Download Treatment of Gout Colchicine Allopurinol Probenecid

Treatment of Gout
Therapeutic strategies for gout involve lowering the uric acid level below the saturation point (<6 mg/dL), thus preventing the deposition of urate crystals.
This can be accomplished by 1) interfering with uric acid synthesis with allopurinol, 2) increasing uric acid excretion with probenecid or sulfinpyrazone, 3) inhibiting leukocyte entry
into the affected joint with colchicine, or 4) administration of NSAIDs.
Drugs
Mechanism of Action
Colchicine
1- 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.
- a plant alkaloid, used for:
1- the treatment of acute &
chronic gout.
2- prophylaxis of recurrent
attacks .
Side effects
2- Furthermore, colchicine blocks cell division by binding to
mitotic spindles.
3- Colchicine also inhibits the synthesis and release of the
leukotrienes (see Figure 41.15).
Allopurinol
It's effective in the treatment
of primary hyperuricemia of
gout and hyperuricemia 2ry
to other conditions, e.g
malignancies , renal disease.
Allopurinol is preferred in
patients with excessive uric
acid synthesis, with previous
histories of uric acid stones,
or with renal insufficiency.
Uricosuric agents:
Probenecid
Sulfinpyrazone
first-line agents for patients
with gout associated with
reduced urinary excretion of
uric acid.
1- nausea, vomiting, abdominal pain, and diarrhea
2- Chronic administration may lead to
myopathy, neutropenia, aplastic anemia, alopecia.
The drug should not be used in pregnancy, and it
should be used with caution in patients with
hepatic, renal, or cardiovascular disease.
It is a purine analog.
1- Hypersensitivity reactions, especially skin
rashes,
It reduces the production of uric acid by competitively
inhibiting the last two steps in uric acid biosynthesis that are
catalyzed by xanthine oxidase.
2- GI side effects, such as nausea and diarrhea.
[Note: 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.]
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.
At therapeutic doses, both drugs block proximal tubular
resorption of uric acid.
3- Allopurinol interferes with the metabolism of the
anticancer agent 6-mercaptopurine and the
immunosuppressant azathioprine, requiring a
reduction in dosage of these drugs.
1- GI side effects, such as nausea and diarrhea.
2- Probenecid blocks the tubular secretion of
penicillin and is sometimes used to increase
levels of the antibiotic.
Glucocorticoids dramatically reduce the manifestations of inflammations
(for example, rheumatoid and osteoarthritic inflammations)
The effect of glucocorticoids on the inflammatory process
includes:
1- redistribution of leukocytes to other body compartments,
thereby lowering their blood concentration.
2- increase the concentration of neutrophils;
Adrenal
steroids
3- decrease the concentration of lymphocytes, basophils,
eosinophils, and monocytes.
4- inhibition of the ability of leukocytes and macrophages to
respond to mitogens and antigens.
5- decreased production of prostaglandins and
leukotrienes is believed to be central to the antiinflammatory action.
6- Reduction the amount of histamine that is released from
basophils and mast cells, thus diminishing the activation
of the kinin system.
Treating acute gout
It results from excessive alcohol consumption, a diet rich in purines, or
kidney disease.
Acute attacks are treated with indomethacin to decrease movement of
granulocytes into the affected area;
[Note: Aspirin is contraindicated, because it competes with uric acid for the organic acid secretion
mechanism in the proximal tubule of the kidney.]
Intra-articular administration of glucocorticoids (when only one or two joints
are affected) is also appropriate in the acute setting.
Treating chronic gout
Chronic gout can be caused by :
1) a genetic defect, such as one resulting in an increase in the rate of purine
synthesis 2) renal deficiency; 3) Lesch-Nyhan syndrome;
4) excessive productionof uric acid associated with cancer chemotherapy
- Treatment strategies for chronic gout include:
1- the use of uricosuric drugs that increase the excretion of uric acid, thereby
…..reducing its concentration in plasma,
2- the use of allopurinol, which is a selective inhibitor of the terminal steps in
…..the biosynthesis of uric acid.