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Exam 1- GI and CVD > Gout > Flashcards

Gout Flashcards

1
Q

What causes this build-up of uric acid- increased production or decreased excretion?

A

BOTH- gout can be due to an increased production or decreased excretion of uric acid.
- 10 % = increased rate of synthesis of purine precursors of uric acid
- 90% = Decreased elimination of uric acid by kidneys
Can be a combination of the 2

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2
Q

What is gout?

A

It is a form of arthritis caused by an increased concentration of uric acid in the blood that can lead to the formation of crystals in the joints and soft tissues.

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3
Q

What percentage of the UK population have gout?

A

2.49%
1.77/1000 people per year

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4
Q

In what gender is gout more common?

A

Males- ratio of men to females = 4.3:1

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5
Q

What age group is gout most common?

A

Common in people aged 30-60 years and incidence increases further with age
- is rare in young people

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6
Q

Is gout genetic?

A

There is a genetic link and gout often runs in families.

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7
Q

How is uric acid synthesised?

A
  • Uric acid is an end product of purine nucleotide metabolism which is catalysed by the enzyme xanthine oxidase.

Hypoxanthine –> Xanthine –> Uric acid
Both of these steps are catalysed by xanthine oxidase

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8
Q

Which enzyme catalyses the breakdown of xanthine to uric acid?

A

Xanthine oxidase

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9
Q

How is uric acid normally excreted?

A

Normally excreted via the kidneys and filtered by the glomerulus:

  • 90-100% is reabsorbed in the proximal tubule of the kidney via the URAT-1 anion transporter
  • Then 50% is actively secreted back out into the distal tubule and 40-45% of this undergoes further post-secretory reabsorption
  • Therefore, 5-10% of the original glomerular load is excreted into the urine.
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10
Q

What is the process of secreting uric acid by the kidneys and what is the percentage breakdown of that that reaches the urine?

A
  • 90-100% is reabsorbed in the proximal tubule of the kidney via the URAT-1 anion transporter
  • Then 50% is actively secreted back out into the distal tubule and 40-45% of this undergoes further post-secretory reabsorption
  • Therefore, 5-10% of the original glomerular load is excreted into the urine.
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11
Q

How much of uric acid is excreted in urine and how much is excreted through bile into the GI tract?

A

2/3 in urine
1/3 as bile

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12
Q

What percentage of gout is caused by an increased rate of synthesis of purine precursors of uric acid?

A

10%

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13
Q

What percentage of gout is caused by a decreased elimination of uric acid from the kidneys?

A

90%

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14
Q

What are the 2 types of gout?

A

PRIMARY: Due to rare inborn errors of metabolism or excretion
SECONDARY (mostly all): Due to drugs or consequences of other conditions

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15
Q

What is the difference between primary and secondary gout and which is more common?

A

PRIMARY (rare): Due to rare inborn errors of metabolism or excretion
SECONDARY (mostly all): Due to drugs or consequences of other conditions

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16
Q

What are some of the causes of secondary gout?

A
  • Overconsumption of foods that are high in purines such as oily fish, seafood, offal (liver, kidney, hearts), yeast
  • Overproduction of uric acid (10%) e.g. due to excessive cell turnover in conditions such as psoriasis, neoplastic disease, anaemia or due to cell lysis caused by chemotherapy or radiotherapy or due to rare enzyme mutation defects
  • Under excretion (90%) - Hyperuricaemia- Hugh conc in blood meaning lots of uric acid is filtered through the glomerulus = increased uric acid reabsorption to avoid dumping of insoluble uric acid into the urinary tract = decreased tubular secretion in distal tubule = less is excreted
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17
Q

What are some examples of conditions that cause overproduction of uric acid due to excessive cell turnover?

A

Psoriasis
Neoplastic disease
Anaemia
Also, cell lysis due to chemo or radiotherapy
Rare defects in enzymes

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18
Q

What is hyperuricaemia?

A

High uric acid concentration
Hyperuricemia is defined as an elevated serum uric acid level, usually greater than 6 mg/dL in women and 7 mg/dL in men

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19
Q

What serum uric acid levels are deemed hyperuricaemic?

