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GOUT

By
Dr: Abd El Hameed Fureeh
MD, Lecturer of Internal Medicine, Mansoura
faculty of Medicine
Diabetes, endocrinology and Metabolism unit

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What is gout?
▲ Gout is a syndrome caused by the
inflammatory response to tissue
deposition of monosodium urate
crystals (MSU).
▲ Nicknamed the “Disease of Kings”
because it can be caused by rich foods,
alcohol, and royalty often had it.
Prevalence
▲ The prevalence of asymptomatic
hyperuricemia is 5 to 8%.
▲ The prevalence of gout is 13 cases per
1000 men and 6.4 cases per 1000
women.
▲ The higher the uric acid, the higher the
risk to develop gout.
▲ 90% of patients with primary gout are
men.
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Prevalence
▲ Women rarely develop gout before the
menopause, because estrogens are
thought to be uricosuric.
▲ Peak incidence in men is in the fifth
decade.
▲ Primary gout is associated with: obesity,
hyperlipidemia, diabetes mellitus,
hypertension and atherosclerosis.
Etiology
▲ Hyperuricemia is the common
denominator in gout.
▲ Two-thirds of uric acid are excreted by
the kidney and the rest in the GI tract.
▲ 90% of cases of gout are secondary to
under-excretion.
▲ Overproduction is secondary to defects
in the HGPRT or PRPP.
Etiology
▲ The inflammatory response is
secondary to the response of the
leukocytes to the MSU crystals.
▲ Acute gout is most likely secondary to
the formation of new crystals.
▲ Factors that precipitate gout includes:
surgery, trauma, alcohol, starvation and
medications.
GOUT RISK FACTORS
▲ Male
▲ Postmenopausal
female
▲ Older
▲ Hypertension
▲ Pharmaceuticals:

Diuretics, ASA,
cyclosporine

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GOUT RISK FACTORS


▲ Transplant
▲ Alcohol intake
Highest with beer
Not increased with wine
▲ High BMI (obesity)
▲ Diet high in meat & seafood

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Pathology
▲ The most frequent sites of deposition of
MSU crystals are: cartilage, epiphyseal
bone, periarticular structures and the
kidney.
▲ A tophus is a foreign body reaction that
includes the MSU crystals surrounded
by fibrous tissue.
▲ In the kidney the deposition of MSU
crystals causes interstitial fibrosis and
arteriosclerosis.
Clinical course
4 clinical phases if untreated:
▲  asymptomatic hyperuricemia,
▲  acute/recurrent gout,
▲  intercritical gout,
▲  chronic tophaceous gout

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Asymptomatic Hyperuricemia
▲ elevated urate levels without symptoms of gout,
nephrolithiasis, or kidney stones.
▲ Hyperuricemia is defined:
>7 mg/dL (0.42mmol/L) in men and postmenopausal
women
>6 mg/dL (0..36mmol/L) in premenopausal women.
▲ urate <7 mg/dL  0.1% annual incidence of gout
urate >=9 mg/dL  4.9% annual incidence.
▲ the clustering of glucose intolerance, central obesity,
dyslipidemia, hypertension, and increased prothrombotic
and antifihrinolytic factors in an individual.

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Cause of hyperuricemia
-- decreased renal excretion
Primary Secondary
 Hypertension
 Idiopathic  Hyperparathyroidism
 Myxoedema
 Familial juvenile
 Down’s syndrome

gouty nephropathy  Increased level of organic level


 Lead nephropathy
 Sarcoidosis
 Bartter’s syndrome
 Beryllium poisoning
 Drug: diuretics, B-blocker, ACEI,
salicylates (low dose), PEA, EMB,
cyclosporin, nicotinic acid
 Chronic renal failure
 Volume depletion
 NDI

