Lecture 9 Musculoskeletal Disorders Gout University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY II PHCY 410 Lecture 9 Musculoskeletal Disorders Gout Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcomes Upon completion of this lecture the students will be able to Describe etiology, clinical manifestations and diagnosis of gout. Develop skills for monitoring drug therapy and patient education in patients with gout and hyperuricemia. Explain drug related problems and develop pharmaceutical care plan in patients with gout.

The term gout describes a heterogeneous clinical spectrum of diseases including elevated serum urate (hyperuricemia). recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, deposits of monosodium urate crystals (tophi) in tissues in and around joints, interstitial renal disease, and uric acid nephrolithiasis. Hyperuricemia may be an asymptomatic condition, with an increased serum uric acid concentration. Urate concentration greater than 7.0 mg/dL is abnormal and associated with an increased risk for gout.

PATHOPHYSIOLOGY In humans, uric acid is the end product of the degradation of purines. This excess accumulation may result from either overproduction or underexcretion. Uric acid may also be overproduced as a consequence of increased breakdown of tissue nucleic acids. About two-thirds of the uric acid produced each day is excreted in the urine. The remainder is eliminated through the GI tract after enzymatic degradation by colonic bacteria.

Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes include diuretics, nicotinic acid, salicylates (less than 2 g/day), ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, and cytotoxic drugs. The average human produces 600 to 800 mg of uric acid daily and excretes less than 600 mg in urine. Individuals who excrete more than 600 mg after being on a purine-free diet for 3 to 5 days are considered overproducers. Hyperuricemic individuals who excrete less than 600 mg of uric acid per 24 hours on a purine-free diet are defined as underexcretors of uric acid.

On a regular diet, excretion of more than 1,000 mg per 24 hours reflects overproduction; less than this is probably normal. Deposition of urate crystals in synovial fluid results in an inflammatory process involving chemical mediators. Phagocytosis of urate crystals by leukocytes results in rapid lysis of cells and a discharge of proteolytic enzymes into the cytoplasm. Uric acid nephrolithiasis occurs in 10% to 25% of patients with gout. Predisposing factors include excessive urinary excretion of uric acid, acidic urine, and highly concentrated urine.

CLINICAL PRESENTATION Acute attacks of gouty arthritis are characterized by rapid onset of excruciating pain, swelling, and inflammation. The attack is typically monoarticularat first, most often affecting the first metatarsophalangeal joint (podagra), and then, in order of frequency, the insteps, ankles, heels, knees, wrists, fingers, and elbows. Attacks commonly begin at night, with the patient awakening from sleep with excruciating pain. The affected joints are erythematous, warm, and swollen. Fever and leukocytosis are common.

Attacks may be precipitated by stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of serum uric acid by ingestion of uric acid–lowering agents, and ingestion of certain drugs.

TREATMENT ACUTE GOUTY ARTHRITIS Nonpharmacologic Therapy Patients may be advised to reduce their intake of foods high in purines (e.g., organ meats), avoid alcohol, increase fluid intake, and lose weight if obese. Joint rest for 1 to 2 days should be encouraged, and local application of ice may be beneficial. Pharmacologic Therapy Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with short term use. Therapy should be initiated with maximum recommended doses for gout at the onset of symptoms and continued for 24 hours after complete resolution of an acute attack, then tapered quickly over 2 to 3 days.

The most common adverse effects involve the GI system (gastritis, bleeding, and perforation), kidneys (renal papillary necrosis, reduced creatinine clearance [CLcr ]), cardiovascular system (sodium and fluid retention, increased blood pressure), and CNS (impaired cognitive function, headache, dizziness). Co-administration with a proton pump inhibitor should be considered in elderly patients and others at increased GI risk. Colchicine is an antimitotic drug that is highly effective in relieving acute gout attacks but has a low benefit-toxicity ratio. Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack.

It should be reserved for patients with insufficient relief, intolerance, or contraindications to NSAIDs. The usual oral colchicine dose is 1 mg initially, followed by 0.5 mg every 1 hour until the joint symptoms subside, Corticosteroids may be used to treat acute attacks of gouty arthritis. They are reserved primarily for patients with a contraindication or who are unresponsive to NSAID or colchicine therapy. The recommended dose is prednisone 30 to 60 mg (or an equivalent dose of another corticosteroid) orally once daily for 3 to 5 days. Because rebound attacks may occur upon steroid withdrawal, the dose should be gradually tapered in 5-mg increments over 10 to 14 days and discontinued.

