Allopurinol


Article Author:
Ahmad Qurie


Article Editor:
Rina Musa


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
12/14/2018 1:12:20 PM

Indications

Allopurinol is a urate-lowering medication.[1][2][3]

Allopurinol is FDA approved for the following indications:

  1. Gout: Allopurinol is used in recurrent gout flares or if gout arthropathy is seen on imaging. 
  2. Cancer therapy-induced hyperuricemia or tumor lysis syndrome
  3. Calcium oxalate stones

Other non-FDA approved indications include Lesch-Nyhan syndrome-associated hyperuricemia. 

Allopurinol, as part of the different urate-lowering agents, is recommended to be started in the setting of gout in the following situations:

  1. Frequent gout attacks, defined as equal or more than 2 per year
  2. Overproduction of uric acid, with serum uric acid level more than 8 
  3. Uric acid urolithiasis. Allopurinol is used if there are recurrent stones despite adequate hydration and urinary alkalization. It is used to decrease the amount of uric acid excreted in the urine. 
  4. Tophaceous gout 
  5. Chronic persistent gout arthritis

One important point to add is that allopurinol is not recommended for use in asymptomatic hyperuricemia.

Mechanism of Action

Allopurinol is processed in the liver where it is converted into its pharmacologically active metabolite, oxypurinol. Oxypurinol has a long half-life of 24 hours and is renally cleared. Lower dosages are used in renal insufficiency due to renal clearance of allopurinol. Allopurinol and oxypurinol both competitively inhibit xanthine oxidase. This decreases the conversion of hypoxanthine and xanthine into uric acid. As a result, there is an increase in serum hypoxanthine and xanthine which affect pyrimidine metabolism.[4][5]

Administration

Allopurinol can be administered in 2 forms, either intravenous (IV) or oral. While oral is the standard route of administration for gout and calcium oxalate stones, IV is reserved for cancer therapy-induced hyperuricemia.

For long-term gout treatment, allopurinol is usually started at a dosage of 100 mg per day for one week. This dose is increased every 2 to 4 weeks until the serum uric acid level is within goal range. The goal serum uric acid range is 6.0 mg/dL and less. Serum uric acid levels start to decrease within two days after starting allopurinol.

The usual daily dose prescribed for allopurinol is 300 mg daily. The maximum dose is 800 mg.

For renal insufficiency (chronic kidney disease stage 3 and greater), the dosage of allopurinol must be reduced. Oxypurinol's half-life in renal insufficiency is prolonged and may result in increased circulation of allopurinol and oxypurinol. If the creatinine clearance (CrCl) is 10 to 20 mL per minute, allopurinol should be prescribed as 200 mg daily. If the CrCl is 3 to 10 mL per minute, then the allopurinol dose is lowered to 100 mg daily. If the patient has the end-stage renal disease and is on hemodialysis or peritoneal dialysis, the patient may take daily allopurinol since allopurinol and oxypurinol are dialyzable.

For cancer-treatment induced hyperuricemia, oral doses of allopurinol are usually 600 to 800 mg daily for 2 to 3 days. Intravenous doses may also be given as 200 to 400 mg/m2 daily prior to initiating chemotherapy. Doses may be divided instead of being administered as a single infusion.

For recurrent calcium oxalate nephrolithiasis, allopurinol is administered as an oral dose, 200 to 300 mg daily.

Adverse Effects

Most common side effects of allopurinol are listed below:

A rash may occur. The rash may appear as maculopapular or be pruritic. This may occur more frequently in at least 20% of a patient taking amoxicillin or ampicillin.

Gout flares or worsening of a current flare may be precipitated after starting allopurinol treatment to acutely lower serum uric acid This adverse effect may be avoided by starting a low dose urate-lowering treatment, such as colchicine. An alternative to colchicine in this instance is a nonsteroidal anti-inflammatory drug (NSAID).

Gastrointestinal (GI) side effects are seen. Diarrhea and nausea are most commonly experienced.

Hepatic side effects are seen in about 3% to 5% of patients. These include transaminitis and elevated serum alkaline phosphatase. This may occur since the liver metabolizes the medication. Rare but more serious gastrointestinal side effects that may occur are liver necrosis, granulomatous hepatitis or cholestatic jaundice.

Hematologic abnormalities such as leukopenia and thrombocytopenia may also be seen. Evidence of bone marrow suppression is seen more frequently with higher doses of allopurinol.

Several drug interactions exist with allopurinol. Xanthine oxidase also metabolizes both 6-mercaptopurine and azathioprine. Serious agranulocytosis may occur when allopurinol is combined with azathioprine.

Drowsiness may occur. Patients should be educated to avoid driving or operating machinery if this adverse effect occurs.

Other less common adverse effects include interstitial nephritis or vasculitis.

Allopurinol hypersensitivity syndrome (AHS) may occur and is a serious adverse effect. This has a high mortality rate of about 25%. The first 60 days after the start of allopurinol therapy has the most risk for the development of AHS. Major risks factors of AHS include renal insufficiency, thiazide use, HLA-B*5801 genotype, and initiation of allopurinol at higher dosages. Older patients with renal insufficiency and on diuretic medications are prone to allopurinol sensitivity. The mechanism of AHS is due to T-cell activation in response to an increase in serum allopurinol and its active metabolite, oxypurinol.