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Cause of hyperuricemia
-- increased uric acid production
Primary Secondary
 Glycogen storage disease
 Idiopathic
type II (G6PD), type III, V, VII
 HPRT def.  Hereditary fructose intolerance
 Lymphoproliferative and
 PPRT overactivity myeloproliferative diseases
( leukemia, Hodgkin’s d’z,
 Ribose-5- lymphosarcoma, myeloma, PV,
Waldenstrom’s
phosphate macroglobulinemia )
 Cytotoxic drugs
overproduction  Carcinomatosis
 AMP-deaminase  Gaucher’s disease
 Chronic hemolytic anemia
def.  Severe exfoliative psoriasis

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Acute/Recurrent Gout
symptoms: sudden onset of severe pain,
inflammation, limited range of motion, and
warmth at the affected joint(s).
▲ The joints are red, hot, and exquisitely tender;
even a bed sheet on the swollen joint is
uncomfortable, slight fever, leukocytosis,
elevation of ESR, and elevation of CRP
▲ 90% of first attacks are monoarticular with
first metatarsophalangeal joint, known as
podagra.
▲ Left untreated, the symptoms are self-
limiting but may take up to 21 week to
subside.
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90% of gout patients eventually have
podagra : 1st MTP joint

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Table. Characteristics of Classic Gout vs Atypical Gout
Classic Gout Atypical Gout
Can present at any age, including Observed in elderly patients
patients older than 60 years
Predominantly men Diagnosed in as many women as
men
Monarthritis Polyarthritis
Asymmetric Symmetric or asymmetric
Usually in lower extremity Any joint, upper or lower extremity
Tophi rare at presentation Tophi common at presentation
Acute Chronic but can have acute flare-
ups
Can be misdiagnosed as cellulitis Chronic form can be
or infection misdiagnosed as rheumatoid
arthritis or osteoarthritis: acute
flare-ups can be misdiagnosed as
cellulitis or infection
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ADVANCED GOUT
▲ Chronic Arthritis

▲ X-ray Changes

▲ Tophi Develop

▲ Acute Flares continue

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ADVANCED GOUT
▲ Chronic Arthritis
▲ Polyarticular acute
flares with upper
extremities more
involved

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Intercritical Gout
▲ It is the asymptomatic period between
crises, but MSU crystals can still be
recovered if necessary.
▲ The duration of this period varies,
but untreated patients may have a
second episode within two years.
▲ Some patients evolve to chronic
polyarticular gout without pain free
intercritical episodes.

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Chronic Tophaceous Gout
▲ Tophi are usually present after 10 to 20
years of inadequately treated chronic
gout.
▲ Visible tophi occur in 12% of patients after
5 years of gout and in 55% of patients after
20 years.
▲ most common sites of tophaceous gout:
olecranon bursae (elbow) and the joints of
the hand and feet.
 Other sites: the helix of the ear, the
Achilles tendons, and the knees.
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Chronic Tophaceous Gout
▲ Transplant patients treated with
cyclosporine and/or diuretics have an
increased risk for tophaceus gout.
▲ The most common sites for tophi are:
the olecranon, prepatellar bursa, ulnar
surface and Achilles tendon.

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Chronic Tophaceous Gout
▲ Tophi in the hands can cause joint
destruction.
▲ Tophi can ulcerate the skin and excrete
a chalky material composed of MSU
crystals.
▲ Tophi progress insidiously with
increased stiffness and pain.

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TOPHI
▲ Solid urate deposits
in tissues

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TOPHI
▲ Irregular &
destructive

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TOPHI RISK FACTORS

▲ Long duration of hyperuricemia

▲ Higher serum urate

▲ Long periods of active, untreated gout

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Renal disease
▲ Urolithiasis,
▲ Urate nephropathy (deposition of MSU
crystals in the interstitium), and
▲ Uric nephropathy ( deposition of MSU
crystals in the collecting tubes).
▲ The prevalence of urolithiasis is 22% in
primary gout and 42% in secondary
gout.

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Nephrolithiasis
▲ The prevalence of nephrolithiasis
correlates with the serum and urinary
uric acid levels.
▲ Serum urate levels 13 mg/dl
▲ Urinary uric acid excretion > 1100 mg/d

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Urate Nephropathy
▲ Deposits of monosodium urate crystals
surrounded by a giant cell inflammatory
reaction in the medullary intrerstitium
and pyramids.
▲ Clinically: silent or cause proteinuria,
hypertension and renal insufficiency.

