Allopurinol

Last updated

Allopurinol
Allopurinol V.1.svg
Allopurinol 3d structure.png
Clinical data
Trade names Zyloprim, Caplenal, Zyloric, others
AHFS/Drugs.com Monograph
MedlinePlus a682673
License data
Pregnancy
category
Routes of
administration 		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 78±20%
Protein binding Negligible
Metabolism Liver (80% oxipurinol, 10% allopurinol ribosides)
Elimination half-life 2 h (oxipurinol 18–30 h)
Identifiers
  • 1H-Pyrazolo[3,4-d]pyrimidin-4(2H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.684 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H4N4O
Molar mass 136.114 g·mol−1
3D model (JSmol)
  • C1=NNC2=C1C(=O)NC=N2
  • InChI=1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10) Yes check.svgY
  • Key:OFCNXPDARWKPPY-UHFFFAOYSA-N Yes check.svgY
   (verify)

Allopurinol is a medication used to decrease high blood uric acid levels. [5] It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. [6] [7] It is taken orally (by mouth) or intravenously (injected into a vein). [7]

Contents

Common side effects when used orally include itchiness and rash. [7] Common side effects when used by injection include vomiting and kidney problems. [7] While not recommended historically, starting allopurinol during an attack of gout appears to be safe. [8] [9] In those already on the medication, it should be continued even during an acute gout attack. [8] [6] While use during pregnancy does not appear to result in harm, this use has not been well studied. [1] Allopurinol is in the xanthine oxidase inhibitor family of medications. [7]

Allopurinol was approved for medical use in the United States in 1966. [7] It is on the World Health Organization's List of Essential Medicines. [10] Allopurinol is available as a generic medication. [7] In 2022, it was the 39th most commonly prescribed medication in the United States, with more than 15 million prescriptions. [11] [12]

Medical uses

Gout

Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndrome; glucose 6-phosphatase including glycogen storage disease; phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase; adenine phosphoribosyltransferase.

It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.

Tumor lysis syndrome

Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia; [13] however, it has gradually been replaced by urate oxidase therapy. [14] Intravenous formulations are used in this indication when people are unable to swallow medication. [4]

Inflammatory bowel disease

Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohn's disease who do not respond to thiopurine monotherapy. [15] [16] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD. [17] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient's genetic status for thiopurine methyltransferase. [18]

Psychiatric disorders

Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features). [19] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment. [19]

Cardiovascular disease

There is a correlation between uric acid levels and cardiovascular disease and mortality, and so allopurinol has been explored as a potential treatment to reduce risk of cardiac disease. [20] However, the data is inconsistent and conflicting, and the use of allopurinol for use in cardiovascular disease is controversial. Independently of its effects on uric acid, it may also have effects on oxidative stress and inflammation. [21]

Side effects

Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex. [22] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring. [23] [24]

Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and worsened renal function, collectively referred to as DRESS syndrome. [23] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions. [23] More common is a less-serious rash that leads to discontinuing this drug. [23]

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis. [25]

Drug interactions

Drug interactions are extensive, and are as follows: [13]

Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction: [13]

Co-administration of the following drugs may make allopurinol less active or decrease its half-life: [13]

Co-administration of the following drugs may cause hypersensitivity or skin rash: [13]

Allopurinol.svg

Pharmacology

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase. [26] The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol's effect. [27]

Mechanism of action

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase. [5] Xanthine (1H-Purine-2,6-dione) oxidase is responsible for the successive oxidation of hypoxanthine to xanthine and subsequently uric acid, the product of human purine metabolism. [5] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribonucleotides, hypoxanthine can be salvaged to the purine ribonucleotides adenosine and guanosine monophosphates. Increased levels of these ribonucleotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis. [28]

Pharmacogenetics

The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). [29] [30] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. [31] The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity. [29] [30] As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN. [32] However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug. [33] The Clinical Pharmacogenetics Implementation Consortium (CPIC) [34] guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele. [35] [36]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926–1992), in a search for antineoplastic agents. [5] [37] Allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and was later tested by Wayne Rundles in collaboration with Gertrude Elion's lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine. [5] [38] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential therapeutic for gout. [39] Allopurinol was first marketed as a treatment for gout in 1966. [38]

Society and culture

Pure allopurinol is a white powder. Allopurinol substance photo.jpg
Pure allopurinol is a white powder.

Formulations

Allopurinol is sold as an injection for intravenous use [4] and as a tablet. [13]

Brands

A package of Milurit 100mg (a brand of allopurinol) Milurit 100mg allopurinolum.jpg
A package of Milurit 100mg (a brand of allopurinol)

Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim. [40] Allopurinol was marketed at the time by Burroughs Wellcome. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron. [41]

See also

Related Research Articles

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Xanthine oxidase</span> Class of enzymes

Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

<span class="mw-page-title-main">Hyperuricemia</span> Excess uric acid in the blood

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for males, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

<span class="mw-page-title-main">Azathioprine</span> Immunosuppressive medication

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.

<span class="mw-page-title-main">Lesch–Nyhan syndrome</span> Rare genetic disorder

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Mercaptopurine</span> Chemical compound

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis. For acute lymphocytic leukemia it is generally used with methotrexate. It is taken orally.

<span class="mw-page-title-main">Thiopurine methyltransferase</span>

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

<span class="mw-page-title-main">Hypouricemia</span> Lack of uric acid in the blood

Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 μmol/L (6 mg/dL) for women and 619 μmol/L (7 mg/dL) for men. Hypouricemia usually is benign and sometimes is a sign of a medical condition.

<span class="mw-page-title-main">Tioguanine</span> Chemical compound

Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) or tabloid is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">Febuxostat</span> Chemical compound

Febuxostat, sold under the brand name Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. It is taken by mouth.

<span class="mw-page-title-main">Hyperuricosuria</span> Excess uric acid in the urine

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

<span class="mw-page-title-main">Oxipurinol</span> Chemical compound

Oxipurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels. By inhibiting xanthine oxidase, it reduces uric acid production. High serum uric acid levels may result in gout, kidney stones, and other medical conditions.

<span class="mw-page-title-main">Tisopurine</span> Chemical compound

Tisopurine is a drug used in the treatment of gout in some countries. It reduces uric acid production through inhibiting an early stage in its production.

A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhibit xanthine oxidase are indicated for treatment of hyperuricemia and related medical conditions including gout. Xanthine oxidase inhibitors are being investigated for management of reperfusion injury.

<span class="mw-page-title-main">Lesinurad</span> Pharmaceutical drug for the treatment of gout

Lesinurad is a urate transporter inhibitor for treating high blood uric acid levels associated with gout. It is recommended only as an adjuvant with either allopurinol or febuxostat when these medications are not sufficient.

<span class="mw-page-title-main">Gout suppressants</span> Drugs to control and prevent gout attacks

Gout suppressants are agents which control and prevent gout attacks after the first episode. They can be generally classified into two groups by their purpose: drugs used for induction therapy and that for maintenance therapy.

References

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