In order to diagnose ASH, there must be at least two major criteria, one major and at least one minor criteria, or rash only and/or additional minor criteria. 

  • Major criteria: acute hepatocellular injury, worsening renal function, rash. Different rashes of ASH include toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash.
  • Minor criteria: Fever, elevated white blood cell count, eosinophilia

In order to lower the possibility of developing, allopurinol is started at lower doses, such as 100 mg daily.

Contraindications

The HLA-B*5801 genotype is more susceptible to developing allopurinol hypersensitivity syndrome. This genotype is found to occur more in Koreans with chronic kidney disease, Han Chinese, or Thai descent. It is particularly seen in populations of East and Southeast Asia and may also be seen in those of African descent. Susceptible populations should be screened for HLA-B*5801 genotype through polymerase chain reaction (PCR) testing. It is recommended to avoid treating patients with HLA-B*5801 genotype with allopurinol due to the high risk of developing AHS.

Monitoring

Monitoring parameters for allopurinol include measuring serum uric acid levels every 2 to 5 weeks during dose titration until desired levels are achieved, hydration status, response to therapy, and CBC. Measure serum uric acid level before and after allopurinol therapy is started. 

If there is suspicion of noncompliance with allopurinol therapy, oxypurinol levels may be measured.

Enhancing Healthcare Team Outcomes

Allopurinol is a relatively safe drug and has been in use for more than half a century. Still, healthcare workers including nurse practitioners who prescrribe this agent should measure uric acid levels on a regular basis to determine drug compliance. The rare patient may develop a mild transaminitis and thus follow up on liver function is necesary.


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Allopurinol - Questions

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Allopurinol should be avoided in a patient receiving which of the following drugs?



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A 28-year-old is undergoing chemotherapy for a lymphoma. He was having problems with gout and was started on medical treatment. Over the next few days, he became profoundly anemic, neutropenic and thrombocytopenic. What most likely caused this condition?



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Which of the following is not a side effect of allopurinol?



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Which of the following drugs has been associated with doughnut-type granulomas?



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Why is allopurinol used to treat gout?



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Which of the following is a side effect of allopurinol?



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Which of the following laboratory findings will confirm the effectiveness of allopurinol?



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Which of the following medications inhibits uric acid production?



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What enzyme does allopurinol inhibit?



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What condition is most commonly treated with allopurinol?



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Which of the following drugs can reduce serum uric acid level?



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Which of the following drugs can be used to reduce the formation of uric acid?



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Which of the following drugs can precipitate an acute attack of gout?



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Which of the following medications can inhibit uric acid formation?



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Which of the following is not an appropriate instruction for patients treated with allopurinol?



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In which of the following ways is allopurinol helpful in disease states where uric acid excretion is elevated?



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What type of medication is allopurinol?



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Which of the following should be part of the education of patients using allopurinol?



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Which drug has the least amount of binding to plasma protein?



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Which drug minimally binds to plasma protein?



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Which drug minimally binds to plasma protein?



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Why might a patient be given allopurinol along with a course of chemotherapy?



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Which of the following drugs decreases the production of endogenous uric acid?



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Which of the following is used prophylactically to prevent exacerbations of chronic gout?



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Of the following agents used in gout management, which one prevents the formation of uric acid?



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A female patient who has had 3 episodes of gout was recently started on allopurinol. She would like to know the risk of adverse effects of this agent. What should she be told?



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A patient is on allopurinol because in the past he had 3 episodes of gout. He now appears to be stable. According to the American College of Rheumatology guidelines, when should uric levels be measured?



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A patient has been successfully treated for a second acute gout attack. It is decided to start the patient on the drug allopurinol. What is true regarding allopurinol? Select all that apply.



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Allopurinol - References

References

Mikuls TR,Cheetham TC,Levy GD,Rashid N,Kerimian A,Low KJ,Coburn BW,Redden DT,Saag KG,Foster PJ,Chen L, A Pharmacist-Led Intervention to Improve Gout Medication Adherence and Outcomes with Urate Lowering Therapy: A Site Randomized Trial. The American journal of medicine. 2018 Nov 29     [PubMed]
Shim JS,Yun J,Kim MY,Chung SJ,Oh JH,Kang DY,Jung JW,Cho SH,Kang HR, The presence of HLA-B75, DR13 homozygosity or DR14 additionally increases the risk of allopurinol induced severe cutaneous adverse reactions in HLA-B*58:01 carriers. The journal of allergy and clinical immunology. In practice. 2018 Dec 6     [PubMed]
Hill-McManus D,Marshall S,Soto E,Lane S,Hughes D, Impact of Non-Adherence and Flare Resolution on the Cost-Effectiveness of Treatments for Gout: Application of a Linked Pharmacometric/Pharmacoeconomic Model. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018 Dec     [PubMed]
Alušík Š,Paluch Z, Controversies in the treatment of gout. Vnitrni lekarstvi. 2018 Fall     [PubMed]
Robinson PC, Gout - An update of aetiology, genetics, co-morbidities and management. Maturitas. 2018 Dec     [PubMed]

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