Drug Therapy of Gout

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• Drug Therapy of Gout

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What Is Gout?
A medical condition caused by an increase in the
level of uric acid gtgt urate crystals , causing
inflammatory responses around some joints of the
body ( Gouty arthritis )
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Case presentation ( Gouty arthritis)

• 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

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Gout - acute arthritis
acute synovitis, ankle first MTP joints
Redness and swelling are noticed around those
joints in particular
The metatarsophalangeal articulations are the
joints between the metatarsal bones of the foot
and the proximal bones
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Gout - acute bursitis
acute olecranon bursitis
Bursitis is inflammation of the fluid-filled sac
(bursa) that lies between a tendon and skin, or
between a tendon and bone
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Gouty arthritis - characteristics

• sudden onset
• middle aged males
• severe pain
• distal joints
• Intense inflammation

• recurrent episodes
• influenced by diet ( since uric acid level is
  influenced by our dietary intake of purines)
• bony erosions on Xray

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Monosodium urate crystals
These crystals show
1-needle shape 2-negative birefringence
(Birefringence double streams of light, usually
in prisms, etc)
Diagnosis is done by taking a biopsy from the
synovial fluid and then examined either by
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Crystal-induced inflammation (from gout to gouty
arthritis )
PMN is critical component of crystal-induced
inflammation
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Gouty arthritis - characteristics

• sudden onset
• middle aged males
• severe pain
• distal joints
• intense inflammation

• recurrent episodes
• influenced by diet
• bony erosions on Xray
• Hyperuricemia (always)

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Hyperuricemia
hyperuricemia results when production exceeds
excretion (either by over production or less
excretion )
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Hyperuricemia
net uric acid loss results when excretion exceeds
production
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Chronic tophaceous gout
tophus localized deposit of monosodium urate
crystals could also be in several places in
the body
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Gout - tophus
classic location of tophi on helix of ear
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Gout - X-ray changes
DIP (Distal interphalangeal joint) joint
destruction
phalangeal bone cysts
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Gout - X-ray changes
bony erosions
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Gout - cardinal manifestations
kidneys should be functioning well in order to
use classical treatment
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Drug therapy of gout
Treatment targets either 1- Decrease Uric Acid
Formation 2- Increase Uric Acid Excretion
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Uric acid
The Role of Uric Acid in Gout

• end product of purine metabolism
• serum uric acid level dependent upon
• rate of uric acid production
• efficiency of renal uric acid excretion

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Uric acid metabolism
One method of reducing uric acid levels , is
inhibition of the enzyme xanthine oxidase
xanthine oxidase catalyzes hypoxanthine to
xanthine xanthine to uric acid
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Renal handling of uric acid
Fate of uric acid in kidneys
Uric acid

• glomerular filtration
• tubular reabsorption
• tubular excretion
• post-secretory reabsorption
• net excretion

Uric acid
Uric acid
Uric acid
The goal of some Gout Drugs, is to Increase the
net excretion of uric acid from the kidneys.
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The goal of some Gout Drugs, is to Increase the
net excretion of uric acid from the kidneys Non
steroidal anti-inflammatory Drugs are sometimes
used in the treatment of Gout ( cause increase in
excretion ) Aspirin on the other hand is never
used
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Gout - problems

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

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Treating acute gouty arthritis

• colchicine
• NSAIDs
• steroids
• rest, analgesia, ice, time

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Drugs used to treat gout
Urate Lowering Drugs For chronic cases
Acute Arthritis Drugs
Its a new drug thats being developed
rest analgesia time
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Drugs used to treat gout

• NSAIDs
• Indomethacin (Indocin) 25 to 50 mg four times
  daily
• Naproxen (Naprosyn) 500 mg two times daily
• Ibuprofen (Motrin) 800 mg four times daily
• Sulindac (Clinoril) 200 mg two times daily
• Ketoprofen (Orudis) 75 mg four times daily

Dont memorize the doses, just the names
Remember that Aspirin is never used
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Colchicine - plant alkaloid
colchicum autumnale (autumn crocus or meadow
saffron)
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Correction for the previous lecture
Colchicine is used to prevent the polymerization
of the cells cytoskeleton by binding to TUBULIN
( not Actin)
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Colchicine

