional to lean body weight
how does age influence renal drug excretion
renal function decrease 50% with age
how does pregnancy influence renal drug excretion
renal function increases by 50%
how does disease influence renal drug excretion
renal disease and heart disease decrease renal function
what does competitive inhibition of tubular secretion do to renal drug excretion and what does this do to the drug effects
decreases secretion to prolong drug effects
what does increasing pH do to excretion
increase ionisation of weak acids which decreases tubular reabsorption thus increasing excretion
what does increased urinary flow do to the rate of excretion
increased urinary flow rate dilutes conc in tubule therefore decreasing the conc gradient for passive reabsorption of drug increases enhanced effect
what is the effect of pH on urinary excretion of methamphetamine
what happens if you make the urine more acidic or alkaline
treatment with ammonium chloride to increase excretion of amphetamine in overdose
taking baking soda to make urine more alkaline decreases excretion of amphetamine and prolong the effect
what does low GFR do to drug and metabolites accumulation
leads to accumulation
GFR is used as what for dosage adjustment of potentially toxic drugs which are excreted primarily via kidney
index of renal function for dosage adjustment
what is inulin and what can it be used to do
used to measure GFR
intert polysaccharidde with no active secretion or reabsorption
why is inulin impractical for measuring GFR
invasive and 24h collection is impractical
why is inulin useful for measuring GFR
eliminated by glomerular filtration only as there is no protein binding in plasma
what is alternative to using inulin to measure GFR
why is this method inaccurate and why is it better than inulin
creatine not as accurate as it undergoes bit of secretion so may overestimate GFR
only requires single blood flow to estimate GFR
what is CrCL equation
(140-age) x (weight in kg) x 0.85 if female
divide whole thing by 72 x Cr
how are many IV administered contrast agent eliminated
contrast agents are water soluble compounds that are renally eliminated
what is a pro and con about elimination of contrast media
metabolism isnt significant enough to cause problems but downside is that renal function plays very important role for excretion and renal risk need to be indentified
