Seminar on gout

Tushar
Pharm d Vth year
170518882026

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 ⚫ 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,
⚫ interstitial renal disease, and
⚫ uric acid nephrolithiasis.
⚫ Hyperuricemia may be an asymptomatic condition with an
increased serum uric acid level as the only apparent
abnormality.
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 ⚫ Studies have shown that serum urate concentration
(and consequently the risk of gout) correlates with age,
serum creatinine level, blood urea nitrogen level, male
gender, blood pressure, body weight, and alcohol
intake.
⚫ In gout, the mean serum urate concentration values are
6.8 mg/dL for men and 6.0 mg/dL for women.

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 ETIOLOGY AND
PATHOPHYSIOLOGY
⚫ In humans, uric acid is the end product of the degradation of
purines.
⚫ Uric acid serves no known physiologic purpose and therefore
is regarded as a waste product.
⚫ In lower animals, the enzyme uricase breaks down uric acid
to the more soluble allantoin, and thus uric acid does not
accumulate.
⚫ Under normal conditions, the amount of accumulated uric
acid is about 1200 mg in men and about 600 mg in women.
⚫ The size of the urate pool is increased several fold in
individuals with gout.
⚫ This excess accumulation may result from either
4 overproduction or underexcretion.
 OVERPRODUCTION OF URIC ACID
⚫ The purines from which uric acid is produced originate
from three sources:
⚫ dietary purine,
⚫ conversion of tissue nucleic acid to purine nucleotides,
⚫ and de novo (afresh) synthesis of purine bases.
⚫ The purines derived from these three sources enter a
common metabolic pathway leading to the production of
either nucleic acid or uric acid.
⚫ Under normal circumstances, uric acid may accumulate
excessively if production exceeds excretion.
⚫ The average human produces about 600 to 800 mg of uric
acid each day.
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 UNDEREXCRETION OF URIC ACID
⚫ Uric acid does not accumulate as long as uric acid
production is balanced with elimination.
⚫ Uric acid is eliminated in two ways.
⚫ About two-thirds of the uric acid produced each day is
excreted in the urine.
⚫ The rest is eliminated through the gastrointestinal tract
after enzymatic degradation by colonic bacteria.
⚫ A decline in the urinary excretion of uric acid to a level
below the rate of production leads to hyperuricemia and
an increased miscible pool of sodium urate.

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 ⚫ Almost all the urate in plasma is freely filtered across the
glomerulus.
⚫ The concentration of uric acid appearing in the urine is
determined by multiple renal tubular transport processes
in addition to the filtered load.
⚫ Evidence favors a four-component model including
glomerular filtration, tubular reabsorption, tubular
secretion, and postsecretory reabsorption.
⚫ Approximately 90% of filtered uric acid is reabsorbed in
the proximal tubule

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 ⚫ Drugs that decrease renal clearance of uric acid
through modification of filtered load or one of the
tubular transport processes.
⚫ Eg-: Diuretics, Ethanol, Ethambutol, Nicotinic acid,
Pyrazinamide, Cytotoxic drugs, Salicylates (<2
g/day),Levodopa, Cyclosporine.

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 ⚫ Normal individuals produce 600 to 800 mg of uric acid
daily and excrete less than 600 mg in urine.
⚫ Individuals who excrete more than 600 mg on a purine-
free diet may be considered overproducers.
⚫ Hyperuricemic individuals who excrete less than 600 mg
of uric acid per 24 hours on a purine-free diet may be
classified as underexcretors of uric acid.
⚫ On a regular diet, excretion of greater than 1000 mg per
24 hours reflects overproduction; less than this is probably
normal.

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 CLINICAL PRESENTATION
⚫ Gout is a disease diagnosed by symptoms rather than
laboratory tests of uric acid.
ACUTE GOUTY ARTHRITIS
⚫ Acute attacks of gouty arthritis are characterized by rapid
onset of piercing pain, swelling, and inflammation.
⚫ The attack typically is monarticular at first, most often
affecting the first metatarsophalangeal joint (great toe) and
then, in order of frequency, the insteps (arched middle part of
the foot between toes and ankle), ankles, heels, knees, wrists,
fingers, and elbows.

