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Azathioprine and Mercaptopurine – Full Drug Summary

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A full drug summary about the high risk immunosuppressant drugs, azathioprine and its metabolite, 6-mercaptopurine.

Hi guys today we’re going to be talking about azathioprine and mecaptapurine two fairly high risk drugs um used in a range of conditions that we’re going to look into just now so first of all guys um these drugs are used in mainly conditions where you need the immune system to be suppressed now that is in gastrointestinal conditions such as crohn’s disease or

Ulcerative colitis where we want to keep the patient in remission and prevent further flare-ups and deteriorations in their health we also use it in rheumatology particularly in rheumatoid arthritis that does not respond to standard treatment so if they keep on getting flare-ups you want to see them on something that will control them long-term and often you’ll

Put them on azathioprine and another area is organ transplantation because you don’t want the organ to be rejected following a transplant that is so just briefly before we go into what azathioprine actually does it’s worth looking back at this which is probably something we learned early on in school medical school or pharmacy school and probably in actual high

School too so if we look towards the right hand side we can see the the dna at the very top now if we pan over to the left-hand picture this is a diagram of the dna essentially we’ve got the the d and the p’s on either side here and these are the um the the helix essentially this makes up the backbone of the dna so the blue parts that we see here in between

We see the nucleotide bases now these are the things that are made up of adenine thymine cytosine and guanine and this makes up the code in the middle now adenine and guanine are purines cytosine and thymine are pyrimidines and that’s important because in terms of azathioprine and mechapurine’s mechanism of action they act upon the purines only so the a’s and

The g’s and they prevent their synthesis so as you can imagine if we don’t have the purines being produced so a and g has gone from here a and g has gone from here we have a complete break in this dna helix and that means transcription can’t occur translation can’t occur we don’t get a nice selection of amino acids and then subsequently we don’t get formation of

Proteins and other subsequent cells and functions in the body once one such function is the the lymphocyte one of the blood cells of the body quite important and in autoimmune conditions can often lead to flare-ups and lead to damage for example in rheumatoid arthritis to the joints in crohn’s ulcerative colitis to the bowel um or on crohn’s anywhere uh from

Top to bottom of the gi tract uh and in transplantation um in terms of mounting an immune response against the the organ the foreign organ so ultimately just before i touch on the the mechanism of action finally it it’s important to mention that six megapirinomacaptopurine is a metabolite of azathioprine and azathiopians broken down into mecopter purine and macap

To purine is further broken down into the main active substances um is a thioper is a lot more common certainly in the united kingdom um so next as soon as you take a tablet there’s a thioprint or capsule or 6-megapirin once it gets to its main active substances it inhibits the synthesis of the purines with which we’ve just touched on adenine and guanine thereby

Inhibiting dna and rna replication and that is necessary for lymphocyte production and without these purines and subsequent dna and rna needed for lymphocyte production we get a reduction in the number of lymphocytes overall in the body and hence a lower immune system and we get immunosuppression which benefits all the conditions that we’ve mentioned now in terms

Of the metabolism and excretion of vasothiaprine there are two enzymes in particular there’s thiopurine methyl transferase or tpmt for short and the xanthine oxidase now tpmt is something that has to be tested before starting azathioprine or 6-megapirin because this is a very important enzyme it’s one of the the main metabolic pathways in the body in patients

Who have a low level they’re going to have a low level of the enzyme they’re going to have slightly higher levels of azothiaprint in the body people who don’t have the enzyme at all uh in that case there’s a greater risk of toxicity just because there’s an enzyme missing that would normally break isothiprine down so you’re going to have more azathioprine in the

Body for a longer period of time and that’s where you can get the myelo suppression or the bone marrow suppression if you will so it’s definitely worth measuring tpmt if it’s normal fantastic if it’s low you’d like you could start it but only under specialist supervision and it would well you could probably start at a lower dose if it’s missing completely you

Probably would not want to start it um or at least it would be down to the to the specialist to decide the other enzyme is xanthine oxidase and if you’ve studied gout or looked into allopurinol one of the main gout preventative medications you’d know that in gout uric acid is produced because purines are broken down into uric acid via this enzyme xanthine oxidase

And allopurinol works by blocking this enzyme and that’s dangerous again because if you use azathioprine and allopurinol but allopurinol is blocking xanthine oxidase one of the m again metabolic pathways of azathioprine that means again we’re going to have more azathioprine in the body for a longer period of time and hence there’s a risk of toxicity uh we’re going

To cover that later i believe however i’ll just mention it now that if it comes to a situation or a scenario where you need both allopurinol and azathioprine then you have to reduce the azathioprine dose to a quarter of the original dose so when you look at the bnf the british national formula azeothyrous generally dosed via weight by weight so let’s say a

Patient uh ultimately the dosing is to be 100 milligrams once a day okay in that case we would quarter the dose which would mean or rather give one quarter of the entire dose which would be 25 milligrams once a day instead next in terms of side effects um the big one that we’ve mentioned is bone marrow suppression that is uh low white blood cells low platelets and

