Gout Is recurrent inflammatory disorder characterized by hyperuricemia and episodes of severe joint pain , typically in the first metatarsial joint. Hyperuricemia occur through two mechanisms: (1)excessive uric acid production and (2) impaired renal excretion of uric acid .

Acute attacks are precipitated by crystallization of sodium urate (the sodium salt of uric acid ) in the synovial space .Deposition of urate crystals promotes inflammatory processes. Feature of inflammatory processes is infiltration of leukocytes inside of synovial cavity , these cells phagocytize urate crystals and then break down, causing release of destructive lysosomal enzymes . Gout progresses through four stages : Asymptomatic hyperuricemia. Attacks of gouty arthritis. Asymptomatic intercritical period, in which symptoms subside. Tophaceous gout , is characterized by development of tophi in joints.

Pharmcology of the drugs used for gout . Colchicine Is an anti-inflammatory agent whose effects are specific for gout. The drug is not active against other inflammatory disorders, is not an analgesic and does not relief pain in conditions other than gout.

Mechanism of action. We don’t fully understand the mechanism by which colchicines relieves or prevents episodes of gout, as the drug does not influence either the production or excretion of uric acid. An important contributory action is inhibition of leucocytes infiltration ; in the absence of leucocytes, there is no phagocytosis of uric acid and no subsequent release of destructive lysosomsl enzymes . leucocytes migration is inhibited by disruption of microtubules , the structure required for cellular motility , and cell division . Since microtubule required for cell division , colchicines is very toxic for any tissue that has a large percentage of proliferating cells. Disruption of cell division underlies the GIT toxicity of colchicine.

Pharmacokinetics Colchicine is rapidly absorbed after oral administration , large amount re-enter the intestine via the bile (entero-hepatic circulation ). Excreted in the feces .

Therapeutic uses ; Has 3 distinct applications in gout: Can be used to: (1) treat acute gouty attacks, (2) reduce the incidence of attacks in chronic gout , and (3) abort an impending attack . Mosby items and derived items © 2007, 2004 by Mosby, Inc., an affiliate of Elsevier Inc.

Acute gouty arthritis. Colchicine produces a dramatic relief of acute gouty attacks, within hours , inflammation disappears completely within 2-3 days. Administration either IV or oral , with IV administration ,symptoms resolve sooner than with oral and GIT reactions are minimal. Prophylaxis of gouty attacks. When taken during the asymptomatic intercritical period, small doses of colchicine (0.5 to 1mg.) can decrease the frequency and intensity of acute attacks. Abortion of an impending attack. Patients may experience prodromal signs of a developing gouty attack , if large doses of colchicines (0.5mg. every 2 hours) are taken immediately , the attack may be prevented .

Adverse effects. Mostly are nausea ,vomiting, diarrhea , result from injury to the rapidly proliferating cells of the GI epithelium .If GIT symptoms develop , the drug must be discontinued immediately . In IV administration ,extravasation can cause local necrosis. Since the drug can cause fetal harm , it should be avoided during pregnancy.

Preparation, dosage and administration . Colchicines is dispensed in tablets ( 0.5 or 0.6 mg.) for oral administration , and in solution of 1mg for IV administration . Oral : for an acute gouty attack , the dosage is 0.5 to 1.2 mg. initially followed by 0.5 mg. every 1to 2 hours .administration is repeated until pain relieved or until sign of GI toxicity appear, but should not exceed 8 mg. The dosage for prophylaxis is 0.5mg. to 1.0mg per day. The dosage for aborting an impending attack is 0.5mg. every 2 hours. Intravenous . Intravenous admin. can be used to treat an acute gouty attack.. relief can be achieved by a single 2mg. injection . extravasation can cause local necrosis.

Allopurinol Is used to reduce blood levels of uric acid. It is indicated for primary hyperuricemia of gout and for hyperuricemia secondary to cancer chemotherapy . Mechanism of action Xanthine oxidase catalyzes the final two reactions that lead to formation or uric acid from breakdown of DNA.: Allopurinol and its active metabolite –alloxanthine- reduce uric acid production, by inhibition of xanthine oxidase , an enzyme required for uric acid formation. DNA ---- hypoxanthine --------------------Xanthine-------------- uric acid Xanthine oxidase xanthine oxidase

Uses : Chronic tophaceous gout. Allopurinol is the drug of choice for chronic tophaceous gout. By reducing blood levels of uric acid , the drug prevents tophus formation and promotes regression of tophi that have already formed . During the initial months of treatment , allopurinol may increase the incidence of acute gouty attack, therefore colchicines or indomethscin must be co-administered. Secondary hyperuricemia . Hyperuricemia may occur secondary to treatment with anticancer drugs. Uric acid levels are elevated due to breakdown of DNA that occur following cell death. Allopurinol should be administered prior to initiation of chemotherapy .

Adverse effects . The most serious toxicity is a rare but fatal hypersensitivity syndrome characterized by rash, fever , eosinophilia and dysfunction of the liver and kidneys. Mild side effects seen occasionally include GI reactions ( nausea, vomiting , abdominal discomfort ) and neurological effects (drowsiness , headache, metallic taste). Prolonged use (more than 3 years) of allopurinol may cause cataracts .

Preparation, dosage and administration . Allopurinol is dispensed in 100 and 300mg. tablet for oral use . For treatment of chronic tophaceous gout , the objective is to decrease plasma urate level to less than 7mg. dl. The initial dose is 100mg. daily , the dose is then increased by 100mg. at interval of 1 week until urate has been reduced to acceptable level, usually at doses of 200-300mg.per day . For secondary hyperuricemia ; in adult dosage ranged from 100-800mg .day. for children aged 6-10 years 300mg. day . children under 6 years the dose is 150mg. per day.

Indomethacin . Is an NSAID used to treat acute gouty arthritis , the drug efficacy is equivalent to that of colchicine . it does not reduce hyperuricemia, it suppresses inflammation . . The adult dose for relief of acute gouty arthritis is 50mg. followed by 25mg. three times daily .

Probenecid . Act on renal tubules to inhibit reabsorption of uric acid , as a result excretion of uric acid is increased and hyperuricemia is reduced. By lowering plasma urate levels, probenecid prevents formation of new tophi and facilitate regression of tophi that have already formed. The drug may exacerbate acute episodes of gout, therefore treatment should be delayed until the attack has been controlled. During the first months of therapy, may precipitate an acute gouty attack . if an attack occur , colchicines or indometacin sould be added to the regimen.

Adverse effects Mild GIT effects ( nausea, vomiting, anorexia). Hypersensitivity reactions . Renal injury may occur from deposition of urate in the kidney , this risk can be minimized by consuming 2.5- 3 lit.of fluid daily during the first days of treatment. Preparation, dosage and administration ; Probenecid is dispensed in 500mg.tablets. the initial dose is 250mg.twice daily .Therapy should not be initiated during an acute gouty attack.

Sulphinpyrazone Like probenecid ,sulphinpyrazone is a uricosuric agent emplyed to reduce hyperuricemia in patients with chronic gout. The drug lacks anti-inflammatory and analgesic effects and is of no benefit during an acute gouty attack. During the first months of therapy, may precipitate an acute gouty attack . the risk of an attack can be reduced by concurrent use of colchicines or indometacin. Adverse effects GIT effects ( nausea, vomiting, abdominal pain ), can exacerbate GI ulcers . as with probencid ther is a risk of deposition of urate in the kidney , this risk can be minimized by alkalizing the urine and consuming a large volumes of fluids . Preparation, dosage and administration : is dispensed in 100 mg.tablets and 200mg. capsule. the initial dose is 100mg.to 200mg. twice daily .