The current presentation include the pharmacotherapy of drugs for acute and chronic gout. Details include definition, classification of drugs, mechanism, pharmacokinetics, adverse effects, uses and contraindications.

1. DRUGS FOR GOUT
Anusha Shaji, B.Pharm, M.Pharm
Assistant Professor
Department of Pharmacology
Nirmala College of Pharmacy,
Muvattupuzha, Ernakulam

2. Gout
It is a metabolic disorder characterized by hyperuricaemia
(normal plasma urate 2–6 mg/dl).
Hyperuricaemia: Elevated uric acid
Uric acid, a product of purine metabolism, has low water
solubility, especially at low pH.
When blood levels are high, it precipitates and deposits in joints,
kidney and subcutaneous tissue (tophy).

4. Secondary hyperuricaemia occurs in:
(a) Leukaemias, lymphomas, polycythaemia- especially when
treated with chemotherapy or radiation: due to enhanced nucleic
acid metabolism and uric acid production.
(b) Drug induced- thiazides, furosemide, pyrazinamide,
ethambutol, levodopa reduce uric acid excretion by kidney.

9. ACUTE GOUT
Acute gout manifests as sudden onset of severe inflammation in a
small joint (commonest is metatarso-phalangeal joint of great toe)
due to precipitation of urate crystals in the joint space.
The joint becomes red, swollen and extremely painful: requires
immediate treatment.

10. 1. NSAIDs
One of the strong antiinflammatory drugs, e.g. naproxen,
piroxicam, diclofenac, indomethacin or etoricoxib is given in
relatively high and quickly repeated doses.
They are quite effective in terminating the attack
But may take 12–24 hours, i.e. response is somewhat slower than
with colchicine
But they are generally better tolerated
Majority of patients prefer them over colchicine.

11. 2. Colchicine
It is an alkaloid from Colchicum autumnale which was used in
gout since 1763.
The pure alkaloid was isolated in 1820.
Colchicine is neither analgesic nor antiinflammatory, but it
specifically suppresses gouty inflammation.
It does not inhibit the synthesis or promote the excretion of uric
acid.
Thus, it has no effect on blood uric acid levels.

12. Mechanism of action
Colchicine binds to tubulin, a microtubular protein → causing its
depolymerization.
This disrupts cellular functions, such as the mobility of
granulocytes, thus decreasing their migration into the affected area.
Furthermore, colchicine blocks cell division by binding to mitotic
spindles.
Colchicine also inhibits the synthesis and release of the
leukotrienes

13. Therapeutic uses
The anti-inflammatory activity of colchicine is specific for gout,
usually alleviating the pain of acute gout within 12 hours.
NSAIDs have largely replaced colchicine in the treatment of
acute gouty attacks.
Colchicine is currently used for prophylaxis of recurrent attacks
and will prevent attacks in more than 80 percent of patients.

14. Pharmacokinetics
Colchicine is administered orally, followed by rapid absorption
from the GI tract.
It is also available combined with probenecid
Colchicine is recycled in the bile and is excreted unchanged in
feces or urine.
Use should be avoided in patients with a creatinine clearance of
less than 10 mL/min.

16. 3. Corticosteroids
Intraarticular injection of a soluble steroid suppresses symptoms
of acute gout.
Crystalline preparations should not be used.
It is indicated in refractory cases and those not tolerating
NSAIDs/colchicine.
Systemic steroids are rarely needed.
They are highly effective and produce nearly as rapid a response
as colchicine

17. But are reserved for patients with renal failure/history of peptic
ulcer bleed in whom NSAIDs are contraindicated or for cases not
responding to or not tolerating NSAIDs.
Prednisolone 40–60 mg may be given in one day, followed by
tapering doses over few weeks

18. CHRONIC GOUT
When pain and stiffness persist in a joint between attacks, gout
has become chronic.
Other cardinal features are hyperuricaemia, tophi (chalk-like
stones under the skin in pinna, eyelids, nose, around joints and
other places) and urate stones in the kidney.
In majority of patients, hyperuricaemia is due to undersecretion
of uric acid, while in few it is due to over production.
Chronic gouty arthritis may cause progressive disability and
permanent deformities.

