Download Drug Therapy of Gout LSU Clinical Pharmacology Reginald D Sanders, MD

LSU Clinical Pharmacology
Drug Therapy of Gout
Reginald D Sanders, MD
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?
Drug therapy of gout
We have excellent drugs for managing gout
The drugs used in treating gout make sense!
Drug therapy of gout
What Is Gout?
Drug therapy of gout
Case Presentation
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 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
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
arthrocentesis
acute synovitis,
ankle & first MTP
joints
Monosodium urate crystals
needle shape
negative
birefringence
polarized light
red compensator
Crystal-induced inflammation
hyperuricemia
inflammation
crystal deposition
crystals engulfed
protein binding
influx of PMN’s
receptor binding
cytokine release
PMN is critical
component of
crystal-induced
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
hyperuricemia results when production exceeds excretion
Hyperuricemia
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
tophi
arthritis
acute &
chronic
HYPERURICEMIA
nephrolithiasis
nephropathy
Drug therapy of gout
The Role of Uric
Acid in Gout
Hyperuricemia & gout
Serum Uric
Acid Level
Annual
Incidence
5-Year
Prevalence
> 10 mg/dl
70
30%
< 7 mg/dl
0.9
0.6%
Serum uric acid levels & age
13.0
12.0
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
Gouty Male
Normal Male
Gouty Female
Normal Female
10
20
30
40
50
Age (years)
60
Uric acid metabolism
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown
Renal handling of uric acid
•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•net excretion
Hyperuricemia - mechanisms
excessive
production
inadequate
excretion
hyperuricemia
Hyperuricemia - mechanisms
overproducers
underexcretors
hyperuricemia
Classifying hyperuricemia
•serum uric acid level
•urine uric acid excretion (24-hour)
serum uric acid
urine uric acid
overproduction
high
high
underexcretion
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
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
rest + analgesia + time
Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
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
•“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
Colchicine
•mechanism of action poorly understood
•reduces inflammatory response to deposited
crystals
•diminishes PMN phagocytosis of crystals
•blocks cellular response to deposited
crystals
Crystal-induced inflammation
hyperuricemia
inflammation
crystal deposition
crystals engulfed
protein binding
influx of PMN’s
receptor binding
cytokine release
PMN is critical
component of
crystal-induced
inflammation
Colchicine - indications
Dose
Indication
high
treatment of acute gouty arthritis
low
prevention 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 attacks
colchicine 0.6 mg qd - bid
•declining use in acute gout (high dose)
Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
rest + analgesia + time
Hyperuricemia - mechanisms
excessive
production
inadequate
excretion
hyperuricemia
Urate-lowering drugs
block
production
enhance
excretion
net reduction in total body pool of
uric acid
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
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown
Allopurinol (Zyloprim™)
•inhibitor of xanthine oxidase
•effectively blocks formation of uric acid
•how supplied - 100 mg & 300 mg tablets
•pregnancy category C
allopurinol
Chemical structures
N
N
HN
N
NH
O
hypoxanthine
N
N
N
HO
O
allopurinol
N
NH
N
N
OH
xanthine
Uric acid metabolism
dietary intake
purine bases
cell breakdown
oxypurinol
hypoxanthine
allopurinol
inhibits xanthine
oxidase
xanthine
uric acid
allopurinol
allopurinol
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
Allopurinol effect
allopurinol lowers serum uric acid levels
Component
Hypoxanthine
Xanthine
Uric acid
Serum Level
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 (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
PEG-uricase
•investigational drug
•PEG-conjugate of recombinant porcine
uricase
•treatment-resistant gout
•uricase speeds resolution of tophi
•further research needed
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-indications
history of nephrolithiasis
elevated urine uric acid level
existing renal disease
•less effective in elderly patients
Choosing a urate-lowering drug
excessive
production
inadequate
excretion
xanthine
oxidase
inhibitor
uricosuric
agent
hyperuricemia
Urate-lowering therapy
•mild gout
•renal disease
•nephrolithiasis
•high 24-hr UUA
•elderly
•tophaceous gout
uricosuric
allopurinol
allopurinol
allopurinol
allopurinol
allopurinol
Treating acute gout
What is the role of uratelowering 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 - rule #309
Concept
“Don’t mess with the uric acid level”
Don’t change your urate-lowering
therapy during an acute gout attack
Gout - therapeutic problems
•renal disease
•nephrolithiasis
•transplantation
•allopurinol allergy
Drug therapy of gout
Case Presentation
Case presentation - therapy
NSAID
NSAID
steroid
colchicine (low-dose)
allopurinol
days 1-10
days 11-365
days 365+
LSU Clinical Pharmacology
Drug Therapy of Gout
Reginald D Sanders, MD