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Drug Therapy of Gout

Drug Therapy of Gout

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Drug Therapy of Gout. Drug therapy of gout. What Is Gout?. Case presentation. 55 y/o male 12 hours “pain in my big toe & ankle” went to bed last night feeling fine felt as if had broken toe this morning PMH of similar problems in right ankle & left wrist. Gout - acute arthritis. - PowerPoint PPT Presentation

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Page 1: Drug Therapy of Gout

Drug Therapy of Gout

Page 2: Drug Therapy of Gout

Drug therapy of gout

What Is Gout?

Page 3: Drug Therapy of Gout

Case presentation• 55 y/o male• 12 hours “pain in my big toe & ankle”• went to bed last night feeling fine• felt as if had broken toe this morning• PMH of similar problems in right

ankle & left wrist

Page 4: Drug Therapy of Gout

Gout - acute arthritis

acute synovitis, ankle & first MTP

joints

The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

Page 5: Drug Therapy of Gout

Gout - acute bursitis

acute olecranon bursitis

Bursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone

Page 6: Drug Therapy of Gout

Gouty arthritis - characteristics• sudden onset• middle aged males• severe pain• distal joints• Intense

inflammation

• recurrent episodes• influenced by diet• bony erosions on Xray

Page 7: Drug Therapy of Gout

Monosodium urate crystals

polarized light red compensator

needle shape

negative birefringence

Page 8: Drug Therapy of Gout

Crystal-induced inflammation

PMN is critical

component of crystal-induced

inflammation

crystal deposition

hyperuricemia

protein binding

receptor binding

cytokine release

influx of PMN’s

crystals engulfed

inflammation

Page 9: Drug Therapy of Gout

Gouty arthritis - characteristics• sudden onset• middle aged males• severe pain• distal joints• intense

inflammation

• recurrent episodes• influenced by diet• bony erosions on

Xray• hyperuricemia

Page 10: Drug Therapy of Gout

Hyperuricemia

production excretion

hyperuricemia results when production exceeds excretion

Page 11: Drug Therapy of Gout

Hyperuricemiaproduction

excretion

net uric acid loss results when excretion exceeds production

Page 12: Drug Therapy of Gout

Chronic tophaceous gout

tophus = localized deposit of monosodium urate

crystals

Page 13: Drug Therapy of Gout

Gout - tophus

classic location of tophi on helix

of ear

Page 14: Drug Therapy of Gout

Gout - X-ray changesDIP (Distal interphalangeal joint) joint destructionphalangeal bone cysts

Page 15: Drug Therapy of Gout

Gout - X-ray changes

bony erosions

Page 16: Drug Therapy of Gout

Gout - cardinal manifestations

nephrolithiasis

nephropathy

arthritis tophi

HYPERURICEMIA

acute &

chronic

Page 17: Drug Therapy of Gout

Drug therapy of gout

The Role of Uric Acid in

Gout

Page 18: Drug Therapy of Gout

Uric acid metabolismcell

breakdowndietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

Page 19: Drug Therapy of Gout

Renal handling of uric acid

•glomerular filtration•tubular reabsorption•tubular excretion•post-secretory

reabsorption•net excretion

Page 20: Drug Therapy of Gout

Gout - problems• excessive total body levels of uric acid

• deposition of monosodium urate crystals in joints & other tissues

• crystal-induced inflammation

Page 21: Drug Therapy of Gout

Treating acute gouty arthritis• colchicine• NSAID’s• steroids• rest, analgesia, ice, time

Page 22: Drug Therapy of Gout

Drugs used to treat gout

allopurinol

probenecid

febuxostat?

steroids

NSAID’s

colchicine

Acute Arthritis Drugs

Urate Lowering Drugs

rest + analgesia + time

Page 23: Drug Therapy of Gout

NSAID’s

•Indomethacin (Indocin) 25 to 50 mg four times daily•Naproxen (Naprosyn) 500 mg two times daily•Ibuprofen (Motrin) 800 mg four times daily•Sulindac (Clinoril) 200 mg two times daily•Ketoprofen (Orudis) 75 mg four times daily

Drugs used to treat gout

Page 24: Drug Therapy of Gout

Colchicine - plant alkaloid

colchicum autumnale

(autumn crocus or meadow

saffron)

Page 25: Drug Therapy of Gout

Colchicine• “only effective in gouty arthritis”• not an analgesic• does not affect renal excretion of uric

acid• does not alter plasma solubility of uric

acid• neither raises nor lowers serum uric acid

Page 26: Drug Therapy of Gout

Colchicine• Colchicine inhibits microtubule

polymerization by binding to tubulin, one of the main constituents of microtubules

