Gout = Inflammatory Arthritis
Gout is a painful inflammatory arthritis caused by uric acid crystals
forming in the joints. Attacks of gout often start suddenly during sleep and
feel like a joint is "on fire."
Gout occurs acutely as intermittent attacks of inflammatory arthritis with
severe joint pain, swelling, redness and warmth of affected joint. In some
individuals, it can be a progressive, crippling chronic disease that also
damages the kidneys. Gout affects more than one million Canadians and Americans.
Painful attacks of joint pain can occur at any age, but the first attack often
affects men between the ages of 40 and 50. Gout is 20 times commoner in men than
women; however, the number of postmenopausal women who have gout is increasing.
Obesity, high blood pressure and atherosclerotic heart disease are often
associated. A familial pattern is observed in up to15% of cases.
Historically, attacks of gout have been associated with drinking and high
living; a penance for indulgent lifestyles. Most modern gout suffers, however
are more temperate folk and have a genetic tendency to gout or are predisposed
for a variety of other reasons. They do not have to be party animals, voracious
eaters or alcoholics to suffer gout, although overindulgence in the wrong food
and drink will definitely aggravate the tendency. Gout affects more than one
million Canadians and Americans.
A Gout attack is a severe inflammatory arthritis usually in one joint; the
severe joint pain and swelling
red or purple skin around the joint
extreme tenderness -the area may be so tender that even the touch of a bed
sheet may be unbearable.
Uric Acid Crystals Cause Inflammation
The pain and swelling of gout are caused by uric acid crystals that form in
the joint. Uric acid is a waste product of purine metabolism. Uric acid is
dissolved in the blood and is excreted through the kidneys into the urine. In
people with gout, the uric acid level increases and uric acid crystals are
deposited in joints and other tissues. These needle-shaped crystals trigger an
immune response that produces intense local inflammation with severe pain,
tenderness and swelling. After several years of increased serum uric acid, uric
acid crystals can build up in the joint(s) and surrounding tissues. They form
deposits that are sometimes apparent as firm lumps (tophi) under the skin. Tophi
often are found in or near severely affected joints, on or near the elbow, over
the fingers and toes, and in the outer edge of the ear. Uric acid crystals can
also form stones in the kidneys, in the ureters and in the bladder. Stones form
when the uric acid concentration in the urine is too high - this is cause by low
water intake, diuretics, and overly acidic urine. A diet rich in purines may be
Uric Acid Production
Uric acid substance is a product of the chemical breakdown of the purine
bases that compose the genetic material, DNA and RNA. As cells die and release
DNA from their chromosomes, purines are converted into uric acid which is
excreted in the urine and, to a lesser extent, the intestinal tract. The
concentration of uric acid in the blood is related to the balance between uric
acid production and excretion. The normal level in children is about 2 mg/dl. At
puberty, the level increases in males by 1 mg/dl, but it does not increase in
females; the normal range is 3 to 7 mg/dl in adult males and 2 to 6 mg/dl in
adult females. At concentrations greater than 6.5 to 7.0 mg/dl in water, urate
precipitates in the form of sodium urate crystals. When blood levels are above
10 mg/dl, the chance of an acute attack of gout is greater than 90 percent.
Only 10% of people with hyperuricemia are over-producers of uric acid caused
by diseases of the blood and bone marrow, inherited enzyme abnormalities and
metabolic alterations due to obesity. In patients who overproduce uric acid
because of a deficiency of hypoxanthine-guanine phosphoribosyltransferase, gout
attacks may begin before puberty.
Increased destruction of body cells leads to increased uric acid production;
examples are malignancies, particularly lymphoreticular cancers, hemolytic
anemia, polycythemia, leukemias and nonmalignant conditions of increased
cellular proliferation (e.g., psoriasis). Uric acid production will also
increase with the accelerated breakdown of adenosine triphosphate (ATP) in
glucose-6-phosphatase deficiency, tissue ischemia and myophosphorylase
Decreased urinary excretion of urate most often contributes to
hyperuricemia. Patients with urate clearances of 6 to 7 ml per minute are more
likely to have hyperuricemia after a purine load than those with clearances of
12 to 14 ml per minute. The assessment of renal handling of urate may be part of
medical investigation designed to provide information about urate production,
renal function, urine flow and the contribution of dietary purine intake to
serum and urine urate.