A

Greater than 6 mg/dL in women and 7 mg/dL in men

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20
Q

What are the risk factors can cause high uric acid levels and lead to gout?

A
  • Renal failure
  • Alcohol consumption- Beer and red wine have high levels of purine
  • Drugs e.g. diuretics- especially thiazide-like diuretics e.g. bendroflumethiazide
    also, aspirin, ciclosporin, omeprazole. ethambutol,
  • Physical stress on joints e.g. tight shoes, joint trauma, hiking
  • Hypertension
  • Obesity
  • Hypertriglyceridaemia
  • conditions such as chronic kidney disease, osteoarthritis, diabetes,
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21
Q

What is deposited at the joints in gout?

A

Monosodium urate crystals

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22
Q

What is the relationship between uric acid and urate?

A

Uric acid is a weak acid with a pKa of 5.8
At physiological pH = uric acid is ionised to monosodium urate and can lead to the formation of long and thin crystals

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23
Q

What happens to uric acid at physiological pH?

A

It os a weak acid and is so ionised to monosodium urate

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24
Q

What factors can increase the risk of solubility and deposition of crystals in gout?

A
  • Temperature
  • pH
  • Cation concentration
  • Articular dehydration
  • Presence of nucleating agents e.g. insoluble collagens
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25
Q

If crystals can be present for years without causing any symptoms, what happens to cause the development of gout symptoms?

A

Symptoms only occur when the crystals are shred into the Bursa
- Bursa are small sacs of synovial fluid that surround the joints
- This shredding can be caused by trauma, dehydration, rapid weight loss, illness, surgery

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26
Q

What can urate crystals do at the joint?

A

They can initiate and sustain inflammatory responses causing inflammation, tenderness, and pain.
They do this by activating the complement system via stimulating the cleavage of C5 and the formation of complement membrane attack complexes. This leads to the secretion of pro-inflammatory cytokines e.g TNF and IL-8, chemokines, and inflammatory cells e.g. monocytes and mast cells

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27
Q

What are the 5 stages of clinical presentation of gout?

A
  1. Asymptomatic hyperuricaemia- the period before gout manifests
  2. Acute gouty arthritis
  3. Interval/Intercritical gout
  4. Chronic tophaceous gout
  5. Gouty nephropathy
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28
Q

What is the acute gouty arthritis stage?

A

This is usually the first attack of gout- 90% of cases only affect one joint (monoarticular) and 80% of these are in the first metatarsophalangeal joint of the big toe

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29
Q

What joint is affected in 80% of patients’ first gout attack (acute gouty arthritis phase)?

A

80% of these are in the first metatarsophalangeal joint of the big toe

30
Q

What are the symptoms of a gout attack?

A
  • Severe pain
  • Joint is hot, red, swollen
  • Attack is abrupt- max intensity at 8-12 hours
  • Hard to weight-bear on the joint
  • Synovitis- inflammation of the synovial joint
  • Leucocytosis- raised WBC count
  • Elderly may present confused
31
Q

What factors can trigger a gout attack?

A
  • Certain food consumption
  • Alcohol consumption
  • Dehydration
  • Starting on a diuretic medicine
31
Q

What happens if you leave a gout attack untreated?

A

Will right itself in about 7 days
But would cause desquamation (shredding of the outer layer of skin)

32
Q

What is desquamation?

A

The shredding of the outer layer of the skin.

33
Q

What is the intercritical gout phase?

A

This is the time in between gout flare-ups.
This can be months to years without any symptoms

34
Q

What are tophi?

A

Tophi are white deposits where monosodium urate crystals have accumulated around the joints and appear as lumps under the skin.
- They form nodules that can be visible in the subcutaneous and periarticular layer of ear lobes and Achilles tendon and fingers.

35
Q

What happens in the chronic tophaceous phase of gout?

A

This occurs when uric acid levels are not well controlled and lead to the formation of tophi-nodules and lumps of crystals under the skin.

  • Tophi that form in the small joints of the fingers can cause physical changes and restrict movement. Tophi in the cartilage and bone can eventually lead to joint damage and deformity, and tophi under the skin can be unsightly and become infected and sometimes painful.
36
Q

What happens in the gouty nephropathy phase?

