gout and anti gout drugs pharmacology

Drugs Used in Gout
Mr. RVS Chaitanya Koppala
Assistant professor,
Lovely professional University, punjab

Drugs Used in 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.

Pathophysiology :
 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.

 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.

Drugs used in acute and chronic
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
 For chronic gout/hyperuricaemia :
 Uricosurics agent : probenecid, sulfinpyrazone
 Uric acid Synthesis inhibitor : Allopurinol.

Colchicine
 Is neither analgesic nor anti –
inflammatory, but it suppress gouty
inflammation.
 It does not inhibit the synthesis or promote
the excretion of uric acid, and has no effect
on blood uric acid levels.

Pharmacokinetics
 Absorbed readily after oral administration
and reaches peak plasma levels within 2
hours.
 Metabolites are excreted in the intestinal
tract and urine.

Pharmacodynamics
 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.
 MOA :
 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

 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.

Indications
 Acute gouty arthritis
 For the prophylaxis of recurrent episodes of gouty arthritis
 Adverse Effects :
 Diarrhea , nausea, vomiting, and abdominal pain
 Rarely cause hair loss and bone marrow depression as well as peripheral
neuritis and myopathy.
 Acute intoxication: burning throat pain, bloody diarrhea,
hematuria, and oliguria. Fatal ascending central nervous system
depression has been reported.
 Treatment is supportive.

Dosage
 Prophylactic dose : 0.6 mg one to three times daily.
 attack of gout, initial dose of 0.6 or 1.2 mg,
followed by 0.6 mg every 2 hours until pain is
relieved or nausea and diarrhea appear.
 Total dose can be given intravenously if necessary,
but it should be remembered that as little as 8 mg
in 24 hours may be fatal.

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.
 Doses : 50 mg xtds or qid; when a response occurs,
the dosage is reduced to 25 mg three or four times
daily for about 5 days.

 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.

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
 Prednisolone : 40 – 60mg in one day, followed by
tapering doses over few weeks.

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.
 And 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.
 The initial phase of therapy with uricosuric drugs is the most
dangerous period.
 Until uricosuric drug levels build up sufficiently to fully inhibit uric
acid reabsorption as well as secretion, there may be a temporary
increase in uric acid blood levels that significantly increases the
risk of an acute gouty attack.
 Therefore, it is wise to begin therapy with the administration of
small amounts of Colchicine before adding a uricosuric drug to
the therapeutic regimen.
 In addition,the initial rise in urinary uric acid concentrations during
uricosuric drug therapy may result in renal stone formation.

Pharmacokinetics
 Probenecid is completely absorbed orally, 90%
plasma protein binding, conjugated in liver, is
metabolized very slowly, T1/2 is 8-10 hours and
excreted by kidney.
 Sulfinpyrazone is rapidly excreted by the kidneys.
Even so, the duration of its effect after oral
administration is almost as long as that of
probenecid.

Pharmacodynamics
 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.

 Probenecid was originally developed to
prolong penicillin blood levels.
 As the urinary excretion of uric acid increases, the
size of the urate pool decreases, although the
plasma concentration may not be greatly reduced.
 With the increase in uric acid excretion, a
predisposition to the formation of renal stones is
augmented .

Indications
 Initiated if several acute attacks of gouty arthritis have
occurred,
 When evidence of tophi appears, or
 When plasma levels of uric acid in patients with gout are
so high.
 Therapy should not be started until 2–3 weeks after an
acute attack.

Adverse Effects
 Gastrointestinal irritation, but sulfinpyrazone is more
active in this regard.
 Probenecid (allergic dermatitis), but a rash may
appear after the use of either compound.
 Nephrotic syndrome has resulted from the use of
probenecid.
 Both sulfinpyrazone and probenecid may rarely cause
aplastic anemia.

Contraindications &
Cautions
 The drug is contraindicated in patients
with a history of renal calculi.
 Essential to maintain a large urine
volume to minimize the possibility of
stone formation.

Dosage
 Probenecid : 0.5 g orally daily in divided doses,
progressing to 1 g daily after 1 week.
 Sulfinpyrazone : 200 mg orally daily,
progressing to 400– 800 mg daily.
 It should be given in divided doses with
food to reduce adverse gastrointestinal
effects.

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.

Pharmacokinetics
 Approximately 80% absorbed after oral
administration.
 Like uric acid, allopurinol is itself metabolized by
xanthine oxidase.
 The resulting compound, alloxanthine, retains
the capacity to inhibit xanthine oxidase and
has a long enough duration of action so that
allopurinol need be given only once a day.

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

Indications
First urate-lowering drug used, its most rational indications are
as follows:
(1) in chronic tophaceous gout, in which reabsorption of tophi is more rapid than
with uricosuric agents;
(2) in patients with gout whose 24 hour urinary uric acid on purine-free diet
exceeds 600–700 mg;
(3) when probenecid or sulfinpyrazone cannot be used because of adverse effects
or allergic reactions, or when they are providing less than optimal therapeutic
effect;
(4) for recurrent renal stones;
(5) in patients with renal functional impairment; or
(6) when serum urate levels are grossly elevated.

Adverse Effects
 Gastrointestinal intolerance, including nausea,
vomiting, and diarrhea, may occur. Peripheral neuritis
and necrotizing vasculitis, depression of bone marrow
elements, and, rarely, aplastic anemia may also occur.
 An allergic skin reaction
 In very rare cases, allopurinol has become bound to the
lens, resulting in cataracts.

Interactions & Cautions
 Inhibits the metabolism of probenecid and
oral anticoagulants.
 Safety in children and during pregnancy has
not been established.

gout and anti gout drugs pharmacology

In this document

More Related Content

What's hot

Viewers also liked

Similar to gout and anti gout drugs pharmacology

More from Dr. Koppala R.V.S. Chaitanya

Recently uploaded

gout and anti gout drugs pharmacology