Drugs Used in Gout

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Chapter: Essential pharmacology : Antirheumatoid and Antigout Drugs

Gout It is a metabolic disorder characterized by hyperuricaemia (normal plasma urate 1–4 mg/ dl). Uric acid, a product of purine metabolism, has low water solubility, especially at low pH. When blood levels are high, it precipitates and deposits in joints, kidney and subcutaneous tissue (tophy).



Gout It is a metabolic disorder characterized by hyperuricaemia (normal plasma urate 1–4 mg/ dl). Uric acid, a product of purine metabolism, has low water solubility, especially at low pH. When blood levels are high, it precipitates and deposits in joints, kidney and subcutaneous tissue (tophy).


Secondary Hyperuricaemia Occurs In:


·      Leukaemias, lymphomas, polycythaemia— especially when treated with chemotherapy or radiation: due to enhanced nucleic acid metabolism and uric acid production.


·      Drug induced—thiazides, furosemide, pyrazinamide, ethambutol, levodopa, clofibrate reduce uric acid excretion by kidney.


Drugs used in gout are:


For Acute Gout


a)     NSAIDs

b)    Colchicine

c)     Corticosteroids



For Chronic Gout / Hyperuricaemia


1. Uricosurics    


Probenecid, Sulfinpyrazone


2. Synthesis inhibitor




Acute Gout


Acute gout manifests as sudden onset of severe inflammation in a small joint (commonest is metatarsophalangeal joint of great toe) due to precipitation of urate crystals in the joint space.

The joint becomes red, swollen and extremely painful: requires immediate treatment.




One of the strong anti-inflammatory drugs, e.g. indomethacin, naproxen, piroxicam, diclofenac or etoricoxib is given in relatively high and quickly repeated doses. They are quite effective in terminating the attack, but may take 12–24 hours, i.e. response is somewhat slower than with colchicine, but they are generally better tolerated; majority of patients prefer them over colchicine. Their strong anti-inflammatory (not uricosuric) action is responsible for the benefit. Naproxen and piroxicam specifically inhibit chemotactic migration of leucocytes into the inflamed joint. After the attack is over, they may be continued at lower doses for 3–4 weeks while drugs to control hyper-uricaemia take effect. They are not recommended for long term management due to risk of toxicity.


The NSAIDs have also substituted colchicine for covering up the period of initiation of therapy (6–8 weeks) with allopurinol or uricosurics in chronic gout.


2. Colchicine


It is an alkaloid from Colchicum autumnale which was used in gout since 1763. The pure alkaloid was isolated in 1820.


Colchicine is neither analgesic nor anti-inflammatory, but it especifically suppresses gouty inflammation. It does not inhibit the synthesis or promote the excretion of uric acid. Thus, it has no effect on blood uric acid levels.


An acute attack of gout is started by the precipitation of urate crystals in the synovial fluid. They start an inflammatory response, chemotactic factors are produced granulocyte migration into the joint; they phagocytose urate crystals and release a glycoprotein which aggravates the inflammation by:


·        Increasing lactic acid production from inflammatory cells local pH is reduced more urate crystals are precipitated in the affected joint.


·        Releasing lysosomal enzymes which cause joint destruction.


Colchicine does not affect phagocytosis of urate crystals but inhibits release of the glycoprotein and the subsequent events. By binding to fibrillar protein tubulin, it inhibits granulocyte migration into the inflamed joint and thus interrupts the vicious cycle. Other actions of colchicine are:


·        Antimitotic: causes metaphase arrest by binding to microtubules of mitotic spindle. It was tried for cancer chemotherapy but abandoned due to toxicity. It is used to produce polyploidy in plants.


·        Increases gut motility through neural mechanisms.




Colchicine is rapidly absorbed orally, partly metabolized in liver and excreted in bile—undergoes enterohepatic circulation; ultimate disposal occurs in urine and faeces over many days.


Toxicity      is high and dose related.


Nausea, vomiting, watery or bloody diarrhoea and abdominal cramps occur as dose limiting adverse effects. Accumulation of the drug in intestine and inhibition of mitosis in its rapid turnover mucosa is responsible for the toxicity. In overdose, colchicine produces kidney damage, CNS depression, intestinal bleeding; death is due to muscular paralysis and respiratory failure.


Chronic therapy with colchicine is not recommended because it causes aplastic anaemia, agranulocytosis, myopathy and loss of hair.




