Drugs used in Gout

Lamere Nsangou Philippe N.K. Medical student, FMBS.

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Gout
Inflammatory response to increased uric acid level
purines in humans and must be eliminated
Increased production or decreased excretion Uric acid is the end-metabolic product of

Uric acid crystals deposited in synovial space Four stages of disease progression;

Asymptomatic hyperuricaemia Attacks of gouty arthritis Asymptomatic inter-critical period Tophaeceous gout

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Drug Therapy for Gout

Drug targets
Inhibition of uric acid synthesis Increase uric acid secretion (uricosuric

agents) Inhibit leukocyte migration into the joint Relief of inflammation

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Inhibition of uric acid synthesis

Prototype drug: Allopurinol (ZYLORIC ) Mechanism of action:
reduces synthesis of uric acid by inhibiting

Xanthine Oxidase competitively It is an analogue of hypoxanthine Allopurinol is converted to alloxanthine by xanthine oxidase and this metabolite which has a long half-life is an effective noncompetitive inhibitor of the enzyme.

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Mechanism of action of allopurinol

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PK of allopurinol
Allopurinol is Well absorbed, half-life of

2-3hrs Metabolised to alloxanthine (or oxypurinol), Alloxanthine has a half-life of 25 hrs and is responsible for most of the action,
as a result, allopurinol could be administered

once a day

Alloxanthine undergoes renal

elimination

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Adverse effects of allopurinol

Acute attacks of gouty arthritis occur early in treatment with allopurinol, when urate crystals are being withdrawn from the tissues and plasma levels are below normal.
(To prevent acute attacks, colchicine or indomethacin)

Gastrointestinal intolerance,
including nausea, vomiting, and diarrhea

Peripheral neuritis and necrotizing vasculitis, Depression of bone marrow An allergic skin reaction
characterized by pruritic and maculopapular lesions Isolated cases of exfoliative dermatitis have been

reported.

Increases transaminases (liver enzymes)

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Toxicity and drug-drug interactions of allopurinol

Toxicity of allopurinol
Mild GIT reactions Drowsiness, headache, metallic taste Rare fatal hypersensitivity syndrome

Drug interactions
Allopurinol inhibits the metabolism of oral anti-

coagulants

Outcome: increasing the risk of haemorrhage

It increases the effects of mercaptopurine and

Outcome: severe bone marrow suppression

cyclophosphamide (by inhibiting liver metabolism of the drug) aminophylline.

Increases plasma concentration of theophylline and

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Clinical uses of allopurinol

Special indications of allopurinol
Chronic tophaceous gout, Treatment of gout when probenecid or

sulfinpyrazone cannot be used because of adverse effects or allergic reactions, or when they are providing less than optimal therapeutic effect; for recurrent renal stones associated with high blood uric levels Treatment of gout in patients with renal functional impairment !!! Indicated to prevent the massive uricosuria following chemotherapy of leukemia. (Uricosuria could lead to renal calculi)
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uricosuric agents
Probenecid and sulfinpyrazone
Mechanism of action
Inhibit re-absorption of uric acid at the proximal

tubules of kidneys

Adverse effects
Mild GIT symptoms Uric acid deposits in kidney
Alkalise urine

Drug interactions
Probenecid blocks tubular excretion of penicillin

(therefore use to increase levels of the antibiotics) Inhibits excretion of naproxen, ketoprofen and indomethacin

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Febuxostat:(ADENURIC) Non- Purine Selective Inhibitor of XO

Mechanism of action
Uric acid is the end product of purine

metabolism in humans and is generated in the cascade of hypoxanthine xanthine uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar.
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Febuxostat:(ADENURIC) Non- Purine Selective Inhibitor of XO

inhibit both the oxidized and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase. Aug-12 13
Febuxostat has been shown to potently

Febuxostat:(ADENURIC) Non- Purine Selective Inhibitor of XO

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Colchicine
It is plant alkaloid (autumn crocus, Colchicum autumnale). M.O.A:
Binds to tubulin (a micro-tubular protein), then

causes it depolymerisation. This disrupts cellular functions such as the mobility of granulocytes and release of histamine containing granules from mast cells. Colchicine blocks cell division by binding to mitotic spindles Inhibit leucocyte migration into the joint

Other actions of colchicine

It lowers body temperature, It enhances gastrointestinal activity by neurogenic
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stimulation but depresses it by a direct effect, and alters neuromuscular function

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Colchicine
Chemistry. The structural formula of colchicine is:

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Colchicine (contd)
PK:

Oral administration Rapid absorption It is available combined with probenecid Colchicine is recycled in the bile and excreted unchanged in the feces and urine

Adverse effects
Diarrhoea (very frequent) Nuasea, vomiting, abdominal pains and

diarrhoea Chronic administration: agranulocytosis, aplastic anaemia, alopecia

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Uses colchicine
Acute gout Colchicine is now used for the

prophylaxis of recurrent episodes of gouty arthritis, is effective in preventing attacks of acute Mediterranean fever, a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis.

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