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Uric acid nephropaty
▲ Precipitation in renal tubules and collecting
ducts cause obstruction to urine flow.

▲ Following sudden urate overproduction and


marked hyperuricaciduria:
◆ Dehydration and acidosis
◆ Lymphoma
◆ Cytolytic therapy

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Complication of gout
▲ Joint: destruction
▲ Soft tissue
▲ nerve entrapment syndrome: CTS,
tarsal tunnel syndromes
▲ kidney: uric acid calculi(10-15%),
chronic urate nephropathy, and
acute uric acid nephropathy
▲ Heart: ischemic heart disease

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GOUTY ARTHRITIS & TOPHI

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Diagnosis of gout
▲ Clinicaldiagnosis: Triad of
1- hyperurecemia
2- Acute monoarticular arthritis
3- Response to colchicine
▲ Laboratory diagnosis
▲ Differential diagnosis

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Criteria for clinical diagnosis
American Rheumatism Association sub-committe on classification criteria for gout 1977

▲ presence of characteristic urate crystals in the joint fluid


▲ Tophus proved to contain urate crystals by negative polarized light
microscopic study
▲ If none of above, diagnosis is 6/12 clinical, radiographic, and
laboratory criteria include:
1. more than one attack of acute arthritis
2. Maximum inflammation within 24 hours
3. Attack of monoaricular arthritis
4. Joint redness observed
5. first MTP joint painful or swollen
6. Unilateral attack involving first MTP
7. Unilateral attack involving tarsal joint
8. Suspected tophus
9. Hyperuricemia
10. Asymmetric swelling within a joint ( roentgenogram )
11. Subcortical bone cysts without erosions ( roentgenogram )
12. Negative synovial culture during attack of joint inflammation

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Laboratory Diagnosis
▲ Even the clinical appearance strongly
suggests gout. The diagnosis should be
confirmed by needle aspiration of acute or
chronically inflamed joints or tophaceous
deposits.
▲ Acute septic arthritis several of the other
crystalline – associated arthropathies, and
psoriatic arthritis may present with similar
clinical features.

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SYNOVIAL FLUID ANALYSIS
(Polarized Light Microscopy)
▲ The Gold standard

▲ Crystals intracellular during attacks

▲ Needle & rod shapes

▲ Strong negative birefringence meaning that


the crystals are yellow when aligned parallel
to the slow ray of the compensator and that
they are blue when they are perpendicular.

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SYNOVIAL FLUID

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SYNOVIAL FLUID
▲ Presence of MSU crystals do not
exclude the possibility of septic arthritis,
for this reason it is also recommended
to request a Gram smear.

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SYNOVIAL FLUID
- Cloudy due to leukocytes and a large
amounts crystals ocassionally produce a
thick pasty or chalky joint fluid.
-Increased leukocytes: >15,000/cc WBCs,
primarily PMNs

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SERUM URATIC ACID LEVELS
▲ This is the most misused test in the diagnosis
of gout.
▲ Not reliable

▲ May be normal with flares

▲ May be high with joint Sx from other causes

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Serum uric acid
-Normal range:
male 3-8 mg/dl
female 1.5-6 mg/dl
children 3-4 mg/dl
("normal" values may vary between laboratories)
-False elevation by:
levodopa if colorimetric method used

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Uric acid in 24-hour urine sample
▲ 24 urine collection for uric acid
determination is useful in assessing the
risk of renal stones and planning for
therapy.
▲ Urinary levels above 750 mg/dl in 24h
in gout or > 1100 mg/dl in asymptomatic
hyperuricemia indicates urate
overproduction.

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Radiographic Features
▲ Cystic changes, well-defined erosions
described as punched-out lytic lesion.
▲ Soft tissue calcified masses (chronic
tophaceous gout)
▲ Is helpful to exclude other kinds of
arthritis.

