1. Antiuricaemic drugs
Dr A.W Olusanya

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

3. 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

4. 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,

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

6. Nephron

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

8. 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

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

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

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

12. 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

13. 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.

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

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

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

18. Adverse effects Gastrointestinal disturbances
Allergic reactions – skin rashes

19. 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.

20. Newer agents

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

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

24. 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.