(a)  Treatment of acute gout


Colchicine is the fastest acting drug to control an acute attack of gout; 1 mg orally followed by 0.25 mg 1–3 hourly till control of the attack is achieved (occurs in 4– 12 hour), or till total dose 6 mg is reached, or diarrhoea starts. The response is dramatic, so much so that it may be considered diagnostic. However, because of higher toxicity, most physicians prefer using a NSAID. Maintenance doses (0.5–1 mg/day) may be given for 4–8 weeks in which time control of hyperuricaemia is achieved with other drugs.


(b)  Prophylaxis


Colchicine 0.5–1 mg/day can prevent further attacks of acute gout, but NSAIDs are generally preferred.


Taken at the first symptom of an attack, small doses (0.5–1.5 mg) of colchicine abort it.




3. Corticosteroids


Intraarticular injection of a soluble steroid suppresses symptoms of acute gout. Crystalline preparations should not be used. It is indicated in refractory cases and those not tolerating NSAIDs/ colchicine.


Systemic steroids are rarely needed. They are very effective and produce nearly as rapid a response as colchicine, but are reserved for patients with renal failure/history of peptic ulcer bleed in whom NSAIDs are contraindicated or for cases not responding to or not tolerating NSAIDs. Prednisolone 40–60 mg may be given in one day, followed by tapering doses over few weeks.


Chronic Gout


When pain and stiffness persist in a joint between attacks, gout has become chronic. Other cardinal features are hyperuricaemia, tophi (chalklike stones under the skin in pinna, eyelids, nose, around joints and other places) and urate stones in the kidney. Chronic gouty arthritis may cause progressive disability and permanent deformities.




1. Probenecid


It is a highly lipid soluble organic acid developed in 1951 to inhibit renal tubular secretion of penicillin so that its duration of action could be prolonged. It competitively blocks active transport of organic acids by OATP at all sites; that in renal tubules being the most prominent. This transport is bidirectional: net effect depends on whether secretion or reabsorption of the particular organic acid is quantitatively more important, e.g.:


·        Penicillin is predominantly secreted by the proximal tubules, its reabsorption is minimal. Net effect of probenecid is inhibition of excretion; more sustained blood levels are achieved.


·        Uric acid is largely reabsorbed by active transport, while less of it is secreted; only 1/10th of filtered load is excreted in urine. Probenecid, therefore, promotes its excretion and reduces its blood level.


Probenecid does not have any other significant pharmacological action; it is neither analgesic nor anti-inflammatory.




i.          In addition to penicillins, probenecid inhibits the urinary excretion of cephalosporins, sulfonamides, Mtx and indomethacin.


ii.          It inhibits biliary excretion of rifampicin. Pyrazinamide and ethambutol may interfere with uricosuric action of probenecid.


iii.          Probenecid inhibits tubular secretion of nitrofurantoin which may not attain antibacterial concentration in urine.


iv.          Salicylates block uricosuric action of probenecid.




Probenecid is completely absorbed orally; 90% plasma protein bound: partly conjugated in liver and excreted by the kidney; plasma t½ is 8–10 hours.


Adverse Effects


Probenecid is generally well tolerated.

Dispepsia is the most common side effect (upto 25% incidence with high doses). It should be used cautiously in peptic ulcer patients. Rashes and other hypersensitivity phenomena are rare. Toxic doses cause convulsions and respiratory failure.




1. Chronic gout and hyperuricaemia: Probenecid is a second line/adjuvant drug to allopurinol. Started at 0.25 g BD and increased to 0.5 g BD, it gradually lowers blood urate level; arthritis, tophi and other lesions may take months to resolve. Colchicine/NSAID cover is advised during the initial 1–2 months to avoid precipitation of acute gout.


Probenecid and other uricosurics are ineffective in the presence of renal insufficiency (serum creatinine > 2 mg/dl). Plenty of fluids should be given with probenecid to avoid urate crystallization in urinary tract.


2. Probenecid is also used to prolong penicillin or ampicillin action by enhancing and sustaining their blood levels, e.g. in gonorrhoea, SABE.


BENEMID, BENCID 0.5 g tab.


2. Sulfinpyrazone


It is a pyrazolone derivative related to phenylbutazone having consistent uricosuric action, but is neither analgesic nor anti-inflammatory. At the usual therapeutic doses, it inhibits tubular reabsorption of uric acid, but smaller doses can decrease urate excretion as do small doses of probenecid. Its uricosuric action is additive with probenecid but antagonised by salicylates. It inhibits platelet aggregation.




Sulfinpyrazone is well absorbed orally; 98% plasma protein bound—displacement interactions can occur. Excretion is fairly rapid, mainly by active secretion in proximal tubule. Uricosuric action of a single dose lasts for 6–10 hours.