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RADIOLOGIC SIGNS

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Blood chemistry
▲ Renal function before deciding on therapy
▲ Plasma glucose: Patients with gout are at an increased
risk of developing diabetes mellitus.
▲ Abnormal liver function tests need to be considered
when therapy is selected.
▲ CBC count: The WBC count may be elevated in patients
during the acute gouty attack, particularly if it is
polyarticular.
▲ Lipids: Hypertriglyceridemia and low high-density
lipoproteins are associated with gout.
▲ Urinalysis: Patients with gout are at an increased risk of
renal stones

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Differential diagnosis
Acute Chronic
 Infective arthritis  Nodular rheumatoid
 Bursitis, cellulitis, tenosynovitis
 Other crystal arthropathy arthritis
( pseudogout, apatite or  Psoriatic arthritis
brushite arthritis or periarthritis )
 Traumatic arthritis  Osteoarthritis with
 Hemoarthrosis
 RA with palindromic onset
Heberden’s and
 Reactive arthritis Bouchard’s nodes
 Spondarthritis with peripheral  Sarcoid arthritis
involvement
 Psoriatic arthritis  xanthomatosis
 Sarcoid arthritis
 Rheumatic fever

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Gout vs. CPPD

▲ Similar Acute attacks


▲ Different crystals under Micro;
Rhomboid, irregular in CPPD
Pseudogout crystals are positively birefringent.
Pragmatically, this means that their colors are
opposite those of gout. Thus, pseudogout crystals
are blue when aligned parallel to the slow ray of
the compensator and yellow when they are
perpendicular.

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Gout vs CPPD

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Crystal-Induced Arthritis
Characteristic Gout Pseudogout
Prevalence 1.5 to 2.6 cases per 1000 individuals; <1 case per 1000 individuals; increases
increases with age in men and with age
postmenopausal women; 15/1000 at
age 58; men:28/1000, women:11/1000

Crystals
  Chemistry Monosodium urate Calcium pyrophosphate dihydrate
  Appearance Negatively birefringent; needle-shaped Weakly positively birefringent; linear or
rhomboidal

Articular involvement Monoarticular > oligoarticular; Monoarticular > oligoarticular


polyarticular < 30%

Most frequently affected joints First MTP joint Knee, wrist other
 - initially 50%
 - eventuall 90%
Ankles, knees, other

Predisposing conditions/risk factors Hyperuricemia*, obesity, hypertension, Hypothyroidism, hemochromatosis,


hyperlipidemia, alcohol ingestion, lead OA, chronic renal insufficiency,
ingeation, hereditary enzyme defect diabetes, hyperparathyroidism,
(rare) hereditary (rare)

Therapeutic options Acute attacks: Acute attacks:


 - NSAIDs, corticosteroids,  - NSAIDs, corticosteroids,
colchicine colchicine
Chronic management Chronic management
 - Urate-lowering agents, colchicine  - NSAIDs ± colchicine
*Drugs associated with hyperuricemia include diuretios, low-dose salicylates, nicotinic acid, oyclosporine, ethanol and
ethambutol.
Adapted from Am J Med 1997; 103 : 68S. 53
RA vs Gout

▲ Both have polyarticular, symmetric


arthritis

▲ Tophi can be mistaken for RA nodules

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RA vs Gout

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Treatment of gout

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TREATMENT GOALS
▲ Rapid and safe pain relieve (end
acute flares)
▲ Protect against future flares
▲ Prevent disease progression
▲ Correct metabolic cause

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ENDING ACUTE FLARES
▲ Control inflammation & pain & resolve
the flare
▲ Not a cure
▲ Crystals remain in joints
▲ Don’t try to lower serum urate during a
flare
▲ Choice of med not as critical as alacrity
& duration

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Acute Flare Med Choices

▲ NSAIDS

▲ Colchicine

▲ Corticosteroids

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Colchicine
1. Mechanism of action
-decreases inflammatory response through binding of
microtubular proteins which interferes with granulocyte
mobility
2. Efficacy: somewhat diagnostic for gout because
-90% respond to colchicine if treatment is initiated
within a few hours after onset, response rates decline if
acute attack is >24hrs old
-colchicine is relatively specific therapy for acute gout

