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1. Reviews pathopatho-physiology of Gouty arthritis 2. Lists clinical features of Gout 3. Identify general categories of drugs used to treat Gout 4. Understand mechanism of action, pharmacokinetics of
clinical drugs used to treat Gout

5. Lists side effects and drug interactions of drugs used to

treat Gout
366 326-24 slides lid PSPS-55 1 2

CLINICAL PRESENTATION:
is crystal crystal-induced disease in which monosodium urate crystals y are deposited p in tissues
leading g to the release of cytokines, y , inflammatory y mediators, , and molecules that enhance adhesion of leukocytes to the endothelial cells and release mediators from the leukocytes le koc tes
Soft tissue swelling g& Bone erosion

Tophi (pl.) (Tophus)

Podagra

(pain in the first metatarsophalangeal Joint( big toe)) 3

Break through skin> chalky nodule

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Causes of hyperuricemia
Clinical feature: Acute arthritis Hyperuricemia Deposit of f urate in joints , subcutaneous tissues (tophi), kidney
Excessive uric acid synthesis antineoplastic or radiotherapy
cyclosporine, l i mercaptopurine, t i pyrazinamide, i id nicotinic i ti i acid, id inborn error (lack of enzyme) high purine diet alcohol consumption Decreased renal excretion some drugs e.g., thiazide, loop diuretics, low dose aspirin renal disease
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XO
xanthine thi

HGPRT + PRPP i i t + PPi inosinate h hypoxanthine thi HGPRT G Guanylate l t + PPi guanine + PRPP Salvage pathway

1) Treat acute gouty arthritis (antiinflammatory)

Colchicine NSAIDs e.g. Indomethacin

XO
Uric acid
Salvage pathway for recycling of purine bases to form nucleotide, inosinate, and guanylate HGPRT = hypoxanthine guanine phosphoribosyltransferase PPi = pyrophosphate PRPP = 5-phosphoribosylphosphoribosyl 1-pyrophosphate pyrophosphate XO = xanthine oxidase

2) Restoring the plasma urate concentration to normal 2.1 Decreasing uric acid formation
Allopurinol (Xanthine oxidase inhibitor) Febuxostat

2.2 Uricosuric agents

Probenecid Sulfinpyrazone Benzbromarone

Sodium urate crystals

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1) Colchicine
Mechanism of action Binds to tubulin (microtubular protein) t i )

Alkaloid of Colchicum autumnale

Therapeutic uses
Immobility of granulocytes

depolymerization

Acute gout attack (antiinflammatory activity, activity within 12 hr) Prophylactic in chronic gout, especially frequent recurrent of attacks
Pharmacokinetics Ph ki ti oral, intravenous, absorb rapidly from GI tract, enterohepatic circulation, long half-life, half life excreated unchanged in feces or urine narrow therapeutic window (2nd line drug) Adverse effects GI irritate, N/V diarrhea*, alopecia leukocytosis l k i (i (increase iimmature WBC) WBC), , bone b marrow suppression), agranulocytosis, aplastic anemia, anemia, neuromyopathy Contraindication Gastrointestinal, Hepatic failure Blood dyscrasias y Should not be use in p pregnancy g y

Blocks cell division by binding to mitotic spindles (interfere with microtubule and spindle formation)

Decreasing migration to inflammatory area

Inhibits the synthesis and release of the leukotriene B4 (rigid cell membrane of neutrophils) & inhibit phagocytosis

Inhibits leucocytes migration into the joint

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Anti-inflammatory & analgesic effects Anti(Anti(Anti -COX2 COX2: Anti PG)

Short h half alf life, maximal dose 3-4 days Indomethacin*, Ibuprofen, Diclofenac, Naproxen, Naproxen Sulindac, Sulindac Celecoxib, Celecoxib Etoricoxib

Except for: Aspirin (uric acid effect)& phenylbutazone

Pathophysiology p y gy in gouty g y joint j Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear
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Therapeutic use: Delayed to see MD. No contraindication of NSAIDs Quit NSAIDs after disappearing of acute arthritis (Taper dose 7-10 days)
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(purine analog)
M h i Mechanism of f action ti
hypoxanthine (more soluble) xanthine (more soluble) Oxypurinol (alloxanthine) Pharmacokinetics
metabolized t b li d b by XO (lik (like uric i acid), id) bioavialability bi i l bilit 80 % Alloxanthine has a long action, given once dai daily
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uric acid

allopurinol
Blockade of uric acid synthesis by allopurinol and its oxidation agent, oxypurinol. XO = xanthine oxidase 13

