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Dr. Koppala R.V.S. Chaitanya, profile picture
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gout and anti gout drugs pharmacology

This document discusses drugs used to treat gout, including colchicine, NSAIDs, corticosteroids, uricosuric agents like probenecid and sulfinpyrazone, and the uric acid synthesis inhibitor allopurinol. It provides details on the pathophysiology of gout, mechanisms of action, pharmacokinetics, indications, dosages and adverse effects of these drugs for both acute gout attacks and long-term treatment of chronic gout and hyperuricemia.

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Drugs Used in Gout Mr. RVS Chaitanya Koppala Assistant professor, Lovely professional University, punjab
Drugs Used in Gout  Gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage.  Formation of uric acid calculi in the kidneys may also occur.  It is usually associated with high serum levels of uric acid, a poorly soluble substance that is the major end product of purine metabolism.  In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans.  Treatment of gout is aimed at relieving the acute gouty attack and preventing recurrent gouty episodes and urate lithiasis.
Pathophysiology :  Urate crystals are initially phagocytosed by synoviocytes, which then release prostaglandins, lysosomal enzymes, and interleukin-1 which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages).  Attracted by these chemotactic mediators, polymorphonuclear leukocytes and mononuclear phagocytes migrate into the joint space and amplify the ongoing inflammatory process.  In the later phases of the attack, increased numbers of mononuclear phagocytes (macrophages) appear, ingest the urate crystals, and release more inflammatory mediators.
 This sequence of events suggests that the most effective agents for the management of acute urate crystal-induced inflammation, are those that suppress different phases of leukocyte activation.  Before starting chronic therapy for gout, patients in whom hyperuricemia is associated with gout and urate lithiasis must be clearly distinguished from those who have only hyperuricemia.  In an asymptomatic person with hyperuricemia, the efficacy of long-term drug treatment is unproved.
Drugs used in acute and chronic gout  Acute gout : Sudden onset of severe inflammation in a small joint (metatarso-phalangeal joint of greater toe) due to precipitating of urate crystal in the joint space.  Drugs : Colchicine NSAIDs Corticosteroids  For chronic gout/hyperuricaemia :  Uricosurics agent : probenecid, sulfinpyrazone  Uric acid Synthesis inhibitor : Allopurinol.
Colchicine  Is neither analgesic nor anti – inflammatory, but it suppress gouty inflammation.  It does not inhibit the synthesis or promote the excretion of uric acid, and has no effect on blood uric acid levels.
Pharmacokinetics  Absorbed readily after oral administration and reaches peak plasma levels within 2 hours.  Metabolites are excreted in the intestinal tract and urine.
Pharmacodynamics  Colchicine dramatically relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects.  MOA :  It is thought that colchicine somehow prevents the release of the chemotactic factors and/or inflammatory cytokines from the neutrophils, and this in turn decreases the attraction of more neutrophils into the affected area  Colchicine renders cell membranes more rigid and decreases the secretion of chemotactic factors by activated neutrophils
 Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules (arresting neutrophil motility) and leading to the inhibition of leukocyte migration and phagocytosis.  It also inhibits the formation of leukotriene B4.  Several of colchicine's adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.
Indications  Acute gouty arthritis  For the prophylaxis of recurrent episodes of gouty arthritis  Adverse Effects :  Diarrhea , nausea, vomiting, and abdominal pain  Rarely cause hair loss and bone marrow depression as well as peripheral neuritis and myopathy.  Acute intoxication: burning throat pain, bloody diarrhea, hematuria, and oliguria. Fatal ascending central nervous system depression has been reported.  Treatment is supportive.
Dosage  Prophylactic dose : 0.6 mg one to three times daily.  attack of gout, initial dose of 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until pain is relieved or nausea and diarrhea appear.  Total dose can be given intravenously if necessary, but it should be remembered that as little as 8 mg in 24 hours may be fatal.
NSAIDs  In addition to inhibiting prostaglandin synthase, indomethacin and other NSAIDs also inhibit urate crystal phagocytosis.  Indomethacin is commonly used as initial treatment of gout as the replacement for colchicine.  Doses : 50 mg xtds or qid; when a response occurs, the dosage is reduced to 25 mg three or four times daily for about 5 days.
 All other NSAIDs except aspirin, have been successfully used to treat acute gouty episodes.  Oxaprozin, which lowers serum uric acid, is theoretically a good NSAID though it should not be given to patients with uric acid stones because it increases uric acid excretion in the urine.
Corticosteroids  The use of corticosteroids is often suggested for elderly patients with chronic tophaceous gout.  Intraarticular injection : those not tolerating NSAIDs/colchicine  Systemic steroids are rarely needed  Prednisolone : 40 – 60mg in one day, followed by tapering doses over few weeks.