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Colchecine
Dosing:
-colchicine has a narrow therapeutic index
-doses should be decreased in renal and
hepatic
dysfunction, but there are no standard
guidelines
-PO: 1.2mg stat, then 0.6mg every hour until:
response is achieved, or gastrointestinal
toxicity (diarrhea, abd. pain), or maximum
dose of 12 tablets is taken
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Colchecine
-IV: 2mg in 20cc NS infused slowly, may repeat with 1mg
after 6hrs but no more than 4mg in 24hours
-Decrease total dose to 2mg/24hrs in elderly patients
or patients who have been on colchicine maintenance
-Give only to patients who cannot tolerate the oral
tablets
-Avoid extravasation because it causes soft tissue
necrosis

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Colchecine
Adverse reactions
-Gastrointestinal: diarrhea, nausea, vomiting, hemorrhagic
colitis, occurs in 70-80% of patients on oral therapy, less
frequent with IV therapy but may see with high doses
-Bone marrow depression: cumulative toxicity
-Renal dysfunction: toxic side effect seen after large doses,
hematuria, oliguria
-Necrosis of soft tissue after extravasation: do not give
IM/SC

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NSAID
Mechanism of action:
-anti-inflammatory effects through
inhibition of prostaglandin
synthesis and inhibition of motility of
PMNs
-not specific for gout—adequate doses
will relieve inflammation from any
cause

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NSAID
Agents and Dosing
-Indomethacin: 75mg stat, 25-50mg q6hr, taper as
symptoms resolve
-avoid in elderly
-Any non-salicylate NSAID should be effective if
given in anti-inflammatory doses
-avoid salicylates because of effect on uric acid
elimination

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NSAIDS
▲ NSAIDS :
Interaction with
warfarin
Contraindicated in:
Renal disease
PUD
GI bleeders
ASA-induced RAD

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Intra-articular Steroids
-Effective anti-inflammatory agents
-Reserve for patients who cannot tolerate oral
colchicine or NSAID therapy and who are not
candidates for IV colchicine
-Limited to 4 injections per joint per year
Can use:
-Methylprednisolone (Depomedrol)
-Triamcinolone hexocetanide

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Syst. Corticosteroids

-IM injection of depot corticosteroid product


(e.g. DepoMedrol ) or ACTH
-Tapering effect of depot product prevents rebound
gout attacks
-Efficacy comparable to NSAID in studies
-Limited toxicity due to short term use
- Worse glycemic control
May need to use mod-high doses

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PROTECTION VS. FUTURE
FLARES
▲ Colchicine : 0.5-1.0 mg/day
▲ Low-dose NSAIDS

▲ Both decrease freq & severity of flares


▲ Prevent flares with start of urate-lowering RX
Best with 6 mos of concommitant RX
EBM
▲ Won’t stop destructive aspects of gout

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PREVENT DISEASE
PROGRESSION
▲ Lower urate to < 6 mg/dl : Depletes
Total body urate pool
Deposited crystals
▲ RX is lifelong & continuous
▲ MED choices :

Uricosuric agents
Xanthine oxidase inhibitor

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PREVENT THIS

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Uricosuric agents
▲ Indicated in patients with normal renal
function, under-excretion and no
evidence of tophi.
▲ Patients taking uricosuric agents are at
risk for urolithiasis. This can be
decreased by ensuring high urinary
output and by adding sodium
bicarbonate 1 gram TID.

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Uricosuric agents
▲ The available agents include:
probenecid (1-2 g/day) and
sulfinpyrazone (50-400 mg BID).
▲ Dose should be increased to decrease
uric acid < 6.0 mg/ml

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Sulfinpyrazone (Anturane)
Uricosuric: has Increased potency vs probenecid
Has antiplatelet effect at doses of 600-800mg/day
Dosing: 50mg bid-400mg/day, may go up to
800mg/day
Adverse reactions:
-Hypersensitivity reactions (uncommon): rash, may
cause bronchoconstriction in patients with ASA
intolerance, contraindicated in patients allergic to
phenylbutazone/pyrazoles
-Gastrointestinal irritation: take with food or milk
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XANTHINE OXIDASE
INHIBITOR

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Allopurinol
▲ Blocks conversion of hypoxanthine to
uric acid
▲ Decreases uric acid in overproducers
and underexcreters; it is also indicated
in patients with a history of urolithiasis,
tophaceus gout, renal insufficiency and
in prophylaxis of tumor lysis syndrome.