Sulfinpyrazone inhibits metabolism of sulfonylureas and warfarin.


Adverse effects


Gastric irritation is the most common side effect—contraindicated in patients with peptic ulcer.


Rashes and other hypersensitivity reactions are uncommon.


Unlike phenylbutazone, it does not produce fluid retention or blood dyscrasias.




In chronic gout, the results are comparable to probenecid; same precautions should be exercised. Start with 100–200 mg BD, gradually

increase according to response, maximal dose 800 mg/day.




Benzbromarone is another uricosuric drug marketed in Europe, but not in India.






This hypoxanthine analogue was synthesized as a purine antimetabolite for cancer chemotherapy. However, it had no antineoplastic activity but was a substrate as well as inhibitor of xanthine oxidase, the enzyme responsible for uric acid synthesis (Fig. 15.1).



Allopurinol itself is a short acting (t½ 2 hrs) competitive inhibitor of xanthine oxidase, but its major metabolite alloxanthine (oxypurine) is a long acting (t½ 24 hrs) and noncompetitive inhibitor— primarily responsible for uric acid synthesis inhibition in vivo. During allopurinol administration, plasma concentration of uric acid is reduced and that of hypoxanthine and xanthine is somewhat increased. In place of uric acid alone, all 3 oxipurines are excreted in urine. Since xanthine and hypoxanthine are more soluble, have a higher renal clearance than that of uric acid and each has its individual solubility, precipitation and crystallization in tissues and urine does not occur.


Because of raised levels of xanthine and hypoxanthine, some feedback inhibition of de novo purine synthesis and reutilization of metabolically derived purine also occurs.




About 80% of orally administered allopurinol is absorbed. It is not bound to plasma proteins; metabolized largely to alloxanthine. During chronic medication, it inhibits its own metabolism and about 1/3rd is excreted unchanged, the rest as alloxanthine.




a)    Allopurinol inhibits the degradation of 6mercaptopurine and azathioprine: their doses should be reduced to 1/3rd, but not that of thioguanine, because it follows a different metabolic path (Smethylation).


b)  Probenecid given with allopurinol has complex interaction; while probenecid shortens t½ of alloxanthine, allopurinol prolongs t½ of probenecid.


c)   Allopurinol can potentiate warfarin and theophylline by inhibiting their metabolism.


d)  A higher incidence of skin rashes has been reported when ampicillin is given to patients on allopurinol.


e)   Iron therapy is not recommended during allopurinol treatment. The exact nature of interaction is not known, but interference with mobilization of hepatic iron stores is suggested.


Adverse Effects


These are uncommon. Hypersensitivity reaction consisting of rashes, fever, malaise and muscle pain is the most frequent. It subsides on stopping the drug. Renal impairment increases the incidence of rashes and other reactions to allopurinol.


Stevens-Johnson syndrome is a rare but serious risk.


Gastric irritation, headache, nausea and dizziness are infrequent; do not need withdrawal. Liver damage is rare.


Precautions And Contraindications


Liberal fluid intake is advocated during allopurinol therapy.

It is contraindicated in hypersensitive patients, during pregnancy and lactation.

It should be cautiously used in the elderly, children and in kidney or liver disease.




Allopurinol is the first choice drug in chronic gout. It can be used in both over producers and under excretors of uric acid, particularly more severe cases, with tophi or nephropathy. Uricosurics are infrequently used in India; they are less effective when g.f.r. is low and are inappropriate in stone formers. The two classes of drugs can also be used together when the body load of urate is large.


With long term allopurinol therapy, tophi gradually disappear and nephropathy is halted, even reversed.


Secondary hyperuricaemia due to cancer chemotherapy/radiation/thiazides or other drugs: can be controlled by allopurinol. It can even be used prophylactically in these situations.


To potentiate 6-mercaptopurine or azathioprine in cancer chemotherapy and immunosuppressant therapy.


Dose: Start with 100 mg OD, gradually increase to maintenance dose of 300 mg/day; maximum 600 mg/day.

ZYLORIC 100, 300 mg tabs., ZYLOPRIM, CIPLORIC 100 mg cap.




Allopurinol as well as uricosurics should not be started during acute attack of gout. During the initial 1–2 months of treatment with these drugs, attacks of acute gout are more common—probably due to fluctuating plasma urate levels favouring intermittent solubilization and recrystallization in joints; cover with NSAIDs/colchicine may be provided.




Allopurinol inhibits Leishmania by altering its purine metabolism. It is used as adjuvant to sodium stibogluconate in resistant kalaazar cases (see Ch. No. 60).

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