URICOSURIC AGENTS  The uricosuric drugs (or urate diuretics) are anions that are somewhat similar to urate in structure; therefore, they can compete with uric acid for transport sites.  Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion.  And at high dosages these same drugs increase uric acid elimination by inhibiting its proximal tubular reabsorption.
 The two most clinically important uricosuric drugs, Probenecid and Sulfinpyrazone, are organic acids.  The initial phase of therapy with uricosuric drugs is the most dangerous period.  Until uricosuric drug levels build up sufficiently to fully inhibit uric acid reabsorption as well as secretion, there may be a temporary increase in uric acid blood levels that significantly increases the risk of an acute gouty attack.  Therefore, it is wise to begin therapy with the administration of small amounts of Colchicine before adding a uricosuric drug to the therapeutic regimen.  In addition,the initial rise in urinary uric acid concentrations during uricosuric drug therapy may result in renal stone formation.
Pharmacokinetics  Probenecid is completely absorbed orally, 90% plasma protein binding, conjugated in liver, is metabolized very slowly, T1/2 is 8-10 hours and excreted by kidney.  Sulfinpyrazone is rapidly excreted by the kidneys. Even so, the duration of its effect after oral administration is almost as long as that of probenecid.
Pharmacodynamics  Uric acid is freely filtered at the glomerulus. Like many other weak acids, it is also both reabsorbed and secreted in the middle segment of the proximal tubule.  Uricosuric drugs— Probenecid, Sulfinpyrazone, and large doses of aspirin—affect these active transport sites so that net reabsorption of uric acid in the proximal tubule is decreased.  Because aspirin in small doses causes net retention of uric acid by inhibiting the secretory transporter, it should not be used for analgesia in patients with gout.
 Probenecid was originally developed to prolong penicillin blood levels.  As the urinary excretion of uric acid increases, the size of the urate pool decreases, although the plasma concentration may not be greatly reduced.  With the increase in uric acid excretion, a predisposition to the formation of renal stones is augmented .
Indications  Initiated if several acute attacks of gouty arthritis have occurred,  When evidence of tophi appears, or  When plasma levels of uric acid in patients with gout are so high.  Therapy should not be started until 2–3 weeks after an acute attack.
Adverse Effects  Gastrointestinal irritation, but sulfinpyrazone is more active in this regard.  Probenecid (allergic dermatitis), but a rash may appear after the use of either compound.  Nephrotic syndrome has resulted from the use of probenecid.  Both sulfinpyrazone and probenecid may rarely cause aplastic anemia.
Contraindications & Cautions  The drug is contraindicated in patients with a history of renal calculi.  Essential to maintain a large urine volume to minimize the possibility of stone formation.
Dosage  Probenecid : 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week.  Sulfinpyrazone : 200 mg orally daily, progressing to 400– 800 mg daily.  It should be given in divided doses with food to reduce adverse gastrointestinal effects.
Uric acid Synthesis inhibitor  Allopurinol is the drug of choice in the treatment of chronic tophaceous gout and is especially useful in patients whose treatment is complicated by renal insufficiency.  Allopurinol : alternative to increasing uric acid excretion in the treatment of gout is to reduce its synthesis by inhibiting xanthine oxidase with allopurinol.
Pharmacokinetics  Approximately 80% absorbed after oral administration.  Like uric acid, allopurinol is itself metabolized by xanthine oxidase.  The resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol need be given only once a day.
Mechanism of Action  Nucleic acids are converted to xanthine or hypoxanthine and oxidized to uric acid .  Allopurinol in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption.  This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid.  After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine
Indications First urate-lowering drug used, its most rational indications are as follows: (1) in chronic tophaceous gout, in which reabsorption of tophi is more rapid than with uricosuric agents; (2) in patients with gout whose 24 hour urinary uric acid on purine-free diet exceeds 600–700 mg; (3) when probenecid or sulfinpyrazone cannot be used because of adverse effects or allergic reactions, or when they are providing less than optimal therapeutic effect; (4) for recurrent renal stones; (5) in patients with renal functional impairment; or (6) when serum urate levels are grossly elevated.
Adverse Effects  Gastrointestinal intolerance, including nausea, vomiting, and diarrhea, may occur. Peripheral neuritis and necrotizing vasculitis, depression of bone marrow elements, and, rarely, aplastic anemia may also occur.  An allergic skin reaction  In very rare cases, allopurinol has become bound to the lens, resulting in cataracts.
Interactions & Cautions  Inhibits the metabolism of probenecid and oral anticoagulants.  Safety in children and during pregnancy has not been established.
THE END……