A

This is when the patient can develop hyperuricaemia-induced renal disease.
- Causes kidney damage as the crystals become deposited around the renal tubules, usually in the ducts leading to an inflammatory response (interstitial nephritis)
- Can cause problems such as proteinurea, renal impairment and kidney stones

37
Q

How is gout diagnosed?

A
  • Clinical history and examination
  • Blood test- check uric acid levels (however, is not always raised in acute gout attacks in about 1/3 of patients = redo blood tests 2-3 weeks later)
  • Main test = Joint fluid microscopy (if sure of diagnosis, this isn’t necessary due to infection risk)- involves looking at a sample of fluid drawn from the joint under a microscope to look for the presence of crystals
  • Also rule out infection- similar presentation to septic arthritis
  • Joint x-ray
  • Blood test- look at renal function, lipids, blood glucose
38
Q

What is the main test for diagnosing gout?

A

Joint fluid microscopy (if sure of diagnosis, this isn’t necessary due to infection risk)- involves looking at a sample of fluid drawn from the joint under a microscope to look for the presence of crystals

39
Q

What are the management and treatment recommendations for an acute attack?

A

-REST
1st line:
+ Prompt full therapeutic dose NSAID treatment for 24-48 hours and then lower the dose for 7-10 days e.g ibuprofen or Naproxen
+ Considerr gastroprotection with high dose NSAID e.g. Lansoprazole

(but NOT Aspirin as Aspirin competes with uric acid for excretion and so can worsen attack- low-dose salicylates induce kidney retention of uric acid)

2nd line: if NSAIDs are CId e.g. in CVD, renal disease, GI toxicity
= Colchicine, administer asap
Dose of 0.5mg 2-4 x a day until relief- max 6mg (12 tabs) per course. Dont repeat course within 3 days
Lower the dose in the elderly or renally impaired e.g. 0.5m every 8 hours

Alternative treatments:
- Corticosteroids- oral, short-course e.g. 30-35mg presnisolone OD for 5 days
- Articular corticosteroid- injection into the joint e.g. Triamcinolone

40
Q

Why is Aspirin not to be used as an NSAID for gout treatment?

A

Aspirin competes with uric acid for excretion and so can worsen attack- low-dose salicylates induce kidney retention of uric acid

41
Q

What serum uric acid level is diagnostic of gout?

A

Serum urate level of 360 micromol/litre [6 mg/dl] or more

  • If serum urate level is below 360 micromol/litre (6 mg/dl) during a flare and gout is strongly suspected, repeat the serum urate level measurement at least 2 weeks after the flare has settled.
42
Q

When would NSAIDs be contraindicated for gout attacks?

A

CVD
Renal impairment
GI toxicity

43
Q

Does Colchicine have a slower or quicker onset than NSAIDs?

A

Slower, hence while NSAIDs are first line

44
Q

What is the MOA of Colchicine in gout attacks?

A

Inhibits neutrophil migration into the joint via blocking microtubule formation therefore suppressing inflammation.

45
Q

What are the side effects of Colchicine?

A

Nausea
Vomiting
Diarrhoea- if gets, stop treatment immediately as is a sign of mucosal damage
Abdominal pain
Rashes

46
Q

What is the maximum dose of colchicine per course?

A

6mg - 12 tabs

47
Q

When would you give a lower dose of colchicine?

A

In the elderly or renally impaired- 0.5mf every 8 hours

48
Q

What are the interactions for colchicine?

A
  • CYP 3A4 inhibitors e.g. clarithromycin, erythromycin, verapamil, diltiazem
  • Potent glycoprotein inhibitors- Abciximab, Eptifibatide

As these increase colchicine levels

  • reduce dose by 75% (to one quarter of usual dose) with concurrent use of potent inhibitors of CYP3A4 or P-glycoprotein inhibitors
  • reduce dose by half with concurrent use of moderate inhibitors of CYP3A4
49
Q

What treatment is used for prophylaxis of re-occurring gout attacks?

