gout and anti gout drugs pharmacology

gout, anit gout drugs , pharmacology of gout

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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

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

8. 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

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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 .

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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

27. 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.

28. 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.

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

30. THE END……