Antigout PDF

DRUGS USED IN GOUT
 Gout is a metabolic disease characterized by recurrent

episodes of acute arthritis due to deposits of monosodium
urate in joints and cartilage.
 Renal calculi, tophi, and interstitial nephritis may also occur.
 Gout is usually associated with a high serum uric acid level

(hyperuricemia), a poorly soluble substance that is the major
end product of purine metabolism.
 In most mammals, uricase converts uric acid to the more soluble

allantoin; this enzyme is absent in humans.
 While clinical gouty episodes are associated with hyperuricemia,

most individuals with hyperuricemia may never develop a
clinical event from urate crystal deposition.
COLCHICINE
 Although NSAIDs, corticosteroids, or

colchicine are first-line drugs for acute
gout, colchicine was the primary treatment
for many years.
 Pharmacokinetics: Colchicine is absorbed readily after oral
administration, reaches peak plasma levels within 2 hours, and is
eliminated with a serum half-life of 9 hours. Metabolites are
excreted in the intestinal tract and urine.
 Pharmacodynamics: Colchicine relieves the pain and

inflammation of gouty arthritis in 12–24 hours without altering
the metabolism or excretion of urates and without other
analgesic effects. Colchicine produces its anti-inflammatory
effects by inhibition of leukocyte migration and phagocytosis. It
also inhibits the formation of leukotriene B4 and IL-1β.
 Several of colchicine’s adverse effects are produced by its

inhibition of tubulin polymerization and cell mitosis.
 Indications: Colchicine is indicated for gout
and is also used between attacks (the
“intercritical period”) for prolonged
prophylaxis (at low doses).
 Although it has been given intravenously, this
route is no longer approved by the FDA (2009)
 Adverse Effects: Colchicine often causes
diarrhea and may occasionally cause
nausea, vomiting, and abdominal pain.
 Hepatic necrosis, acute renal failure,
disseminated intravascular coagulation, and
seizures have also been observed.
 Colchicine may rarely cause hair loss and bone

marrow depression, as well as peripheral
neuritis, myopathy, and, in some cases, death.
 Dosage: In prophylaxis (the most common
use), the dosage of colchicine is 0.6 mg one
to three times daily.
 For terminating a gouty attack, a
regimen of 1.2 mg followed by a single
0.6 mg oral dose was as effective as
higher dose regimens and adverse events
were less with this lower dose regimen.

NSAIDS IN GOUT
 In addition to inhibiting prostaglandin synthase, NSAIDs inhibit
urate crystal phagocytosis.
 Aspirin is not used because it causes renal retention of uric

acid at low doses (≤ 2.6 g/d).
o It is uricosuric at doses greater than 3.6 g/d.
 Indomethacin is commonly used in the initial treatment of

gout as a replacement for colchicine.
o For acute gout, 50 mg is given three times daily; when a response
occurs, the dosage is reduced to 25 mg three times daily for 5–7 days.
 Oxaprozin, which lowers serum uric acid, is theoretically a

good choice.
URICOSURIC AGENTS
 Probenecid and sulfinpyrazone are
uricosuric drugs employed to decrease the
body pool of urate in patients with
tophaceous gout or in those with
increasingly frequent gouty attacks.
 In a patient who excretes large amounts of

uric acid, the uricosuric agents should not
be used.
 Probenecid is completely reabsorbed by the
renal tubules and is metabolized slowly with
a terminal serum half-life of 5–8 hours.
 Sulfinpyrazone or its active hydroxylated

derivative is excreted by the kidneys.
 Even so, the duration of its effect after oral
administration is almost as long as that of
probenecid, which is given once or twice daily.
 Pharmacodynamics: Because aspirin in
doses of less than 2.6 g daily causes net
retention of uric acid by inhibiting the
secretory transporter, it should not be used
for analgesia in patients with gout.
 The secretion of other weak acids (eg,
penicillin) is also reduced by uricosuric agents.
 As the urinary excretion of uric acid increases, the size of
the urate pool decreases, although the plasma
concentration may not be greatly reduced.
 Indications: Uricosuric therapy should be initiated in gouty

