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PHA223 > Gout therapeutics (SD) > Flashcards

Gout therapeutics (SD) Flashcards

1
Q

What is gout?

A
  • crystal induced arthritis

- associated with persistently raised plasma uric acid (urate) concentration

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2
Q

source of plasma uric acid

A

catabolism of the nucleic acid purine bases guanine and adenine

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3
Q

Why does uric acid form crystals?

A

it’s relatively insoluble in water and too much leads to uric acid crystal formation

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4
Q

most common site for gout

A

big toe

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5
Q

Is gout more prevalent in men or women?

A

men

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6
Q

risk factors for gout

A
  • age
  • sex - males x4
  • ethicity - African Americans
  • obesity - BMI/cholesterol
  • genetics/FH
  • diet - alcohol/red meat/seafood (purines)
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7
Q

What foods can increase liklihood of gout?

A

high purine foods

  • beer, meat, seafood, sugar/sweetened drinks
  • they increase uric acid levels
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8
Q

foods that can decrease risk of gout

A 
veg proteins
dairy
coffee
vitamin C
cherries
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9
Q

What part of the body is responsible for uric acid excretion/reabsorption?

A

proximal convoluted tubule in the kidney

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10
Q

What transporters in the kidney are important for urate transport/reabsorption?

A

URAT1
GLUT9
NPT1
ABCG2

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11
Q

Where is the URAT1 transporter and what does it transport?

A

brush border of proximal tubules in the kidney

urate

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12
Q

What is the GLUT9 transporter used for?

A

used for urate reabsorption

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13
Q

What does ABCG2 stand for?

A

ATP binding casette G2

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14
Q

Where is ABCG2 also found?

A

intestines

-> some urate lost in faeces

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15
Q

What is uric acid the end product of?

A

purine nucleic acid degradation

-> adenine and guanine

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16
Q

purine metabolism

A
  • adenine and guanine metabolised through same pathway
  • both converted to XANTHINE by xanthine oxidase
  • then converted to uric acid
  • uric acid renally excreted
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17
Q

What enzyme metabolises uric acid (humans don’t have this)?

A

uric oxidase

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18
Q

Why do some animals metabolie uric acid? (birds/reptiles/insects)

A

to reserve water and secrete it as a paste (not urinating a lot)

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19
Q

2 deficiencies that are genetic that can cause gout

A

HGPRT
PRPP

-> mutations increases uric acid

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20
Q

MSU

A

monosodium urate crystals

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21
Q

Where are MSU found?

A

deposited in cartilage in the joint space

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22
Q

What casues deposition of MSU?

A

sustained hyperuricaemia

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23
Q

levels of hyperuricaemia

A

> 9mg/dL

only 5% of patients

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24
Q

stages of MSU crystal formation

A

reduced solubility (supersaturation)
nucleation
crystal growth

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25
Q

pH of uric acid

A

pH 5.8 (weak acid)

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26
Q

What happens above 6.8 mg/dL of uric acid?

A

crystallisation can occur

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27
Q

factors affecting solubility of uric acid

A
  • synovial fluid pH
  • water concentration (in joint, less water then more precipitation)
  • electrolytes
  • proteoglycans/collagen levels
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28
Q

What is uric acid excreted by?

A

kidneys

-> kidney function important, elderly CKD/impairment, water/elecrrolyte levels change

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29
Q

4 causes of gout

A
  1. idiopathic decrease in uric acid excretion (75%)
  2. impaired uric acid excretion from thiazide diuretics, chronic renal failure
  3. inc uric acid production due to inc cell turnover (tumour) and inc purine synthesis (enzyme defects)
  4. high dietary purine intake
30
Q

2 casues of hyperuricaemia

A

overproduction of uric acid

reduced renal excretion of uric acid

31
Q

What happens when there is hyperuricemia?

A
  • precipitation of urate crystals in joints
  • activation of immune system
  • > neutrophils, macrophages, cytokine release
  • > inflammation and pain
32
Q

What does MSU activate?

A

NLRP3 inflammasome

33
Q

What inflammatory factors are released?

A 
IL-10
IL-37
TGF beta
IL-1Ra
-> try to resolve the crystals after release of IL-1
34
Q

What do neutrophils do?

A

break down the MSU crystals

35
Q

What initiates pain/inflammation in gout?

A

IL-1

-> target this

36
Q

What are the 4 stages of gout presentation?

A
  1. asymptomatic gout
  2. acute ‘gouty arthritis’
  3. asymptomatic inter-critical period
  4. chronic tophaceous gout
37
Q

What is ‘gouty arthritis’?

A
  • swollen joints with inflammation
  • pyrexia and erythematous (red)
  • caused by uric acid in the joint
  • gout flares
38
Q

What is chronic tophaceous gout?

