Download - 2009 gout pharmacology
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Reginald D Sanders, MDReginald D Sanders, MD
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
The drugs used in treating gout make sense!
We have excellent drugs for managing gout
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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 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
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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
• 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
arthrocentesis
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Monosodium urate crystals
polarized light red compensator
needle shape
negative birefringence
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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
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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
productionexcretion
hyperuricemia results when production exceeds excretion
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Hyperuricemia
productionexcretion
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
nephrolithiasis
nephropathy
arthritis tophi
HYPERURICEMIA
acute &
chronic
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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
> 10 mg/dl
< 7 mg/dl
Annual Incidence
70
0.9
5-Year Prevalenc
e
30%
0.6%
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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
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Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine
uric acid
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
hyperuricemia
excessive production
inadequate excretion
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Hyperuricemia - mechanisms
hyperuricemia
overproducers underexcretors
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Classifying hyperuricemia
• serum uric acid level• urine uric acid excretion (24-hour)
overproduction underexcretion
serum uric acid high highurine uric acid high normal/ low
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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• NSAID’s• steroids• rest, analgesia, ice, time
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Drugs used to treat gout
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Acute Arthritis Drugs
Urate Lowering Drugs
rest + analgesia + time
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Drugs used to treat gout
Acute Arthritis Drugs
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Urate Lowering Drugs
rest + analgesia + time
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Benjamin Franklin (1706 - 1790)
suggests gout sufferers use
l’Eau 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
crystal deposition
hyperuricemia
protein binding
receptor binding
cytokine release
influx of PMN’s
crystals engulfed
inflammation
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Colchicine - indications
Dose Indication
hightreatment of acute gouty arthritis
lowprevention 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 attackscolchicine 0.6 mg qd - bid
• declining use in acute gout (high dose)
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Drugs used to treat gout
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Acute Arthritis Drugs
Urate Lowering Drugs
rest + analgesia + time
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Hyperuricemia - mechanisms
hyperuricemia
excessive production
inadequate excretion
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Urate-lowering drugs
net reduction in total body pool of uric acid
block production
enhance excretion
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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
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine
uric acid
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
allopurinol
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Chemical structures
N
N
O
N
N
allopurinol
N
HN
O
N
NH
hypoxanthine
xanthine
N
N
NH
N
HO
OH
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Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine
uric acid
allopurinol inhibits
xanthine oxidase
allopurinol
allopurinol
oxypurinol
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Allopurinol effects
Effect of Allopurinol on Total Serum Levels of Xanthine + Hypoxanthine
Normal 0.15 mg/dl
Allopurinol 0.35 mg/dl
saturation level of xanthine & hypoxanthine > 7 mg/dl
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Allopurinol effect
Component Serum Level
Hypoxanthine
Xanthine
Uric acid
allopurinol lowers serum uric acid levels
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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 < 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-indicationshistory of nephrolithiasiselevated urine uric acid levelexisting renal disease
• less effective in elderly patients
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Choosing a urate-lowering drug
hyperuricemia
excessive production
inadequate excretion
xanthine
oxidase inhibito
r
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“Don’t mess with the uric acid level”
Don’t change your urate-loweringtherapy 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
NSAID
steroid
colchicine (low-dose)
allopurinol
NSAID
days 1-10 days 11-365 days 365+
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Reginald D Sanders, MDReginald D Sanders, MD
LSU Clinical Pharmacology
Drug Therapy of Gout