[khanar]

If a patient on Azathioprine then the dose must be adjusted if he's also taking Allopurinol.
Please explain this concept as am quite confused about it

 

[ath.pantelis]

Azathioprine & 6-mercaptopurine essentially belong to purines. Allopurinol inhibits xanthine oxidase, which is a key enzyme in the metabolism of purines to uric acid. So, if a pt already on azathioprine starts allopurinol (a very probable scenario, considering that a pt taking azathioprine may manifest gout), the levels of azathioprine will go up because the drug won't get metabolized. You, the always alert physician, will then have to lower the dose of azathioprine, orelse you will precipitate or worsen the pt's gout. Is that clear?

 

[khanar]

What about Mercaptopurine?

OK, let's now talk about Mercaptopurine and Allopurinol.
Is it exactly the same story as Azathiprine and Allopurinol or is there something else playing here?

 

[ath.pantelis]

What makes you believe something else is going on here? The job of xanthine oxidase is to add oxygen subgroups in the purine backbone (hypoxanthine<-->xanthine & xanthine<-->uric acid), regardless of what extras are attached to this backbone.

 

[khanar]

What makes you believe something else is going on here? The job of xanthine oxidase is to add oxygen subgroups in the purine backbone (hypoxanthine<-->xanthine & xanthine<-->uric acid), regardless of what extras are attached to this backbone.

Because Allopurinol and 6MP also blocks PRPP Amidotransferase which is the rate limiting enzyme in purine synthesis. However, in order for them to do that they have to be converted to their nucleotide versions by the action of HPRT.
Add to this that Allopurinol blocks Xanthine Oxidase while 6MP is deactivated by Xanthine Oxidase.
So there's kind of complex interrelations that bugging my head

 

[ath.pantelis]

I now understand your confusion to its full extent. Well, I'll try to explain it the way I have understood it (perhaps in a kindergarden manner), but I'll try to keep it comprehensible as well.

Hypoxanthine and guanine in general have two fates, either to be metabolized into uric acid and be excreted in the urine (metabolic pathway No 1) or to undergo metabolism through PRPP & HGPRT and produce IMP and GMP respectively (metabolic pathway No 2). Ok so far?

Once 6MP is activated by HGPRTase, it blocks PRPP. This blockade of PRPP will shift the metabolism of ENDOGENOUS hypoxanthine & guanine towards the production of uric acid (thus precipitating gout). This shift of purine metabolism to uric acid production will also affect 6MP itself. So, if you also block metabolic pathway No 1 with allopurinol, you force purines not to be metabolized in any way. The fact that 6MP is deactivated by XO only adds to the problem, because allopurinol also inhibits this surplus inhibitory alternative, thus rendering high circulating levels of the drug. The net effect will be a compilation of endogenous purines and 6MP.

Am I making a mistake in this rationale?

 

[khanar]

Woow

@ ath.pantelis
You are the smarted USMLEr I have ever met on the Internet!
God bless you

 

[ath.pantelis]

Thank you for your compliments, I'm flattered! However, I don't consider myself extraordinarily smart, I just try to demystify the underlying mechanisms of disease and decompose complicated concepts into small & comprehensible ones. This is not always possible, but I try to do my best (as everybody else does, I suppose. And of course I go back to my personal notes all the time! Having passed the exams doesn't mean that I have mastered every single piece of knowledge for the rest of my life!!! You are welcome, anyway!

 

[ath.pantelis]

By the way, I would like to say thank you to every single one of you who is uploading a new basic science or clinical topic. This is the best way for one to keep in shape, especially if they come to realize that many "guaranteed" concepts turn out to be not that much of "guarantee" (this "one" includes me first of all!!!)