DRUGS AND THE LIVER Flashcards
what is metabolism?
all the chemical reactions involved in maintaining the living state of cells and the organism
what is intrinsic clearance?
the ability of the liver to remove drug in the absence of flow limitations and binding to cells or proteins in the blood
what is conjugation?
the addition of chemical groups to drugs during metabolism
what is hydrolysis?
the chemical breakdown of a compound due to reaction with water
what is reduction?
the loss of oxygen/gain of electrons within a chemical reaction
what is oxidation?
the gain of oxygen/loss of electrons within a chemical reaction
why can the metabolism of amino acids tie in with drug metabolism?
as they are important for conjugation in phase 2 metabolism
why can changes in plasma protein levels affect drug metabolism?
amount of free drug and amount bound to plasma proteins can be affected depending on plasma protein levels. Only the free drug can be excreted by the liver.
outline the oxygen gradient within liver lobules?
the periportal region (near portal triad) has a high oxygen level
the perivenal region has low levels of oxygen
whats the main conjugation type at the periportal region?
sulfonation
whats the main conjugation type at the perivenal region?
glucuronidation
what are the main activities at the periportal region?
glucose delivery glyconeogeneiss urea synthesis fatty acid oxidation salvation
what are the main activities at the perivenal region?
glucose uptake glycolysis lipogenesis and ketogenesis bile acid synthesis glucoronidation
what are the 2 ways drugs can be excreted?
renal excretion
in the bile via the liver
why can some drugs be excreted unchanged
because they do not need to undergo biotransformation to increase their water solubility
what is hepatic clearance of oral drugs dependant on?
liver blood flow - reduction reduces delivery of drugs to the liver
intrinsic clearance
protein binding levels
what is the extraction ratio?
hepatic clearance of drug: flow of hepatic blood
what are phase 1 reactions in drug metabolism?
oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. However this can sometimes be more active or toxic
what are phase 2 reactions in drug metabolism?
Phase II reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine.
this produces a molecule which is less reaction, less toxic and more polar
whats the main purpose of drug metabolism?
to render the drug non-reactive and non-toxic, whilst making it easy to excrete, preferentially by the kidney.
outline the mechanism of CYP450 enzymes?
the drug combines with CYP450
enzyme-substrate complex gets reduced by NADPH which causes Fe3+ to turn to Fe2+
oxygen molecule oxidises the iron to Fe3+ and oxygen gets reduced
NADPH reduces the complex but the electron is accepted by the oxygen atom
2H+ are added and water is produced
remaining oxygen gets transferred over to the substrate and CYP450 releases it.
CYP450 is ready to begin the cycle again
what is glucuronidation?
conjugation reaction whereby glucuronic acid is covalently linked to a substrate
what is amino acid conjugation?
◦ conjugatuon with glutamine or glycine produces conjugates that are readily excreted in urine but not extensively secreted in the bile
outline the metabolism of aspirin?
Aspirin undergoes phase 1 hydrolysis to salicylic acid. In phase 2 it is congugated with either glycine or glucoronic acid forming a range of ionised metabolytes that can then be excreted in the urine - these include salicylic acid, salicyl acyl glucuronide and salicyl phenolic glucuronide