Gout medications are used to:
- Relieve the pain and swelling of an acute attack: nonsteroidal
anti-inflammatory drugs (NSAIDs), colchicine, codeine, Demerol, corticosteroid
- Prevent future episodes: colchicine, probenecid, sulfinpyrazone, and
- Prevent or treat tophi: probenecid, sulfinpyrazone, and allopurinol.
- Prevent the formation of uric acid kidney stones: allopurinol
has been used to treat gout for over 2,400 years. It relieves the pain and
swelling of acute attacks. It works best if taken immediately after the onset of
an attack. When taken by mouth, colchicine can cause diarrhea, nausea, and
abdominal cramps. Colchicine is less popular now than in the past because of its
slow onset of action and frequent gastrointestinal side effects. Colchicine
interferes with neutrophil phagocytosis and chemotaxis -early events in the
production of joint inflammation and is most effective when started soon after
the onset of an attack of gouty arthritis. The beneficial effect of colchicine
declines the longer treatment is delayed.
My drug of choice is dexamethasome 4 mg with
the onset of gout symptoms. Sometimes a half tablet (2mg) is enough to stop an
attack if it is taken as soon as pain and/or swelling becomes apparent.
Dexamethasone will increase blood glucose so if you are diabetic on insulin a
temporary increase in the insulin dose is usually required.
Nonsteroidal anti-inflammatory drugs
(NSAIDs) are used to relieve the pain and swelling of an acute attack. They
usually begin working within 24 hours. These medications are as effective as
colchicine but may have less frequent side effects. Side effects from NSAIDs may
include stomach upset, headache, skin rashes, and sometimes ulcers.
Medications that Reduce the Rate of Uric Acid Production
Allopurinol (Lopurin, Zurinol, Zyloprim) reduces the amount of uric acid in
the blood and urine by slowing the rate of production of uric acid. It is the
best medicine for people who have kidney problems or kidney stones caused by
uric acid. Occasional side effects include skin rash and stomach upset.
Infrequently, allopurinol can cause an allergic reaction - skin rash, hives,
itching, fever, nausea, and muscle pain are typical symptoms.
Medications that Help Eliminate Uric Acid
Some drugs lower the uric acid level by increasing the amount of uric acid
passed in the urine. They help dissolve tophi and prevent uric acid deposits in
joints. Probenecid (Benemid, Parbenem, Probalan) and sulfinpyrazone (Anturane).
Common side effects include nausea, skin rash, stomach upset, or headaches.
Increase water intake to about 10 x 8 ounce glasses per day.
Avoid aspirin with these drugs because it blocks their effects on the
kidneys. At first, probenecid or sulfinpyrazone may increase the risk of kidney
stones by increasing the uric acid content in the urine. Adding baking soda to
the water will make the urine more alkaline, increase the solubility of uric
acid and help to reduce the risk of urinary tract stones. Probenecid,
sulfinpyrazone, and allopurinol also may cause more frequent gout attacks at
first. You may have to take colchicine or an NSAID for the first few months of
preventive drug therapy to prevent a gout attack.
Some drugs lower the uric acid level by
increasing the amount of uric acid passed in the urine. They help dissolve
tophi and prevent uric acid deposits in joints. Probenecid (Benemid,
Parbenem, Probalan) and sulfinpyrazone (Anturane). Common side effects
include nausea, skin rash, stomach upset, or headaches. Increase water
intake to about 10 x 8 ounce glasses per day. Avoid aspirin with these
drugs because it blocks their effects on the kidneys. At first, probenecid
or sulfinpyrazone may increase the risk of kidney stones by increasing the
uric acid content in the urine. Maintenance of a large volume of alkaline
urine increases the solubility of uric acid and thus reduces the risk of
stone formation in the kidneys.
Adding baking soda to the water will
make the urine more alkaline, increasing the solubility of uric acid,
improving excretion and helping
to reduce the risk of urinary tract stones.
Probenecid is indicated in patients with
disabling attacks of gout. When uric acid concentrations exceed 9 mg/dL
increased joint changes and renal complications are likely and treatment
should begin even in the absence of gout attacks. The goal of probenecid
therapy is to lower serum urate concentrations to about 6 mg/dL. By
decreasing serum urate concentrations, probenecid prevents or reduces
chronic joint changes and tophi formation, eventually reduces the frequency
of acute gout attacks, and may improve renal function in gouty patients.
