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end of y3 > gout > Flashcards

gout Flashcards

1
Q

general gout

A

inflammation caused by

  • imbalance in purine metabolism
  • deposition of monosodium urate (MSU) crystal in articular and periarticular tissues
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2
Q

heterogenous clinical spectrum for gout

A

1) recurrent gouty arthritis

  • urate crystals in synovium joint

2) tophi

  • deposition of monosodium urate crystals in tissues and surrounding joint

3) interstitial renal diseases

  • gouty nephritis

4) uric acid nephrolithiasis

  • uric acid kidney stones
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3
Q

risk factors for gout

A

1) obese > non obese
2) male > female but gender gap narrow after menopause
3) occurrence in male < 30 yo and premenopausal women indicate inherited enzyme deficit or presence of renal disease
4) alcohol, red meat, sugar beverages, sedentary lifestyle

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4
Q

physiology for normal times pre gout

A
  • nucleic acid -> guanine and adenine -> hypoxanthine
    ** salvage pathway: hypoxanthine and guanine recycled to form nucleic acid
  • hypoxanthine oxidised to xanthine by xanthine oxidase
  • xanthine oxidised to uric acid by xanthine oxidase
  • uric acid excreted in humans
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5
Q

pathophysiology of gout

A
  • increase in uric acid -> precipitate as monosodium urate crystals -> trigger deposition of urate crystals -> inflammation
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6
Q

pathophysiology of gout - why increase in uric acid concentration

A

1) overproduction of uric acid (urate concentration > 2 -7 mg/dL)

  • primary cause: inborn errors of metabolism
  • secondary cause
    ** condition that increase cell turnover and purine generation
    ** drug/diet induced purine/urate overproduction

2) under excretion of uric acid via kidneys

  • drug/diet induced decreased uric acid clearance
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7
Q

pathophysiology of gout - how inflammation occur

A

1) Activation of inflammasome through 2 signals

  • signal 1 occur naturally
  • signal 2 triggered by monosodium urate crystals -> activate inflammasome

2) inflammasome activate caspase 1 which:

  • catalyse maturation of pro-IL-1b to IL-1b -> stimulate innate immune response -> act on IL-1 receptive cells -> stimulate transcription factor P650P50 through phosphorylation cascade -> transcription of cytokines and chemokines -> promote inflammation
  • catalyse cleavage of gasdermin D -> cell death -> formation of pyrototic pores in membrane -> allow IL-1b and other intracellular shit to escape -> damage

3) efflux of K+ out of cell through K+ channel -> mitochondria produce RoS -> Activate inflammasome

4) precipitation of urate crystals in joint -> activate neutrophils to mobilise and phagocytose crystals

  • if unsuccessful -> crystals lyse w neutrophils -> re-release of crystals and release of lysosomal enzymes -> damage at joints -> further inflammation and release of leukotrienes and prostaglandins -> further inflammation (+ve feedback loop)
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8
Q

clinical presentation of gout

A

1) monoarticular at 1st MTP of big toe
2) inflammation at big toe -> red, swell, warm, pain
3) sudden onset over night

  • can wake up w excruciating pain
  • can occur when drop in temperature

4) swelling, discomfort for days to wks after
5) can be self-limiting

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9
Q

stages of gout

A

1) asymptomatic hyperuricemia
2) acute gout (1st attack)
3) inter-critical phase (between flares)
4) chronic gout

  • hyperuricemia
  • development of tophi (uric acid crystals in soft tissue and joints change underlying structure of soft tissue and joints -> bumps)
  • recurrent attack of acute gout
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10
Q

diagnosis of gout

A

based on presence of monosodium urate crystals in

  • synovial fluid
  • tissue sections of tophaceous deposits
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11
Q

non pharmaco for gout

A

1) ICE to alleviate flares
2) reduce risk of flares

  • limit alcohol intake
  • limit purine-rich food
    ** asparagus, cauliflower, mushroom, red meat, anchovies, durian, peanut, organ meat
  • limit fructose corn syrup
  • weight management

3) meds management

  • switch hydrochlorothiazide to losartan/ACEi for uricosuric effect
  • X stop low dose aspirin treatment
  • X add/switch cholesterol lowering agents to fenofibrate
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12
Q

tldr treatment of acute gout

A

treated ASAP within 24 hrs

1) colchicine
2) PO NSAID
3) PO corticosteroids
4) intra-articular corticosteroids (X take PO meds)

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13
Q

why give colchicine ASAP

A

not as effective after 36h cuz +ve feedback loop and inflammation went on

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14
Q

colchicine dosing

A
  • 1 off treatment 1mg loading dose then 0,5mg one hour later OR
  • 0.5mg 2-3 times per day until acute flare resolve
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15
Q

MOA of colchicine

A
  • bind to bilirubin
  • prevent tubulin polymerisation into microtubules
  • inhibit leukocyte migration and phagocytosis -> block +ve feedback
  • inhibit leukotrienes B4 and prostaglandin production
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16
Q

colchicine SE

A

1) muscle weakness, unusual bleeding, pale lips, change in urine output
2) GI: N/V, D, abdominal pain, bleeding

  • increase freq w higher dose and longer duration of use
  • why bleed?
    ** cells in GI tract rapidly dividing cells
    ** when cells divide they need microtubule skeleton to divide effectively
    ** colchicine impair cell division (esp actively dividing)
    ** need dose titration to control output
17
Q

colchicine DDI

A

macrolide Abx, azoles, statins

18
Q

colchicine caution

A

renal and hepatic impairment need dose adjust

19
Q

PO NSAID types to use

A

1) non-selective: naproxen, indomethacin
2) selective: celecoxib

20
Q

what to do for acute flare if alr on ULT?

