E in ADME Flashcards
what is a one compartment model?
single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood
how do you work out the conc. of drug in a one compartment model?
conc = dose/Vd
where is majority of drugs eliminated/cleared?
mainly in the kidney or liver
less importantly - excretion via lung/saliva/sweat
how does pulmonary drug excretion occur?
excretes gaseous and volatile substances
how can pulmonary drug excretion be tested?
alcohol breathalysers tests - excretion of ethanol
how does salivary drug excretion occur?
bind to saliva - depending on pH partition and protein binding
saliva drug conc. could be used to indicate drug plasma conc.
how does renal drug excretion occur?
main excretion
via urine thru the kidneys during regulation of fluid volume and composition within the body
what is an issue with swallowed saliva in terms of excretion?
saliva bound to drug depending on pH partition and protein binding = drug reabsorption
how do the kidneys eliminate drug substances?
- metabolism (sometimes)
- excretion in the urine
what processes handle renal excretion?
- glomerular filtration
- tubular secretion
- tubular reabsorption - active/passive
what molecules are excreted in glomerular filtration?
free drug - unbound drug
small, water soluble drugs
depends on size - fit thru pores
what molecules are excreted in tubular secretion?
secreted molecules
specialised active transport systems
what molecules are excreted in tubular reabsorption?
lipophilic and unionised drug crosses
Hydrophilic and ionised drugs cannot cross
influenced by drug lipophilicity
what is GFR?
Rate of blood filtering in the glomeruli = glomerular
filtration rate
what is the GFR in a normal adult male?
125 mL/min in normal adult male
what can lower GFR?
impaired kidney functions
what drugs are excreted via tubular secretion?
weak acids
penicillins
how can we alter renal eliminiation?
change urine pH
what happens when reduce urine pH?
acidic urine
- weakly acidic drugs = unionised + reabsorbed = reduced elimination
- weakly basic drugs = ionised = increased elimination
how can you get acidic urine?
protein rich diets
ascorbic acid co-administration
what happens when increase urine pH?
basic urine
- weakly basic drugs = unionised + reabsorbed = reduced elimination
- weakly acidic drugs = ionised = increased elimination
how can you get basic urine?
co-administer bicarbonates
how do you calculate the renal excretion?
glomerular filtration + tubular secretion - tubular reabsorption
how is the rate of renal elimination calculated?
determining the renal clearance of creatinine
what is creatinine?
calculates rate of renal elimination
endogenous compound
eliminated by the kidney only - tests kidney function
how are drugs excreted in the liver?
mainly via drug metabolism. - phase
how are drugs excreted in the liver?
mainly via drug metabolism. - phase1 AND phase 2 reactions
what drug metabolism reactions undergo in the liver?
phase 1 - drug oxidised/reduced/hydrolysed polar groups
phase 2 - couples the drug to an endogenous molecule to form a metabolite to become pharmacologically inactive and highly water soluble
pathology of drugs eliminated in the liver
must enter hepatocytes, may be metabolised, secreted into the blood or bile
bile enters the small intestine ( some material may resorb into the blood) or excreted in faeces
what is enterohepatic circulation?
material reabsorbed into the blood from the bile in the small intestine
what drugs enter enterohepatic circulation?
NSAIDs
opioids
digoxin
warfarin
some antibiotics
how does drugs MW impact excretion route in the liver?
Drugs with MW <300 are excreted almost exclusively into urine
Drugs with MW 300-500 are excreted in both urine and bile
Drugs with MW >500 are excreted almost exclusively into bile
what is drug clearance influenced by?
dose
blood flow
function of liver/kidney
plasma protein binding
how do you work out the clearance of a drug?
(ELIMINATION RATE CONSTANT)/fraction of drug cleared per unit time x Vd
what drugs bind to albumin?
acidic drugs
what reduces albumin binding?
disease state e.g. cancer
competition e.g. presence of a second acidic drug
what does reduce albumin binding mean?
more free drug = more drug able to be excreted
describe the total body clearance?
overall clearance of a drug by all eliminating organs
describe the organ body clearance?
clearance of a drug by a specific organ e.g. renal clearance = volume of plasma/blood cleared of drug per unit time by the kidney
how do you calculate total body clearance?
renal Cl+ hepatic Cl+ other organs Cl
renal Cl (CLr) + metabolic Cl (CLm)
blood flow to the organ (Q) X extraction rate of the organ (E)
how do you work out the renal elimination rate constant?
renal clearance/ Vd
how do you work out the metabolic elimination rate constant?
metabolic clearance/Vd
what is Fe?
fraction of the (bioavailable) drug dose that is unchanged in urine
how do you workout Fe?
CLr/CLt
kR/ke
what is hepatic extraction?
Hepatic extraction = the rate at which the liver extracts drug from the blood – by metabolism and removal into bile
what does the hepatic extraction rate depend on?
hepatic blood flow (HBF)
intrinsic ability of the liver to handle (e.g. metabolise) the drug
how do you workout the maximum hepatic extraction rate?
drug conc x HBF (hepatic blood flow)
what is the extraction ratio (E)?
Fraction of drug amount presented to the organ which is eliminated during a single pass through the organ
what do the extraction values (E) mean?
0 - most of the drugs escapes elimination during a single pass through the organ
1 - most of the drug is eliminated during a single pass through the organ
how do you workout the extraction rate (E)?
(conc in - conc out)/ conc in
what is the value for hepatic blood flow?
1.5L/min
what are low extraction drugs?
diazepam, warfarin, salicylic acid, phenytoin, and procainamide
what are high extraction drugs?
lidocaine, propranolol, morphine, verapamil
what does it mean if the hepatic extraction ratio <0.3?
low extraction ratio drugs
what does it mean if the hepatic extraction ratio >0.7?
high extraction ratio drugs
what does it mean if the hepatic extraction ratio 0.3-0.7?
intermediate extraction ratio drugs
what are low extraction ratio drugs affected by?
unchanged by changes in blood flow
what are high extraction ratio drugs affected by?
greatly affected by changes in blood flow
hepatic blood flow increase = during meal digestion
hepatic blood flow decrease = exercise/ cirrhosis/ heart failure/ old age
when does hepatic blood flow increase?
during meal digestion
when does hepatic blood flow decrease?
exercise/ cirrhosis/ heart failure/ old age
