Used in the Therapy of Gout

Would opiate analgesics be useful in the therapy of gout ... 

Loop diuretics exacerbate gout, because these drugs enter the tubule lumen through the organic acid secretory system. Because uric acid utilizes this system for transport into the renal tubule and subsequent elimination, competition exists for the transporter. This results in both increased levels of uric acid and increased plasma drug levels. In the same way, the drug interferes with the tubular secretion of probenecid, which is used in the therapy of gout. 

Examination of the urine of patients with this disease reveals in addition to the high uric acid an elevated hypoxanthine to xanthine ratio (L4). Furthermore, it was found that upon the administration of allopuri-nol, an inhibitor of xanthine oxidase that is widely used in the treatment of gout, the total output of purine is not reduced. This is in contrast to the reduction in total oxypurine output seen in normal or most gouty individuals. In addition, the ratio of hypoxanthine to xanthine is not reduced i.e., Lesch-Nyhan patients still maintained elevated hypoxanthine to xanthine ratios. These data have suggested an interference with hypoxanthine metabolism or reutilization, since the reduction in purine output after aUopurinoI therapy is due to anabolism of the hypoxanthine to inosinate (B4). It was shown by Seegmiller and his associates that there was an absence of hypoxanthine phosphoribosyltransferase in the red cells of subjects with Lesch-Nyhan syndrome. 

Colchicine (6) is used in the treatment of a broad range of diseases including acute gout and Mediterranean fever [28] and induces depolymerization of tubulin. This compound (6) distorts the tubulin/microtubule equilibrium by binding to the tubulin dimer and halting mitosis in the metaphase. The reason this approach is such a successful target in cancer therapy is that... 

Allopurinol is used not only in treating the hyperuricemia associated with gout but also in the secondary hyperuricemia associated with the use of antineoplastic agents. Therefore, allopurinol may be used in the management of patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy that causes elevations of serum and urinary uric acid levels. Allopurinol may interfere with the metabolism of antineoplastic agents such as azathioprine and 6-mercaptopurine. 

Probenecid inhibits renal tubular reabsorption of water and by this meehanism enhanees the urinary excretion of uric acid. This lowers the level of urate in the serum. It thus serves as a potent uricosuric agent in the treatment of gout. Probenecid also blocks the renal tubular seeretion of penicillins and cephalosporins. It is, therefore, used as an adjuvant therapy with penicillin V or G, ampicillin, cloxacillin, oxacillin, methicillin and naficillin to increase and prolong their plasma levels. Besides it also enhances the plasma levels of anti-inflammatory agents like naproxen and indomethacin, and a host of medicinal compounds such as sulphonamides, sulphonylureas, dapsone, etc. 

It is employed for acute and long-term therapy for the relief of symptoms of osteoarthritis and rheumatoid arthritis. It also possesses uricosuric actions and has been used in the treatment of acute gout. 

Although colchicine is more specific in gout than the NSAIDs, NSAIDs (eg, indomethacin and other NSAIDs [except aspirin]) have replaced it in the treatment of acute gout because of the troublesome diarrhea sometimes associated with colchicine therapy. Colchicine is now used for the prophylaxis of recurrent episodes of gouty arthritis, is effective in preventing attacks of acute Mediterranean fever, and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Although it can be given intravenously, this route should be used cautiously because of increased bone marrow toxicity. 

Therapeutic uses Phenylbutazone is prescribed chiefly in shortterm therapy of acute gout and in acute rheumatoid arthritis when other NSAID agents have failed. The usefulness of phenylbutazone is limited by its toxicity. Aspirin and newer NSAIDs are superior to phenylbutazone in most applications. 

Allopurinol, which affects both the penultimate and ultimate steps in the production of uric acid, is used to lower plasma uric acid levels in conditions associated with excessive urate production (e.g., gout, hematologic disorders, and antineoplastic therapy). Sodium urate has a... 

Probenecid, a uricosuric agent (initially 0.25 g t.i.d. for 1 week), is indicated in the treatment of hyperuricemia associated with gout and gouty arthritis. In addition, probenecid is used as an adjunct to therapy with penicillins or cephalosporins, and for elevation and prolongation of plasma levels of these antibiotics. 

Recurrent attacks of gout can be prevented with the use of colchicine (e.g., 0.6 mg daily or on alternate days). Indomethacin (25 mg/day) also has been used. These agents are used early in the course of uricosuric therapy when mobilization of urate is associated with a temporary increase in the risk of acute gouty arthritis. 

Toxicity The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperhpidemia, and gum hyperplasia. Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemia. Nephrotoxicity occurs in the majority of patients treated and is the major indication for cessation or modification of therapy. Hypertension occurs in -50% of renal transplant and almost all cardiac transplant patients. Combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, although this apparently is more problematic in patients treated with tacrohmus see below). Especially at risk are obese patients, African American or Hispanic recipients, or those with family history of type 2 diabetes or obesity. Cyclosporine, as opposed to tacrolimus, is more hkely to produce elevations in low-density lipoprotein (LDL) cholesterol. 

It is generally used for the reduction of fever and the relief of pain. It also possesses anti-inflammatory actions similar to aspirin. It is recommended in acute rheumatic fever and in the symptomatic therapy of gout. 

An early form of therapy involves eliminating the substrate either by excluding the substrate from the diet, as in phenylketonuria, or by administering drugs—such as penicillamine in Wilson s disease or allopurinol in gout. Orotic aciduria can be corrected by the administration of uridine, which provides the substrate for the biosynthesis of the nucleosides used in RNA and DNA synthesis and is also a substrate for the biosynthesis of inhibitors of the carbamyl aspartate synthetase, the first enzyme in the formation of orotic acid. By this feedback inhibition, the levels of orotic acid in the urine are reduced by the administration of uridine. 

---