Transcript No Slide Title

Drug Therapy of Gout
What Is Gout?
A medical condition caused by an increase in the level of uric acid >> urate
crystals , causing inflammatory responses around some joints of the body (
Gouty arthritis )
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
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
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
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
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:
1-polarized light
2-red compensator
Crystal-induced inflammation (from gout to gouty arthritis )
hyperuricemia
inflammation
crystal deposition
(blood stream)
crystals engulfed
influx of PMN’s
protein binding
receptor binding
(Synovial joints )
(Macrophages )
cytokine release
PMN is critical
component of
crystal-induced
inflammation
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)
Hyperuricemia
hyperuricemia results when production exceeds excretion (either
by over production or less excretion )
Hyperuricemia
net uric acid loss results when excretion exceeds production
Chronic tophaceous gout
tophus = localized
deposit of
monosodium urate
crystals
** could also be in several
places in the body
Gout - tophus
classic location of
tophi on helix of ear
Gout - X-ray changes
DIP (Distal
interphalangeal joint)
joint destruction
phalangeal bone cysts
Gout - X-ray changes
bony erosions
Gout - cardinal manifestations
tophi
arthritis
acute &
chronic
HYPERURICEMIA
Nephrolithiasis
(Kidney stones)
chronic
nephropathy
*kidneys should be functioning well in order to use classical treatment
Drug therapy of gout
Treatment targets either :
1- Decrease Uric Acid Formation
2- Increase Uric Acid Excretion
Uric acid metabolism
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown
One method of
reducing uric acid
levels , is inhibition
of the enzyme
xanthine oxidase
Renal handling of uric acid
Fate of uric acid in kidneys :
•glomerular filtration
Uric acid
•tubular reabsorption
Uric acid
•tubular excretion
Uric acid
•post-secretory
reabsorption
Uric acid
•net excretion
The goal of some Gout Drugs, is to Increase the net
excretion of uric acid from the kidneys.
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
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
Drugs used to treat gout
Urate Lowering Drugs
Acute Arthritis Drugs
colchicine
For chronic cases
allopurinol
steroids
probenecid
NSAID’s
febuxostat?
It’s a new drug that’s being
developed
rest + analgesia + time
Drugs used to treat gout
NSAID’s
•
•
•
•
•
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
*Don’t memorize the doses, just the names
** Remember that Aspirin is never used
Colchicine - plant alkaloid
colchicum
autumnale
(autumn crocus or
meadow saffron)
Correction for the previous lecture
Colchicine is used to prevent the polymerization of the
cell’s cytoskeleton by binding to TUBULIN ( not Actin)
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
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
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
Colchicine - indications
Dose
Indication
high
treatment of acute gouty arthritis
low
prevention of recurrent gouty arthritis
It’s better to use xanthine oxidase inhibitors for
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
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)
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 .)
Hyperuricemia - mechanisms
excessive
production
inadequate
excretion
hyperuricemia
Urate-lowering drugs
block
production
enhance
excretion
net reduction in total body pool of
uric acid
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
Drug therapy of gout
Drugs That Block
Production of Uric Acid
Uric acid metabolism
dietary intake
xanthine oxidase
catalyzes
hypoxanthine to
xanthine &
xanthine to uric
acid
purine bases
hypoxanthine
xanthine
uric acid
cell breakdown
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 it’s risks
in order for it to be used.
allopurinol
Allopurinol - usage indications
•management of hyperuricemia of gout
•management of hyperuricemia associated
with chemotherapy
•prevention of recurrent calcium oxalate
kidney stones
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 .
Allopurinol - serious reactions
•fever, rash, toxic epidermal necrolysis
•hepatotoxicity, marrow suppression
•vasculitis
•drug interactions (ampicillin(antibiotic),
thiazides(diuretic ), mercaptopurine,
azathioprine(anti-cancer)
•death
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
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 (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
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
Drug therapy of gout
Drugs That Enhance
Excretion of Uric Acid
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
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
production
inadequate
excretion
xanthine
oxidase
inhibitor
uricosuric
agent
hyperuricemia
Drug therapy of gout
Case Presentation
Refer to the third
slide
Case presentation - therapy
NSAID
NSAID
steroid
colchicine (low-dose)
Antiinflammatory
days 1-10
Maintenance
dose
allopurinol
Chronic condition
days 11-365
days 365+
Done by Anas Khalil
With the help of shaima shahin’s Notes