Gout is a metabolic disoreder which is caused due to the accumulation of urate crystals in a joint.
GOUT
The term gout describes a disease associated with monosodium urate crystals in leukocytes found in synovial fluid, deposits of monosodium urate crystals in tissues, interstitial renal disease, and uric acid nephrolithiasis.
Pathophysiology:
The gout is occurred due to the abnormality of purine metabolism, that leads to the over production of uric acid. Increased uric acid production leads to deposition of sodium urate microcrystals at the joints and in kidneys.
Symptoms: Acute attacks of pains, swelling of joints and inflammation, fever and leukocytosis.
Diagnosis: Identification of intracellular crystals of monosodium urate monohydrate in synovial fluid leukocytes.
Drug therapy: This can be complete by
1) Increasing uric acid excretion with probenecid or sulfinpyrazone
2) Interfering with uric acid synthesis with allopurinol
3) Inhibiting leukocyte entry into the affected joint with colchicines
4) Administration of NSAIDs.
Acute gout: This attack can results from a number of conditions, including excessive alcohol consumption, a diet rich in purine, or kidney disease. Acute attacks are treated with indomethacin to decrease movement of granulocytes into the affected area. Other than NSAIDs, indomethacin is also effective at decreasing pain and inflammation. Intra-articular administration of glucocorticoids is also suitable in the acute conditions. Patients are candidates for prophylactic therapy if they have had more than two attacks per year, the first attack is severe or complicated with kidney stones, serum urate is greater than 10 mg/dL, or urinary urate excretion exceeds 1000 mg per 24 hours.
Chronic gout: It can be caused by 1) Lesch-Nyhan syndrome 2) excessive production of uric acid associated with cancer chemotherapy. 3) a genetic defect, such as one resulting in an increase in the rate of purine synthesis 4) renal deficiency. The Treatment levels for chronic gout include the use of a uricosuric drug, which can increase the excretion of uric acid, thereby reducing the plasma concentration. The use of allopurinol, which is a selective inhibitor of the terminal, steps in the biosynthesis of uric acid. Uricosuric agents are first-line agents for patients with gout associated with reduced urinary excretion of uric acid. Allopurinol is preferred in patients with excessive uric acid synthesis, with previous histories of uric acid stones, or with renal insufficiency.
Classification of drugs:
Colchicines: Colchicines, a plant alkaloid, has been used for the treatment of acute gouty attacks as well as chronic gout. It is neither an analgesic agent, nor a uricosuric agent but it relieves pain in acute attacks of gout. Colchicine does not prevent the acute gouty arthritis, it does have a suppressive, prophylactic effect that reduces the frequency of acute attacks and relieves pain.
Mechanism of action: The drug binds to the tubulin, the tublin is a microtubular protein, causing its depolymerization. This disrupts cellular function i.e, the mobility of granulocytes, thus by decreasing their migration into the affected area. Furthermore, it blocks the cell division by binding with mitotic spindles. Colchicine also inhibits the synthesis and release of the leukotrienes.
Therapeutic uses: The colchicine is specific for gout due to the anti-inflammatory activity, usually alleviating the pain of acute gout within 12 hours. NSAIDs have largely replaced colchicine in the treatment of acute gouty attacks. Currently Colchicine is used for prophylaxis of recurrent attacks and will prevent attacks in more than 80 percent of patients.
Pharmacokinetics: Colchicine is administered orally, followed by rapid absorption from the GI tract. It is also available combined with probenecid. The drug is recycle in the bile and is excreted in the feces or urine. Use should be avoided in patients with a creatinine clearance of less than 50 mL/min.
Adverse effects: Colchicine treatment may cause diarrhea, nausea, vomiting, and abdominal pain. Chronic administration may lead to myopathy, neutropenia, aplastic anemia, and alopecia. The drug should not be used in pregnancy, and it should be used with caution in patients with hepatic, renal, or cardiovascular disease. The fatal dose has been reported as low as 7 to 10 mg.
Phenylbutazone: It has uricosuric effect and anti-inflammatory effect. At a dose of 600 mg daily, it produces relief of both pain and immobility of joints.
Indomethacin: It is effective in acute attacks of gout. It is administered at a dose of 25 to 50 mg.every 4-8 hours. It relieves pain even within 2 hours after the first dose.
Corticosteroids: Prednisone or ACTH is effective in acute attacks of gout. The effect is due to suppression of inflammatory reaction. Relapse may occur when these drugs are withdrawn.
Azapropazone: It is also a uricosuric agent like sulphinpyrazon. It is also used in the treatment of arthritis. It has anti-inflammatory, analgesic and antipyretic effects.
Uricosuric agents: The uricosuric drugs are weak organic acids that promote renal clearance of uric acid by inhibiting the anionic urate exchanger in proximal tubule that mediates the urate reabsorption. sulfinpyrazone, a derivative of phenylbutazone and Probenecid, a general inhibitor of the tubular secretion of organic acids, and At therapeutic doses, they block proximal tubular reabsorption of uric acid, are the two most commonly used uricosuric agents. These drugs have few adverse effects, although gastric distress may force discontinuance of sulfinpyrazone. Probenecid blocks tubular secretions of penicillin and is sometimes it is used to increase the levels of the antibiotic. It also inhibits excretion of naproxen, ketoprofen, and indomethacin. These agents are appropriate for patients who have a creatinine clearance of less than 60 mL/min, under secrete uric acid (<700 mg/day), and do not have a history of kidney stones.
Allopurinol: It is a purine analog, used to reduce the production of uric acid by competitively inhibiting the uric acid biosynthesis that is catalyze by xanthine oxidase.
Therapeutic uses: Allopurinol is effective in the treatment of primary and secondary hyperuricemia of gout and other conditions, such as that associated with certain malignancies or in renal disease. This agent is the drug of choice in those with a history of kidney stones or if the creatinine clearance is less than 50 mL/day.
Pharmacokinetics: Allopurinol is completely absorbed after oral administration. The primary metabolite is oxypurinol (alloxanthine), it is also a xanthine oxidase inhibitor with a half-life of 15 to 18 hours, the half-life of allopurinol, is 2 hours. The drug and its active metabolite are excreted in the feces and urine.
Adverse effects: Allopurinol is well tolerated by most patients. Nausea and diarrhea are common. Hypersensitivity reactions, especially skin rashes, are the most common adverse reactions. Allopurinol interferes with the metabolism of immunosuppressant azathioprine and the anticancer agent 6-mercaptopurine.
Gout, hyperurecimia, urate crystals
