NASRUHAN ARIFIANTO, S.Farm., M.Farm.Klin., Apt.

STIFAR SUNAN GIRI - PONOROGO

1
Epidemiology
men women
mean age of onset 49 60
incidence (age 32-64) 2.8% 1.5%

 the lower incidence and later onset of gout in women is

attributed to more efficient urate excretion
 attack before the age of 30 is rare and suggest a genetic
metabolic disorder
Pathophysiology
 Gout is caused by disorders of purine metabolism
resulting in elevated levels of uric acid
 > 7 mg/dl in men
 > 6 mg/dl in women
 prolonged hyperuricemia leads to formation of
monosodium urate monohydrate crystals
Serum Urate Level
 during a gouty attack, serum urate levels are normal in
about 20% of cases
 repeat blood tests eventually detect hyperuricemia
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 PMN is critical

component of
crystal-induced
inflammation
protein binding influx of PMN’s

receptor binding cytokine release

Gouty arthritis - characteristics
 sudden onset  recurrent episodes
 middle aged males  influenced by diet
 severe pain  bony erosions on
 distal joints Xray
 intense  hyperuricemia
inflammation
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
Serum uric acid levels & age
13,0
12,0
11,0
10,0
Gouty Male
9,0
Normal Male
8,0
Gouty Female
7,0
6,0 Normal Female
5,0
4,0
3,0
10 20 30 40 50 60
Age (years)
Uric acid metabolism
dietary intake purine bases cell breakdown

xanthine hypoxanthine
oxidase
catalyzes
hypoxanthine to xanthine
xanthine &
xanthine to uric
acid uric acid
Hyperuricemia - mechanisms
overproducers underexcretors

hyperuricemia
Classifying hyperuricemia
 serum uric acid level
 urine uric acid excretion (24-hour)

overproduction underexcretion
serum uric acid high high
urine 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
Treating acute gouty arthritis
 colchicine
 NSAID’s
 steroids
 rest, analgesia, ice, time
 COLCHICINE
Acute Arthritis Drugs Urate Lowering Drugs

colchicine allopurinol
colchicine
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
Colchicine - indications

Dose Indication

high treatment of acute gouty arthritis

prevention of recurrent gouty

low
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)

 ALLOPURINOL
Acute Arthritis Drugs Urate Lowering Drugs

colchicine allopurinol

steroids probenecid

NSAID’s febuxostat?

rest + analgesia + time

Hyperuricemia - mechanisms
excessive inadequate
production excretion

hyperuricemia
Urate-lowering drugs
block enhance
production 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
Uric acid metabolism
dietary intake purine bases cell breakdown

xanthine hypoxanthine
oxidase
catalyzes
hypoxanthine to xanthine
xanthine &
xanthine to uric
acid uric acid
Allopurinol (Zyloric™)
 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
N
N N H N
N N
O H
HN N N
O N
H
allopurinol O
O H
hypoxanthi xanthine
ne
Uric acid metabolism
dietary intake purine bases cell breakdown

oxypurinol
hypoxanthine

allopurinol
xanthine allopurino
allopurinl
inhibits l
xanthine
oxidase
uric acid
Allopurinol effect
allopurinol lowers serum uric acid
levels

Component Serum Level

Hypoxanthine

Xanthine

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 - serious reactions
 fever, rash, toxic epidermal necrolysis
 hepatotoxicity, marrow suppression
 vasculitis
 drug interactions (ampicillin, thiazides, mercaptopurine,
azathioprine)
 Death

Allopurinol - common reactions

 diarrhea, nausea, abnormal liver tests
 acute attacks of gout
 rash
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
 Renal handling of uric acid
•glomerular
filtration
•tubular
reabsorption
•tubular excretion
•post-secretory
reabsorption
•excretion
Probenecid - Uricosuric therapy
 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)
Choosing a urate-lowering drug
excessive inadequate
production excretion
xanthine
oxidase uricosuric
inhibitor agent

hyperuricemia
Urate-lowering therapy
 mild gout uricosuric
 renal disease allopurinol
 nephrolithiasis allopurinol
 high 24-hr UUA allopurinol
 elderly allopurinol
 tophaceous gout allopurinol
Gout - therapeutic problems
 renal disease
 nephrolithiasis
 transplantation
 allopurinol allergy
Non- Pharmacologic Treatments
 Immobilization of Joint
 Abstinence of Alcohol
 Consumption can increase serum urate levels by
increasing uric acid production. When used in excess it
can be converted to lactic acid which inhibits uric acid
excretion in the kidney
 Dietary modification
 Low carbohydrates
 Increase in protein and unsaturated fats
 Decrease in dietary purine-meat and seafood. Dairy and
vegetables do not seem to affect uric acid
 Bing cherries and Vitamin C
 SELESAI….

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