drug therapy of gout - overview what is gout? what happens to patients with gout & why? what...

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

Case presentation

• can barely walk (due to pain)• right elbow swollen• exam shows left first MTP joint & left

ankle to be red, swollen & tender to touch

• right elbow also swollen

Case presentation

• lab studiesserum uric acid = 11.5 mg/dl24-hour uric acid excretion = 300 mg

• left foot X-rays show bony erosion with overhanging edge, medial side of first metatarsal head

Case presentation

What does he have?

What can do we do about it?

Gout - acute arthritis

acute synovitis, ankle & first MTP

joints

Gout - acute bursitis

acute olecranon

bursitis

Gouty arthritis - characteristics

• sudden onset• middle aged males• severe pain• distal joints• Intense

inflammation

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

Drug therapy of gout

What Happens To Gout Patients & Why?

Gout - acute arthritis

acute synovitis, ankle & first MTP

joints

arthrocentesis

Monosodium urate crystals

polarized light red compensator

needle shape

negative birefringence

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

Gouty arthritis - characteristics

• sudden onset• middle aged males• severe pain• distal joints• intense

inflammation

• recurrent episodes• influenced by diet• bony erosions on

Xray• hyperuricemia

Hyperuricemia

productionexcretion

hyperuricemia results when production exceeds excretion

Hyperuricemia

productionexcretion

net uric acid loss results when excretion exceeds production

Chronic tophaceous gout

tophus = localized deposit of monosodium urate

crystals

Gout - tophus

classic location of tophi on helix

of ear

Gout - X-ray changes

DIP joint destruction

phalangeal bone cysts

Gout - X-ray changes

bony erosions

Gout - cardinal manifestations

nephrolithiasis

nephropathy

arthritis tophi

HYPERURICEMIA

acute &

chronic

Drug therapy of gout

The Role of Uric Acid in

Gout

Serum uric acid levels & age

3.04.05.06.07.08.09.0

10.011.012.013.0

10 20 30 40 50 60

Age (years)

Gouty Male

Normal Male

Gouty Female

Normal Female

Uric acid metabolism

cell breakdown

dietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

Renal handling of uric acid

•glomerular filtration

•tubular reabsorption

•tubular excretion

•post-secretory reabsorption

•net excretion

Hyperuricemia - mechanisms

hyperuricemia

overproducers underexcretors

Classifying hyperuricemia

• serum uric acid level• urine uric acid excretion (24-hour)

overproduction underexcretion

serum uric acid high highurine uric acid high normal/ low

Gout - problems

• excessive total body levels of uric acid

• deposition of monosodium urate crystals in joints & other tissues

• crystal-induced inflammation

Drug therapy of gout

What Drugs Are Available For Treating

Gout?

Treating acute gouty arthritis

what strategies might be effective?

Treating acute gouty arthritis

• colchicine• NSAID’s• steroids• rest, analgesia, ice, time

Drugs used to treat gout

allopurinol

probenecid

febuxostat

steroids

NSAID’s

colchicine

Acute Arthritis Drugs

Urate Lowering Drugs

rest + analgesia + time

Benjamin Franklin (1706 - 1790)

suggests gout sufferers use

l’Eau Medicinale d'Husson

(secret French medicine containing colchicine)

Colchicine - plant alkaloid

colchicum autumnale

(autumn crocus or meadow

saffron)

Colchicine

• not only effective in gouty arthritis• some what effective in other arthropathies

ie. pseudogout, sarcoid, etc. etc.• 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

Colchicine

• mechanism of action poorly understood• reduces inflammatory response to

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

crystals

Colchicine - indications

Dose Indication

hightreatment of acute gouty arthritis

lowprevention of recurrent gouty arthritis

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

Treating acute gout

What is the role of colchicine in treating acute gouty arthritis?

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)

Drugs used to treat gout

allopurinol

probenecid

febuxostat

steroids

NSAID’s

colchicine

Acute Arthritis Drugs

Urate Lowering Drugs

rest + analgesia + time

Hyperuricemia - mechanisms

hyperuricemia

excessive production

inadequate excretion

Urate-lowering drugs

net reduction in total body pool of uric acid

block production

enhance excretion

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

Drug therapy of gout

Drugs That Block Production of Uric Acid

Uric acid metabolism

cell breakdown

dietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

Allopurinol (Zyloprim™)

• inhibitor of xanthine oxidase• effectively blocks formation of uric

acid• how supplied - 100 mg & 300 mg

tablets• pregnancy category C

allopurinol

Uric acid metabolism

cell breakdown

dietary intake

purine bases

hypoxanthine

xanthine

uric acid

allopurinol inhibits

xanthine oxidase

allopurinol

allopurinol

oxypurinol

Allopurinol effect

Component Serum Level

Hypoxanthine

Xanthine

Uric acid

allopurinol lowers serum uric acid levels

Allopurinol

What are the clinical consequences of

blocking production of uric acid?

Allopurinol

• 90% absorption from the gut• metabolized to oxypurinol• once daily dosing• lowers serum uric acid levels• lowers urine uric acid levels• side effects rare, but potentially lethal

Allopurinol - usage indications

• management of hyperuricemia of gout

• management of hyperuricemia associated with chemotherapy

• prevention of recurrent calcium oxalate kidney stones

Allopurinol – black box warning

THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF ASYMPTOMATIC HYPERURICEMIA

ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS OF AN ALLERGIC REACTION

Allopurinol - common reactions

• diarrhea, nausea, abnormal liver tests

• acute attacks of gout• rash

Allopurinol - serious reactions

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

mercaptopurine, azathioprine)• death

Stevens-Johnson syndrome

target skin lesions

mucous membrane erosions

epidermal necrosis with skin detachment

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

Febuxostat

• recently approved by FDA • 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

PEG-uricase

• Just approved drug• PEG-conjugate of recombinant

porcine uricase• treatment-resistant gout• uricase speeds resolution of tophi• Iv with significant toxicity issues

Drug therapy of gout

Drugs That Enhance Excretion of Uric Acid

Renal handling of uric acid

•glomerular filtration

•tubular reabsorption

•tubular excretion

•post-secretory reabsorption

•excretion

Uricosuric therapy

• probenecid• blocks tubular reabsorption of uric

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

Uricosuric therapy

• moderately effective• increases risk of nephrolithiasis• not used in patients with renal disease• frequent, but mild, side effects• some drugs reduce efficacy (e.g.,

aspirin)

Uricosuric therapy

• contra-indicationshistory of nephrolithiasiselevated urine uric acid levelexisting renal disease

• less effective in elderly patients

Choosing a urate-lowering drug

hyperuricemia

excessive production

inadequate excretion

xanthine

oxidase inhibito

r

uricosuric agent

Urate-lowering therapy

• mild gout uricosuric• renal disease allopurinol• nephrolithiasis allopurinol• high 24-hr UUA allopurinol• elderly allopurinol• tophaceous gout allopurinol

Treating acute gout

What is the role of urate-lowering drugs like

allopurinol or probenecid in treating acute gouty

arthritis?

Urate-lowering therapy

• no anti-inflammatory activity• can precipitate acute gout• can prolong attack of gout• advice?

Gout – Rules of engagement

Concept“Don’t mess with the uric acid level”

Don’t change your urate-loweringtherapy during an acute gout attack

Gout - therapeutic problems

• renal disease• nephrolithiasis• transplantation• allopurinol allergy

Case presentation - therapy

NSAID

steroid

colchicine (low-dose)

allopurinol

NSAID

days 1-10 days 11-365 days 365+