March 28, 2023

In this video, we explore the mechanism of allopurinol, a drug used in the treatment of gouty arthritis.

In the previous two videos we discussed hyperuricemia and gout and we’re going to continue along those lines by discussing the mechanism of action of a drug called allopurinol now recall that all purines whether it’s adenine guanine ionicine are eventually all degraded into hypoxanthine this is part of the catabolic pathway so hypoxanthine is eventually converted

Into this molecule called xanthine by the action of the enzyme xanthine oxidase which uses water and molecular oxygen to perform the reaction if you look here at the six-membered ring this carbon right here between these two nitrogen atoms this carbon gets oxidized by the enzyme and you end up with this double bond oxygen called a carbonyl added to that carbon you’ll

Notice that in this picture xanthine has been flipped 180 degrees but if you at least follow the carbon atoms you can see that oxidation reaction and then xanthine oxidase performs a second reaction on xanthine whereby it oxidizes this carbon of the five-membered ring between the two nitrogen atoms and you see that oxidation right here with this carbonyl functional

Group added right there and this compound is uric acid also called urate so again all purines are eventually degraded to uric acid but uric acid is a metabolic dead end it doesn’t get metabolized any further in humans because humans lack the enzyme urate oxidase which would normally degrade it further into a molecule called 5-hydroxyisoburate which then in other

Organisms can be degraded even further now in humans uric acid is a metabolic dead end we lack the next enzyme in the sequence which is urate oxidase that would convert uric acid into 5-hydroxy isourate which is then metabolized by other enzymes in other organisms to other end products that are eliminated but this uric acid can build up in humans if the production

Of it exceeds the elimination of it and when that happens you can develop crystals of gout and those crystals lead to the activation of this enzyme nadph phagosome oxidase which is involved in the production of reactive oxidative species so free radicals those free radicals damage cells which then causes inflammation and then the inflammation causes further damage

To those cells particularly around the joints where the gouty crystals normally reside so if we think from a pharmalogical perspective how could we reduce the activation of this enzyme nadph phagosome oxidase how can we reduce the formation of these reactive oxidative species or free radicals how can we reduce the degree of inflammation well we need to reduce

The formation of these gouty crystals and to do that we need to reduce the formation of uric acid and one way we could do that is by inhibiting the enzyme xanthine oxidase if we inhibit this enzyme then the formation of uric acid is going to be reduced and that’s actually what allopurinol does indirectly so this is the chemical structure of the drug allopurinol

If you look it’s almost identical to this molecule hypoxanthine the only difference is in this five-membered ring in hypoxanthine notice these two nitrogen atoms are separated by a carbon atom whereas in allopurinol the nitrogen atoms are adjacent to one another they’re bonded to one another well allopurinol is similar enough in structure to hypoxanthine that

Xanthine oxidase can react with allopurinol and convert it to this molecule called allozanthine again aloe xanthine is almost identical to xanthine except for that component of the five-membered ring in xanthine the two nitrogens are still separated by a carbon atom whereas an allosanthe and the two nitrogen atoms are adjacent to one another but again xanthine

Oxidase performs the same reaction on allopurinol it’s going to oxidize that carbon right here of the membered ring so aloxanthine is going to be an inhibitor of xanthine oxidase and by inhibiting that enzyme this hypoxanthine is not converted into xanthine so there’s much less xanthine and now there’s less conversion of that xanthine to uric acid so levels of

Uric acid are going to drop well beneath the clearance or elimination of uric acid and that should theoretically allow the blood levels of uric acid to go down and the crystals to shrink and shrink and shrink which helps to reduce the formation of gout but allopurinol is not used during an acute case of gout that would actually tend to make the gout worse instead

You would wait until the gout has completely resolved and you’re in remission and then you could start using aloperinol as a preventative measure so when the gout is in remission then you’re not having an acute flare up the allopuranol does this it inhibits xanthine oxidase and prevents hypoxanthine from being converted into xanthine which in turn produces the

Uric acid formation and allows the clearance or elimination of uric acid to stay above the production and it should reduce the frequency of gout attacks so hopefully this video gave you a good understanding of the mechanism of action valopyranol and when it is typically used thank you for all your support be sure to check out my instagram for cool science and not science stuff

Transcribed from video
Allopurinol Mechanism of Action for Gout By Catalyst University