Drugs Used to Treat Gout Flashcards
MANAGEMENT OF ACUTE GOUT: AGENTS THAT SUPPRESS LEUKOCYTE RECRUITMENT AND ACTIVATION
Acute gouty attacks can result from a number of conditions, including excessive alcohol consumption, a diet rich in purines, or kidney disease.
Agents Used: NSAIDS, Glucocorticoids, and Colchicine
NSAIDS
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
NSAIDs are currently the first-line drugs for acute gout.
Indomethacin is one of the NSAIDs used most often to treat acute attacks of gout.
NSAIDs other than indomethacin are also effective.
ASPIRIN IS CONTRAINDICATED, because it competes with uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney.
ADVERSE EFFECTS
The serious adverse effects of NSAIDs include bleeding, salt and water retention, and renal insufficiency.
COX-2 selective inhibitors are potentially useful for the management of acute gout attacks because they may decrease the risk of gastrointestinal bleeding, although concerns about adverse cardiovascular effects limit their long-term use.
Colchicine
COLCHICINE
Colchicine binds to tubulin, inhibiting its polymerization and preventing formation of microtubules. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area. Furthermore, colchicine blocks cell division by disrupting the mitotic spindle. Colchicine also inhibits synthesis and release of leukotrienes.
Colchicine must be administered within 24 to 48 hours of the onset of the attack to be effective.
Colchicine usually alleviates the pain of acute gout within 12 hours.
ADVERSE EFFECTS
Colchicine treatment may cause nausea, vomiting, abdominal pain, and diarrhea.
Chronic administration may lead to myopathy, neutropenia, aplastic anemia, and alopecia.
The drug should not be used in pregnancy, and it should be used with caution in patients with hepatic, renal, or cardiovascular disease.
Although colchicine is more specific in gout than the NSAIDs, NSAIDs (except aspirin) have replaced it in the treatment of acute gout because of the troublesome diarrhea sometimes associated with colchicine therapy.
Glucocorticoids
GLUCOCORTICOIDS
Glucocorticoids have powerful anti-inflammatory and immunosuppressive effects.
Glucocorticoids inhibit several steps in the inflammatory response during an acute attack of gout.
Because of their widespread adverse effects when given systemically, glucocorticoids are used in the treatment of acute polyarticular gout or when there are contraindications (such as renal insufficiency) to other effective therapies.
When an acute attack of gout occurs in a single joint and is unresponsive to NSAIDs or colchicine, depot preparations of a glucocorticoid can be injected directly into the site of inflammation.
MANAGEMENT OF CHRONIC GOUT: AGENTS THAT LOWER PLASMA URATE CONCENTRATION
AGENTS THAT DECREASE URIC ACID SYNTHESIS: Allopurinol
AGENTS THAT ENHANCE URIC ACID EXCRETION (URICOSURIC AGENTS): Probenecid, Sulfinpyrazone
AGENTS THAT ENHANCE URIC ACID METABOLISM: Rasburicase
Allopurinol
AGENTS THAT DECREASE URIC ACID SYNTHESIS ALLOPURINOL
Allopurinol is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.
Allopurinol facilitates the dissolution of tophi and prevents development or progression of chronic gouty arthritis by lowering the uric acid concentration in plasma below the limit of its solubility.
The formation of uric acid stones virtually disappears with therapy, which prevents development of nephropathy.
The incidence of acute attacks of gouty arthritis may increase during the early months of therapy with allopurinol as a consequence of the mobilization of tissue stores of uric acid. Therefore, an NSAID or colchicine is coadministered during the first 4-6 months of allopurinol therapy to reduce the chance of precipitating an acute attack of gout.
ADVERSE EFFECTS
Allopurinol is well tolerated by most patients.
Hypersensitivity reactions, especially skin rashes, are the most common adverse reactions, occurring in approximately three percent of patients. In rare instances the rash may progress to Steven-Johnson syndrome. For this reason all patients who develop a cutaneous reaction to allopurinol should discontinue the drug.
