PHARMACOTHERPY OF GOUT .treatment of goutpptx

gout treatment

1. PHARMACOTHERAPY OF GOUT

2. OBJECTIVES: Pathophysiology of Gout Treatment of Acute Gouty Arthritis Treatment of Chronic Gout/Hyperuricemia

3. WHAT IS GOUT? Gout is a metabolic disorder characterised by recurrent attacks of acute inflammatory arthritis associated with hyperuricemia. Associated with precipitation of mono sodium urate crystals in metatarsophalangeal joints, kidney and subcutaneous tissue. Acute gout presents as painful distal monoarthritis . Can cause subcutaneous tophi, renal calculi and joint destruction.

4. URIC ACID METABOLISM: XANTHINE OXIDASE XANTHINE OXIDASE

5. WHAT GOES WRONG? XANTHINE OXIDASE XANTHINE OXIDASE GOUT INCREASED URIC ACID SYNTHESIS DECREASED RENAL EXCRETION

6. SECONDARY HYPERURICEMIA: INCREASED URIC ACID PRODUCTION: Leukaemia Lymphoma Polycythaemia REDUCE URIC ACID EXCRETION: Drug induced – Thiazides, Furosemide, Pyrazinamide, Ethambutol, Levodopa. CHEMOTHERAPY/RADIATION

7. NATURAL HISTORY OF GOUT: STAGE FEATURES PHARMACOLOGICAL INTERVENTION 1. Asymptomatic hyperuricemia Plasma rate> 60mg/dl – women >70mg/dl - men None 2. Acute Gout Acute arthritis – 1 st metatarsophalangeal joint Excruciating pain NSAIDs Colchicine Glucocorticoids 3. Intercritical phase Asymptomatic hyperuricemia -10% may never have another attack. None 4. Chronic Gout Hyperuricemia Development of Tophi Recurrent attacks of Acute Gout. Alloprinol Probenecid Sulfinpyrazone

8. MECHANISM OF INFLAMMATORY RESPONSE TO URATE CRSTALS:

9. GOALS OF TREATMENT: 1. Decrease the symptoms of an acute attack. 2. Decrease the risk of recurrent attacks. 3. Lower serum urate levels.

10. PHARMACOTHERAPY OF GOUT:

11. SITE OF ACTION OF DRUGS: XANTHINE OXIDASE XANTHINE OXIDASE GOUT URICOSURIC AGENTS - PROBENECID XANTHINE OXIDASE INHIBITORS - ALLOPURINOL DECREASED URIC ACID SYNTHESIS

12. MANAGEMENT OF ACUTE GOUT : NSAIDs: MECHANISM: NSAIDs inhibits Cyclooxygenase – Inhibits Prostaglandin & Thromboxane synthesis – reduce inflammatory response to urate crystals. DRUGS: Naproxen, Piroxicam, Diclofenac, Indomethacin and etoricoxib – strong inflammatory action. Terminate an attack in 12-24 hours. Complete resolution – 5 to 10 days Naproxen & Piroxicam – inhibit chemotactic immigration of leukocytes into inflamed joint. SIDE EFFECTS: Bleeding , salt water retention and renal insufficiency.

13. COLCHICINE: Alkaloid obtained from Colchicum autumnale . MECHANISM : Colchicine binds tubulin inhibits its polymerisation and prevents formation of microtubules and inhibits cell division – G1 phase. Inhibits MSU crystal induced NALP3 inflammasome activation and subsequent production of IL1 β and IL18. Inhibits neutrophil activation: Decreased trafficking of phagocytosed particles to lysosomes.

14. Decrease release of chemotactic factor. Decrease motility and adhesion of neutrophils. Decreases tyrosine phosphorylation of neutrophil proteins – decrease LTB4 synthesis.

15. MECHANISM OF ACTION OF COLCHICINE

16. PHARMACOKINETICS: Well absorbed orally. Metabolised in liver by glucuronidation & demethylation by CYP3A4 excreted in bile via MDR protein. Undergoes – extensive hepatic circulation – leads to diarrhoea. Concentrates in liver, spleen and kidney. Substrate of P-Glycoprotein efflux.

17. TOXICITY : Nausea, vomiting , abdominal cramps and diarrhoea – drug accumulation and inhibits intestinal epithelial cell turnover. Myelosuppression, leukopenia, granulocytopenia , aplastic anaemia and rhabdomyolysis. Kidney damage , CNS depression and intestinal bleeding. Death due to muscular paralysis and respiratory failure.