patients with underexcretion of uric acid when allopurinol
or febuxostat is contraindicated or when tophi are present.
 Therapy should not be started until 2–3 weeks after an

acute attack regard.
 Nephrotic syndrome has occurred after the
use of probenecid. Both sulfinpyrazone and
probenecid may rarely cause aplastic
anemia.
 Contraindications and Cautions: It is
essential to maintain a large urine volume
to minimize the possibility of stone
formation.
ALLOPURINOL
 The preferred and standard-of-care therapy for gout
during the period between acute episodes is allopurinol, which
reduces total uric acid body burden by inhibiting xanthine
oxidase.
 Allopurinol is approximately 80% absorbed after oral
administration and has a terminal serum half-life of 1–2
hours.
 Like uric acid, allopurinol is metabolized by xanthine oxidase,
but the resulting compound, alloxanthine, retains the
capacity to inhibit xanthine oxidase and has a long enough
d ti f ti th t ll i l i i l
 Indications: Allopurinol is often the first-line agent for
the treatment of chronic gout in the period between
attacks and it tends to prolong the intercritical period.
 As with uricosuric agents, the therapy is begun with the

expectation that it will be continued for years if not for
life.
 When initiating allopurinol, colchicine or NSAID should be

used until steady state serum uric acid is normalized or
decreased to less than 6 mg/dL and they should be
continued for 6 months or longer.
 Thereafter, colchicine or the NSAID can be cautiously

stopped while continuing allopurinol therapy
 Interactions and Cautions: When
chemotherapeutic purines (eg, azathioprine)
are given concomitantly with allopurinol,
their dosage must be reduced by about
75%.
 Allopurinol inhibits the metabolism of
probenecid and oral anticoagulants and
may increase hepatic iron concentration.

FEBUXOSTAT
 Febuxostat is a non-purine xanthine oxidase inhibitor that was
approved by the FDA in 2009.
 Pharmacokinetics: Febuxostat is more than 80% absorbed following

oral administration. With maximum concentration achieved in
approximately 1 hour and a half-life of 4–18 hours, once-daily dosing
is effective. Febuxostat is extensively metabolized in the liver.
 Pharmacodynamics: Febuxostat is a potent and selective inhibitor of

xanthine oxidase,
 Febuxostat at daily dosing of 80 mg or 120 mg was more

effective in lowering serum urate levels than allopurinol at a
standard 300 mg daily dose.
 The urate-lowering effect was comparable regardless of the

pathogenic cause of hyperuricemia—overproduction or
underexcretion
 Indications: Febuxostat is approved at doses of 40 or 80 mg for
the treatment of chronic hyperuricemia in gout patients.
 Adverse Effects: As with allopurinol, prophylactic treatment with

colchicine or NSAIDs should be started at the beginning of
therapy to avoid gout flares.
 Febuxostat is well tolerated in patients with a history of

allopurinol intolerance.
 There does not appear to be an increased risk of cardiovascular

events.
 Dosage: The recommended starting dose of febuxostat is
40 mg daily.
 No dose adjustment is necessary for patients with renal

impairment since it is highly metabolized into an
inactive metabolite by the liver.
PEGLOTICASE
 Pharmacokinetics and Dosage: The recommended dose for
pegloticase is 8 mg every 2 weeks administered as an
intravenous infusion.
 Pegloticase is highly soluble and can be easily

eliminated by the kidney.
 It has been shown to maintain low urate levels for up to