DRUG INTERACTIONS
The anticancer drug mercaptopurine and the immunosuppressant azathioprine are purine analogues which are metabolized by xanthine oxidase. Inhibition of xanthine oxidase by allopurinol can result in toxic levels of coadministered mercaptopurine or azathioprine. Therefore, a dose reduction of these drugs is required.
Stevens-Johnson syndrome: begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters. Then the top layer of the affected skin dies and sheds.
Stevens-Johnson syndrome is a medical emergency that usually requires hospitalization.
Probenecid
AGENTS THAT ENHANCE URIC ACID EXCRETION (URICOSURIC AGENTS)
Uricosuric agents increase the rate of excretion of uric acid.
In humans, urate is filtered, secreted, and reabsorbed by the kidneys. Reabsorption predominates, and the amount excreted usually is about 10% of that filtered. This process is mediated by a specific transporter, which can be inhibited.
The first step in urate reabsorption is its uptake from tubular fluid by a transporter that exchanges urate for either an organic or an inorganic anion. Uricosuric drugs compete with urate for the brush-border transporter, thereby inhibiting its reabsorption via the urate–anion exchanger system.
PROBENECID
In patients with gout, probenecid is useful for the treatment of chronic hyperuricemia. Probenecid shifts the balance between renal excretion and endogenous formation of urate, thereby lowering plasma urate, dissolving urate crystals, and reversing the crystal deposition in synovial joints.
Concomitant colchicine or NSAIDs are indicated early in the course of therapy to avoid precipitating an attack of gout, which may occur in up to 20% of gouty patients treated with probenecid alone.
Probenecid should not be used in gouty patients with nephrolithiasis or with overproduction of uric acid.
Probenecid is ineffective in patients with renal insufficiency. Because probenecid inhibits the secretion of most anions, the dose of other drugs excreted by this pathway should be reduced when probenecid is coadministered.
Low-dose aspirin may antagonize probenecid action.
ADVERSE EFFECTS
Mild gastrointestinal irritation. The risk is increased at higher doses. Caution should be used in patients with a history of peptic ulcer.
Hypersensitivity reactions; usually mild. Serious hypersensitivity is extremely rare.
A liberal fluid intake should be maintained throughout therapy to minimize the risk of renal stones.
Sulfinpyrazone
SULFINPYRAZONE
Uricosuric agent that acts by the same mechanism as probenecid. It is rarely used today.
Sulfinpyrazone is ineffective in patients with renal insufficiency.
ADVERSE EFFECTS
Gastrointestinal irritation is more frequent than with probenecid.
Hypersensitivity reactions, usually a rash with fever, occur less frequently than with probenecid.
Depression of hematopoiesis occurs; periodic blood cell counts are advised during prolonged therapy.
Sulfinpyrazone should not be used by patients with underlying blood dyscrasias.
A liberal fluid intake should be maintained throughout therapy to minimize the risk of renal stones.
DRUG INTERACTIONS
Sulfinpyrazone inhibits warfarin metabolism. The anticoagulant effects of warfarin are markedly increased by sulfinpyrazone and serious bleeding has occurred.
NOTE: Certain drugs, particularly thiazide diuretics and immunosuppressant agents (especially cyclosporine) may impair urate excretion and thereby increase the risk of gout.
Rasburicase
AGENTS THAT ENHANCE URIC ACID METABOLISM
RASBURICASE
Most mammals other than humans express the enzyme uricase. This enzyme oxidizes uric acid to allantoin, a soluble compound that is easily excreted by the kidney.
In cancer chemotherapy, the rapid lysis of tumor cells can liberate free nucleotides and greatly increase plasma urate levels. By this mechanism, tumor lysis syndrome can lead to massive renal injury. Exogenous uricase can be coadministered with cancer chemotherapy to reduce plasma urate levels rapidly, and thereby to prevent renal damage. Allopurinol can also be used to prevent this component of tumor lysis syndrome.
A recombinant version of Aspergillus uricase, rasburicase, is available in the US. It is indicated for the initial management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and significant hyperuricemia.