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 ⚫ Abnormalities in the enzyme systems that regulate
purine metabolism may result in overproduction of
uric acid. PRPP
HGPRT
Synthetase

PRPP (Key
metabolism of
determinant in
guanine and
purine
hypoxanthine
synthesis )

Uric Acid

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 ⚫ Phagocytosis of urate crystals by the leukocytes results in
rapid lysis of cells and a discharge of proteolytic enzymes
into the cytoplasm.
⚫ The ensuing inflammatory reaction is associated with
intense joint pain, erythema, warmth, and swelling.
⚫ Fever is common, as is leukocytosis.
⚫ Untreated attacks may last from 3 to 14 days before
spontaneous recovery

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 ⚫ Conditions that precipitate an attack include stress,
trauma, alcohol ingestion, infection, surgery, rapid
lowering of serum uric acid by ingestion of uric acid–
lowering agents, and ingestion of certain drugs known to
elevate serum uric acid concentrations.
⚫ The diagnosis is best accomplished by aspiration of
synovial fluid from the affected joint and identification of
intracellular crystals of monosodium urate monohydrate in
synovial fluid leukocytes.

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 URIC ACID NEPHROLITHIASIS
⚫ Nephrolithiasis occurs in 10 to 25% of patients with gout.
⚫ Factors that predispose individuals to uric acid
nephrolithiasis include excessive urinary excretion of uric
acid, an acidic urine, and a highly concentrated urine.
⚫ The risk of renal calculi approaches 50% in individuals
whose renal excretion of uric acid exceeds 1100 mg/day.

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 ⚫ In addition to pure uric acid stones, hyperuricosuric
individuals are at increased risk for mixed uric acid–
calcium oxalate stones and pure calcium oxalate
stones.
⚫ Uric acid stones are usually small, round, and
radiolucent (transparency to X rays).
⚫ Uric acid stones containing calcium are radiopaque
(opacity to x rays).

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 ⚫ When urine is acidic, uric acid exists primarily in the less
soluble form.
⚫ When the urine pH is 7.0, the solubility of uric acid in
urine is increased to 200 mg/dL.
⚫ In patients with uric acid nephrolithiasis, urinary pH
typically is less than 6.0
⚫ When an acidic urine is saturated with uric acid,
spontaneous precipitation of stones may occur.

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 GOUTY NEPHROPATHY
⚫ There are two types of gouty nephropathy: acute uric
acid nephropathy and chronic urate nephropathy.
⚫ In acute uric acid nephropathy, acute renal failure
occurs as a result of blockage of urine flow secondary
to massive precipitation of uric acid crystals in the
collecting ducts and ureters.

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 ⚫ Chronic urate nephropathy is caused by the long-term
deposition of urate crystals in the renal parenchyma.
⚫ A decrease in the kidney’s ability to concentrate urine and
the presence of proteinuria may be the earliest
pathophysiologic disturbances.
⚫ Hypertension and nephrosclerosis are common associated
findings.

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 TREATMENT
Goals:
⚫ The immediate goal in the treatment of an acute attack of
gout is to relieve pain and inflammation.
⚫ The immediate goal of therapy should not be aimed at
decreasing the serum uric acid concentration with
hypouricemic agents
⚫ Terminate the acute attack, prevent recurrent attacks of
gouty arthritis, and prevent complications associated with
chronic deposition of urate crystals in tissues.

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ACUTE GOUTY ARTHRITIS
⚫ Acute attacks of gouty arthritis may be treated successfully
with colchicine or any of a variety of nonsteroidal anti-
inflammatory drugs (NSAIDs).
⚫ Colchicine can be given orally or parenterally.
⚫ The major problem associated with the use of oral colchicine
is that it causes gastrointestinal side effects in 50% to 80% of
patients before the relief of the attack.

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 ⚫ This high incidence of gastrointestinal side effects may be
controlled by administering colchicine intravenously.
⚫ Except in patients with renal insufficiency, the initial
intravenous dose of colchicine is 2 mg.
⚫ If relief is not obtained, an additional 1-mg dose may be
given at 6 and 12 hours to a total dose of 4 mg for a
specific attack.
⚫ The colchicine should be diluted with 20 mL normal
saline before administration to minimize sclerosis of the
vein.

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 ⚫ Indomethacin is as effective as colchicine in the
treatment and the acute gastrointestinal toxicity occurs
far less frequently with indomethacin than with
colchicine.
⚫ Side effects unique to indomethacin include headache
and dizziness.
⚫ All NSAIDs have been implicated in the cause of
gastric ulceration and bleeding, but unlikely with
short-term therapy.

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 ⚫ A number of other NSAIDs (e.g., naproxen, fenoprofen,
ibuprofen,
⚫ and piroxicam) are also effective in relieving the
inflammation of acute gout.
⚫ All NSAIDs should be used with caution in individuals
with a history of acid peptic disease, heart failure, chronic
renal failure, or coronary artery disease.

