Download GOUT LEARNING OBJECTIVES • At the end of lecture students

GOUT
LEARNING OBJECTIVES
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At the end of lecture students should be able to know,
What is gout?
Clinical features of gout.
Treatment of gout.
Mechanism of action.
Side effects.
Prevention of recurrent attacks of gout.
Drug interaction.
GOUT
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Gout is a familial metabolic disorder characterized by episodes of acute arthritis
due to the deposition of monosodium urate (uric acid crystals) in joints and
cartilage.
 Deposits of uric acid crystals are often known as tophi and gout is frequently
called tophaceous gout.
 Gout is always associated with increased uric acid levels in blood
(hyperuricemia), but hyperuricemia may or may not be associated with gout.
Deposition of uric acid in kidney may cause uric acid stone formation.
 Uric acid is formed from purines, it is filtered at glomerulus is reabsorbed from
proximal tubules, and is secreted at distal tubules and is excreted in urine.
 Uric acid is poorly soluble, in many mammalians it can be converted to soluble
allantoin by urease; this enzyme is absent in human.
 Increased amounts of uric acid are formed when large quantities of purines are
taken in diet or liberated during tissue breakdown due to various cancers or
anticancer drugs.
 Uric acid crystals are phagocytosed by synovial cells, which then release
prostaglandins, lysosomal enzymes and interleukin-I.
 These mediators of inflammation attract neutrophils and macrophages that
augment inflammatory process by releasing more mediators of inflammation and
produce an acute attack of gout.
 Excretion of uric acid is increased by probenecid and sulfinpyrazone.
 Treatment of gout is aimed at relieving acute gouty attack and prevention of
recurrent gouty episodes.
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CLINICAL FEATURES
Gout is a chronic disorder that has frequent acute attacks.
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An acute attack is presented by:
Severe pain and swelling of the affected joint.
Typically meta-tarsophalangeal joint of big toe is affected, but any joint may be
involved.
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TREATMENT OF ACUTE GOUT:
COLCHICINE
NSAIDS
 INDOMETHACIN
 PHENYLBUTAZONE
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PREVENTION OF RECURRENT ATTACKS:
ALLOPURINOL
PROBENECID
SULFINPYRAZONE
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TREATMENT OF ACUTE GOUT:
Drugs used for the treatment of acute gout are colchicine, indomethacin and
phenylbutazone.
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COLCHICINE:
It is an alkaloid derived from the plant colchicum autumnale.
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PHARMACOKINETICS:
Colchicine is well absorbed after oral administration, metabolized in liver and
metabolites are excreted in bile & urine.
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MECHANISM OF ACTION:
Colchicine has no effect on metabolism and excretion of uric acid.
It suppresses inflammatory process only in gout. Although it is not analgesic but
it relieves pain in acute attack of gout as it suppresses inflammatory process.
Colchicine binds with tubulin and inhibits the migration of macrophages and
neutrophils at the site of inflammation.
It also inhibits the formation of leukotrienes (LTB4) and release of histamine from
mast cells.
SIDE EFFECTS:
Most troublesome side effect of colchicine is diarrhea, it may cause nausea,
vomiting and abdominal pain.
Rarely it causes hair loss, myopathy, peripheral neuropathy and bone marrow
depression.
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USES:
Acute gout, it is used with NSAIDs.
It can also be used for prevention of recurrences.
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NSAIDs
In addition to inhibiting prostaglandin synthesis, indomethacin and
phenylbutazone also inhibit the uric acid crystal phagocytosis. These agents can
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be used as initial treatment of gout or as alternative drug when colchicine is
unsuccessful or can not be tolerated.
Acute attack of gout is rapidly relieved following the therapy with indomethacin.
All NSAIDs except aspirin, salicylates and tolmetin are effective to treat acute
attack of gout
PREVENTION OF RECURRENT GOUTY ATTACK (CHRONIC GOUT):
Agents that lower uric acid levels in blood can be used for the prevention of gout.
Serum uric acid levels can be decreased by:
Decreasing the formation of uric acid e.g. Allopurinol
Increasing excretion of uric acid (uricosuric effect) e.g.
o Probenecid and Sulfinpyrazone.
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ALLOPURINOL:
It is purine analog, it is well absorbed through gut and is metabolized to
alloxanthine that is also an active metabolite.
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MECHANISM OF ACTION:
Both allopurinol and alloxanthine inhibit the enzyme xanthine oxidase, thus
interfere with the formation of uric acid.
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SIDE EFFECTS:
Acute attack of gout may be precipitated by allopurinol due to the mobilization of
uric acid from tissues.
Therefore allopurinol should be given with colchicine during acute attack.
Nausea, vomiting, diarrhea, peripheral neuropathy and bone marrow depression
and hypersensitivity reactions may occur.
DRUG INTERACTIONS:
Allopurinol increases effects of cyclophosphamide. It inhibits metabolism of
probenecid and oral anticoagulants.
THERAPEUTIC USES:
Chronic gout.
During cancer chemotherapy.
Hyperuricemia.
Uric acid renal stones.
o Cochicine or NSAIDs should be given during 1st week of allopurinol
therapy to prevent acute attack.
URICOSURIC AGENTS (PROBENECID AND SULFINPYRAZONE)
o PHARMACOKINETICS:
They are well absorbed after oral administration, probenecid is slowly
metabolized in body, sulfinpyrazone is rapidly metabolized and its metabolites
are excreted in urine.
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MECHANISM OF ACTION:
They block the renal tubular reabsorption of uric acid and increase its excretion.
Aspirin also block the renal tubular reabsorption of uric acid and increase its
excretion; but this effect is seen at high doses. In low doses it decreases the
tubular secretion of uric acid, therefore it should not be given in gout.
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SIDE EFFECTS:
GI disturbances & aplastic anemia occur with both agents;
Nephrotic syndrome and allergic dermatitis occur with probenecid.
Increased uric acid stone formation is the possibility with uricosuric agents
(Maintenance of high urine volume and alkaline urine decrease this possibility).
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DRUG INTERACTIONS:
Probenecid decreases urinary excretion of penicillins and prolongs the duration
of action of penicillin.
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USES:
Chronic gout: Therapy with these agents must be started 2–3 weeks after acute
attack .
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