drugs for crystal arthropathies Flashcards
facts about gout
an inflammatory arthritis
common in men
associated with an incease in cardiovascular mortality
normal upper range of uric acid
in men - 0.42mmol/L (saturation point)
in women - 0.36 mmol/L
hyperuricaemia
levels > 0.42 mmol/L
when uric acid is above saturation point
monosoodium urate crystals deposit into joint and peri articualr tissues throughout the body
hyperuricaemia will cause gout
false
not everyone with increased uric acid get gout
uric acid may not be increased in acute gout
however, 80-90% of patients with gout are hyperuicaemic
uric acid/uate is derived from
diet (1/3)
endogenoous liver biosynthesis (2/3)
- final product of purine metabolism (in humans)
uric acid/urate is eliminated by
gut (1/3)
kidneys (2/3)
uric acid solubility
is a weak organic acid - poorly soluble in acidic pH (urine) and low temperatures (why peripheraal joints are more severely effected)
uric acid biosynthesis
derived from purine metabolism in the liver
uric acid excretion
100% uric acid is filtered through the glomerulus
99% is reabsorbed in proximal tubule
6-10% secreted in the distal proximal tubule
genetic component of gout
90% of hyperuraemics under excrete uric acid
what is gout
inflammatory arthritis
chronic asymptomatic hyperuricaemia leads to supersaturation of body tissues with urate crystals
uric acid - decreased solubility in acidic and cold conditions
crystals depsit around joints, especially extremities
crystals shed into joint
definitive diagnosis of gout
urate crystals in synovial fluid
causes of gout
exact cause uncertain in most cases
polygenic but mostly due to decreased renal excretion of uric acid
men 3x more than women
dietary triggers
obesity
increased purine intake
increased fructose
meta, seafoood, sugary drinks, beer, spirits,
good foods for diet
coffee
dairy products
vit C
other risk factors for gout
urate transporter mutations hyperrtension metabolic syndrome chronic renal failure drugs transplantation - kidney and heart
drugs triggering gout
thiazide and loop diuretics (for hypertension)
low dose aspirin (causes problems with renal excretion)
cyclosporin (used to prevent transplant rejection)
main cause of gout
decreased renal excretion in distal proximal tubule
increased purines in diet (alcohol, meat, seafood)
increased purine turnover (alcohol, fructose, obesty, tumour lysis)
monosodium urate crystals building up into the tissues
get shed into the joints
set up inflammatory response
kinin, complement and plasmin systems
neutrophilc infiltration - engulf crystals
release of toxic oxygen metabolites
tissues lysis and release of proteolytic enzymes
preclinical gout
asymptomatic hyperuricaemia
crystall deposits increase in tissues fro years then finally crystals may shed into the joint
two clinical phases of gout
intermittent acute gout - s symptoms of gout or signs of tophi between attacks
chronic tophaceous gout - if raised uric acid not adequately treated
acute gout
intermittanet pauci-articular inflammatory arthritis
sudden onset
red and intensely painful
extensive swelling
50% first attacks occur in 1st metatarsophalangeal joint (podagra)
acute gout is assciated with
fever
can be poly articular (especially in eldery and women)
self limiting
chronic gout
recurrent attacks + inadequate urate lowering treatment leads to chronic toophaceous gout
erosion of neighbouring joints - deformity and restricted movement
tophi are
large crystal deposits oon the extensor surfaces (fingers/hands, elbows, tendons, ear)
chronic gout can lead to
nephrolithiasis and renal tissue depsits - chronic renall faillure
contributes to cardioovascular disease and stroke
podagra
sudden onset gout in the first metatarsophalangeal joint
treatment approach for chronic gout
much earlier use of urate-lwering therapies to treat underlying disease
treatment of acute gout - pain relief
pain relief
- NSAIDs
- colchicine
- glucocorticoids - oral and intra-articular (not if septic arthritis)
treatment of acute gout - urate lowering therapy
maintain ULT if previously diagnosed gout
start urate lowering therapy if new diagnosis - lowest dose and increase dose very slowly
colchicine
alkaloid product of autumn crocus - ancient remedy
mechanism of action not fully understood but binds tubulin - stops microtubule assembly to reduce
- cell division
- neutrophil motility
- chemokine production
inflammatory cell recruitment stops
colchicine is absorbed
rapidly orally
why isnt colchicine given as a first line therapy
vomiting and diarrhoea - very common first sign of toxicity
muscle damage, myelosuppression, multple organ failure and there is no antidote
do not prescribe colchicine if
kidney or liver function is poor
watch for DDIs
how long does acute gout last
two week
aim of treating chronic gout
long term decrease in uric acid
lifestyle - diet, alcohol, and weight loss
3 main drug group for chroonic gout
xanthine oxidase inhibitors
uricosuric agents
uricase agents
start during acute attack - better capture and compliance
main xanthine oxidase inhibitor
allopurinol
allopurinol
xanthine oxidase inhibitor
hypoxanthine analogue
competitively inhibits XO to decrease uric acid production
XO also converts allopurinol to alloxanthine/oxypurinol
alloxanthine non competitively inhibits XO
pharmacological action is largely alloxanthine
drug of choice for long term treatment of gout
allopurinol
prescribing allopurinol
well absorbed orally
single daily dose
renally excreted
decrease dose and titrate more slowly in RF
why start low, go slow
dose esclaltion strategy
decreases risk of acute flare
aims of long term urate lowering therapy
decrease urc acid concentration to <0.36 mmol/L
disolve tophi, calculi and urate crystals in other tissues
maintain dose when SUA reaches 0.36
preventing of acute gout flare treatment during SUA
prophylactic NSAIDs or cochicine
adverse effects of allopurinol
mostly GI
allopurinol hypersensitivity syndrome - drug reaction, rash with eosinophilia and systemic symptoms
alloopurinol hypersensitivity syndrome
if rash i severe - stevens-johnson syndrome - rare but potentially fatall
risk increased if starting dose is high
east asian patients at higher risk
consider testing patients (PCR)
dangerous drug interactions with allopurinol
mercaptopurne and azathioprine
purine analogues metabolised by XO
allopurinol increases their effects by blocking XO
affects fast replicating tissues, myelosuppression, diarrhoea, life threateneing
feboxostat
non purine selective inhibitor of XO not a purine analogue metabolised mainly in theliver useful in pateints with renal failure or those who cannot tolerate allopurinol much more expensive than allopurinol
uricosuric agents
blocks urate re uptake in proximal tubule
useful for under excreters
uricase agents
rasburicase and pegloticase
dervides from aspergillus fluvus
catalyses conversion of uric acid to allantion
rapidly decreases serum uric acid levels
IV only
short half life
single use in tumour lysis syndromes