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 ⚫ Corticosteroids may be used to treat acute attacks of gouty
arthritis, but they are reserved primarily for resistant cases
or for patients with a contraindication to colchicine and
NSAID therapy.
⚫ Prednisone may be administered orally in doses of 30 to
60 mg for 3 to 5 days in patients with multiple-joint
involvement.
⚫ Because rebound attacks may occur on steroid
withdrawal, the dose should be tapered gradually by 5-mg
decreases over 10 to 14 days and discontinued.

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 NEPHROLITHIASIS
⚫ The medical management of uric acid nephrolithiasis
includes
⚫ hydration sufficient to maintain a urine volume of 2 to 3 L/day,
⚫ alkalinization of urine,
⚫ avoidance of purine-rich foods,
⚫ moderation of protein intake, and
⚫ reduction of urinary uric acid excretion.

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 ⚫ Maintenance of a 24-hour urine volume of 2 to 3 L with
an adequate intake of fluids is desirable for all gouty
patients, but especially for those with excessive (>1
g/day) uric acid excretion.
⚫ Alkalinizing agents should be used with the objective of
making the urine less acidic.
⚫ Urine pH should be maintained at 6 to 6.5.

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 ⚫ Reduction of urine acidity can be accomplished by the
administration of sodium bicarbonate or Shohl’s solution
(40 g citric acid and 98 g sodium citrate per liter).
⚫ With the former(sodium bicarbonate ), 2 to 6 g/day is
given in equally divided doses at 6- to 8-hour intervals.
⚫ A dose of 20 to 60 mL of Shohl’s solution per day, given
in three or four divided doses, provides an equivalent
amount of alkali.
⚫ If use of a sodium salt is contraindicated, potassium citrate
may be used instead.

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⚫ The mainstay of drug therapy for recurrent uric acid lithiasis
( calculi) is allopurinol.
⚫ It is effective in reducing both serum and urinary uric acid
levels, thus preventing the formation of calculi.
⚫ One must keep in mind that older patients with uric acid
kidney stones also may have hypertension, congestive heart
failure, or renal insufficiency, and obviously should not be
exposed to overload with alkalinizing sodium salts or
unlimited fluid intake.

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 Prophylaxis
⚫ Recurrences of acute gouty arthritis may be prevented
with continuous low-dose daily oral colchicine or by uric
acid–lowering therapy with either uricosuric agents or
inhibition of xanthine oxidase with allopurinol.
⚫ Combination therapy consisting of colchicine plus a
uricosuric agent or allopurinol may be employed in
resistant cases.
⚫ Prophylactic therapy with low-dose oral colchicine, 0.5 to
0.6 mg twice daily, may be effective in preventing
recurrent arthritis

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 ⚫ Patients do not become resistant to or tolerant of daily
colchicine, and if they sense the beginning of an acute
attack, they should increase the dose to 1 mg every 2
hours; in most instances the attack will abort after 1 or
2 mg of colchicine.
⚫ If the serum urate concentration is within the normal
range and the patient has been symptom-free for 1
year, maintenance colchicine may be discontinued.

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 ⚫ Colchicine at a dose of 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.

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 URICOSURIC DRUGS
⚫ Uricosuric drugs 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.
⚫ The maintenance of adequate urine flow and alkalinization
of the urine with sodium bicarbonate or Shohl’s solution
during the first several days of uricosuric therapy further
diminish the possibility of uric acid stone formation.

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 ⚫ Probenecid is given initially at a dose of 250 mg twice
a day for 1 to 2 weeks and then 500 mg twice a day for
2 weeks.
⚫ Thereafter the daily dose is increased by 500-mg
increments every 1 to 2 weeks until satisfactory
control is achieved or a maximum dose of 2 g is
reached.

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⚫ The major side effects associated with uricosuric therapy are
gastrointestinal irritation, rash and hypersensitivity,
precipitation of acute gouty arthritis, and stone formation.
⚫ These drugs are contraindicated in patients who are allergic
to them and in patients with impaired renal function (a
creatinine clearance<50 mL/min), a history of renal calculi,
and in patients who are overproducers of uric acid.
⚫ For such patients, allopurinol should be used.

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 XANTHINE OXIDASE INHIBITOR
⚫ Currently, allopurinol is the only drug approved for
use in inhibiting uric acid synthesis.
⚫ Both allopurinol and its major metabolite, oxypurinol,
are xanthine oxidase inhibitors and thus impair the
conversion of hypoxanthine to xanthine and xanthine
to uric acid.
⚫ It also lowers the intracellular concentration of PRPP
⚫ An oral daily dose of 300 mg usually is sufficient.
Occasionally, as much as 600 to 800 mg/day may be
necessary.
⚫ Dose adjustments: 200 mg/day for CLcr 60 mL/min or
36 less, and 100 mg/day for CLcr 30 mL/min or less.
 THANK YOU

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