Pharmacology

Drug Therapy of Gout

Maher Khdour. PhD
Clinical Pharmacy and Pharmacology
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?
What Is Gout?

Gout is defined as a peripheral arthritis resulting

from the deposition of sodium urate crystals‫ي تكلس‬
in one or more joints.
Gout
• Typical sequence involves progression
through:
asymptomatic hyperuricemia
acute gouty arthritis‫بدأ‬$$‫ ي‬$‫نه‬$‫ ال‬$‫وجع‬$$‫وا‬
‫مرض ل‬$$‫بدأا‬
‫ ل‬$$‫ي‬
inflammation
chronic or tophaceous gout
Gout - acute arthritis

acute synovitis, ankle

& first MTP joints
Gouty arthritis - characteristics
• sudden onset‫جأة‬
$$$‫حدث ف‬$$‫ي‬ • recurrent episodes ‫وبات‬$‫ن‬
• middle aged males‫صاب‬$$‫ي‬ $‫ال‬ ‫ة‬$‫متكرر‬
‫كبار‬$$‫صيب لا‬$$‫سن ي‬$$‫ار لا‬$$‫صغ‬ • influenced by diet$‫تأثر‬$$‫ي‬
• severe pain‫ديد‬$‫ ش‬$‫وجع‬ ‫ئي‬$‫ذا‬$‫غ‬$$‫ لا‬$‫نظام‬$$‫لا‬
• distal joints$‫صابع‬$‫بعيدة( ا‬$$‫اصل لا‬$‫ف‬$$‫لما‬ • bony erosions on
) $‫م‬$$‫ا‬
‫د‬$‫ لق‬$‫صابع‬$‫يد – ا‬$$‫لا‬
Xray‫ة‬$‫الشع‬$$‫قرحاتعظمية على ا‬
$$$‫ت‬
• Intense inflammation‫اب‬$‫ه‬$$‫لتا‬ ‫سينية‬$$‫لا‬
‫ديد‬$‫ش‬
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

polarized light red compensator

Crystal-induced inflammation
hyperuricemia inflammation

crystal deposition crystals engulfed PMN is critical

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

receptor binding cytokine release

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

e t i o n
e xc r
c t i o n
p ro d u

hyperuricemia results when production exceeds excretion

Hyperuricemia

produ
ction
e xc r e
ti o n

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

arthritis tophi

acute &
chronic
HYPERURICE
MIA
nephrolithiasis nephropathy
Drug therapy of gout

The Role of Uric

Acid in Gout
Hyperuricemia & gout

Serum Uric
Acid Level
> 10 mg/dl
Normal = the upper limit 7mg/dl
< 7 mg/dl
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 oxidase hypoxanthine

catalyzes
hypoxanthine to
xanthine & xanthine
xanthine to uric
acid
uric acid
 Renal handling of uric acid‫جة‬$$‫لا‬$‫مع‬
‫يوريك‬$$‫كلىمنحمض لا‬$$‫لا‬

•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•net excretion‫تيجة‬$‫افي ن‬$‫ص‬
$‫لجسم‬$‫ ل‬$‫رجع‬$$‫ح ي‬$‫ضل را‬
$$$‫ب‬
Hyperuricemia - mechanisms

excessive inadequate
production excretion

hyperuricemia
Hyperuricemia - mechanisms

overproducers underexcretors

hyperuricemia
Pathophysiology
• Primary gout:
Overproducers: 10%
Under-excretors: 90%‫مسيطر‬$$‫هو لا‬
• Secondary gout:
Excess nucleoprotein turnover (lymphoma, leukemia)‫ن‬$‫زيادة دورا‬
) $‫م‬$$‫رطان لدا‬$‫اوية – س‬$‫ف‬$$‫ا‬
‫دد لم‬$‫غ‬$$‫رطان لا‬$‫نووي س‬
( $$‫بروتين لا‬$$‫لا‬

Increased cell proliferation/death (psoriasis)‫موت‬$$‫لا‬ /‫خاليا‬$$‫نتشار زيادة لا‬$‫ا‬

