Antihyperuricemic gout prophylaxis

Gout Eraser

Stop Gout Naturally

Get Instant Access

Gout is an episodic disease, and the number of attacks varies widely from patient to patient. Thus, the benefit of long-term prophylaxis against acute gout flares must be weighed against the cost and potential toxicity of therapy that may not be necessary in all patients.

® Asymptomatic hyperuricemia usually does not require treatment. Nonpharmacologic Therapy

Lifestyle modifications alone usually are insufficient for lowering SUA levels in gout patients. Patients should be advised to lose weight if obese and to discontinue ethanol consumption. Low-purine diets are not well tolerated; instead, dietary recommendations should focus on general nutrition principles. Drugs that may cause or aggravate hyperuricemia should be discontinued if possible. Few patients adhere to lifestyle modifications long term, and pharmacologic therapy usually is needed to treat hyper-

uricemia adequately. Pharmacologic Therapy

Patients with recurrent attacks, evidence of tophi or joint destruction, or uric acid nephrolithiasis are candidates for maintenance therapy with allopurinol, febuxostat, or probenecid to lower SUA levels. Because hyperuricemia is the strongest modifiable risk factor for acute gout, prophylactic therapy involves either decreasing uric acid production or increasing its excretion (Table 59-1). The goal of therapy is to decrease SUA levels significantly, leaving less uric acid available for conversion to MSU crys-tals.11

Ideally, the selection of long-term prophylactic therapy involves determining the cause of hyperuricemia (primarily by analyzing a 24-hour urine collection for uric acid) and tailoring therapy appropriately. If less than 600 mg of uric acid is found in the 24-hour sample, the patient is considered an underexcretor. However, this approach is not used commonly for several reasons. The urine collection is inconvenient for patients and clinicians and does not identify patients who may be both overprodu-cers and underexcretors of uric acid. Also, drugs used to increase uric acid excretion

(uricosurics) generally are not as well tolerated as drugs that decrease production,

and uricosurics increase the risk of uric acid nephrolithiasis.

Because allopurinol (which reduces uric acid production) is effective in both over-producers and underexcretors and is generally well tolerated, many clinicians forego the 24-hour urine collection and treat patients empirically with it.

Allopurinol

Most patients in the United States are treated with allopurinol, which usually is effective if the dosage is titrated appropriately. The drug and its primary active metabolite, oxypurinol, reduce SUA concentrations by inhibiting the enzyme xanthine oxidase, thereby blocking the oxidation of hypoxanthine and xanthine to uric acid.11

Allopurinol is well absorbed with a short half-life of 2 to 3 hours. The half-life of oxypurinol approaches 24 hours, allowing allopurinol to be dosed once daily. Oxy-purinol is cleared primarily renally and can accumulate in patients with reduced kidney function. Allopurinol should not be started during an acute gout attack because sudden shifts in SUA levels may precipitate or exacerbate gouty arthritis. Rapid shifts in SUA can change the concentration of MSU crystals in synovial fluid, causing more crystals to precipitate. Thus some clinicians advocate a prophylactic dose of colchicine (0.6 mg/day) during initiation of antihyperuricemic therapy. This is continued until uric acid levels return to normal or maximum of 3 to 6 months. Acute episodes should be treated appropriately before maintenance treatment is started.

The initial dose of allopurinol is based on the patient's renal function. Patients with a creatinine clearance (CrCl) of 50 mL/min or less should receive a starting dose of less than 300 mg/day, although the product literature and other sources list alternative dosing regimens for those with renal insufficiency. The relationship between dose of

allopurinol and its most severe side effects is controversial. However, the dose can be adjusted upward as needed and tolerated. It is reasonable to reduce the dose temporarily in patients who develop reversible acute renal failure.

SUA levels must be monitored periodically, with the first follow-up level obtained 6 months (or sooner) after starting therapy. The target SUA level is less than 6 mg/dL (357 ^mol/L). The dose should be titrated upward (to a maximum of 800 mg/day) or downward as these levels dictate.

Allopurinol generally is well tolerated; nausea and diarrhea occur in a small percentage of patients. A generalized, maculopapular rash occurs in about 2% of pa-

tients. Although usually mild, this can progress to severe skin reactions such as Stevens-Johnson syndrome. Perhaps the most feared side effect is the allopurinol hy-persensitivity syndrome, which may involve severe desquamating skin lesions, high fever (usually greater than 39°C [102.2°F]), hepatic dysfunction, leukocytosis with predominant eosinophilia, and renal failure. Although rare, this severe reaction has a 20% mortality rate. 6 Patients with a history of the syndrome should never again receive allopurinol (including desensitization) or oxypurinol (which is available outside the United States). Patients with a mild skin rash who require allopurinol can be de-

27 28

sensitized to it using published protocols. '

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited by concomitant allopurinol therapy; the dose of these drugs must be reduced by 75% with allopurinol co-therapy. Patient's taking allopurinol who receive ampicillin are at increased risk of skin rashes.

Febuxostat

In 2009, the FDA approved febuxostat (Uloric), a nonpurine xanthine oxidase inhibitor structurally distinct from allopurinol, for chronic hyperuricemia associated with gout. The initial dose is 40 mg orally once daily. The dose may be increased to 80 mg orally once daily if the SUA does not decrease to 6.0 mg/dL (357 ^mol/L) or less after 2 weeks of treatment. No dosage adjustment is necessary in patients with mild or moderate renal impairment. Because of its potency and rapid reduction of SUA levels, prophylactic low-dose colchicine or an NSAID is recommended for 3 to 6 months during initiation of therapy.

Data from phase III trials suggest that febuxostat may be more effective than allopurinol in achieving target SUA levels of 6.0 mg/dL (357 ^mol/L) or less and may

be more effective in reducing the number of acute gouty flares. However, fixed al-lopurinol doses were used rather than titrating the allopurinol dose to reach the target SUA level, which may confound these findings.

Adverse effects of febuxostat include nausea, arthralgias, rash, and transient elevation of hepatic transaminases. Periodic liver function tests are recommended (e.g., at baseline, 2 and 4 months after starting therapy, and then periodically thereafter). Due to structural differences, febuxostat would not be expected to crossreact in patients with a history of allopurinol hypersensitivity syndrome. The place of febuxostat in therapy of hyperuricemia has not been fully determined.

Probenecid

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindic-ated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the CrCl is 50

mL/min or less. Its uricosuric effect is counteracted by low aspirin doses, which many

2 11

patients receive for prophylaxis of coronary heart disease.

Although generally well tolerated, probenecid can cause GI side effects such as nausea and other adverse reactions including fever, rash, and rarely, hepatic toxicity. Patients should be instructed to maintain adequate fluid intake and urine output to decrease the risk of uric acid stone formation. Some experts advocate alkalinizing the urine to decrease this risk.

Was this article helpful?

0 0
Gaining Weight 101

Gaining Weight 101

Find out why long exhausting workouts may do more harm than good. Most of the body-building workout and diet regimens out there are designed for the guys that gain muscle and fat easily. They focus on eating less and working out more in order to cut the excess fat from their bodies while adding needed muscle tone.

Get My Free Ebook


Post a comment