Antiuricaemic drugs Dr A.W Olusanya

Objectives Classify anti-uricaemic drugs Classify drugs used in the management of gout

Introduction - Uric acid Derived from purine metabolism and diet Normal range <6 for women and <7mg/dl for men Excreted in the kidney -70% and GIT – 30% Elevation – Increased production and REDUCED EXCRETION

Causes of hyperuricaemia Excessive intake – meat, organ meat, sardine, mackerel, Beer Increased production – leukaemia, rhabdomyolysis, cytotoxic therapy, enzyme deficiency HGPRT Defective excretion – glomerulopathy, tubular pathology, diuretics, diabetic ketoacidosis, starvation ketosis,

Uric acid synthesis. Adenosine monophosphate Inosine monophosphate HGPRT Hypoxanthine Xanthine oxidase Xanthine Xanthine oxidase Uric acid

Nephron

Manifestations Asymptomatic Gout- acute monoarthritis big toe or other joints. Nephrolithiasis – flank pain, abdominal pain, nausea , vomiting Uric acid nephropathy Metabolic syndrome

Gout Metabolic disorder/Inflammatory Na urate gets deposited in the synovial membrane Activation of the Inflammatory cascade Monoarticular arthritis – big toe Pain and swelling in the affected joint

Gout - Pathophysiology Uric acid crystals deposits in joints Inflammatory response Destruction of joint Pains, Swelling, LOF

Treatment of gout Gout – Acute treatment – Anti-inflammatiory Long term –Dietary and antiuricaemic drug

Treatment of gout. Non – Pharmacological Dietary – Reduce meat, organ meat, alcohol, sardine, mackerel Pharmacological

Drug treatment of gout Anti-inflammatory Urate lowering drugs Non-steroidal anti-inflammatory drugs Uric acid synthesis inhibitor – Allopurinol, febuxostat Steroids Uricosuric - Probenecid, benzbromarone, sulfinpyrazone Colchicine Selective uric acid reabsorption inhibitor – Lesinurad Recombinant Urate oxidase – Pegloticase, Rasburicase

Colchicine For acute attacks and to prevent gouty attacks on commencement of anti-uricaemic drugs. MOA – inhibits migration of neutrophils to the affected joint by binding to tubulin. Also prevents activation and degranulation of neutrophils to generate inflammatory cytokines. Oral route Adverse effects – nausea, vomiting, abdominal pain.

Allopurinol A xanthine oxidase inhibitor Hypoxanthine analogue Substrate competition – hypoxanthine Converted to alloxanthine / oxypurinol which non competitively inhibits xanthine oxidase.

Pharmacokinetics. Routes of administration – oral, intravenous Bioavailability -49-53% Onset of action -2-3 days Peak plasma time – 0.5 -2 hours Time to peak effect – 7-14 days

Distribution - protein bound <1% Volume of distribution – 1.6-2.4 L/kg Metabolized in the liver – oxypurinol (active) allopurinol riboside Half –life – Parent drug 1-3hours Active metabolites 15-20hors

Adverse effects Gastrointestinal disturbances Allergic reactions – skin rashes

Febuxostat A xanthine oxidase inhibitor First discovered in 1998 Licenced for use in 2008 in Europe and 2009 in the US Less likely to cause severe hypersensitivity reaction Does not inhibit other enzymes involved in purine and pyrimidine synthesis.

Newer agents

Probenecid Competitively inhibits reabsorption of uric acid in PCT Avoid uric acid nephrolithiasis Adverse effects – GI, Hypersensitivity reactions

Other agents Selective uric acid reabsorption inhibitor – Lesinuraud Inhibits URAT1 enzyme and OAT4

Recombinant urate oxidase enzyme Pegloticase and Rasburicase Converts urate to allantoin A soluble form which is excreted in urine. Pegloticase – indicated if xanthine oxidase fails/contraindicated Rasburicase – for prophylaxis and treatment of hyperuricaemia associated with treatment of malignancies.