Gout

Gout is a form of Arthritis in which uric acid

accumulates in increased amounts in the blood
and often is deposited in the joints.
The deposit or collection of urate crystals in the
joints causes the symptoms (pain, redness,
swelling, joint deformity).
 Pathophysiologic events
• Urate crystals are initially
phagocytosed by synoviocytes,
• Which then release prostaglandins,
lysosomal enzymes, and
interleukin-1.
• Attracted by these chemotactic
mediators, polymorphonuclear
leukocytes migrate into the joint
space and amplify the ongoing
inflammatory process.
• In the later phases of the attack,
increased numbers of mononuclear
phagocytes (macrophages) appear,
ingest the urate crystals, and
release more inflammatory
mediators.
Accumulation of uric acid
• The accumulation of uric acid causes deposits in the joints and
kidneys:
▫ Kidney stones
▫ Kidney failure
▫ Gouty arthritis
▫ Hyperuricemia
Therapeutic strategies
• Gout involve lowering the uric acid level below the saturation point
(below 6 mg/dL)
• This can be accomplished by
• 1) interfering with uric acid synthesis with allopurinol
• 2) Increasing uric acid excretion with probenecid or sulfinpyrazone,
• 3) inhibiting leukocyte entry into the affected joint with colchicine,
• 4) administration of NSAIDs.
Aspirin in Gout
• Aspirin is contraindicated, because it competes
with uric acid for the organic acid secretion
mechanism in the proximal tubule of the kidney
Colchicine
• An alkaloid isolated from the
autumn crocus, Colchicum
autumnale.
• Colchicine does not prevent
the progression of gout to
acute gouty arthritis
• It reduces the frequency of
acute attacks and relieves pain
Pharmacokinetics:
▫ absorbed readily after oral
administration.
▫ Peak plasma levels within 2
hours.
▫ A serum half-life of 9 hours.
▫ Metabolites are excreted in
the intestinal tract and urine.
• Pharmacodynamics:
▫ Binds to the intracellular
protein tubulin, thereby
preventing its polymerization
into microtubules and leading
to the inhibition of leukocyte
migration and phagocytosis.
▫ colchicine blocks cell division
by binding to mitotic
spindles.
▫ Colchicine also inhibits the
synthesis and release of the
leukotrienes
Therapeutic Effect
Adverse Effect
• The anti-inflammatory activity
• Gastrointestinal bleeding
of colchicine is specific for
• Neuritis
gout,
• Colchicine is currently used for • Myopathy
prophylaxis of recurrent • Alopecia
attacks and will prevent • Bone marrow depression
attacks in more than 80 • Not first-line drug
percent of patients.
NSAIDs
• Indomethacin is commonly used in the initial treatment of gout as the
replacement for colchicine.
• All other NSAIDs except aspirin, salicylates, and tolmetin have been
successfully used to treat acute gouty episodes.
Allopurinol
• Purine analog
• It reduces the production of uric acid by competitively inhibiting the
last two steps in uric acid biosynthesis that are catalyzed by
xanthine oxidase
• Xanthine oxidase is inhibited, the circulating purine derivatives
• Xanthine and hypoxanthine are more soluble and, therefore, are less
likely to precipitate.
• Therapeutic uses:
▫ Allopurinol is effective in the treatment of primary
hyperuricemia of gout
▫ hyperuricemia secondary to other conditions, such as
that associated with certain malignancies
• Adverse effects
▫ Hepatotoxicity and skin rash
Febuxostat
• a new xanthine oxidase inhibitor
• Potent and selective inhibitor of xanthine oxidase.
Uricosuric Agents
• Probenecid and sulfinpyrazone.
• The uricosuric drugs are weak organic acids that promote renal
clearance of uric acid by inhibiting the urate-anion exchanger in the
proximal tubule that mediates urate reabsorption
• At therapeutic doses, they block proximal tubular resorption of uric
acid.
• May predispose a pateient for renal stones,
▫ Urine volume should be maintained at high level.
▫ pH should kept above 6.
• Adverse Effects.
▫ Gastrointestinal irritation.
▫ Rashes.
▫ Nephrotic syndrome has
occurred after the use of
probenecid.
▫ May rarely cause aplastic
anemia.