• reduces inflammatory response to deposited crystals

• diminishes PMN phagocytosis of crystals• blocks cellular response to deposited crystals

Page 27: Drug Therapy of Gout

Crystal-induced inflammation

PMN is critical

component of crystal-induced

inflammation

crystal deposition

hyperuricemia

protein binding

receptor binding

cytokine release

influx of PMN’s

crystals engulfed

inflammation

Page 28: Drug Therapy of Gout

Colchicine - indications

Dose Indication

high treatment of acute gouty arthritis

low prevention of recurrent gouty arthritis

Page 29: Drug Therapy of Gout

Colchicine - toxicity• gastrointestinal (nausea, vomiting,

cramping, diarrhea, abdominal pain)• hematologic (agranulocytosis,

aplastic anemia, thrombocytopenia)• muscular weakness

adverse effects dose-related & more common when patient has renal or hepatic disease

Page 30: Drug Therapy of Gout

Gout - colchicine therapy• more useful for daily prophylaxis (low

dose)prevents recurrent attackscolchicine 0.6 mg qd - bid

• declining use in acute gout (high dose)

Page 31: Drug Therapy of Gout

Hyperuricemia - mechanisms

hyperuricemia

excessive production

inadequate excretion

Page 32: Drug Therapy of Gout

Urate-lowering drugs

net reduction in total body pool of uric acid

block production

enhance excretion

Page 33: Drug Therapy of Gout

Gout - urate-lowering therapy• prevents arthritis, tophi & stones by

lowering total body pool of uric acid• not indicated after first attack• initiation of therapy can worsen or

bring on acute gouty arthritis• no role to play in managing acute gout

Page 34: Drug Therapy of Gout

Drug therapy of gout

Drugs That Block Production of Uric Acid

Page 35: Drug Therapy of Gout

Uric acid metabolismcell

breakdowndietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

Page 36: Drug Therapy of Gout

Allopurinol (Zyloprim™)• inhibitor of xanthine oxidase• effectively blocks formation of uric

acid• how supplied - 100 mg & 300 mg

tablets• pregnancy category C allopurinol

Page 37: Drug Therapy of Gout

Allopurinol - usage indications• management of hyperuricemia of

gout• management of hyperuricemia

associated with chemotherapy• prevention of recurrent calcium

oxalate kidney stones

Page 38: Drug Therapy of Gout

Allopurinol - common reactions• diarrhea, nausea, abnormal liver

tests• acute attacks of gout• rash

Page 39: Drug Therapy of Gout

Allopurinol - serious reactions• fever, rash, toxic epidermal necrolysis• hepatotoxicity, marrow suppression• vasculitis• drug interactions (ampicillin, thiazides,

mercaptopurine, azathioprine)• death

Page 40: Drug Therapy of Gout

Stevens-Johnson syndrome

target skin lesionsmucous membrane erosionsepidermal necrosis with skin detachment

Page 41: Drug Therapy of Gout

Allopurinol hypersensitivity• extremely serious problem• prompt recognition required• first sign usually skin rash• more common with impaired renal

function• progression to toxic epidermal necrolysis

& death

Page 42: Drug Therapy of Gout

Febuxostat• recently approved by FDA (not on market)• oral xanthine oxidase inhibitor• chemically distinct from allopurinol• 94% of patients reached urate < 6.0 mg/dl• minimal adverse events• can be used in patients with renal disease

Page 43: Drug Therapy of Gout

PEG-uricase• investigational drug• PEG-conjugate of recombinant

porcine uricase• treatment-resistant gout• uricase speeds resolution of tophi• further research needed

Page 44: Drug Therapy of Gout

Drug therapy of gout

Drugs That Enhance Excretion of Uric Acid

Page 45: Drug Therapy of Gout

Uricosuric therapy• probenecid• blocks tubular reabsorption of uric

acid• enhances urine uric acid excretion• increases urine uric acid level• decreases serum uric acid level

Page 46: Drug Therapy of Gout

Uricosuric therapy• moderately effective• increases risk of nephrolithiasis• not used in patients with renal

disease• frequent, but mild, side effects

Page 47: Drug Therapy of Gout

Uricosuric therapy• contra-indications

history of nephrolithiasiselevated urine uric acid levelexisting renal disease

• less effective in elderly patients

Page 48: Drug Therapy of Gout

Choosing a urate-lowering drug

hyperuricemia

excessive production

inadequate excretion

xanthine

oxidase inhibito

r

uricosuric agent

Page 49: Drug Therapy of Gout

Drug therapy of gout

Case Presentation

Page 50: Drug Therapy of Gout

Case presentation - therapyNSAID

steroid

colchicine (low-dose)

allopurinol

NSAID

days 1-10 days 11-365 days 365+