)‫صدفية‬$$‫(مرض لا‬
Rare genetic disorder‫ادر‬$‫ثي ن‬$‫بورا‬$‫ضطرا‬$‫ا‬
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 acid‫مجموع مستويات‬
‫يوريك‬$$‫لحمض لا‬$‫رط ل‬$‫ف‬$$‫ا‬
‫ لم‬$‫جسم‬$$‫لا‬
• deposition of monosodium urate crystals in
joints & other tissues$‫ي‬$$‫ ف‬$‫صوديوم‬$$‫حادية لا‬$‫تأ‬$‫يورا‬$$‫ت لا‬$‫لورا‬$$$‫رسب ب‬$$$‫ت‬
‫ألخرى‬$$‫ألنسجة ا‬$$‫اصل وا‬$‫ف‬$$‫ا‬
‫لم‬
• crystal-induced inflammation ‫ عن‬$‫ناجم‬$$‫ل لا‬$$‫كريستا‬$$‫لا‬ ‫اب‬$‫ه‬$$‫لتا‬
Drug therapy of gout

What Drugs Are Available

For Treating Gout?
Drugs used in Gout
Colchicine
NSAIDs
Uricosuric agents:
Probenecid
Sulfinpyrazone
Xanthine Oxidase inhibitors:
Allopurinol
Febuxostat
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 $‫الم‬$$‫يسمسكن ا‬$‫ل‬
• does not affect renal excretion of uric acid‫كلى‬$$‫فراز لا‬$‫ؤثر إ‬$$‫ ي‬$‫ال‬
‫يوريك‬$$‫حامض لا‬$‫ل‬
• does not alter plasma solubility of uric acid‫ذوبان‬$$‫غير لا‬$$‫ ي‬$‫ال‬
‫يوريك‬$$‫بالزما منحمض لا‬$$‫لا‬
• neither raises nor lowers serum uric acid‫خفض‬$$‫ وال ي‬$‫رفع‬$$‫ ي‬$‫ال‬
$‫م‬$$‫ل لدا‬$‫يمص‬
$$$‫يوريك ف‬$$‫حمض لا‬
Colchicine
• mechanism of action poorly understood ‫ومة‬$‫عملغير مفه‬$$‫لا‬ ‫ية‬$$‫لآ‬

• reduces inflammatory response to deposited

crystals‫ترسب‬$$$‫ت ت‬$‫بلورا‬$‫ابية ل‬$‫ته‬$‫الل‬$$‫الستجابة ا‬$$‫قللمن ا‬$$‫ي‬
• diminishes PMN phagocytosis of crystals‫قلل‬$$‫ي‬
PMN‫ت‬$‫لورا‬
$$$‫بلعمة من ب‬$$‫لا‬
• blocks cellular response to deposited crystals‫تل‬$‫ك‬
‫ترسب‬
$$$‫ت ت‬$‫لورا‬$$‫ة لب‬$‫خلوي‬$$‫ة لا‬$‫الستجاب‬$$‫ا‬
Crystal-induced inflammation
hyperuricemia inflammation

crystal deposition crystals engulfed PMN is critical

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

receptor binding cytokine release

Pharmacodynamics
Relieves the pain and inflammation of gouty
arthritis in 12–24 hours
Binds to the intracellular protein tubulin ‫خاليا‬$$‫خل لا‬$‫ربط دا‬$$$‫ب‬
‫وبيلين‬
$$$‫روتين ت‬
$$$‫ب‬

‫*** مهم‬Prevents its polymerization into

microtubules Leads to inhibition of leukocyte
migration ‫تهاجم‬and phagocytosis
Also inhibits formation of leukotriene B4.
Colchicine – indications ‫دواء‬$$‫عطى لا‬$$‫ي‬ ‫ماذا‬$‫ل‬

Dose Indication

high treatment of acute gouty arthritis

prevention of recurrent‫كرار‬
$$$‫ ت‬gouty
low
arthritis
Colchicine – toxicity (side effect)
• gastrointestinal (nausea, vomiting, cramping,
diarrhea, abdominal pain)
• hematologic (agranulocytosis, aplastic anemia,
thrombocytopenia‫صفائح‬$$‫لة لا‬$$‫) ق‬
• 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)‫كثر‬$‫ا‬
‫يومية‬$$‫لوقاية لا‬$‫ائدة ل‬
$$$‫ف‬
prevents recurrent attacks ‫متكررة‬$$‫هجمات لا‬$$‫ من لا‬$‫منع‬$$‫ي‬
colchicine 0.6 mg qd - bid