A

continue ULT during flare

21
Q

indication for ULT

A

1) frequent acute gout flare (2/> per yr)
2) tophaceous formation
3) imaging shows damage to joint/gouty arthropathy
4) history of urolithiasis

22
Q

treatment target on ULT

A

1) non-tophaceous gout: < 6mg/dL
2) tophaceous gout: < 5mg/dL

23
Q

initiation of ULT

A

1) start low go slow
2) initiate 2 - 4 wks after acute gout flares

  • why not initiated during acute gout flares?
    ** ULT dramatically lower plasma urate concentration -> increase gradient from joint to plasma -> increase mobilisation of crystals out of joint -> recognised by immune cell -> inflammation and pain -> make acute attack worse
  • what situations can initiate wo waiting for resolution?
    ** when got chance patient don’t come back to take ULT drugs
    ** when pt highly motivated to start regardless of chance of acute flare
    ** increase in flare frequency

3) initiated w colchicine 0.5mg BD for 3-6 months to prevent acute gout flare due to ULT initiation

24
Q

types of ULT

A

1) uric acid synthesis inhibitors (xanthine oxidase inhibitors)

  • allopurinol (1st line)
  • feboxustat

2) uricosuric agents

  • probenecid
25
Q

allopurinol dose

A
  • initiation 100mg OD
    ** ≤ 50mg OD if CKD stage ≥ 3
  • titration in 50-100mg increments every 2-8 wks
    ** monitor SU, clinical response, drug toxicity
  • usual maintenance > 300mg/day
    ** ok for renal impairment too
  • max dose 800-900 mg/day if normal renal function
26
Q

MOA of allopurinol

A

decrease uric acid production

27
Q

SE of allopurinol

A

1) allopurinol hypersensitivity syndrome (AHS)
2) SCAR

  • hypersensitivity on skin that occur within wks to months of initiation
  • bad skin reaction, increased temperature until skin peel -> stop meds and A&E
  • also flu-like symptoms, body ache, mild ulcer, sore throat, rashes w/wo peeling

3) N/V/D, fever, stomach pain, dark urine, jaundice

28
Q

allopurinol cautino

A

1) renal adjustment
2) genetic testing for HLA-B*5801

  • patient w risk factors for SCAR
    ** renal impairment (CrCl < 60)
    ** concomitant meds (diuretics)
    ** high starting dose or rapid titration
    ** old age
    ** Han Chinese/Thai/Korean
  • but not routinely tested for new pt cuz low +ve predictive value + lack of cost-effective alternatives
  • why HLA-B5801?
    ** allopurinol bind to self-peptide then bind to HLA-B    5801 -> complex activate T cell -> cytotoxicity -> SCAR
29
Q

allopurinol DDI

A

1) increase bone marrow suppression w azathioprine, cyclophosphamide
2) increase hypersensitivity reaction/toxicity of allopurinol w ACEi/diuretic/ampicillin,/amoxicillin
3) monitor treatment of carbamazepine, warfarin, theophylline
4) increase AE/toxic effect of pegloticase

30
Q

feboxostat dose

A
  • initiation ≤ 40mg/day
  • titration by 80mg/day if treatment target not met after 2-4 wks
31
Q

feboxostat caution

A

avoid if HF or CHD cuz associated w MACES

32
Q

probenecid indication

A

1) allopurinol CI in tophaceous gout
2) increasingly freq gouty attack

33
Q

probenecid dose

A

1) start 2-3 wks after acute attack
2) initiation 250mg BD for 1 wk then 500mg BD
3) titration in 500mg every 4 wks as tolerated if symptoms not controlled
4) usual maintenance ≤ 2g/day

34
Q

probenecid MOA

A
  • inhibit proximal tubule anion transport
  • inhibit uric acid reabsorption
  • increase uric acid excretion
35
Q

probenecid SE

A

N/V, painful urination, lower back pain, allergic reaction, rash

36
Q

probenecid precaution

A

1) hydration > 2L to prevent kidney stone formation
2) keep urine pH > 6 by administration of alkaline (potassium citrate)
3) ineffective in CKD
4) risk of haemolytic anaemia if G6PD deficiency

37
Q

probenecid CI

A

urolithiasis

38
Q

ULT treatment duration

A
  • stop once remission (X gout flare and tophi formation for >/= 1 yr)
  • but if therapy well tolerated and not burdensome then can choose to continue treatment

end of y3 (8 decks)

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