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Allopurinol
▲ usual dose is 300 mg/day. Maximal
recommended dose is 800 mg/day.
▲ In renal insufficiency dose should be
decreased to 200 mg/day for creatinine
clearance < 60ml/min and to 100
mg/day if clearance < 30 ml/min).

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Allopurinol
▲ Start with small doses of allopurinol to
reduce the risk of precipitating an acute
gout attack.
▲ Most common side effects are rash (2%
of patients) but rarely patients can
develop exfoliative dermatitis that can
be lethal.
▲ Chronic use of colchicine (0.6-1.2
mg/day) is used as prophylaxis for
acute attacks.
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Allopurinol Dosing
-Start at 100mg per day, increase weekly as
needed
-70% of patients will be controlled on
300mg/day
-May give up to 1200mg/day if necessary
-May be given once daily because of long
half life of active metabolite, but divided
doses recommended if total daily dose
>300mg
-Renal disease requires dose adjustment
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Allopurinol Adverse Reactions


Hypersensitivity rash:
maculopapular/purpuric: usually occurs within
1st5weeks , resolves with drug DC . rechallenge
cautiously, may cause fatal reactions
severe hypersensitivity more common in pts with
impaired renal function & ampicillin treatment
Gastrointestinal:
nausea, vomiting,abdominal pain, hepatomegaly.

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Febuxostat
▲ Potentnew xanthine oxidase inhibitor
▲ Metabolized by the liver (used in RI)
▲ No hypersensitivity reaction
▲ Dose: 80-120 mg/d

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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)

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Purine nucleotides

hypoxanthine Allopurinol
xanthine Xanthine
oxidase
Oxypurinol
Uric acid

Urinary Alimentary Tissue deposition


excretion excretion in excess

Urate crystal microtophi


uricosurics
Phagocytosis
colchicine with acute
NSAID
inflammation
and arthritis 83
NEW AGENTS
▲ RX gaps :
▲ Can’t always get urate < 6
▲ Allergies
▲ Drug interactions
▲ Allopurinol intolerance
▲ Worse Renal disease

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URICASE ENZYMES
(Stay Tuned)

▲ Catabolize urate to allantoin:


More soluble, excretable form

▲ Currently approved for hypoeruricemia in


tumor lysis syndrome

▲ Some concerns: fatal immunogenicity &


unknown long-term effects

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Treating the Asymptomatic
Hyperuricemic Patient:
Controversial, no set guidelines, but consider
in the following patient groups:
A. Develops symptoms
B. Excretes >900mg of uric acid/24hr: risk for
kidney stones
C. Serum uric acid >12mg/dl,
D. Patient with malignancy using
chemotherapy

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Diet
▲ Usually impractical, ineffective and
rarely adhered to in clinical practice.
▲ Indications for pharmacological therapy
includes: inability to reverse secondary
causes, tophaceus gout, recurrent
acute gout and nephrolithiasis.

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Prophylaxis A. When to treat


1. Recurrent attacks: choice of treatment
will depend on the frequency of the
attacks. Attacks once yearly may be
better treated with colchicine/NSAID
acutely rather than exposing the
patient to yearlong therapy. Frequency
of attacks >1-2/year are a good
indication for prophylactic or uric acid
lowering therapy.

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Prophylaxis A. When to treat
2. Tophi: indicator of long-standing
disease, will regress/disappear with
uric acid lowering therapy, patients
with tophi should be treated e even if
gout attacks are not frequent
3. Uric acid nephrolithiasis: treatment
will prevent further stones (and
development of renal dysfunction due
to gouty nephropathy?)

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QUESTIONS

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