• declining use in acute gout (high dose)$‫ي‬$$‫ف‬ $‫مه‬$‫ستخدا‬$‫قل ا‬$$‫ي‬

‫حاد‬$$‫نقرس لا‬$$‫لا‬
 NSAIDS IN GOUT
• Inhibiting prostaglandin synthase, indomethacin and other
NSAIDs also inhibit urate crystal phagocytosis
• ‫اسم دواء‬Indomethacin is commonly used as initial
treatment of gout as the replacement‫ بديل‬for colchicine
• All other NSAIDs except aspirin, salicylates, and tolmetin
have been used in acute gout.
• ‫اسم دواء‬Oxaprozin, which lowers serum uric acid, a good
choice (not in pts. with uric acid stones because it
increases urate excretion in the urine)
Drugs used to treat gout

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 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 purine bases cell breakdown

xanthine oxidase hypoxanthine

catalyzes
hypoxanthine to
xanthine & xanthine
xanthine to uric
acid
uric acid
Allopurinol (Zyloprim™) xanthine
oxidase inhibitor

• 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
NH O N

allopurinol O
O H
hypoxanthine xanthine
Uric acid metabolism
dietary intake purine bases cell breakdown

oxypurinol
hypoxanthine

allopurinol
inhibits xanthine xanthine allopurinol
allopurinol
oxidase

uric acid
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 Serum Level

Hypoxanthine

Xanthine

Uric acid
Allopurinol

What are the clinical

consequences of blocking
production of uric acid?
Allopurinol
• 90% absorption from the gut 90%‫اء‬$‫المع‬$$‫متصاص ا‬$‫من ا‬
• metabolized to oxypurinol
• once daily dosing
• lowers serum uric acid levels
• lowers urine uric acid levels
• side effects rare, but potentially lethal
Allopurinol - usage
indications‫دواء‬$$‫عطى لا‬$$‫ماذا ي‬$‫ل‬
• 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
• oral xanthine oxidase inhibitor
• chemically distinct ‫يميائيا‬$‫ متميزة ك‬from‫ من‬allopurinol
• 94% of patients reached urate < 6.0 mg/dl
• minimal adverse events
• can be used in patients with renal disease
(PEG-uricase)
• Pegylated Recombinant Mammalian
Uricase (PEG-uricase)‫مؤتلف‬//‫لفيروسات لا‬/‫مضاد ل‬
‫وريكاز‬//‫ثدييات ي‬//‫لا‬
• (a chemically modified recombinant
mammalian enzyme that degrades uric acid)
‫حط حمض‬$$‫يميائيا وهذا ي‬$‫دلة ك‬$‫مؤتلفمع‬$$‫ثدييات لا‬$$‫ لا‬$‫نزيم‬$‫ا‬
‫يوريك‬$$‫لا‬
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 inadequate
production excretion
xanthine
uricosuric
oxidase
agent
inhibitor
hyperuricemia
Urate-lowering therapy
• mild gout uricosuric
• renal disease allopurinol
• nephrolithiasis allopurinol
• high 24-hr UUA allopurinol
• elderly allopurinol
• tophaceous gout allopurinol
Treating acute gout

What is the role of urate-

lowering drugs like allopurinol
or probenecid in treating acute
gouty arthritis?
WHICH AGENT
• Base choice on above considerations &
whether pt is an overproducer or underexcretor
: Need to get a 24-hr. urine for urate excretion:
< 700 --- underexcretor
(uricosuric)
> 700 --- overproducer
(allopurinol)
Urate-lowering therapy
• no anti-inflammatory activity
• can precipitate acute gout
• can prolong attack of gout
• advice?
Other drugs that increase ur ic
acid excret ion
• Losar tan (Cozaar ) only ARB
lower serum ur ic acid levels by inhibi t ing the uptake of
uric acid by the urate anion exchange transporter in the
proximal tubule
• Fenof ibrate
decrease serum ur ic levels by increasing
renal uric acid clearance
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