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DRUG TREATMENT FOR GOUT

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Pathophysiology

Uric acid is end product of purine metabolism and is excreted by the kidneys

Causes of hyperuricemia- excess alcohol, obesity Rich foods have a higher concentration of

protein Diet high in purines will not cause gout, but may

trigger an attack in a susceptible person Great toe joint most common first manifestation;

other joints may be the foot, ankle, knee, or wrist

Pathophysiology

Drugs used in gout

ACUTE GOUT Inhibit neutrophil migration into the joints-

COLCHICINE, Inhibition Of Inflammation And Pain-

NSAIDs, PREDNISOLONE, CHRONIC GOUTWhich inhibit uric acid synthesis-

ALLOPURINOL, FEBUXOSTATWhich increase uric acid excretion:

PROBENACID, SULPHINPYROZONE, BENZBROMARONE

Colchicine

Alkaloid from COLCHICUM AUTOMNALE It supresses the gouty inflammatory response and gives

relief within 24-48 hours Prevents granulocyte migration into the inflamed joint Inhibit the release of glycoproteinlactic acidrelease of

lysosomal enzymesjoint destruction Binding to intracellular protein TUBULIN and cause

depolymerization and disappearance of microtubules in granulacytes prevents migration of granulocyte drunken walk

It inhibits formation of leukotriene B4

Colchicine

INDICATIONS-prophylactic dose-0.5mg/kg-treatment of acute gout

ADVERSE EFFECTS-Diarrhoea, vomiting, abd’inal painAcute intoxication-bloody diarrhoea, hematuriaChronic- agranulacytosis, peripheral neuritisFatal ascending CNS depressionDRUG INTERACTION : Statins, Macrolides,

CyclosporineCONTRAINDICATED in dialysis pt.sCAUTIOUS USE in : renal or liver dysfunction; active

infection, age > 70

NSAIDs

INDOMETHACIN, NAPROXEN, PIROXIXCAM Inhibition of prostaglandin synthase Inhibit urate crystal phagocytosis and chemotactic

migration of leukocytes into inflamed joint ASPIRIN—uricosuric at doses >3.6g/day OXAPROZIN-lowers serum uric acid, but should be

used cautiously in uric acid stones

Corticosteroids

Reserved for refractory cases not tolerating NSAIDs and colchicine

Prednisolone 40-60mg/day Tapering dose Intra articular injection of soluble steroid

Drugs used for chronic gout

Uric acid synthesis inhibitor: ALLOPURINOL Purine anti-metabolite but not analgesic, not anti-

inflammatory Blocks conversion of hypoxanthine to uric acid by

competatively inhibiting enzyme xanthine oxidase Alloxanthine –major metabolite-is long acting-24hrs Decrease concentrtn of insoluble urates in tissues,

plasma, urine Effective in overproducers May be effective in under excretors

Uric acid synthesis inhibitor: ALLOPURINOL

It has longer duration of action-ODUses Chronic gout, gouty tophi, or nepropathyRecurrent urate stonesPatients allergic to uricosuric drugsSecondary hyperuricemia due to Ca chemotherapyKalazar- allopurinal+ sod.stibogluconate-alters purine

metabolism

Adverse effects

Oxypurinol, allopurinol metabolite, cleared by kidney and accumulates in patients with renal failure

Oxypurinol inhibits xanthine oxidase Increased oxypurinol related to risk of allopurinol

hypersensitivity syndrome GIT distress, ph. Neuritis and cataract formation

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allopurinol oxypurinol

Xanthine Oxidase

Stevens-Johnson Syndrome

Allopurinol Hypersensitivity Syndrome

Toxic Epidermal Necrolysis

Drug interaction

1. Interferes with metabolism of hep.iron stores2. It reduces metabolism of 6-mercaptopurine3. Azathioprine dose is decreased to 1/4th

4. Inhibits metabolism of oral anticoagulants and thiophylline

Febuxostat

Potent inhibitor of xanthine oxidase decreases uric acid

Treatment of chronic gout or secondary hyperuricemia

Suitable in patients intolerant to allopurinol ADR-liver dysfunction, diarrhoea,

URICOSURIC AGENTS

PROBENACID-acts by promoting the excretion of uric acid by inhibiting active reabsorption from renal tubules

Reverses most common physiologic abnormality in gout ( 90% pt.s are under excretors)

Urine excretion of uric acid increases, size of urate pool decreases and tophacious deposits of urate are reabsorbed with relief from arthritis

Not an analgesic or anti-inflammatory drug

URICOSURIC AGENTS

Uses- treatment of secondary hyperuricemia Should not be used in acute goutcan be given with

NSAIDsDrug interaction- prolong penicillin or cephalosporin

levels, inhibits biliary excretion of rifampicin, low dose aspirin blocks uricosuric action of probenacid

ADR- should be given with plenty of water and urinary alkaliniser GIT distress, dyspepsiaallergic dermatitis,higher doses- nephrotic syndrome

Sulfinpyrazone

Structurally related to phenyl butazone At sub therapeutic doses, prevents secretion of uric

acid into tubular fluid. At therapeutic doses- prevents resorption of uric

acid, increases excretion in urine If urate is high, urinary alkaliniser is added

D/I-In chronic gout- uricosuric action is additive to probenacid.

It inhibits metabolism of warfarin and sulfonylureas

BENZBROMARONE

Newer more potent uricosuric drug Used in patients allergic or refractory to probenacid

and sulfinpyrazone MOA- reversible inhibiitor of tubular reabsorption With allopurinol more effective With aspirin/ sulfinpyrazone-antagonistic action ADR- GIT distress

Pegloticase

Newest urate lowering therapy Recombinant mammalian uricase that is covalently

attached to mPEG Declines uric acid levels within 24-72hrs T1/2 - 6.4-13.8 days Urate oxidase enzyme absent in humans, converts

uric acid to allantoinADR- Infusion reaction, neprolithiasis, UTI

Interleukin-1 inhibitors

ANAKINRA, CANAKINUMAB, RILONACEPT

Drugs targeting IL-1 pathway Tried in patients refractory to traditional drugs It is fully human anti-IL1β monoclonal antibody It prevents gouty flares during urate lowering therapy It can provide rapid and sustained pain relief

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