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Drugs used in Gout

Lamere Nsangou Philippe N.K.

Medical student, FMBS.

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Gout

• Inflammatory response to increased uric acid level– Increased production or decreased

excretion– Uric acid is the end-metabolic product of

purines in humans and must be eliminated

• 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 non-competitive 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• Acute attacks of gouty arthritis occur early in treatment with allopurinol, when urate crystals are being withdrawn from the tissues and plasma levels are below normal.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)04/07/23

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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 cyclophosphamide (by inhibiting liver metabolism of the drug)• Outcome: severe bone marrow suppression

– Increases plasma concentration of theophylline and aminophylline.

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Clinical uses of allopurinol

• Special indications of allopurinolChronic 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. 04/07/23 12

Febuxostat:(ADENURIC)Non- Purine Selective Inhibitor of

XO– Febuxostat has been shown to

potently 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. 04/07/23 13

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 stimulation but depresses it by a direct effect, and

• alters neuromuscular function 04/07/23

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Colchicine

• Chemistry. The structural formula of colchicine is:

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Colchicine (cont’d)

• 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 04/07/23

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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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