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Drugs used in treatment of gout

This document discusses drugs used to treat gout. It begins by classifying the objectives and associated drugs for treating gout, including relieving inflammation/pain with NSAIDs and colchicine, and preventing attacks by inhibiting uric acid formation with allopurinol and febuxostat or augmenting excretion with probenecid. It then provides details on the mechanisms, pharmacokinetics, indications, interactions and adverse effects of various drugs including colchicine, probenecid, allopurinol, febuxostat, NSAIDs and corticosteroids. It concludes by recommending NSAIDs as first line for acute gout and allopurinol as first line for chronic g

Health & Medicine◦
Drugs used in Treatment of Gout Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Lecturer, Lumbini Medical College & TH 22 March 2019 (8 Chaitra 2075), Friday
By the end of this class, MBBS 1st Sem students will be able to:  Classify drugs used in the treatment of gouty arthritis  Discuss the pharmacology of drugs used in gouty arthritis
Gout  Is marked by transient attacks of acute arthritis initiated by crystallization of monosodium urate within and around joints  May also get deposited in kidneys and subcutaneous tissue (tophi)  Is always preceded by hyperuricemia
Drugs useful in gout Objective of treatment Drugs Relieve inflammation and pain NSAIDs, colchicine, glucocorticoids Prevent inflammatory responses NSAIDs, colchicine Inhibit urate formation Allopurinol, febuxostat Augment urate excretion Probenecid
Drugs useful in Gout Acute Gout Chronic Gout NSAIDs: • Naproxen • Indomethacin • Diclofenac Uricosuric: • Probenecid • Lesinurad • Benzbromarone • Sulfinpyrazone Colchicine Synthesis inhibitor: • Allopurinol • Febuxostat Corticosteroids: • Prednisolone Increase metabolism: • Pegloticase • Rasburicase
Colchicine  Alkaloid derived from C. autumnale  Specifically suppresses gouty inflammation  Faster acting than NSAIDs  Control of attack 6-12 hrs  Complete resolution 3-5 days  Higher toxicity than NSAIDs
Colchicine: Mechanism of action  Acts by:  Inhibiting release of chemotactic factors and glycoproteins  Binds to fibrillar protein and inhibits granulocyte migration to joints  Also has amitotic action and increases gut motility • Subsequent steps Inhibited • Vicious cycle interrupted
Colchicine: Pharmacokinetics  Rapidly absorbed orally  Partly metabolised by liver and excreted in bile  Undergoes hepatic circulation  Takes long to get eliminated  Metabolised by CYP3A4 isoenzymes  Drug interactions with enzyme inhibitors/inducers  Gets eliminated in urine and faeces  Dose reduction in renal impairment
Colchicine: Adverse effects  Dose limiting side effects:  Nausea, vomiting, abdominal pain, diarrhoea  Chronic administration:  Myopathy, neutropenia, aplastic anaemia, alopecia  Overdose:  Kidney damage, CNS depression, intestinal bleeding  Death: muscular paralysis and respiratory failure  Fatal dose: 7-10 mg
Colchicine: Uses  To abort an attack of gout:  0.5-1.5 mg stat  To control an acute attack of gout:  Second line, fastest acting  0.5 mg 1-3 hourly, 4 doses in a day  Maximum dose: 6 mg over 3-4 days  As maintenance dose in gout:  0.5-1 mg/d (4-8 weeks)
Probenecid  Enhances excretion of uric acid by:  Blocking Urate transporter-1 (URAT-1)  A type of organic anion transport protein (OATP)  Predominant reabsorption of uric acid in kidney (PCTs)  Reabsorption of uric acid in PCT inhibited  Excretion enhanced, blood urate level falls
Probenecid: Interactions  Inhibits urinary excretion of:  Indomethacin, naproxen  Penicillin, sulphonamides, methotrexate  Inhibits biliary excretion of rifampicin  Inhibits tubular excretion of nitrofurantoin  Action of probenecid decreased by:  Pyrazinamide, ethambutol  Aspirin
