Anti-Gout Drugs

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GOUT: 

GOUT Dr Sadia Batool Senior Lecturer Pharmacology Dept

Gout: 

Gout Gout is defined as a peripheral arthritis resulting from the deposition of sodium urate crystals in one or more joints.

Gout: 

Gout Typical sequence involves progression through: asymptomatic hyperuricemia acute gouty arthritis chronic or tophaceous gout

Pathophysiology: 

Pathophysiology Primary gout: Overproducers: 10% Under- excretors : 90% Secondary gout: Excess nucleoprotein turnover (lymphoma, leukemia) Increased cell proliferation/death (psoriasis) Rare genetic disorder Lesch-Nyan Syndrome

Signs and Symptoms: 

Signs and Symptoms Acute attack: Over hours frequently nocturnal Excruciating pain Swelling, redness and tenderness 1 st MTP classic presentation May effect knees, wrist, elbow, and rarely hips. Chronic: Destructive tophaceous Much greater chance if untreated Rarely presents as a chronic

Drugs used in Gout: 

Drugs used in Gout Colchicine NSAIDs Uricosuric agents : Probenecid Sulfinpyrazone Xanthine Oxidase inhibitors: Allopurinol Febuxostat

COLCHICINE: 

COLCHICINE NSAIDs are now the first-line drugs for acute gout C olchicine was the primary treatment for many years Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale

Pharmacokinetics : 

Pharmacokinetics A bsorbed readily after oral administration P eak plasma levels within 2 hours Metabolites are excreted in the intestinal tract and urine

Pharmacodynamics : 

Pharmacodynamics R elieves the pain and inflammation of gouty arthritis in 12–24 hours B ind s to the intracellular protein tubulin P revent s its polymerization into microtubules L ead s to inhibition of leukocyte migration and phagocytosis A lso inhibits formation of leukotriene B 4 .

Indications : 

Indications M ore specific in gout than the NSAIDs P rophylaxis of recurrent episodes of gouty arthritis Mediterranean fever sarcoid arthritis and hepatic cirrhosis Although it can be given intravenously, this route should be used cautiously because of increased bone marrow toxicity.

Adverse Effects : 

Adverse Effects D iarrhea , occasionally nausea, vomiting, and abdominal pain H air loss and bone marrow depression P eripheral neuritis and myopathy. Acute intoxication : B urning throat pain, B loody diarrhea, S hock, H ematuria, and oliguria. Fatal ascending central nervous system depression .

NSAIDs in Gout : 

NSAIDs in Gout 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 All other NSAIDs except aspirin, salicylates, and tolmetin have been used in acute gout. Oxaprozin , which lowers serum uric acid, a good choice (not in pts with uric acid stones because it increases ur ate excretion in the urine )

Uricosuric Agents : 

Uricosuric Agents Probenecid and sulfinpyrazone are uricosuric drugs D ecrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used.

Slide 14: 

Chemistry Uricosuric drugs are organic acids A ct at the anionic transport sites of the renal tubule Sulfinpyrazone is a metabolite of an analog of phenylbutazone

Pharmacokinetics : 

Pharmacokinetics Probenecid is completely reabsorbed by the renal tubules M etabolized slowly with a terminal serum half-life of 5–8 hours Sulfinpyrazone or its active hydroxylated derivative is rapidly excreted by the kidneys

Pharmacodynamics : 

Pharmacodynamics Uric acid is freely filtered at the glomerulus. Like many other weak acids, is both reabsorbed and secreted in the middle segment (S 2 ) of the proximal tubule. Uricosuric drugs — probenecid, sulfinpyrazone , and large doses of aspirin —affect these active transport sites N et reabsorption of uric acid in the proximal tubule is decreased.

ASPIRIN USE IN GOUT: 

ASPIRIN USE IN GOUT A spirin in doses of less than 2.6 g daily causes net retention of uric acid by inhibiting the secretory transporter S hould not be used for analgesia in patients with gout. At higher doses it is uricosuric therefore more toxic and not used.

Slide 18: 

The secretion of other weak acids (eg, penicillin) is also reduced by uricosuric agents. Probenecid was originally developed to prolong penicillin blood levels.

Slide 19: 

Increased u rinary excretion of uric acid leads to decrease in urate pool T ophaceous deposits of urate are resorbed, with relief of arthritis and remineralization of bone. I ncrease in uric acid excretion leads to predisposition of formation of renal stones , therefore: T he urine volume should be maintained at a high level E arly in treatment the urine pH should be kept above 6.0 by the administration of alkali.

Indications : 

Indications Uricosuric therapy should be initiated in gouty underexcretion of uric acid when allopurinol or febuxostat is contraindicated or when evidence of tophi appears. Therapy should not be started until 2–3 weeks after an acute attack

Adverse Effects : 

Adverse Effects G astrointestinal irritation. A rash may appear after the use of either compound. Nephrotic syndrome has occurred after the use of probenecid. Both sulfinpyrazone and probenecid may rarely cause aplastic anemia

Cautions : 

Cautions It is essential to maintain a large urine volume to minimize the possibility of stone formation

Allopurinol : 

Allopurinol The preferred and standard-of-care therapy for gout is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase

Slide 24: 

Allopurinol Alloxanthine Xanthine Oxidase Hypoxanthine Xanthine Uric acid

Pharmacokinetics : 

Pharmacokinetics Approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. U ric acid, allopurinol is itself metabolized by xanthine oxidase T he resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

Pharmacodynamics : 

Pharmacodynamics Dietary purines are not an important source of uric acid. I mportant amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid.

Slide 27: 

Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased

Indications : 

Indications Treatment of gout Allopurinol is often the first urate-lowering drug used. U sed as an antiprotozoal agent P revent the massive uricosuria following therapy of blood dyscrasias that could otherwise lead to renal calculi.

Adverse Effects : 

Adverse Effects Gastrointestinal intolerance N ausea, vomiting, and diarrhea, may occur Peripheral neuritis and necrotizing vasculitis B one marrow depression -- aplastic anemia Hepatic toxicity and interstitial nephritis have been reported An allergic skin reaction characterized by pruritic maculopapular lesions In very rare cases, allopurinol has become bound to the lens, resulting in cataract s

Interactions & Cautions : 

Interactions & Cautions T heir dosage must be reduced by about 75%. when given with mercaptopurines M ay also increase the effect of cyclophosphamide. I nhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration Safety in children and during pregnancy has not been established

Febuxostat : 

Febuxostat Febuxostat is the first nonpurine inhibitor of xanthine oxidase.

Pharmacokinetics : 

Pharmacokinetics M ore than 80% absorbed following oral administration. Maximum concentration is reached in approximately 1 hour. E xtensively metabolized in the liver. All of the drug and its metabolites appear in the urine although less than 5% appears as unchanged drug.

Pharmacodynamics : 

Pharmacodynamics P otent 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.

Adverse Effects : 

Adverse Effects L iver function abnormalities, diarrhea, headache, and nausea. Febuxostat appears to be well tolerated in patients with a history of allopurinol intolerance