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Gout and Hyperuricemia
Definitions :
The term gout describes a disease spectrum including hyperuricemia, recurrent attacks of acute
arthritis associated with monosodium urate crystals in leukocytes found in synovial fluid,
deposits of monosodium urate crystals in tissues (tophi), interstitial renal disease, and uric
acid nephrolithiasis.
Hyperuricemia may be an asymptomatic condition, with an increased serum uric acid
concentration as the only apparent abnormality. A urate concentration greater than 7.0
mg/dL is abnormal and associated with an increased risk for gout.
Pathophysiology:
1-In humans, uric acid is the end product of the degradation of purines. This excess accumulation
may result from either underexcretion (90% of cases) or overproduction (2) :
The most common cause of poor excretion is due to renal disease. Drugs(e.g. thiazide diuretics,
alcohol, aspirin, and cyclosporine,……) are also a common cause of decreased urate excretion (3).
Abnormalities in the enzyme systems that regulate purine metabolism may result in
overproduction of uric acid. Uric acid may also be overproduced as a consequence of increased
breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative disorders
(particularly after initiation of chemotherapy.)Dietary purines play an unimportant role in the
generation of hyperuricemia (1).
When serum uric acid concentrations are above 7 mg/dL (0.42 mmol/L), urate crystals are likely
to form (3). Deposition of urate crystals in synovial fluid results in an inflammatory reaction that is
associated with intense joint pain, erythema, warmth, and swelling (1).
Uric acid nephrolithiasis(stone ) occurs in 10% to 25% of patients with gout. Factors that
predispose individuals to uric acid stone include excessive urinary excretion of uric acid, acidic
urine, and highly concentrated urine.
Tophi (urate deposits) are uncommon in gouty subjects and are a late complication of
hyperuricemia. The most common sites of tophi deposits are the base of the great toe, the helix of
the ear, knees, wrists, and hands (1).
Another important point to remember in regard to the pathophysiology of Gout is that the
solubility of uric acid decreases in cold weather and under low pH conditions. This most likely
accounts for why Gout primarily affects the joints of the extremities (big toe), particularly when
the weather is cold(3).
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Clinical Presentation:
Acute attacks of gouty arthritis are characterized by rapid onset of severe pain, swelling, and
inflammation(1) . The attack is typically affects a single joint, with the first joint of the big toe
affected in 50% of cases.. Other commonly affected joints include the tarsal joints, ankles, and
knees. However, Gout can affect any joint in the body, including joints of the wrists, fingers, and
elbows(3).
Attacks commonly begin at night, with the patient awakening from sleep with severe pain. The
affected joints are erythematous, warm, and swollen. Fever is common. Untreated attacks may
last from 3 to 14 days before spontaneous recovery(1).
Diagnosis(1)
1-The definitive diagnosis is accomplished by aspiration of synovial fluid from the affected joint
and identification of intracellular crystals of urate in synovial fluid leukocytes.
2-When joint aspiration is not a viable option, diagnosis of acute gouty arthritis may be made on
signs and symptoms, as well as the response to treatment.
Desired Outcome
The goals in the treatment of gout are to terminate the acute attack, prevent recurrent attacks of
gouty arthritis, and prevent complications associated with chronic deposition of urate crystals in
tissues (1).
Treatment
1-Acute Gouty Arthritis :
A-Nonpharmacologic Therapy
Patients may be advised to reduce their intake of foods high in purines (e.g., organ meats), avoid
alcohol, and lose weight if obese.
B- pharmacologic Therapy:
Guideline For the treatment of Acute Gouty Arthritis Can represented by Figure 1:
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Figure 1. Treatment algorithm for acute gouty arthritis
Pharmacological therapy for the treatment of acute Gouty Arthritis includes :
1--Indomethacin and Other NSAIDs
Indomethacin is as effective as colchicine in the treatment of acute gouty arthritis and is preferred
because acute gastrointestinal toxicity occurs far less frequently than with colchicines(1).
Clinical response may require12-24 hours, and initial doses should be high, followed by rapid
tapering over 2-8 days .. One approach is to use indomethacin, 50 mg PO q6h for 2 days, followed
by 50 mg PO q8h for 3 days and then 25 mg PO q8h for 2-3 days (2). Side effects unique to
indomethacin include headache and dizziness. All NSAIDs can cause gastric ulceration and
bleeding, but this is unlikely with short-term therapy(1).
Other NSAIDs are also effective in relieving the inflammation of acute gout (Table 1). NSAIDs
should be used with caution in individuals with a history of peptic ulcer disease, heart failure,
chronic kidney disease, or coronary artery disease.
Table 1 Dosage Regimens of some NSAIDs for Treatment of Acute Gouty
Arthritis
Drug
Dose
Ibuprofen
Naproxen
Piroxicam
600-800 mg q.i.d
750 mg initially, then 250 mg q 8 h
40 mg/day
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2-Colchicine
Colchicine is most effective if given in the first 12-24 hours of an acute attack and usually brings
relief in 6-12 hours. In view of the efficacy and tolerability of a short course of NSAIDs, colchicine
is not commonly used to treat gout but is useful when NSAIDs are contraindicated or not
tolerated (2).