19. Uricosuric agents: Probenecid and sulfinpyrazone
The uricosuric drugs are weak organic acids that promote renal
clearance of uric acid by inhibiting the urate-anion exchanger in the
proximal tubule that mediates urate reabsorption.
Probenecid a general inhibitor of the tubular secretion of organic
acids, and sulfinpyrazone, a derivative of phenylbutazone, are the
two most commonly used uricosuric agents.
At therapeutic doses, they block proximal tubular resorption of
uric acid.
At low dosage, these agents block proximal tubular secretion of
uric acid.

20. Probenecid blocks the tubular secretion of penicillin and is
sometimes used to increase levels of some antibiotics.
It also inhibits excretion of naproxen, ketoprofen, and
indomethacin.
Probenecid should be avoided if the patient’s creatinine
clearance is less than 50 ml/min.
Sulfinpyrazone is contraindicated in patients with bone marrow
suppression and periodic complete blood count monitoring is
commended during treatment with sulfinpyrazone.
In the United States, sulfinpyrazone is rarely used today.

21. Probenecid: Interactions
1. In addition to penicillins, probenecid inhibits the urinary
excretion of cephalosporins, sulfonamides, Mtx and indomethacin.
2. It inhibits biliary excretion of rifampicin.
Pyrazinamide and ethambutol may interfere with uricosuric
action of probenecid.
3. Probenecid inhibits tubular secretion of nitrofurantoin which
may not attain antibacterial concentration in urine.
4. Salicylates block uricosuric action of probenecid.

22. Pharmacokinetics
Probenecid is completely absorbed orally
90% plasma protein bound
Partly conjugated in liver and excreted by the kidney
Plasma t½ is 6–8 hours.
Adverse effects
Probenecid is generally well tolerated.
Dispepsia is the most common side effect
It should be used cautiously in peptic ulcer patients.
Rashes and other hypersensitivity phenomena are rare.
Toxic doses cause convulsions and respiratory failure.

23. B. URIC ACID SYNTHESIS INHIBITORS
Allopurinol
Allopurinol is a purine analog.
It reduces the production of uric acid by competitively inhibiting
the last two steps in uric acid biosynthesis that are catalyzed by
xanthine oxidase
Uric acid is less water soluble than its precursors.
When xanthine oxidase is inhibited, the circulating purine
derivatives (xanthine and hypoxanthine) are more soluble and,
therefore, are less likely to precipitate.

25. Therapeutic uses
Primary hyperuricemia of gout
Hyperuricemia secondary to other conditions, such as that
associated with certain malignancies or in renal disease.
This agent can be used if the patient’s creatinine clearance is less
than 50 mL/min, in which case, the dosage should be reduced.

26. Pharmacokinetics
Allopurinol is completely absorbed after oral administration.
The primary metabolite is alloxanthine (oxypurinol), which is
also a xanthine oxidase inhibitor with a half-life of 15 to 18 hours.
The half-life of allopurinol is 2 hours.
Thus, effective inhibition of xanthine oxidase can be maintained
with once-daily dosage.
The drug and its active metabolite are excreted in the feces and
urine.

27. Drug Interactions
(a) Allopurinol inhibits the degradation of 6-mercaptopurine and
azathioprine: their doses should be reduced to 1/3rd, but not that
of thioguanine, because it follows a different metabolic path (S-
methylation).
(b) Probenecid given with allopurinol has complex interaction;
while probenecid shortens t½ of alloxanthine, allopurinol
prolongs t½ of probenecid.
(c) Allopurinol can potentiate warfarin and theophylline by
inhibiting their metabolism.
(d) A higher incidence of skin rashes has been reported when
ampicillin is given to patients on allopurinol.

28. Adverse effects
These are uncommon.
Hypersensitivity reaction consisting of rashes, fever, malaise
and muscle pain is the most frequent.
Renal impairment increases the incidence of rashes and other
reactions to allopurinol.
Stevens-Johnson syndrome is a rare but serious risk.
Gastric irritation, headache, nausea and dizziness are
infrequent; do not need withdrawal.
Liver damage is rare.

29. Febuxostat
Febuxostat is a new xanthine oxidase inhibitor.
Although it is structurally unrelated to allopurinol, it has the
same indications as those of allopurinol.
The same drug interactions with 6-mercaptopurine,
azathioprine, and theophylline apply.
Its adverse effect profile is similar to that of allopurinol.