• only effective in gouty arthritis ( it only
  works on the inflammation process , and has
  nothing to do with uric acid levels .)
• 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

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Colchicine

• Colchicine inhibits microtubule polymerization by
  binding to tubulin, one of the main constituents
  of microtubules
• reduces inflammatory response to deposited
  crystals
• diminishes PMN phagocytosis of crystals
• blocks cellular response to deposited crystals

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Crystal-induced inflammation
PMN is critical component of crystal-induced
inflammation
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Colchicine - indications
Dose Indication
high treatment of acute gouty arthritis
low prevention of recurrent gouty arthritis
Its better to use xanthine oxidase inhibitors
for
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Colchicine - toxicity
Associated with high doses

• 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
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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)

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Colchicine - Cancers

• Promising studies have recently shown that
  Colchicine could be used for treating tumors
• HOW ?
• Since Colchicine prevents the formation of
  microtubules , this could be useful in limiting
  the mitotic activity of tumors cell by
  preventing the formation of mitotic spindles
  (microtubules .)

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Hyperuricemia - mechanisms
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Urate-lowering drugs
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Gout - urate-lowering therapy
Xanthine Oxidase as an example

• 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

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Drug therapy of gout
Drugs That Block Production of Uric Acid
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Uric acid metabolism
xanthine oxidase catalyzes hypoxanthine to
xanthine xanthine to uric acid
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Allopurinol (Zyloprim)

• inhibitor of xanthine oxidase
• effectively blocks formation of uric acid
• how supplied - 100 mg 300 mg tablets
• pregnancy category C

Drugs are characterized according to their
effects on pregnancy (fetus) into several
categories A,B,C,D,X. A is the safest, X
completely dangerous and should not be given to
pregnant women  benefits from taking the drug
must outweigh its risks in order for it to be
used.
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Allopurinol - usage indications

• management of hyperuricemia of gout
• management of hyperuricemia associated with
  chemotherapy
• prevention of recurrent calcium oxalate kidney
  stones

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Allopurinol - common reactions

• diarrhea, nausea, abnormal liver tests
• acute attacks of gout
• rash

Manufactures are obliged to put a special
indication on each leaflet ( a BLACK BOX) , that
explains the serious side effect for that
particular drug e.g Isotretinoin is a highly
teratogenic Drug that should have a BLACK
BOX For Allopurinol you might find that BLACK
BOX sometimes , because certain people have
shown to have allergy for it .
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Allopurinol - serious reactions

• fever, rash, toxic epidermal necrolysis
• hepatotoxicity, marrow suppression
• vasculitis
• drug interactions (ampicillin(antibiotic),
  thiazides(diuretic ), mercaptopurine,
  azathioprine(anti-cancer)
• death

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Stevens-Johnson syndrome
Another serious side effect , characterized by
Mucocutaenous ulcerations target skin
lesions mucous membrane erosions epidermal
necrosis with skin detachment
Those side effects are treated by systemic
corticosteroids
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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

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Febuxostat

• recently approved by FDA (not on market)
• oral xanthine oxidase inhibitor
• chemically distinct from allopurinol
• 94 of patients reached urate lt 6.0 mg/dl
• minimal adverse events
• can be used in patients with renal disease

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PEG-uricase (Polyethelene Glycol)

• Uricase enzyme that degrades uric acid 
• investigational drug
• PEG-conjugate of recombinant porcine uricase
• treatment-resistant gout
• uricase speeds resolution of tophi
• further research needed

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Drug therapy of gout
Drugs That Enhance Excretion of Uric Acid
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Uricosuric therapy

• probenecid
• blocks tubular reabsorption of uric acid
• enhances urine uric acid excretion
• increases urine uric acid level
• decreases serum uric acid level

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Uricosuric therapy

• moderately effective
• increases risk of nephrolithiasis
• not used in patients with renal disease
• frequent, but mild, side effects

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Uricosuric therapy

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

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Choosing a urate-lowering drug
xanthine oxidase inhibitor
uricosuric agent
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Drug therapy of gout
Case Presentation Refer to the third slide
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Case presentation - therapy
Maintenance dose
Anti-inflammatory
Chronic condition
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Done by Anas Khalil With the help of shaima
shahins Notes