Probenecid: Indications  Chronic gout and hyperuricaemia  Second line drug  0.25 mg twice daily  0.5 mg twice daily  Colchicine/NSAIDs cover needed  Prolong action of penicillin  Gonorrhoea, Sub Acute Bacterial Endocarditis  Prevent cidofovir induced nephrotoxicity  CMV retinitis
Probenecid  Adverse effects:  Generally well tolerated  Dyspepsia  Caution in patients with peptic ulcer disease  Rashes, other hypersensitivity reaction  Avoid in patients with renal insufficiency, renal calculi  Advice to drink plenty of fluids
Allopurinol  Substrate as well as inhibitor of xanthine oxidase enzyme Purines Hypoxanthine Xanthine Uric acid Xanthine oxidase Xanthine oxidase Allopurinol Alloxanthine • Short acting • Competitive inhibitor • Long acting • Non-competitive inhibitor
Allopurinol: Mechanism of action  Inhibits xanthine oxidase (XO)  Directly  By getting converted to alloxanthine  Decreased concentration of uric acid in plasma  Hypoxanthine and xanthine concentration increased  All three metabolites excreted in urine  Increase hypoxanthine and xanthine leads to feedback inhibition of de novo purine synthesis as well
Allupurinol  Pharmacokinetics:  Metabolised largely to alloxanthine  Metabolism inhibited on chronic administration  Interactions:  Inhibits degradation of 6-mercaptopurine, azathioprine, warfarin, theophylline  Complex interaction with probenecid
Allopurinol: Indications  Chronic gout  First line drug  Given for long duration  100 mg/d  300 mg/d; maximum 600 mg/d  Patients advised to drink plenty of water  Secondary hyperuricaemia  Potentiate 6-MP, azathioprine
Allopurinol: Adverse effects  Attacks of acute gout during start of therapy  NSAIDs/Colchicine cover required  Hypersensitivity reaction, Steven-Johnson syndrome  Contraindicated  Gastric irritation, headache, nausea, dizziness  Liver damage
Febuxostat  Non-purine XO inhibitor  Adverse effect:  Liver damage  Hypersensitivity reaction  Diarrhoea, nausea, headache  Used as an alternative to allopurinol  Not to be combined with allopurinol  Dose: 40 mg/d  80 mg/d; maximum 120 mg/d
Pegloticase  Recombinant uricase  Oxidises uric acid to allantoin  Highly soluble  Coupled to methoxy polyethylene glycol  Refractory symptomatic gout  Given intravenously, every 2 weeks  ADRs: infusion reactions, development of antibodies Pegylated For uric acid Metabolising enzyme
NSAIDs in Gout  Naproxen, indomethacin, diclofenac, etoricoxib  Better tolerated than colchicine  Uses:  To terminate the attack of acute gout  Frequent high doses  Takes 12-24 hours, complete resolution in 5-10 days  As a cover till effects of other anti-gout drug effects develops
NSAIDs in gout Drug Dose Naproxen 750 mg stat  250 mg, three times a day till attack subsides Indomethacin 50 mg, three time a day till attack subsides  25 mg three time a day for 5-7 days Diclofenac 50-75 mg, three times a day Etoricoxib 60-120 mg, once daily
Corticosteroids in gout  Suppress symptoms of acute gout  Can be given by:  Intraarterial injection  Triamcinolone 10-30 mg  Avoid crystalline preparation  Indicated when few joints are involved, those not tolerating NSAIDs/colchicine
Corticosteroids in gout  Suppress symptoms of acute gout  Can be given by:  Systemic administration (oral)  Indicated for patients with renal failure/peptic ulcer, non-responders, not tolerating  Prednisolone 40-60 mg  tapered over 1-2 weeks
Conclusion  NSAIDs are the drug of choice for treatment of acute gout  Indomethacin, naproxen  Allopurinol is the drug of choice for treatment of chronic gout  Probenecid cannot be used in patients with renal impairment, and is associated with risk of renal stones
Let’s have a break…  Any queries?  Next class:  Skeletal muscle relaxants  Thank you