- Introduction, Disease definition,
Etiology:
- Familial metabolic
disease: recurring acute arthritic
arthritis -- caused by monosodium urate
deposition in joints and cartilage
- Monosodium urate deposition
associated with:
- chronic
hyperuricemia
- monosodium urate
deposition
- periodic,
recurrent arthritic attacks --
location:lower extremity
- Untreated:
progression may occur to polyarticular
destructive disease
- Uric acid
urolithiasis/urate nephropathy:
frequency = 20%
- Typically, chronic elevation
of plasma urate: necessary for gout
- 20% to 30% of
patients: normal serum puree
during acute attack
- Chronic uricemia
crystallization® joint urate deposit formation
® acute arthritis
- Multiple causes of
hyperuricemia
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Pharmacological
Treatment
- Mechanistic Basis: management of gout
- Sequence of Pathophysiological Events:
- phagocytosis by
synoviocytes of urate crystals
- Synoviocytes release:
- prostaglandins
- interleukin
1 (IL-1)
- lysosomal
enzymes
- These chemotactic
mediators attract:
- polymorphonuclear
leukocytes into the joint space
associated with enhancement of
the ongoing inflammatory process
- Increased numbers of
mononuclear phagocytes (macrophages):
- enter the
joint
- ingest
urate crystals
- release
additional inflammatory mediators
- This sequence suggests most
effective drugs would be those that suppress
different phases of the inflammatory process
(leukocyte activation)
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Colchicine
- Overview:colchicine
- alkaloid (isolated from
autumn crocus)
- Pharmacokinetics:colchicine
- readily absorbed following
oral route administration
- peak plasma levels: two
hours
- Drug metabolites:
intestinal tract & urinary excretion
- Pharmacodynamics:
colchicine
- Dramatic pain relief
- Dramatic reduction of gouty
arthritis (12-24 hours)
- not associated with
altered metabolism
- not associated with
altered urate excretion
- not associated with
other analgesic effects
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- Mechanism of Action:colchicine
- binds to intracellular
protein -- tubulin
®
- consequent inhibition of
tubulin polymerization to form
microtubules®
- inhibition of leukocyte
migration/phagocytosis;inhibition of
leukotriene B4
formation.
- Indications for Clinical Use:colchicine
- Effective in alleviating
inflammation/pain associate with acute
gouty arthritis
- Colchicine: increased gout
specificity compared to NSAIDs
- Diarrhea, associated with
colchicine: has led to NSAIDs being very
frequently used instead
- Colchicine preferred:
- prophylaxis of
recurring gouty arthritis
- Prevention of
acute Mediterranean fever
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- Adverse
Effects:colchicine
- Diarrhea (common)
- nausea, vomiting, the bowel
pain
- Rarely: hair loss;bone marrow
depression, peripheral neuritis, myopathy
- Acute, very large colchicine
doses (non-therapeutic):
- bloody diarrhea,
shock
- hematuria,
oligouria
- CNS depression --
fatal
- Supportive
treatment indicated
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Nonsteroidal Anti-inflammatory Drugs in Gout
- Overview:NSAIDs
- Rationale: NSAIDs-
- inhibit
urate crystal phagocytosis
- inhibit
prostaglandin synthase
- indomethacin:
- initial
treatment (agent most
often used currently)
- alternative
to colchicine (treatment
failure or excessive
discomfort {diarrhea})
- Many other NSAIDs have
been used with success in
managing acute gouty arthritis
except:
- aspirin
- salicylates
- tolmetin
- Oxaprozin should not
be used in patients with uric
acid stones because:
- oxaprozin
lowers serum uric acid,
thereby increasing uric
acid excretion in urine.
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Uricosuric
Drugs
- Overview:uricosuric drugs
- Decreases total body urate
pool in patients with tophaceous gout or
those patients who experience increased
frequency of gouty attacks.
- Uricosuric agents should not
be used in patients secreting large
quantities of uric acid® precipitate uric acid caliculi
- Uricosuric
drugs:
- probenecid
- sulfinpyrazone
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Allopurinol
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- Pharmacodynamics:allopurinol
- Purine source -- mainly
from:
- amino acids
- formate
- carbon dioxide
- Unincorporated
purine ribonucleotides and those from
nucleic acid degradation ® xanthine or
hypoxanthine® uric acid (oxidation step)
- last
step: inhibited by allopurinol,
leading to:
- reduced
plasma urate
- reduced
urate pool size
- increased
in xanthine and
hypoxanthine levels --
both more soluble
compounds
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- Clinical Use/Issues:allopurinol
- Probable long-term use for
management of gout
- Indications:
- chronic tophaceous
gout with enhanced tophi
reabsorption when uricosuric
agents are used
- patients with gout
when 24-hour urinary uric acid
(on purine-free diet) >
600-700 mg
- probenecid or
sulfinpyrazone: cannot be used:
adverse effect/allergic
reaction/inadequate therapeutic
effect
- patients with
recurring renal stones
- patients with
functional renal impairment
- excessively high
serum urate levels
- Other Indications:
- should be used
prevent massive uricosuria
following management of blood
dyscrasia
- antiprotozoal
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- Adverse
Effects:allopurinol
- Increase risk of acute
gouty arthritis early in allopurinol
therapy as urate crystals move from
tissue to plasma
- Acute attacks may be
prevented by using colchicine initially
- alternatively:
allopurinol may be used in
combination with probenecid or
sulfinpyrazone
- Gastrointestinal
disturbances: nausea, vomiting, diarrhea
- Peripheral neuritis,
necrotizing vasculitis, bone marrow
depression, aplastic anemia (rarely)
- Hepatic toxicity
- Interstitial nephritis
- Skin-reactive: puritic
macropapular lesion: frequency 3%
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- Drug-Drug Interactions:allopurinol
- increased effect of
cyclophosphamide
- inhibit probenecid &
oral anticoagulants metabolism
- may increase hepatic iron
- when
chemotherapeutic mercaptopurines are
being given concurrently, their dose must
be reduced to about 25%.
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