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

2. 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?

3. Drug therapy of gout
We have excellent drugs for managing gout
The drugs used in treating gout make sense!

4. Drug therapy of gout
What Is Gout?

5. Drug therapy of gout
Case Presentation

6. 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

7. 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

8. 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

9. Case presentation
What does he have?
What can do we do about it?

10. Gout - acute arthritis
acute synovitis,
ankle & first MTP
joints

11. Gout - acute bursitis
acute olecranon
bursitis

12. Gouty arthritis - characteristics
• sudden onset
• middle aged males
• severe pain
• distal joints
• Intense inflammation
• recurrent episodes
• influenced by diet
• bony erosions on Xray

13. Drug therapy of gout
What Happens To Gout
Patients & Why?

14. Gout - acute arthritis
arthrocentesis
acute synovitis,
ankle & first MTP
joints

15. Monosodium urate crystals
needle shape
negative
birefringence
polarized light
red compensator

16. 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

17. Gouty arthritis - characteristics
• sudden onset
• middle aged males
• severe pain
• distal joints
• intense inflammation
• recurrent episodes
• influenced by diet
• bony erosions on Xray
• hyperuricemia

18. Hyperuricemia
pr
ction
odu
e
ti o n
xcre
hyperuricemia results when production exceeds excretion

19. Hyperuricemia
produ
ction
excre
t
io n
net uric acid loss results when excretion exceeds production

20. Chronic tophaceous gout
tophus = localized deposit of
monosodium urate crystals

21. Gout - tophus
classic location of
tophi on helix of ear

22. Gout - X-ray changes
DIP joint destruction
phalangeal bone cysts

23. Gout - X-ray changes
bony erosions

24. Gout - cardinal manifestations
tophi
arthritis
acute &
chronic
HYPERURICE
MIA
nephrolithiasis
nephropathy

25. Drug therapy of gout
The Role of Uric
Acid in Gout

26. Hyperuricemia & gout
Serum Uric
Acid Level
Annual
Incidence
5-Year
Prevalence
> 10 mg/dl
70
30%
< 7 mg/dl
0.9
0.6%

27. 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

28. Uric acid metabolism
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown

29. Renal handling of uric acid
•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•net excretion

30. Hyperuricemia - mechanisms
excessive
production
inadequate
excretion
hyperuricemia

31. Hyperuricemia - mechanisms
overproducers
underexcretors
hyperuricemia

32. 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

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

34. Drug therapy of gout
What Drugs Are Available
For Treating Gout?

35. Treating acute gouty arthritis
what strategies might be
effective?

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

37. Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
rest + analgesia + time

38. Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
rest + analgesia + time

39. Benjamin Franklin (1706 - 1790)
suggests gout sufferers use
l’Eau Medicinale d'Husson
(secret French medicine
containing colchicine)

40. Colchicine - plant alkaloid
colchicum
autumnale
(autumn crocus or
meadow saffron)

41. 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

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

43. 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

44. Colchicine - indications
Dose
Indication
high
treatment of acute gouty arthritis
low
prevention of recurrent gouty arthritis

45. 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

46. Treating acute gout
What is the role of colchicine in
treating acute gouty arthritis?

47. 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)

48. Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
colchicine
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
rest + analgesia + time

49. Hyperuricemia - mechanisms
excessive
production
inadequate
excretion
hyperuricemia

50. Urate-lowering drugs
block
production
enhance
excretion
net reduction in total body pool of
uric acid

51. 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

52. Drug therapy of gout
Drugs That Block
Production of Uric Acid

53. Uric acid metabolism
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown

54. Allopurinol (Zyloprim™)
• inhibitor of xanthine oxidase
• effectively blocks formation of uric acid
• how supplied - 100 mg & 300 mg tablets
• pregnancy category C
allopurinol

55. Chemical structures
N
N
HN
N
NH
O
hypoxanthine
N
N
N
HO
O
allopurinol
N
NH
N
N
OH
xanthine

56. Uric acid metabolism
dietary intake
purine bases
cell breakdown
oxypurinol
hypoxanthine
allopurinol
inhibits xanthine
oxidase
xanthine
uric acid
allopurinol
allopurinol

57. 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

58. Allopurinol effect
allopurinol lowers serum uric acid levels
Component
Hypoxanthine
Xanthine
Uric acid
Serum Level

59. Allopurinol
What are the clinical
consequences of
blocking production of
uric acid?

60. 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

61. Allopurinol - usage indications
• management of hyperuricemia of gout
• management of hyperuricemia associated
with chemotherapy
• prevention of recurrent calcium oxalate
kidney stones

62. 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

63. Allopurinol - common reactions
• diarrhea, nausea, abnormal liver tests
• acute attacks of gout
• rash

64. Allopurinol - serious reactions
• fever, rash, toxic epidermal necrolysis
• hepatotoxicity, marrow suppression
• vasculitis
• drug interactions (ampicillin, thiazides,
mercaptopurine, azathioprine)
• death

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

66. 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

67. 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

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

69. Drug therapy of gout
Drugs That Enhance
Excretion of Uric Acid

70. Renal handling of uric acid
•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•excretion

71. Uricosuric therapy
• probenecid
• blocks tubular reabsorption of uric acid
• enhances urine uric acid excretion
• increases urine uric acid level
• decreases serum uric acid level

72. 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)

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

74. Choosing a urate-lowering drug
excessive
production
inadequate
excretion
xanthine
oxidase
inhibitor
uricosuric
agent
hyperuricemia

75. Urate-lowering therapy
• mild gout
• renal disease
• nephrolithiasis
• high 24-hr UUA
• elderly
• tophaceous gout
uricosuric
allopurinol
allopurinol
allopurinol
allopurinol
allopurinol

76. Treating acute gout
What is the role of uratelowering drugs like allopurinol
or probenecid in treating acute
gouty arthritis?

77. Urate-lowering therapy
• no anti-inflammatory activity
• can precipitate acute gout
• can prolong attack of gout
• advice?

78. Gout - rule #309
Concept
“Don’t mess with the uric acid level”
Don’t change your urate-lowering
therapy during an acute gout attack

79. Gout - therapeutic problems
• renal disease
• nephrolithiasis
• transplantation
• allopurinol allergy

80. Drug therapy of gout
Case Presentation

81. Case presentation - therapy
NSAID
NSAID
steroid
colchicine (low-dose)
allopurinol
days 1-10
days 11-365
days 365+

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