A
  • after 10yrs
  • tophi
  • can affect surrounding tissues
39
Q

What are tophi?

A

region of chronic foreign body granulomatous response surrounding collections of MSU crystals

-> stick to tissues

40
Q

How to diagnose gout?

A
  • observation
  • x-ray or ultrasound
  • lab tests - serum uric acid (SUA), CRP, ESR *erythrocyte sed. rate)
  • MSU crystal detection in synovial fluid aspirates (gold standard)
  • rule out infection/tumours
  • CVD and renal tests
41
Q

3 types of treatment for gout

A
  1. prophylactic treatment
  2. symptomatic treatment
  3. lifestyle modfications
42
Q

What NSAIDs can be used for acute gout maagement?

A 
diclofenac
indomethacin
naproxen
piroxicam
-> PPIs if needed
43
Q

COX2 inhibitor licenced for gout management

A

etoicoxib

44
Q

corticosteroid for gout

A

prednisolone

45
Q

What is used for acute gout management?

A

NSAIDs
etoicoxib
corticosteroids

46
Q

What is 2nd line treatment for gout or if NSAIDs are c/i?

A

colchicine

47
Q

How does colchicine work?

A
  • modulates pro/anti inflammatory pathways in gout
  • prevents microtubule assembly
  • disrupts inflammasome and neutropil activation
  • prevents microtubule-based inflammatory cell chemotaxis (movement)
  • prevents generation of leukotreines and cytokines
  • prevents phagocytosis
48
Q

Does colchicine effect serum uric acid concentration?

A

NO

49
Q

What is the difference between NSAIDs and colchicine?

A

NSAIDs
- inhibit COX 2 and prostaglandin/leukotrienes to reduce pain/inflammation

colchicine

  • disrupts microtubules within macrophages
  • stops them from functioning properly
  • slows down leukoteienes/PGs, pain/inflam
50
Q

What drug is used 1st line to lower serum uric acid levels?

A

allopurinol

51
Q

What does allopurinol inhibit?

A

it inhibits xanthine oxidase

52
Q

What does xanthine oxidase do?

A

enzyme that converts hypoxanthine to uric acid

53
Q

How does allopurinol work?

A
  • it is convered/metabolised to alloxanthine by xanthine oxidase
  • alloxanthine inhibits xanthine oxidase
  • this inhibits uric acid formation
54
Q

What are the more soluble precursors that allopurinol increases?

A

xanthines and hypoxanthines

55
Q

What does allopurinol reverse?

A

the deposition of urate crystals in tissues (tophi)

56
Q

What is the drug of choice for LT gout treatment?

A

allopurinol

57
Q

half life of allopurinol

A

2-3 hrs

active metabolite (alloxanthine - 18-30hrs

58
Q

How is allopurinol excreted?

A

renally excreted

59
Q

What are the side effects of allopurinol?

A
  • GI disturbances
  • allergic reactions (rashes)
  • toxic epidermal necrolysis and Stevens Johnson syndrome
  • > rare
60
Q

When is allopurinol initiated?

A
  • NOT during an acute attack (can inc pain)
  • after an acute attack as a LT therapy
  • combined with NSAIDs initially
61
Q

What is an alternative to allopurinol?

A

Febuxostat

- if allopurinol not tolerated

62
Q

How does febuxostat work?

A

xanthine oxidase inhibitor

- inhibits urate production, same as allopurinol

63
Q

What are uricosuric agents?

A

increase uric acid excretion by direct action of the renal tubule

  • > block the transporters that reabsorb uric acid
  • > decrease uric acid serum levels
64
Q

When are uricosuric agents used?

A

3rd line
severe recurrent gout
patients who had severe adverse reactions to allopurinol

65
Q

What is given with uricosuric agents?

A

intiated with NSAIDs

66
Q

What transporters in the kidney are invoved in uric acid reabsorption?

A

URAT1

GLUT9

67
Q

examples of uricosuric agents

A

probenecid

benzbromarone - potent, hepatotoxicity

lesinurad - URAT1 inhibitor

68
Q

What can be used if NSAIDs and colchicine are c/i?

A

IL-1 biologics (Ankira)

  • > blocks IL-1
  • > decreases pain/inflammation
69
Q

example of a new iL-1 biologic that could be used for gout treatment

A

Canakinumab

-> sits inside the IL-1 receptor and blocks IL-1

70
Q

What is rasburicase?

A
  • contains uric acid oxidase
  • converts it to allantoin (in animals) in the blood
  • allantoin is more soluble and is readily excreted
71
Q

When is rasburicase given for gout treatment?

A

severe gout

IV infusions
-> because it’s a biologic, digested by GIT

72
Q

another name for Rasburicase

A

PEGylates uricase

PHA223 (43 decks)

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