Actually low red blood cells too and it requires careful monitoring of the full blood count and dose adjustments if need be um looking for neutropenia which is very low neutrophils is important and thrombocytopenia which are low platelets is also key in terms of other side effects nausea is fairly common as it is with many medications um it can often get better

After a few weeks if not you can alter the dose you can split the dose in half and take it twice a day you can take it with food consider antimetrics or even temporarily reducing the dose one such side effect that requires withdrawal of the medication completely is hypersensitivity and if you do get that it’s fairly typical um allergic reaction you get tiredness

Dizziness or malaise or all the dizziness vomiting diarrhea rashes low blood pressure and subsequently you may have joint pains you may have shaking or rigers rather and renal dysfunction otherwise there are other side effects there’s a whole list of them i’m sure you can read including pancreatitis and more patient will get a leaflet with the medication hopefully

So ultimately it’s more about telling them about the main and the most dangerous side effects and when to seek professional help if need be and obviously as i’ve just mentioned the the more common side effects and how to manage them if there’s liver or kidney issues we can also reduce the dose with specialist supervision important advice we’ve just touched on

If they get any signs of milo or suppression or bone marrow suppression that is unexplained bleeding or bruising which would show low platelets malaise fatigue or significant paleness which would show red blood cells or any signs of infection such as a sore throat the fever uh again definitely seek medical attention in transplant patients it’s important even if

They become pregnant that that they don’t stop the medication though it can be teratogenic and they’ve been low birth weights premature births and even spontaneous abortions with it it’s not worth stopping and putting the mother at risk of transplant rejection so that should be something considered prior to becoming pregnant but if it does happen then definitely

Something worth chatting to the to the specialist about and we’ve talked about some of the side effects which may require drug withdrawal which are the hypersensitivity ones mainly now in terms of monitoring you should monitor for toxicity throughout treatment and that starts with the advice that you’d give to the patient and ultimately the in terms of actual

Blood tests you want to look at the full blood count weekly for the first four weeks and then reduce it to once every three months and that that should be a minimum really realistically in practice you never really see full blood count on its own you’ll often see with liver function tests and urea and electrolytes and that way you can look at the the liver

Function and also the kidney function um just in case there’s a risk of hepato toxicity or renal toxicity but full blood count is the main thing and we’ve touched on the symptoms fatigue pale skin you could even get a faster heart rate easy tiring on exertion dizziness shortness of breath easy bleeding bruising infections and so on so forth and i suppose on

That note it’s important to mention the lfts the liver function tests are also done because there’s a risk of cirrhosis in theory with azathioprine so it’s always worth checking and you’d avoid it if the liver function was very severely impaired and likewise with kidney function if it’s very very severely impaired you’d also avoid azathioprine if it’s mildly

Impaired you could just consider reducing the dose in terms of interactions uh we’ve touched on allopurinol in its inhibition of xanthine oxidase which is one of the the pathways of azothioprint um metabolism and if xanthine oxidase is inhibited azathioprine is in the body for a longer period of time at higher concentrations and there’s a risk of toxicity and

There have been deaths recorded with this interaction actually reduce azathioprine to a quarter of its original dose if you’re using them together that is in terms of milo suppression any other medications which can cause uh bone marrow suppression should be noted uh that this can be a risk so things such as amino cell not so much amino silicates but more things

Like methotrexate for example so quite risky um the british national formula also mentions ace inhibitors lisinopril aramipril captopril for example may increase the risk of anemia and leukopenia so lower white blood cells when given with is a thioprin so monitor carefully um so just be aware of it that it’s not one that i knew before researching this topic

Further but it’s worth just having that in your head so it increases the risk of low red blood cells and low leukocytes so in summary that was a whistle-stop tour of azathioprine and its metabolite 6-megapixel we’ve covered what it’s used for we’ve covered the detailed mechanism of action including to the the dna level we’ve covered the role of the enzymes tpnt and

Xanthine oxidase in the metabolism mainly of azathioprine and 6-megapirin though they have excretory functions too we’ve covered the side effects including the main ones to mention to the patient the common ones as well as well at the end of the day they’re going to get a leaflet and advise them to read through it and to just call back or come in and ask if there’s

Any questions we talked about in general important advice important advice in particular with again milo suppression as well as transplantation and pregnancy we’ve talked about monitoring and how full blood count is the main port of call as well as general symptom monitoring however lfts and using these are also done routinely once every three months alongside

The uh the full blood count when the patient is stable and lastly we lastly we covered the interactions of azathioprine and mycaptor purine in conjunction with allopurinol and xanthine oxidase inhibitors ace inhibitors which is a fairly new one and other myelosuppressive and immunosuppressive agents i hope that was beneficial i hope that helped um and i hope

It was uh useful for you in terms of either revision or just learning more about this medication because it is a fairly high risk one if you have any questions feel free to put to put them in the comments section feel free to share it with your fellow university colleagues and friends that would really benefit me and benefit others but otherwise thank you very much and have a great day

Transcribed from video
Azathioprine and Mercaptopurine – Full Drug Summary By Pharmacy Peninsula