Since probenecid has no analgesic or
anti-inflammatory activity, it is of no value in the treatment of acute gout
attacks and will exacerbate and prolong inflammation during the acute phase.
Probenecid should not be started until 2—3 weeks after an acute gout attack.
The drug may increase the frequency of acute attacks during the first 6—12
months of therapy, even when normal or subnormal serum urate concentrations
have been maintained. Acute attacks 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.
The drug is not effective renal
insufficiency exists, particularly in patients with a creatinine clearance
of less than 50 mL/minute. Since uricosuric agents tend to increase urinary
uric acid concentrations and the risk of stone formation, they should be
avoided; allopurinol is preferred in patients with urinary uric acid
excretion of greater than 900 mg/day or with gouty nephropathy, urinary
tract stones or obstruction, or azotemia. Patients who are refractory to or
cannot tolerate probenecid may respond to allopurinol. The activity of
allopurinol and uricosurics is additive and when administered concomitantly,
smaller doses of each drug can be used. Combined use of the 2 types of drugs
is especially effective in the presence of tophaceous deposits.
Probenecid is well tolerated and has a
low incidence of adverse effects. The most frequent adverse effects include
headache, anorexia, nausea, and vomiting. Hypersensitivity reactions which
may be characterized by dermatitis, pruritus, fever, sweating, hypotension,
and anaphylactic reaction occur rarely. Most cases of severe allergic
reactions and anaphylaxis have been reported to occur within several hours
after administration in patients who had previously received the drug. If a
hypersensitivity reaction occurs, the drug should be discontinued.
Allopurinol Reducing Uric Acid Production
Allopurinol (Lopurin, Zurinol, Zyloprim) reduces the amount
of uric acid in the blood and urine by slowing the rate of production of uric
acid. It is the best medicine for people who have kidney problems or kidney
stones caused by uric acid. Occasional side effects include skin rash and
stomach upset. Infrequently, allopurinol can cause allergic reactions: skin
rash, hives, itching, fever, nausea, and muscle pain are typical symptoms. Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the
conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol,
a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting
xanthine oxidase, allopurinol and its metabolite block conversion of the
oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and
urine concentrations of uric acid. The drug differs, therefore, from uricosuric
agents which lower serum urate concentrations by promoting urinary excretion of
uric acid. Xanthine oxidase concentrations are not altered by long-term
administration of the drug. Urinary purine output after treatment with
allopurinol consists of uric acid, xanthine, and hypoxanthine, each having
independent solubility. Thus, the risk of crystalluria is reduced.
Alkalinization of the urine increases the solubility of the purines, further
minimizing the risk of crystalluria. Decreased tubular transport of uric acid
also results in increased renal reabsorption of calcium and decreased calcium
Allopurinol also interferes with pyrimidine nucleotide
synthesis by inhibiting orotidine 5-phosphate decarboxylase. Orotic acid is
excreted in the urine in increased amounts rarely exceeding 10% of the total
pyrimidines synthesized by the body. In rats, allopurinol reportedly increases
liver storage of iron by inhibiting the ferritin-xanthine oxidase system
responsible for mobilization of iron from the liver. Allopurinol may also
inhibit hepatic microsomal enzymes. Allopurinol is not cytotoxic and has no
effect on transplantable tumors. The drug has no analgesic, anti-inflammatory,
or uricosuric activity.
The dose of allopurinol varies with the severity of the
disease and should be adjusted according to the response and tolerance of
the patient. To reduce the possibility of flare-up of acute gouty attacks,
the manufacturers recommend that patients be started on allopurinol dosages
of 100 mg daily and that the daily dose of the drug be increased by 100 mg
at weekly intervals until the serum urate concentration falls to 6 mg/dL or
less, or until the maximum recommended dosage of 800 mg daily is
reached.In the management of mild gout, the usual adult dosage may range from
200—300 mg daily and, for moderately severe tophaceous gout, from
400—600 mg daily. Serum urate concentrations are often reduced more slowly
with allopurinol than with uricosuric drugs and minimum concentrations may
not be reached for 1—3 weeks.After serum urate concentrations are controlled, it may be possible to
reduce dosage; the average adult maintenance dosage is 300 mg daily and the
minimum effective dosage is 100—200 mg daily. Allopurinol therapy should
be continued indefinitely; irregular dosage schedules may lead to increased
serum urate concentrations.
