Drug metabolism tutorial Flashcards
What is paracetemol converted to by phase 1
NAPQI
Normal dose of paracetemol and how many times it can be taken and thus max daily dose
1g every six hours- max 4 grams per day
Overdose is 10-15grams so small therapeutic!
What is the problem with drinking and paracetemol
Ethanol inhibits the cytochrome p450 so paracetemol broken down less well.
What is the dangerous molecule in paracetemol
NAPQI because it is an electrophile- it reacts with glutathione. The biggest problem is not attacking the DNA but of the proteins in the hepatocyte so hepatocellular damage
What phase 2 reactions used with paracetemol?
glutathione conjugation, sulfation or glucuronidation (by glucuronile transferase) and tiny bit of methylation
What does the sulfate react with when conjugating
Hydroxyl groups- so the hydroxyl group at the bottom of the paracetemol using sulphate transferase enzyme
Which co-enzyme is used in glucuronidation
UDPGA
Where is the sugar added in the glucuronidation reaction?
Hydroxyl group
Which 2 carbons are electrophilic in the NAPQI
To either side of the oxygen double bond so this is the site of glutathione conjugation (by glutathione transferase)
What would you do with a paracetemol overdose patient
1) Stomach pump
2) Give methionine
Where would the paracetemol be after 12 hrs
In the blood and thus the liver
Why can glutathione not be given so what do you give instead
It cannot cross biological membranes so cannot get out of the blood into the cell membranes of the liver. Cysteine can be given but we give oral methionine instead (acts in the same way) or i.v n-acetyl cysteine. If it’s within 24 hrs it might be okay, but after that they’ll become unconscious, coma, kidney damage etc.
Problem with the NAPQI relating to the kidney
Damages the kidney such that the NAPQI can then not be excreted
Which metabolite of paracetemol would be found in the bile
Glutathione conjugate, and glucuronide conjugate (some of it)- because these are high molecular weight conjugates (heavy)
Which metabolite of paracetemol would be found in the urine
Sulfate conugates, glucuronide conjugates (some of it) and mercapturic acid derivates (comes as a product of conjugating compounds with cysteine)
Which metabolite of paracetemol would be found in the blood
Paracetemol itself (not 100% first pass metabolism so some will be passing through the liver unmetabolised first time) and all of the metabolites going to the kidney for excretion
Why is plasma half life longer in overdosed patient
Glucuronidation enzymes are at saturation, damage to liver due to the NAPQI so impaired ability to conjugate etc, and damage to the kidneys, and depletion of sulfate
What is acetanilide
Prodrug of paracetemol. Oxidised by cytochrome p450 to make paracetemol (by addition of hydroxyl group- so it’s just paracetemol without a hydroxyl group)
Why isn’t acetanilide used
Causes methaemoglobinaemia
First reaction to the left of parent compound
Hydroxylation by cytochrome p450
Reaction between parent compound and the reaction below it
Reduction of nitrate to the amine, by a reductase (mostly gut bacteria)
What happens from the one directly below the parent molecule, to the one after that
acetyl group added, by an N-acetyl transferase + acetyl CoA
What happens from parent compound to the one to the right
ester to carboxylic acid, so it’s a hydrolysis reaction by enzyme called esterase
What happens from molecule to the right of the parent molecule to the one below it
Glucuronidation by glucornile transferase, UDPGA
What happens from molecule to the right of the parent to get to the molecule further right
Carboxylic acid to the amide, so a carboxylic acid has been added (by glycine), by acyl CoA ligase and glycine (cofactor)
Which metabolite would you NOT get if the drug was administered via a patch
The reductase mediated reaction (because it doesn’t pass through the gut), but if it was taken orally then it would need form the reductase
