LSU Clinical Pharmacology

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LSU Clinical Pharmacology

• Drug Therapy of Gout

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Drug therapy of gout - overview

• what is gout?
• what happens to patients with gout why?
• what drugs are available for managing gout?
• how are those drugs used?

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Drug therapy of gout
We have excellent drugs for managing gout
The drugs used in treating gout make sense!
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Drug therapy of gout
What Is Gout?
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Drug therapy of gout
Case Presentation
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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

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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

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Case presentation

• lab studies
• serum uric acid 11.5 mg/dl
• 24-hour uric acid excretion 300 mg
• left foot X-rays show bony erosion with
  overhanging edge, medial side of first metatarsal
  head

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Case presentation

• What does he have?
• What can do we do about it?

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Gout - acute arthritis
acute synovitis, ankle first MTP joints
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Gout - acute bursitis
acute olecranon bursitis
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Gouty arthritis - characteristics
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Gouty arthritis - characteristics

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

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

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Drug therapy of gout
What Happens To Gout Patients Why?
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Gout - acute arthritis
acute synovitis, ankle first MTP joints
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Monosodium urate crystals
needle shape negative birefringence
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Crystal-induced inflammation
PMN is critical component of crystal-induced
inflammation
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Gouty arthritis - characteristics

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

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

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Hyperuricemia
hyperuricemia results when production exceeds
excretion
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Hyperuricemia
net uric acid loss results when excretion exceeds
production
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Chronic tophaceous gout
tophus localized deposit of monosodium urate
crystals
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Gout - tophus
classic location of tophi on helix of ear
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Gout - X-ray changes
DIP joint destruction
phalangeal bone cysts
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Gout - X-ray changes
bony erosions
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Gout - cardinal manifestations
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Drug therapy of gout
The Role of Uric Acid in Gout
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Hyperuricemia gout
Serum Uric Acid Level gt 10 mg/dl lt 7 mg/dl
Annual Incidence 70 0.9
5-Year Prevalence 30 0.6
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Serum uric acid levels age
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Uric acid

• end product of purine metabolism
• serum uric acid level dependent upon
• rate of uric acid production
• efficiency of renal uric acid excretion

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Uric acid metabolism
xanthine oxidase catalyzes hypoxanthine to
xanthine xanthine to uric acid
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Renal handling of uric acid

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

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Hyperuricemia - mechanisms
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Hyperuricemia - mechanisms
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Classifying hyperuricemia

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

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Gout - problems

• excessive total body levels of uric acid
• deposition of monosodium urate crystals in joints
  other tissues
• crystal-induced inflammation

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Drug therapy of gout
What Drugs Are Available For Treating Gout?
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Treating acute gouty arthritis
what strategies might be effective?
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Treating acute gouty arthritis

• colchicine
• NSAIDs
• steroids
• rest, analgesia, ice, time

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Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
rest analgesia time
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Drugs used to treat gout
Acute Arthritis Drugs
rest analgesia time
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Benjamin Franklin (1706 - 1790)
suggests gout sufferers use lEau Medicinale
d'Husson (secret French medicine containing
colchicine)
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Colchicine - plant alkaloid
colchicum autumnale (autumn crocus or meadow
saffron)
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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

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Colchicine

• mechanism of action poorly understood
• reduces inflammatory response to deposited
  crystals
• diminishes PMN phagocytosis of crystals
• blocks cellular response to deposited crystals

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Crystal-induced inflammation
PMN is critical component of crystal-induced
inflammation
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Colchicine - indications
Dose Indication
high treatment of acute gouty arthritis
low prevention of recurrent gouty arthritis
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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
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Treating acute gout
What is the role of colchicine in treating acute
gouty arthritis?
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Gout - colchicine therapy

• more useful for daily prophylaxis (low dose)
• prevents recurrent attacks
• colchicine 0.6 mg qd - bid
• declining use in acute gout (high dose)

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Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
rest analgesia time
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Hyperuricemia - mechanisms
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Urate-lowering drugs
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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

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Drug therapy of gout
Drugs That Block Production of Uric Acid
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Uric acid metabolism
xanthine oxidase catalyzes hypoxanthine to
xanthine xanthine to uric acid
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Allopurinol (Zyloprim)

• inhibitor of xanthine oxidase
• effectively blocks formation of uric acid
• how supplied - 100 mg 300 mg tablets
• pregnancy category C

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Chemical structures
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Uric acid metabolism
allopurinol inhibits xanthine oxidase
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Allopurinol effects
Effect of Allopurinol on Total Serum Levels of
Xanthine Hypoxanthine
saturation level of xanthine hypoxanthine gt 7
mg/dl
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Allopurinol effect
allopurinol lowers serum uric acid levels
Component Serum Level
Hypoxanthine
Xanthine
Uric acid
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Allopurinol
What are the clinical consequences of blocking
production of uric acid?
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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

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Allopurinol - usage indications

• management of hyperuricemia of gout
• management of hyperuricemia associated with
  chemotherapy
• prevention of recurrent calcium oxalate kidney
  stones

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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

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Allopurinol - common reactions

• diarrhea, nausea, abnormal liver tests
• acute attacks of gout
• rash

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Allopurinol - serious reactions

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

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Stevens-Johnson syndrome
target skin lesions mucous membrane
erosions epidermal necrosis with skin detachment
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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

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Febuxostat

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

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PEG-uricase

• investigational drug
• PEG-conjugate of recombinant porcine uricase
• treatment-resistant gout
• uricase speeds resolution of tophi
• further research needed

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Drug therapy of gout
Drugs That Enhance Excretion of Uric Acid
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Renal handling of uric acid

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

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Uricosuric therapy

• probenecid
• blocks tubular reabsorption of uric acid
• enhances urine uric acid excretion
• increases urine uric acid level
• decreases serum uric acid level

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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)

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Uricosuric therapy

• contra-indications
• history of nephrolithiasis
• elevated urine uric acid level
• existing renal disease
• less effective in elderly patients

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Choosing a urate-lowering drug
xanthine oxidase inhibitor
uricosuric agent
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Urate-lowering therapy

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

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Treating acute gout
What is the role of urate-lowering drugs like
allopurinol or probenecid in treating acute gouty
arthritis?
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Urate-lowering therapy

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

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Gout - rule 309

• Concept
• Dont mess with the uric acid level

Dont change your urate-lowering therapy during
an acute gout attack
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Gout - therapeutic problems

• renal disease
• nephrolithiasis
• transplantation
• allopurinol allergy

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Drug therapy of gout
Case Presentation
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Case presentation - therapy
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LSU Clinical Pharmacology

• Drug Therapy of Gout