4 Gout

Gout and Its Therapy
Dr. apt. Nunuk Aries Nurulta, M.Si.

Faculty of Pharmacy
Universitas Muhammadiyah Purwokerto
Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

UMP UMP UMP UMP farmasi.ump.ac.id
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Gout
 Gout is a familial metabolic disease characterized by recurrent episodes of
acute arthritis due to deposits of monosodium urate in joints and cartilage.
 Formation of uric acid calculi in the kidneys may also occur.
 It is usually associated with high serum levels of uric acid, 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.
 Treatment of gout is aimed at relieving the acute gouty attack and

preventing recurrent gouty episodes and urate lithiasis.

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Gout Pathofisiology
 Urate crystals are initially phagocytosed by synoviocytes, which then release

prostaglandins, lysosomal enzymes, and interleukin-1 which attract and
activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes
(MNP) (macrophages).
 Attracted by these chemotactic mediators, polymorphonuclear leukocytes and

mononuclear phagocytes 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.

Gout Pathofisiology
 This sequence of events suggests that the most effective agents
for the management of acute urate crystal-induced inflammation,
are those that suppress different phases of leukocyte
activation.
 Before starting chronic therapy for gout, patients in whom

hyperuricemia is associated with gout and urate lithiasis must
be clearly distinguished from those who have only
hyperuricemia.
 In an asymptomatic person with hyperuricemia, the efficacy of long-
term drug treatment is unproved.

Gout Pathofisiology

Senyawa Purin

Drugs Used in Gout
 Acute gout : Sudden onset of severe inflammation in a small joint (metatarso-
phalangeal joint of greater toe) due to precipitating of urate crystal in the joint
space.
Drugs : Colchicine, NSAIDs, Corticosteroids
 Chronic gout/hyperuricaemia :
 Uricosurics agent : probenecid, sulfinpyrazone
 Uric acid Synthesis inhibitor : Allopurinol.

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Colchicine
 Colchicine modulates multiple pro- and
antiinflammatory pathways associated
with gouty arthritis.
 Colchicine prevents microtubule assembly
and thereby disrupts inflammasome
activation, microtubule-based
inflammatory cell chemotaxis, generation
of leukotrienes and cytokines, and
phagocytosis.
 It does not inhibit the synthesis or promote
the excretion of uric acid, and has no
effect on blood uric acid levels.

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Colchicine mechanism of action
 Colchicine causes tubulin
depolymerization.
 These lead to less cell
division of inflammatory
cells. Therefore, there are
less inflammatory
biomarkers being
secreted and activated.
 This leads to less
inflammation, less
oxidative stress, and less
endothelial dysfunction.

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Colchicine Mechanism
 Colchicine dramatically 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.
 Mechanism
 It is thought that colchicine somehow prevents the release of the

chemotactic factors and/or inflammatory cytokines from the neutrophils,
and this in turn decreases the attraction of more neutrophils into the
affected area
 Colchicine renders cell membranes more rigid and decreases the secretion
of chemotactic factors by activated neutrophils

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Colchicine Mechanism
 Colchicine produces its anti-inflammatory effects by binding to the

intracellular protein tubulin, thereby preventing its polymerization into
microtubules (arresting neutrophil motility) and leading to the inhibition
of leukocyte migration and phagocytosis.
 It also inhibits the formation of leukotriene B4.
 Several of colchicine's adverse effects are produced by its inhibition

of tubulin polymerization and cell mitosis.

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NSAIDs
 In addition to inhibiting prostaglandin synthase, indomethacin and other

NSAIDs also inhibit urate crystal phagocytosis.
 Indomethacin is commonly used as initial treatment of gout as the
replacement for colchicine.
 All other NSAIDs except aspirin, have been successfully used to treat
acute gouty episodes.
 Oxaprozin, which lowers serum uric acid, is theoretically a good NSAID
though it should not be given to patients with uric acid stones because it
increases uric acid excretion in the urine.

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Corticosteroids
 The use of corticosteroids is often suggested for elderly patients
with chronic tophaceous gout.
 Intraarticular injection : those not tolerating NSAIDs/colchicine
 Systemic steroids are rarely needed

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Uricosuric Agents
 The uricosuric drugs (or urate diuretics) are anions that are
somewhat similar to urate in structure; therefore, they can compete
with uric acid for transport sites.
 Small doses of uricosuric agents will actually decrease the total
excretion of urate by inhibiting its tubular secretion.
 At high dosages these same drugs increase uric acid elimination by
inhibiting its proximal tubular reabsorption.
 The two most clinically important uricosuric drugs, Probenecid
and Sulfinpyrazone, are organic acids.
 In addition,the initial rise in urinary uric acid concentrations during
uricosuric drug therapy may result in renal stone formation.

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Uricosuric Agents Mechanism
 Uric acid is freely filtered at the glomerulus. Like many

other weak acids, it is also both reabsorbed and
secreted in the middle segment of the proximal tubule.
 Uricosuric drugs— Probenecid, Sulfinpyrazone, and

large doses of aspirin—affect these active transport sites
so that net reabsorption of uric acid in the proximal
tubule is decreased.
 Because aspirin in small doses causes net retention of

uric acid by inhibiting the secretory transporter, it
should not be used for analgesia in patients with
gout.

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Uric acid Synthesis inhibitor
 Allopurinol is the drug of

choice in the treatment of
chronic tophaceous gout and is
especially useful in patients
whose treatment is complicated
by renal insufficiency.
 Allopurinol : alternative to
increasing uric acid excretion
in the treatment of gout is to
reduce its synthesis by
inhibiting xanthine oxidase with
allopurinol.

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Mechanism of Action
 Nucleic acids are converted to xanthine or
hypoxanthine and oxidized to uric acid .
 Allopurinol in contrast to the uricosuric drugs,
reduces serum urate levels through a competitive
inhibition of uric acid synthesis rather than by
impairing renal urate reabsorption.
 This action is accomplished by inhibiting xanthine
oxidase, the enzyme involved in the metabolism of
hypoxanthine and xanthine to uric acid.
 After enzyme inhibition, the urinary and blood
concentrations of uric acid are greatly reduced and
there is a simultaneous increase in the excretion of
the more soluble uric acid precursors, xanthine and
hypoxanthine

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 Allopurinol
mechanism of
action.
 Allopurinol is a
xanthine inhibitor.
 The drug lowers uric
acid. This effect
leads to less
inflammation but
also to less oxidative
stress with less free
radicals

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Gout and Its Therapy

Dr. apt. Nunuk Aries Nurulta, M.Si.

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Formation of uric acid calculi in the kidneys may also occur.

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

 Treatment of gout is aimed at relieving the acute gouty attack and

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Urate crystals are initially phagocytosed by synoviocytes, which then release

 Attracted by these chemotactic mediators, polymorphonuclear leukocytes and

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Before starting chronic therapy for gout, patients in whom

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Drugs : Colchicine, NSAIDs, Corticosteroids

 Uricosurics agent : probenecid, sulfinpyrazone

 Uric acid Synthesis inhibitor : Allopurinol.

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 It is thought that colchicine somehow prevents the release of the

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Colchicine produces its anti-inflammatory effects by binding to the

 It also inhibits the formation of leukotriene B4.

 Several of colchicine's adverse effects are produced by its inhibition

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 In addition to inhibiting prostaglandin synthase, indomethacin and other

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Systemic steroids are rarely needed

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Uric acid is freely filtered at the glomerulus. Like many

 Uricosuric drugs— Probenecid, Sulfinpyrazone, and

 Because aspirin in small doses causes net retention of

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

 Allopurinol is the drug of

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi Fakultas Farmasi

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