Uricosuric

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Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. Drugs that reduce blood uric acid are not all uricosurics; blood uric acid can be reduced by other mechanisms (see other Antigout Medications).

Contents

Uricosurics are often used in the treatment of gout, a disease in which uric acid crystals form deposits in the joints. By decreasing plasma uric acid levels, help dissolve these crystals, while limiting the formation of new ones. However, the increased uric acid levels in urine can contribute to kidney stones. Thus, use of these drugs is contraindicated in persons already with a high urine concentration of uric acid (hyperuricosuria). In borderline cases, enough water to produce 2 liters of urine per day may be sufficient to permit use of an uricosuric drug.

By their mechanism of action, some uricosurics (such as probenecid) increase the blood plasma concentration of certain other drugs and their metabolic products. While this is occasionally exploitable to good effect (see oseltamivir), assessment of drug interactions is very important when using uricosuric drugs in the presence of other medications.

Primary uricosurics

The primary uricosuric drugs include probenecid, benzbromarone and sulfinpyrazone.

Secondary uricosurics

Drugs with other primary uses, that have known uricosuric properties, include losartan, [1] atorvastatin, and fenofibrate. Although these drugs may have significant uricosuric action, their other significant pharmacological actions in off-label use as a uricosuric requires careful assessment of the patient to achieve the most benefit and least risk. [2] [3]

Abdominal surgery also has a uricosuric effect, as well as the potential to precipitate an acute attack of gout. [4]

Pharmacology

In general, uricosuric drugs act on the proximal tubules in the kidneys, where they interfere with the absorption of uric acid from the kidney back into the blood. Several uricosurics are known to act in vitro by blocking the function of a protein encoded by the gene SLC22A12, also known as urate transporter 1 or URAT1. URAT1 is the central mediator in the transport of uric acid from the kidney into the blood. In some persons with loss-of-function mutations of URAT1, the uricosurics benzbromarone and losartan had no effect, suggesting these drugs act on URAT1 in vivo . [1] Thus, uricosuric drugs may be candidates for management in a personalized medicine model.

Antiuricosurics

Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics, pyrazinoate, pyrazinamide, ethambutol, niacin, and aspirin. [5] The NSAID diclofenac has an antiuricosuric action, which may be partly responsible for the extraordinary toxicity of this drug in vultures. [6]

Pyrazinamide, a drug indicated only for treatment of tuberculosis, is a potent antiuricosuric [7] and, as a consequence, has an off-label use in the diagnosis of causes of abnormal uric acid clearance. [8] It acts on URAT1. [8]

Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria, but are contraindicated in persons with conditions including hyperuricemia and gout.

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">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">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. 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. It is taken orally or intravenously.

<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.

Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia. This is a potentially fatal complication and patients at increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary. TLS can also occur on its own although this is less common.

<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">Tophus</span> Medical condition

A tophus is a deposit of monosodium urate crystals, in people with longstanding high levels of uric acid (urate) in the blood, a condition known as hyperuricemia. Tophi are pathognomonic for the disease gout. Most people with tophi have had previous attacks of acute arthritis, eventually leading to the formation of tophi. Chronic tophaceous gout is known as Harrison Syndrome.

<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">Pyrazinamide</span> Medication

Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.

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

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

<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.

Acute uric acid nephropathy is a rapidly worsening (decreasing) kidney function that is caused by high levels of uric acid in the urine (hyperuricosuria).

<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">SLC22A12</span> Mammalian protein found in Homo sapiens

Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.

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

Benzbromarone is a uricosuric agent and non-competitive inhibitor of xanthine oxidase used in the treatment of gout, especially when allopurinol, a first-line treatment, fails or produces intolerable adverse effects. It is structurally related to the antiarrhythmic amiodarone.

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">Tsai-Fan Yu</span> American medical academic

Tsai-Fan Yu was a Chinese-American physician, researcher, and the first woman to be appointed as a full professor at Mount Sinai School of Medicine. She helped to develop an explanation for the cause of gout and experimented with early drugs to treat the disease which are still in use today.

<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">Ruzinurad</span> Chemical compound

Ruzinurad (SHR4640) is a selective urate transporter 1 (URAT1) inhibitor in development for hyperuricaemia and gout. It is developed by Jiangsu Hengrui.

<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

  1. 1 2 Hamada T, Ichida K, Hosoyamada M, Mizuta E, Yanagihara K, Sonoyama K, Sugihara S, Igawa O, Hosoya T, Ohtahara A, Shigamasa C, Yamamoto Y, Ninomiya H, Hisatome I (October 2008). "Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients". Am. J. Hypertens. 21 (10): 1157–62. doi: 10.1038/ajh.2008.245 . PMID   18670416.
  2. ↑ Lee SJ, Terkeltaub RA (June 2006). "New developments in clinically relevant mechanisms and treatment of hyperuricemia". Curr Rheumatol Rep. 8 (3): 224–30. doi:10.1007/s11926-996-0029-z. PMID   16901081.
  3. ↑ Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M (2005). "Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia". Curr. Pharm. Des. 11 (32): 4161–75. doi:10.2174/138161205774913309. PMID   16375738. Archived from the original on May 24, 2009.{{cite journal}}: CS1 maint: unfit URL (link)
  4. 1 2 3 Snaith ML, Scott JT (May 1972). "Uric acid excretion and surgery". Ann. Rheum. Dis. 31 (3): 162–5. doi:10.1136/ard.31.3.162. PMC   1005890 . PMID   5032447.
  5. ↑ Ben Salem, C.; Slim, Raoudha; Fathallah, Neila; Hmouda, Houssem (2016). "Drug-induced hyperuricaemia and gout". Rheumatology. 56 (5): 679–688. doi: 10.1093/rheumatology/kew293 . PMID   27498351.
  6. ↑ Naidoo V, Swan GE (August 2008). "Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction". Comp. Biochem. Physiol. C. 149 (3): 269–74. doi:10.1016/j.cbpc.2008.07.014. hdl: 2263/13907 . PMID   18727958.
  7. ↑ Spaia S, Magoula I, Tsapas G, Vayonas G (2000). "Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis". Perit Dial Int. 20 (1): 47–52. PMID   10716583.
  8. 1 2 Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (January 2004). "Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion". J. Am. Soc. Nephrol. 15 (1): 164–73. doi: 10.1097/01.ASN.0000105320.04395.D0 . PMID   14694169.
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