21 days after a single dose at doses of 4–12 mg,
allowing for IV dosing every 2 weeks.
 Adverse Effects: Gout flare can occur during treatment with
pegloticase, especially during the first 3–6 months of
treatment, requiring prophylaxis with NSAIDs or colchicine.
 Large numbers of patients show immune responses to

pegloticase.
 Anaphylaxis occurs in more than 6–15% of patients receiving

pegloticase. Monitoring of plasma uric acid level, with rising level
as an indicator of antibody production, allows for safer
administration and monitoring of efficacy. In addition, other
oral urate-lowering agents should be avoided in order not to
mask the loss of pegloticase efficacy. Nephrolithiasis,
arthralgia, muscle spasm, headache, anemia, and nausea may
occur.
GLUCOCORTICOIDS
 Corticosteroids are sometimes used in the treatment of
severe symptomatic gout, by intra-articular, systemic, or
subcutaneous routes, depending on the degree of pain and
inflammation.
 The most commonly used oral corticosteroid is prednisone.
 The recommended oral dose is 30–50 mg/d for 1–2 days,

tapered over 7–10 days.
 Intra-articular injection of 10 mg (small joints), 30 mg

(wrist, ankle, elbow), and 40 mg (knee) of triamcinolone
acetonide can be given if the patient is unable to take
oral medications.

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DRUGS USED IN GOUT

 Gout is a metabolic disease characterized by recurrent

 Renal calculi, tophi, and interstitial nephritis may also occur.

 Gout is usually associated with a high serum uric acid level

 In most mammals, uricase converts uric acid to the more soluble

 While clinical gouty episodes are associated with hyperuricemia,

 Although NSAIDs, corticosteroids, or

 Pharmacodynamics: Colchicine relieves the pain and

 Several of colchicine’s adverse effects are produced by its

 Colchicine may rarely cause hair loss and bone

use), the dosage of colchicine is 0.6 mg one

to three times daily.

 For terminating a gouty attack, a

regimen of 1.2 mg followed by a single

0.6 mg oral dose was as effective as

higher dose regimens and adverse events

were less with this lower dose regimen.

 Aspirin is not used because it causes renal retention of uric

 Indomethacin is commonly used in the initial treatment of

 Oxaprozin, which lowers serum uric acid, is theoretically a

 In a patient who excretes large amounts of

 Sulfinpyrazone or its active hydroxylated

 Indications: Uricosuric therapy should be initiated in gouty

 Therapy should not be started until 2–3 weeks after an

use of probenecid. Both sulfinpyrazone and

probenecid may rarely cause aplastic

 Contraindications and Cautions: It is

essential to maintain a large urine volume

to minimize the possibility of stone

during the period between acute episodes is allopurinol, which

reduces total uric acid body burden by inhibiting xanthine

 Allopurinol is approximately 80% absorbed after oral

administration and has a terminal serum half-life of 1–2

 Like uric acid, allopurinol is metabolized by xanthine oxidase,

but the resulting compound, alloxanthine, retains the

capacity to inhibit xanthine oxidase and has a long enough

 As with uricosuric agents, the therapy is begun with the

 When initiating allopurinol, colchicine or NSAID should be

 Thereafter, colchicine or the NSAID can be cautiously

chemotherapeutic purines (eg, azathioprine)

are given concomitantly with allopurinol,

their dosage must be reduced by about

 Allopurinol inhibits the metabolism of

probenecid and oral anticoagulants and

may increase hepatic iron concentration.

 Pharmacokinetics: Febuxostat is more than 80% absorbed following

 Pharmacodynamics: Febuxostat is a potent and selective inhibitor of

 Febuxostat at daily dosing of 80 mg or 120 mg was more

 The urate-lowering effect was comparable regardless of the

 Adverse Effects: As with allopurinol, prophylactic treatment with

 Febuxostat is well tolerated in patients with a history of

 There does not appear to be an increased risk of cardiovascular

 No dose adjustment is necessary for patients with renal

pegloticase is 8 mg every 2 weeks administered as an

 Pegloticase is highly soluble and can be easily

 It has been shown to maintain low urate levels for up to

 Large numbers of patients show immune responses to

 Anaphylaxis occurs in more than 6–15% of patients receiving