Fig. 31.1 The pathway for production of uric acid from purines and the sites of action of some of the drugs used in gout and hyperuricaemia.
Hyperuricaemia results from the following factors.
excessive cell destruction (e.g. lymphoproliferative or myeloproliferative disorders, especially during treatment for cancer, Ch. 52),
Reduced renal excretion of uric acid: more than 90% of filtered uric acid is reabsorbed in the early proximal tubule, but an amount equivalent to 6–10% of the filtered load is secreted by an active organic acid transporter in the second part of the proximal tubule (Ch. 14). Renal failure and certain drugs (e.g. loop and thiazide-type diuretics, low-dose aspirin, ciclosporin and lactate formed from excess alcohol) will reduce the tubular secretion of uric acid. Reduced uric acid excretion accounts for at least 80% of cases of gout.A high plasma concentration of uric acid is often an incidental finding and does not lead to symptoms, but when the plasma concentration exceeds about 0.42 mmol⋅L−1 monosodium urate crystals can be deposited in tissues, forming a tophus. If these crystals are shed from a tophus in the synovial membrane or cartilage of a joint they produce an extremely painful acute arthritis that presents with the clinical syndrome of gout. In brief, the crystals are phagocytosed by macrophage cells within the synovium, which release mediators such as interleukin-1β. These mediators activate mast cells and endothelial cells with expression of adhesion molecules and chemokines. Uric acid crystals also provide a surface on which complement C5 is cleaved, with formation of complement membrane attack complex. The activated endothelial cells and complement membrane attack complex attract neutrophil leucocytes which release proteolytic and lysosomal enzymes that enhance tissue inflammation, destroy cartilage and damage the joint. Most attacks of gout are self-limiting, probably in part due to coating of the uric acid crystals with protein, which reduces their irritant properties. Acute gout usually presents with rapid onset of severe joint pain that reaches maximum intensity within 24 h. Pseudogout, due to deposition of calcium pyrophosphate crystals, has a similar clinical presentation.
Gout in younger people usually affects a single joint, with repeated acute attacks if the underlying cause is not treated. In the elderly, a chronic arthritis affecting multiple joints can occur. The diagnosis of gout is confirmed by the finding of monosodium urate crystals in the affected joint. With persistent hyperuricaemia, chronic urate deposits are sometimes found in tendon sheaths and soft tissues. Excess uric acid can also be deposited in the interstitium of the kidney or form stones in the renal calyces, both of which can produce progressive renal damage.
There are two components of drug treatment:
Drugs for the treatment of gout and prevention of hyperuricaemia
Mechanism of action
Colchicine interferes with several steps in the inflammatory cascade, particularly inhibiting recruitment and actions of neutrophil leucocytes in the gouty joint:
it reduces the production of inflammatory mediators by macrophages and downregulates their receptors on synovial and endothelial cells. Colchicine also inhibits the production of chemotaxins, which attract leucocytes into inflamed tissue,
colchicine disrupts the assembly of microtubules in neutrophil leucocytes by forming a complex with tubulin in the cell. This impairs the adhesion of neutrophils to endothelial cells, which reduces their recruitment into the inflamed joint, and also impairs phagocytosis of crystals if the neutrophil does enter the joint. In addition, if crystals are phagocytosed into the neutrophil colchicine inhibits the subsequent release of enzymes and free radicals that damage the joint.All of these actions give colchicine a specific anti-inflammatory effect in the gouty joint; it is ineffective in other forms of inflammatory arthritis. Other uses of colchicine include the management of recurrent pericarditis and familial Mediterranean fever.
Pharmacokinetics
Colchicine is well absorbed from the gut. It is usually given every 6–12 h until symptomatic relief is achieved or unwanted effects occur. Pain relief usually begins after about 18 h and is maximal by 48 h.
Xanthine oxidase inhibitors
Mechanism of action
Allopurinol is an analogue of hypoxanthine, which is an intermediate in the pathway that generates uric acid. Both allopurinol and its major metabolite competitively inhibit the enzyme xanthine oxidase for which hypoxanthine is the natural substrate, thereby reducing uric acid formation (Fig. 31.1). Febuxostat is a non-purine selective xanthine oxidase inhibitor. Although plasma xanthine and hypoxanthine concentrations increase when these drugs are given, they do not crystallize. Because of their greater water solubility, their concentrations remain well below saturation levels even with maximal xanthine oxidase inhibition. Xanthine and hypoxanthine are reincorporated into the purine synthetic cycle, and this decreases the need for de novo purine formation.
Pharmacokinetics
Allopurinol is well absorbed from the gut and converted in the liver to an active metabolite with a long half-life, oxipurinol (alloxanthine). Febuxostat is well absorbed from the gut; it is eliminated by both metabolism and renal excretion and has a variable half-life (1–15 h).
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