18. DOSE: Used to control an acute attack. 0.5 mg 1-3 hourly with a total of 4 doses in a day – maximum 6 mg. Control of attack occurs in 6-12hours, complete resolution – 3-5 days. Second course should not be started before 3-7days. Maintenance dose – 0.5-1 mg/day for 4-8 weeks. High toxicity – preferred second to NSAIDs.

19. CORTICOSTEROIDS: Anti inflammatory and immunosuppressive effects. Intra-articular injection of Triamcinolone acetonide – 10mg in toe/finger joints and 30 mg in wrist. Systemic steroids- Reserved for patients with renal failure/ peptic ulcer in whom NSAIDs are contraindicated. Prednisolone 40-69 mg in one day followed by tapering doses over 1-2 weeks.

20. MANAGEMENT OF CHRONIC GOUT: URICOSURIC DRUGS: PROBENECID: Is a lipid soluble organic acid. Competitively blocks active transport of organic acids by OATP. PHARMACOKINETICS : Completely absorbed orally. 90% bound to plasma protein. Conjugated in liver. Hydroxylated to metabolites that retain carboxyl function and have uricosuric action.

21. DRUG INTERACTIONS: Probenecid inhibits urinary excretion of Penicillin, Cephalosporins, Sulphonamides, Methotrexate and Indomethacin. Aspirin blocks uricosuric action of Probenecid. Probenecid inhibits tubular secretion of Nitrofurantoin. Inhibits biliary excretion of Rifampicin, Ethambutol and Pyrazinamide.

22. USES : CHRONIC GOUT AND HYPERURICEMIA: As second line drug – 0.25g BD to 5g BD. Colchicine/NSAIDs cover advised for initial 1-2 months – avoid precipitation of acute gout. Ineffective in renal insufficiency. Liberal fluid intake - to avoid crystallisation. SIDE EFFECTS – Rash, Hypersensitivity, Dyspepsia.

23. URICOSURIC DRUGS:

24. URIC ACID SYNTHESIS INHIBITOR: ALLOPURINOL: MECHANISM: At low concentration – competitively inhibits XO. At high concentration – non competitively inhibits XO. OXYPURINOL – active metabolite – non competitively inhibits XO. Available for oral and intravenous use.

25. USES: Primary and secondary Gout. Hyperuricemia secondary to malignancies. Calcium oxalate calculi. Lesh-Nyhan syndrome Orphan uses – Chagas disease & ex vivo preservation of cadaveric kidney. SIDE EFFECTS: Hypersensitivity – SJS & Toxic Epidermal Necrosis. Leukopenia/leucocytosis and eosinophilia. Hepatomegaly , renal insufficiency. C/I – Pregnancy & lactating mothers.

26. DRUG INTERACTIONS: Allopurinol inhibits – 6-Mercaptopurine and Azathioprine – dose reduced. Allopurinol prolong T1/2 of Probenecid. Potentiates Warfarin and Theophylline by inhibiting their metabolism. ADVICE: Liberal fluid intake – Avoid Xanthine stones. Given with Colchicine – avoid precipitation of acute Gout.

27. FEBUXOSTAT: MECHANISM: Non purine XO inhibitor. ADME: Rapidly absorbed. Metabolised by UGT1A1,1A3,1A9 and oxidation by CYP1A2, 2C8, 2C9. DOSE: 40/80mg oral tablet. Given with NSAIDs/Colchicine to prevent precipitation of acute Gout. S/E: abnormal LFT, nausea, joint pain, rash, MI, Stroke. D/I: Increases level of theophylline, Mercaptopurine & Azathioprine.

28. URICASE:

29. DRUGS ON PIPELINE: BCX4208 : Oral once daily inhibitor of Purine nucleoside phosphorylase enzyme inhibitor reduces uric acid formation. Completed Phase 1B trial – doses -5mg,10mg,20 & 40 mg combined with allopurinol 300 mg/day. 2 . IL-1 β blockers: Urate crystals induced inflammation lead to IL1. Blockade of this pathway decrease Gout flares. Phase III – Rilonacept -320mg subcutaneous .

30. ANAKINRA – 100 mg S.c. Canakinumab – 25,50,100,200 mg – FDA failed to approve – safety concerns. 3. URAT1 INHIBITION: RDEA594 - Nucleoside reverse transcriptase inhibitor –200, 400, 600 mg- oral once daily dosing – uricosuric drug – completed Phase 3. TRANILAST – Anti inflammatory and immunomodulatory drug. URAT1 and GLUT9 inhibitor. NU1618 – combines Tranilast + Allopurinol.

31. REFERENCES: Essentials of Medical Pharmacology – K.D.Tripathi . The Pharmacological Basis of Therapeutics – Goodman & Gilman. Principles of Pharmacology – David E.Golan .

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