Drug Metabolism and Renal Excretion Flashcards
How do most drugs leave the body?
in urine as unchanged or chemically transformed compounds - occasionally excreted in bile
What does metabolism of drugs act to do?
convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney.
Convert drugs to metabolites that are usually less pharmacologically active than the parent
What can occasionally happen in drug metabolism?
may convert from inactive drugs to active compounds or cause a gain in activity
may have unchanged activity
may possess at different action
What is a drug that may gain activity?
codeine may be converted to morphine
What is a drug that may have unchanged activity?
diazepam - nordiazepam
What is the main organ of drug metabolism?
liver
GI tract, lungs and plasma may also contribute
What is the first phase of drug metabolism?
Oxidation, reduction hydrolysis
What is the function of the first phase of metabolism?
makes the drug more polar and adds a chemically reactive group which allows conjugation
What is the second phase of drug metabolism?
conjugation
What is added during conjugation?
glucoronyl sulphate methyl acetyl glycyl or glutathione
What are the cytochrome P450 monoxygenases?
haem proteins located in the endoplasmic reticulum of liver hepatocytes mediating oxidation reactions
What are the main CYP450 enzymes in the liver?
CYP1,2,3
Where do the oxygens go in the monooxygenase cycle?
one yields ROH, the hydroxyl product
one yields H2O
What is glucuronidation?
a common reaction involving the transfer of glucuronic acid to electron rich atoms of the substrate
What is the enzyme involved in glucuronidation?
UDP-glucuronyl transferase
What sort of endogenous substances are subject to glucuronidation?
bilirubin
adrenal corticosteroids
What are the active processes involved with renal excretion?
glomerular filtration
active tubular secretion
passive reabsorption by diffusion
What kind of drugs can be filtered at the glomerulus?
any free drug with a MW less than 20000
What is the equation for clearance by filtration?
CL = GFR x fraction of unbound drug (fu)
where GFR is typically 120ml min-1
What are the two transporter systems in the proximal tubule?
organic anion transporter
organic cation transporter
What does the anion transporter handle?
acidic drugs, endogenous acids and the marker for renal plasma flow
What does the cation transporter handle?
basic drugs
What is the most effective mechanism for drug elimination?
excretion by tubular secretion
Why is tubular secretion graph a curve?
Because the transporters have a limit
What happens as free drug is excreted?
more drug is freed by the protein into the plasma for excretion
What drugs might the organic anion transporter excrete?
penicillins
probenecid
frusemide
What drugs might the organic cation transporter excrete?
morphine
neostigmine
amiloride
What may happen with use of frusemide and thiazides?
may precipitate gout as uric acid is not so easily excreted
What may occur with probenicid?
may retard excretion of penicillins
What are some factors influencing reabsorption of the drug?
lipid solubility
polarity
urinary flow rate
urinary pH
What is significant about lipid solubility?
highly lipid soluble drugs will be extensively reabsorbed
What is significant about polarity?
polar drugs will be excreted
What is significant about urinary flow rate?
diuresis decreases reabsorption
What is significant about urinary pH?
degree of ionisation of weak acids and bases can influence reabsorption
What does an alkaline pH do?
increase excretion of acids
What does an acidic pH do?
increases excretion of bases
What can urinary alkalinisation be used to accelerate?
excretion of aspirin in cases of overdose