PROPHYLACTIC THERAPY OF INTERCRITICAL GOUT A single intramuscular injection of a long-acting corticosteroid (e.g., methylprednisolone acetate) can be used as an alternative to the oral route if patients are unable to take oral therapy. Prophylactic treatment can be withheld if the first episode of acute gouty arthritis was mild and responded promptly to treatment, the patient’s serum urate concentration was only minimally elevated, and the 24-hour urinary uric acid excretion was not excessive (less than 1,000 mg/24 hours on a regular diet). PROPHYLACTIC THERAPY OF INTERCRITICAL GOUT

Colchicine given in low oral doses (0. 5 to 0 Colchicine given in low oral doses (0.5 to 0.6 mg twice daily) may be effective in preventing recurrent arthritis. Uric Acid–Lowering Therapy: Patients with a history of recurrent acute gouty arthritis and a significantly elevated serum uric acid concentration are probably best managed with uric acid–lowering therapy. Colchicine, 0.5 mg twice daily, is sometimes given during the first 6 to 12 months of antihyperuricemic therapy to minimize the risk of acute attacks that may occur during initiation of uric acid–lowering therapy. Xanthine Oxidase Inhibitor: Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and impair the conversion of hypoxanthine to xanthine and xanthine to uric acid.

It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. The major side effects of allopurinol are skin rash, urticaria, leukopenia, GI problems, headache, and increased frequency of acute gouty attacks with the initiation of therapy. An allopurinol hypersensitivity syndrome characterized by fever, eosinophilia, dermatitis, vasculitis, and renal and hepatic dysfunction occurs rarely.

Uricosuric Drugs:Probenecid and sulfinpyrazone increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. Therapy with uricosuric drugs should be started at a low dose to avoid marked uricosuria and possible stone formation. Probenecid is given initially at a dose of 250 mg twice daily for 1 to 2 weeks, then 500 mg twice daily for 2 weeks. The major side effects associated with uricosuric therapy are GI irritation, rash and hypersensitivity, precipitation of acute gouty arthritis, and stone formation.

* Intercritical Period and Prophylaxis Most patients have a 2nd attack within 6 to 24 months, is often polyarticular, more frequent, severe and enduring. Therapeutic Choices Nonpharmacologic Choices - Reducing intake of foods high in purines (e.g. organ meats) - Lose weight if obese Avoid alcohol Vitamin C 100-1500 mg daily, to increase the urate excretion - Applying ice packs to the joint to decrease pain and swelling - Discontinue drugs that may aggravate hyperuricemia

Pharmacologic Choices A) Urate Lowering Drugs 1- Allopurinol A xanthine oxidase inhibitor, inhibits the production of uric acid. Allopurinol could cause GI adverse effects and rash, but the most serious side effect is allopurinol hypersensitivity syndrome (skin lesions, high fever, hepatic dysfunction, leukocytosis with predominant eosinophilia, and renal failure). 2- Febuxostat Like allopurinol it is a xanthine oxidase inhibitor, but it is a better option than allopurinol for patients with renal insufficiency, as very small quantities are excreted renally.

B) Uricosuric Drugs: Probenecid increase the renal excretion of uric acid by inhibiting its renal tubular reabsorption, therefore: 1- Probenecid is contraindicated in patients with a history of uric acid stones. 2- Probenecid loses its effectiveness when renal function declines and therefore it is also contraindicated in patients with nephropathy if creatinine clearance is 50 mL/min. or less. probenecid should be started at a low dose to avoid marked uricosuria and possible stone formation. Patients receiving probenecid should maintain an adequate fluid intake and urine output to decrease the risk of uric acid stone. Acute attacks may occur in spite of prophylactic therapy, but usually become less severe and are of briefer duration after several months of probenecid therapy. During these acute attacks, probenecid should be continued without changing dosage and full therapeutic doses of colchicine or other anti-inflammatory agents should be administered. sulfinpyrazone increase the renal excretion of uric acid by inhibiting its renal tubular reabsorption. Sulfinpyrazone was used in the past but is no longer available in the United States. Probencid uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. Some experts advocate alkalinizing the urine to decrease this risk eith probencid. Losartan increases both uric acid excretion and urine pH and may be an option in hypertensive patients with gout. Fenofibrate is also a uricosuric and may be appropriate in selected dyslipidemic patients with gout. New agents undergoing investigation for hyperuricemia include febuxostat and polyethylene glycol–bonded uricase.