The most common adverse effect of allopurinol is an itchy maculopapular
rash. Dermatitides of the exfoliative, urticarial, erythematous,
hemorrhagic, and purpuric types have also occurred. Alopecia, fever, and
malaise may also occur alone or in conjunction with dermatitis. In addition,
severe furunculoses of the nose, ichthyosis, and Stevens-Johnson syndrome
have been reported. The incidence of rash may be increased in patients with
renal insufficiency. Skin reactions may be delayed and have been reported to
occur as long as 2 years after initiating allopurinol therapy. Rarely, skin
rash may be followed by severe hypersensitivity reactions which may
sometimes be fatal. Some patients who have developed severe dermatitis
have also developed cataracts, but the exact relationship between
allopurinol and cataracts has not been established. Pruritus, onycholysis,
and lichen planus have also occurred rarely inpatients receiving allopurinol.
Facial edema, sweating, and skin edema have also occurred rarely, but a
causal relationship to the drug has not been established.
Hypersensitivity reactions to
allopurinol have been reported rarely. These reactions are characterized by
fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, rash,
pruritus, nausea, and vomiting. Serious and fatal cases of toxic epidermal necrolysis, hypersensitivity
angiitis, and allergic vasculitis involving erythematous maculopapular rash
with desquamation, severe exfoliative dermatitis, arterial nephrosclerosis,
oliguria, congestive heart failure, and acute onset of permanent deafness
have also been reported during therapy with the drug.
Allopurinol-induced hepatotoxicity may also be a hypersensitivity
reaction to the drug. A generalized hypersensitivity vasculitis has rarely
led to irreversible hepatotoxicity and death. The frequency of allopurinol-induced
hypersensitivity reactions may be increased in patients with decreased renal
function who receive allopurinol and a thiazide diuretic concomitantly.
Allopurinol should usually not be administered to patients who have
previously shown hypersensitivity to it or who have had a serious reaction
to the drug.
Here is an edited version of allopurinol's drug profile
available from Medscape Drug Info online:
“Allopurinol is used to lower serum and urinary uric acid
concentrations in the management of primary and secondary gout. The drug is
indicated in patients with frequent disabling attacks of gout. Because therapy with allopurinol is not without risks, the drug is not
recommended for the management of asymptomatic hyperuricemia. Some clinicians
have suggested that therapy should be initiated when serum urate concentrations
exceed 9 mg/dL because these concentrations are often associated with increased
joint changes and renal complications. Allopurinol is used for the management of
gout when uricosurics cannot be used because of adverse effects, allergy, or
inadequate response; when there are visible tophi or radiographic evidence of
uric acid deposits and stones; or when serum urate concentrations are greater
than 9 mg/dL and a family history of tophi and low urate excretion exists. Allopurinol is also used for the management of primary or secondary gouty
nephropathy. The goal of therapy is to lower serum urate concentration to about
6 mg/dL. Allopurinol will often promote resolution of tophi and uric acid
crystals by decreasing serum urate concentrations. Dosage of allopurinol varies
with the severity of the disease and should be adjusted according to the
response. To reduce the possibility of flare-up of acute gouty attacks, the
manufacturers recommend that patients be started on allopurinol dosages of 100
mg daily and that the daily dose of the drug be increased by 100 mg at weekly
intervals until the serum urate concentration falls to 6 mg/dL or less, or until
the maximum recommended dosage of 800 mg daily is reached. In the management of
mild gout, the usual adult dosage may range from 200—300 mg daily and, for
moderately severe tophaceous gout, from 400—600 mg daily. After serum urate
concentrations are controlled, it may be possible to reduce dosage; the average
adult maintenance dosage is 300 mg daily and the minimum effective dosage is
100—200 mg daily. When allopurinol is added to a therapeutic regimen of
colchicine, uricosuric agents, and/or anti-inflammatory agents, a transition
period of several months may be necessary before the other drugs can be
discontinued. During this period, the drugs should be administered
concomitantly, and allopurinol dosage should be adjusted until serum urate
concentrations are normal and freedom from acute gouty attacks is maintained for
several months. When the uricosuric agent is being withdrawn, dosage of the
uricosuric agent should be gradually reduced over several weeks.