Hyperuricemia allopurinol dosing

Febuxostat is a potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid. No other enzymes involved in purine or pyrimidine metabolism are inhibited. In clinical trials, febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion. 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. 

Pharmacokinetics Intravenous injection of vincristine or vinblastine leads to rapid cytotoxic effects and cell destruction. This in turn can cause hyperuricemia due to the oxidation of purines to uric acid. The hyperuricemia is ameliorated by administration of the xanthine oxidase inhibitor, allopurinol (see p. 417). The agents are concentrated and metabolized in the liver and are excreted into bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction. 

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressive. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressive and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, ami the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurirwl. 

In summary, febuxostat (1), a novel xanthine oxidase inhibitor, is the most recent treatment for gout and hyperuricemia on the market since allopurinol launched 40 years ago. It also offers the convenience of a once-a-day dose and a favorable safety profile. Its original synthesis and academic synthetic approaches have been sununarized in this chapter. 

A 65-year-old man with a history of bilateral ureterohydronephrosis with chronic renal insufficiency, hyperuricemia, and bladder carcinoma reported a 2-month history of prurigi-nous lesions on his trunk and limbs. His medications included long-term allopurinol and calcium, and furosemide (dose not stated), which he had taken for 4 months. The diagnosis was confirmed on skin biopsy. One year after stopping furosemide, his lesions were still present but had become less symptomatic. 

Allopurinol has been used for 16 years at doses ranging from 200 to 800 mg/day for the control of primary and secondary hyperuricemia. At the most commonly used doses of allopurinol (300-400 mg/ day) about 70% of the allopurinol is oxidized to oxipurinol, which is excreted in the urine. Urinary allopurinol and allopurinol riboside each account for about 10% of the dose. Since the degree of xanthine oxidase inhibition is dose-related, not only the oxidation of hypoxanthine and xanthine to uric acid, but also the oxidation of allopurinol to oxipurinol might be expected to be strongly inhibited at high doses of allopurinol. This would lead to increased levels of allopurinol, as well as allopurinol riboside, in plasma and urine. The extent to which this phenomenon occurs was investigated in several laboratory animal species and in man. 

Fig. 1. The time course of dose-dependent inhibition of allan-toxanamide-induced hyperuricemia by allopurinol in rats. Each point represents the mean + S.D. of 6 individual values.

EFFICACY OF SINGLE DAILY DOSE ALLOPURINOL IN GOUTY HYPERURICEMIA... 

Some of the patients were receiving diuretic drugs of the thiazide class, which are known to cause hyperuricemia and hypokalemia. Either or both of these may influence renal function. Therefore in all cases receiving thiazides, special attention was paid to correcting possible hypokalemia and to keeping serum uric acid levels below 5 the dose of Allopurinol. 

Urinary tract A case report was published on anti-neutrophil cytoplasmic antibody (ANCA)-positive pauci-immxme glomerulonephritis during febuxostat treatment. A 63-year-old African started treatment with febuxostat (dose not reported) because he had a history of chronic asymptomatic hyperuricemia which was not adequately controlled by allopurinol therapy. After 6 months of febuxostat therapy he developed AKI, characterised by acute renal failure, nephritic syndrome, proteinuria, microscopic haematuria and aseptic leukocyturia. Within 48 h after discontinuation of febuxostat, serum creatinine levels improved, although nephritic syndrome remained. ANCA-positive pauci-immune glomerulonephritis was confirmed by renal biopsy revealing diffuse crescentic necrotizing glomerulonephritis [60 ]. 

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