2.2) Uricosuric agents: Probenecid

Therapeutic uses Chronic gout with complication eg taphaceous deposits, renal urate stones, advanced renal failure Hyperuricemia associated with malignancy (chemotherapy) or renal disease concurrent prophylactic therapy with colchicine Adverse effects Allergic reaction (skin rash) Hypersensitivity Transient leukopenia or leukocytosis Avoid: Acute attack GA> precipitate acute attack GA
(Including Uricosuric acid)
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Mechanism of action Block proximal tubular re reab absorption sorption of uric acid via urate urate-anion exchanger ,at therapeutic dose By bind to urate transporter (URAT1 (URAT1) to reabsorption Avoid in Pt. Excrete large amount of uric acid ( due to precipitate the formation of uric acid calculi)

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) Uricosuric agents:
Probenecid, Sulfinpyrazone, Benzbromarone
Therapeutic uses : - Chronic gout ( uric acid in urine < 1 g/day) - Combination with colchicine - Force F oral l fluid fl id + sodamint d i t (U (Urine i PH > 6.0) - bid to tid Side effect: Probenecid & sulfinpyrazone: f G irritate, prolong therapy GI depression of hematopoiesis: Leukopenia, thrombocytopenia, bronchoconstriction in patients with asthma

) Uricosuric agents: Side effect: Probenecid: Hypersensitivity (anaphylaxis rare)

p anemia , hepatic p necrosis aplastic

Contraindication: Acute gout attack, Blood dyscrasias, Children

under 2 years of age Coadministration of salicylates (salicylate antagonize the action of uricosuric agents) renal disease (GFR < 50%, renal calculi (Uric acid kidney stones)

Benzbromarone: Potent uricosuric acid

effective ff ti i in Pt Pt. Renal R l insufficiency i ffi i (b t GFR> 20 (but 20%) %) Precaution: Hepatic disease (hepatotoxicity (hepatotoxicity) )
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Uric acid secretion and sites of drugs action

Plasma Uric acid Urate crystals in joints j int d deposited p it d

The first nonpurine inhibitor XO

Thiazolecarboxylic acid

Probenecid and highh h-dose high d salicylates l l

Tubular reabsorption (active transport) Tubular secretion

- 8080-120 mg daily more effective than allopurinol standard dose 300 mg - Well tolerated in pt. with allopurinol intolerance

Diuretics and salicylates (analgesia)

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-Prophylactic P h l ti treatment t t t with ith colchicine l hi i or NSAIDs NSAID , diarrhea, , headache, , - Liver function abnormalities, nausea
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lowlow -dose

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Uric acid metabolism and sites of action of xanthine oxidase inhibitor

Hypoxanthine yp Xanthine (moderate solubility) Uric acid (low solubility)

Common drug interactions associated with therapy for gout and hyperuricemia
Interacting drug
Allopurinol

Affected drug

Effect

XO
Allopurinol

Azathioprine Mercaptopurine

Increased levels of azathioprine Increased levels of mercaptopurine yp effect Decreased hypouricemia Increased indomethacin levels I Increased d naproxen l levels l Increased aspirin levels

Febuxostat

Urate Oxidase (absent in humans) Allantoin (high solubility)

Uricosurics Aspirin (low dose) Probenecid Indomethacin N Naproxen Aspirin

hydrochlorthaiazide Increased uric acid

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Summary:
Drug
Allopurinol Febuxostat

Hyperuricemia: Causes and drug targets

Target
Acute

Target
uric acid product

Drug
Clochicine Cl hi i NSAIDs ( (prophylaxis) h l i )

gout

Do not need to worry about tomorrow If you do your best today and everyday

Hyperuricemia
Uricosurics ( b (probenecid, id sulfinpyrazone benzbromarone)

uric acid excretion

Chronic uric acid id deposition d iti

Allopurinol Febuxostat

(chronic gouty arthritis, tophi, uric i acid id nephropathy) h h )

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