Oral administration is often associated with severe GI toxicity. The dosage during an acute attack
is 0.5-0.6 mg (one tablet) q1-2h for three dosages started at the first sign of the attack.
Alternatively, colchicine 0.6 mg bid in addition to an NSAID can be used(2).
IV colchicine is not recommended for general use and its administration in almost all
circumstances is questionable(2).
The major problem associated with oral colchicine is that gastrointestinal (GI) toxicity (abdominal
discomfort , diarrhea,……) occurs in 50% to 80% of patients before relief of the attack(1).
Note :
The previous dosage regimen of 0.5-0.6 mg (one tablet) q1-2h or 1.0-1.2 mg q2h until symptoms
abate, GI toxicity develops, or the maximum dose of 8 mg in a 24-hour period is reached is not
recommended as primary treatment for most cases due to toxicity.
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3-Corticosteroids
Corticosteroids may be used to treat acute attacks of gouty arthritis, but they are reserved
primarily for resistant cases or for patients with contraindications to colchicine and NSAID
therapy.
Prednisone, 30 to 60 mg orally once daily for 3 to 5 days, may be used in patients with multiplejoint involvement. Because rebound attacks may occur upon steroid withdrawal, the dose should
be gradually tapered in over 10 to 14 days and discontinued.
Triamcinolone 20 to 40 mg given intra-articularly, may be useful for acute gout limited to one or
two joints(1).
2-Prophylactioc Therapy:
General Approach
If the patient had a severe attack of gouty arthritis, a complicated course of uric
acid stone , a substantially elevated serum uric acid (greater than 10 mg/dL), then
prophylactic treatment should be instituted immediately after resolution of the acute episode.
Prophylactic therapy is also appropriate for patients with frequent attacks of gouty
arthritis (i.e., more than two or three per year) even if the serum uric acid concentration is
normal or only minimally elevated.
1-Colchicine
Colchicine given in low oral doses (0.5 to 0.6 mg twice daily) may be effective in preventing
recurrent arthritis (1).
2-Uric Acid Lowering Therapy(Xanthine Oxidase Inhibitor and Uricosuric Drugs)
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, should be administered 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.
The therapeutic objective of antihyperuricemic therapy is to reduce the serum urate concentration
below 6 mg/dL( well below the saturation point).
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A-Xanthine Oxidase Inhibitor(Allopurinol):
Allopurinol inhibits the formation of uric acid from xanthines by inhibiting the enzyme xanthine
oxidase. It therefore decreases serum and urinary uric acid levels(4).
Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or
impaired renal function, and in patients with gout who are overproducers of uric acid (1).
Textbooks recommend an initial dose of 300mg allopurinol daily. However, in practice most
patients are started on 100mg daily and the dose is titrated according to the serum urate level. The
usual maintenance dose of allopurinol is 100mg to 600mg daily A dose of 300mg daily usually
sufficient for most patients (4).
A response to allopurinol, which is reflected by a decrease in the serum urate concentration, is
seen about two days after starting therapy and is maximal after about seven to 10 days.
When starting therapy, acute attacks of gout may occur.(The mechanism for this is poorly
understood). For this reason an NSAID or colchicine (0.5 mg daily) should be given concurrently
for at least three months. The most common reaction is a rash, which occurs in approximately 2
per cent of patients. This usually subsides after allopurinol has been discontinued and may not
recur if therapy is resumed at a lower dose. The most serious side effect, which occurs in fewer
than 1 in 1,000 patients, is exfoliative dermatitis (4).
B-Uricosuric Drugs: Probenecid and sulfinpyrazone increase the renal clearance of uric
acid by inhibiting the renal tubular reabsorption of uric acid.
Future Therapies(3)
A-Uricase
Uricase is an enzyme found in most mammals (except humans) that converts uric acid to
the renally excreted compound allantoin.41 it may be the future treatment of choice for
reduction of serum uric acid levels in the patient with Gouty Arthritis.
B-Febuxostat
Febuxostat is a selective inhibitor of xanthine oxidase . febuxostat was found to be safe
and tolerable in the healthy, as well as renally impaired, patient population.
Evaluation of Therapeutic Outcomes
Patients should be monitored for symptomatic relief of joint pain as well as potential adverse
effects and drug interactions related to drug therapy. The acute pain of an initial attack of gouty
arthritis should begin to ease within about 8 hours of treatment initiation. Complete resolution of
pain, erythema, and inflammation usually occurs within 48 to 72 hours(1)
References :
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
Sixth Edition. Copyright 2005, by The McGraw-Hill Companies, Inc.
2-Cooper, Daniel H.; Krainik, Andrew J.; Lubner, Sam J.; Reno, Hilary E. L.
Washington Manual of Medical Therapeutics, The, 32nd Edition. Copyright 2007 .
Published by Lippincott Williams & Wilkins.
3- Stephen M. Setter, Travis Sonnett,.New Treatment Options in the Management
of Gouty Arthritis. Us pharnmacist july 2006.
4- Jayne Wood. Musculoskeletal disorders . Gout and its management. The
Pharmaceutical Journal Vol 262No 7048 June 05, 1999 .p808-811
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