A

Urate lowering therapy (ULT)
- used to prevent long-term complications e.g. tophi and nephropathy

50
Q

When is it recommended to consider ULT for prophylaxis of gout attacks?

A

When suffering 2 or more acute attacks per year
Or has signs of:
Tophi
joint damage
renal damage
kidney stones
on diuretics
young-onset gout

51
Q

Do you start a patient on prophylaxis during an acute attack- why?

A

NO!
The patient will have had hyperuricaemia for years, so treatment is not needed immediately.
- It isn’t given during an attack as these URT agents used for prophylaxis decrease uric acid levels. The changes in these levels can cause mobilisation of the uric acid stores and can therefore prolong the attack.

52
Q

What is given alongside the ULT prophylaxis when it is first initated?

A

Colchicine at a low dose of 0.5-1mg daily due to the risk of ULT causing an attack.
- if colchicine is CId can give NSAID +PPI

53
Q

What does ULT stand for?

A

Urate lowering therapy

54
Q

What is the first-line drug treatment for gout prophylaxis (ULT)?

A

1st line drug: Allopurinol
Starting dose of 100mg OD
Can increase dose every 3-4 weeks depending on response to reduce serum urate level to <300 mmol/L
Maintenance dose = 300mg once daily (on average)

55
Q

What is the starting dose of allopurinol?

A

100mg OD

56
Q

What is the average maintenance dose for allopurinol? When is this reduced?

A

Average = 300mg OD
But can be 100-600mg
In the renally impaired= 50-100mg

57
Q

What are the side effects of allopurinol?

A

Rashes
Gi disturbance
Hypersensitivity reactions

58
Q

When should Allopurinol be started as prophylaxis following a gout attack?

A

Wait for 1-2 weels after attack has finished.

59
Q

What drug class does Allopurinol belong to?

A

A Xanthine oxidase inhibitor= stops the formation of uric acid

60
Q

As Allopurinol is a prodrug, what is its active metabolite?

A

Allopurinol is metabolised to its active metabolite, Oxypurinol

61
Q

What is the 2nd line prophylaxis treatment of gout?

A

Febuxostat- Xanthine oxidase inhibitor
Dose= 80mg OD (can increase up to 120mg if uric acid levels are >6mg/100ml after 2-4 weeks)

62
Q

What are the possible side effects of febuxostat?

A

GI disturbance
headache
oedema
rask
serious hypersensitivity reactions including stevens-johnson syndrome

63
Q

If 1st line treatment with xanthine oxidase inhibitors (allopurinol, febuxostat) are inadequate/CId etc, what are the second line treatments?

A

Uricosuric agents e.g. Sulfinpyrazone or Benzobromarone (unlicensed)

64
Q

What is the MOA of the uricosuric agents e.g. sulfinpyrazone?

A

Are NOT xanthine oxidase inhibitors, instead they increase uric acid excretion by direct action on the renal tubules- block the URAT1 transporter, in brush border of renal proximal tubular cells.

65
Q

When must uricosuric agents be avoided?

A

In patients with urate nephropathy as it can worsen kidney stones

66
Q

What advice should be given to patients starting a uricosuric agent?

A

They must maintain a high fluid intake to decrease the risk of kidney stones forming

67
Q

What is the 3rd line prophylaxis treatment of gout?

A

The recombinant monoclonal antibody, Canakinumab
- is given by SC injection
- Is only approved for severe refractory tophaceous gout, not approved by NICE for acute flares

68
Q

When is canakinumab contraindicated?

A

In current infection due to sepsis risk

69
Q

How does canakinumab work?

A

It is a recombinant monoclonal antibody that targets IL-1 b which is associated with the inflammatory response induced by urate crystals.

70
Q

Can xanthine oxidase inhibitors and uricosuric agents be used in combination?

A

YES

71
Q

What is the very important drug interaction with Allopurinol?

A

AZATHIOPRINE!!
As azathioprine is metabolised to mercaptopurine and mercaptopurine is metabolised by xanthine oxidase.
As allopurinol inhibits xanthine oxidase= accumulation of azathioprine which can cause fatal bone marrow suppression

Exam 1- GI and CVD (43 decks)

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