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imed3003 > Drug Treatment of Gout > Flashcards

Drug Treatment of Gout Flashcards

1
Q

What is gout?

A

An inflammatory arthritis caused by uric acid

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2
Q

What causes gout?

A

Genetic in origin causing raised uric acid levels.

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3
Q

What joints are commonly affected by gout?

A

Any joint (can be poly-articular)

Pedagra is gout of the big toe.

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4
Q

How does gout change over time?

A

it progresses more and more if not treated. It is a serious disease with functional disability.

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5
Q

How do uric acid levels rise to cause gout?

A

They must rise above 0.42 mmol/L (in men) or 0.36mmol/L in women.

Derived from:

Diet (~1/3)

Endogenous biosynthesis (~2/3)

It is the final product of purine metabolism in humans and eliminated by kidneys (2/3) and GI tract (1/3)

Uric acid is a weak organic acid and is poorly soluble at acidic pH and low temperature meaning it will precipitate in joints.

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6
Q

Why does uric acid cause the pain of gout?

A

Urate crystals deposit in peripheral joints and peri-articular tissues resulting in gout

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7
Q

Does hyperuricaemia always lead to gout?

A

No, there is hyperuricaemia in only about 10% of people with gout.

Uric acid may not be high in acute gout.

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8
Q

How is uric acid produced from endogenous biosynthesis?

A

Purines are converted into hypoxanthine

Hypoxanthine is converted into xanthine which is then converted into uric acid. (Both steps are done via the enzyme xanthine oxidase)

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9
Q

How is uric acid eliminated?

A

Humans don’t have uricase/urate oxidase. Instead they depend on renal + gut excretion.

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10
Q

How is uric acid excreted in the kidneys?

A

100% of uric acid that passes through the glomerulus is filtered through. However it is reabsorbed by GLUT9 (on basolateral membrane) and URAT1 (on apical membrane)

6 - 10% is then secreted in distal proximal tubule so a net loss of ~10% uric acid is the result

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11
Q

How is excretion different in people with gout to other people?

A

90% of hyperuricaemics undersecrete uric acid

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12
Q

What happens in gout?

A

Chronic hyperuricaemia (don’t have to be at time of diagnosis)

Supersaturation of body tissues with urate crystals

Formation of monosodium urate crystals in and around joints

Unidentified triggers cause shedding of crystals into the joint.

Crystals evoke an inflammatory response. (Kinin, complement and plasmin, neutrophilic infiltration which engulf crystals, release of toxic oxygen metabolites, tissue lysis and release of proteolytic enzymes)

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13
Q

How is gout diagnosed?`

A

Urate crystals in synovial fluid

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14
Q

Why is gout diagnosis levels increasing in the population?

A

Ageing population

Obesity

Sweet soft drink consumption

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15
Q

What are the dietary risks that lead to gout?

A

Sugary drinks, beer, fructose, and spirits are high risk.

Coffee, dairy products, vitamin C reduce risk

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16
Q

What are the risk factors for gout?

A

Genetic - Polygenic (urate transporter mutations)

Gender - Males are 3x more likely than females to develop gout.

Hypertension increases risk

Metabolic syndrome

Chronic renal failure

Transplantation - kidney and heart -> drugs

Drugs - thiazide diuretics, low dose aspirin, cyclosporin

Hyperuricaemia is an independent risk factor for CVD and metabolic syndrome

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17
Q

What is the aetiology of gout?

A

Purine nucleotides are converted into uric acid via xanthine oxidase.

Some is excreted via intestine and the rest via kidneys (secretion)

This condition is most commonly associated with a decrease in renal excretion in distal proximal tubule. (~90%) alcohol, obesity, fructose, and renal failure

Also associated with too much causative foods (Alcohol, meat, seafood) or too much purine turnover (caused by alcohol, fructose, BMI, and tumours)

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18
Q

What does coffee and vitamin C do to uric acid?

A

Coffee decreases uric acid formation and increases renal excretion

VitC increases renal excretion

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19
Q

Why does urate precipitate in joints?

A

The cause is unknown at this stage

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20
Q

What are the 2 clinical phases of gout?

A

Preclinical - crystal deposits increase in joint tissues for years then finally crystals shed into joint. (asymptomatic)

2 clinical =

Intermittent attacks of acute gout - no symptoms between attacks

Chronic tophaceous gout - if inadequately treated (visible deposits)

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21
Q

What is the most important feature to consider with acute gout?

A

It is rapid onset and can flare up overnight. (very painful and most common in the metatarsophalangeal joint of the big toe (1st joint)

22
Q

What other symptoms are associated with gout?

A

Fever

Poly-articular

Self-limiting

23
Q

What are tophi? What can they do to surrounding structures?

A

Large crystal deposits on extensor surfaces (fingers, hands, elbows, tendons, and ear)

These deposits can cause erosion of neighbouring joints leading to restricted movement and deformity.

24
Q

What are the renal complications that can result from chronic gout? Also any other systemic disorders that can arise?

A

Can cause kidney stones and renal tissue deposits which lead to chronic renal failure.

It is also expected to contribute to CVD.

25
Q

How is acute gout treated?

A

Pain relief (NSAIDS -> colchicine)

Glucocorticoids (especially if intra-articular and not septic)

Maintain long term treatment for chronic gout.

When newly diagnosed it is advisable to start urate-lowering therapies at lowest dose and titrate up slowly.

26
Q

What is colchicine? What is its mechanism of action?

A

Ancient remedy from the autumn crocus.

It is a “keep in pocket” medication

Mechanism of action is not fully understood but binds to tubulin which stops MT assembly:

Cell division
Neutrophil motility
Decreases chemokine production

Inflammatory cell recruitment stops.

27
Q

How is colchicine absorbed?

A

It is rapidly absorbed orally

28
Q

Where does colchicine concentrate and get excreted?

A

Concentrates in WBCs

Excretion is hepatobiliary (10 - 20% renal)

29
Q

What does colchicine do?

A

Good pain relief within 12 - 24 hours

Use analgesia while waiting for relief

30
Q

What are the side effects and potential complications associated with taking colchicine? What are the DDIs?

A

It is toxic and causes vomiting and diarrhoea. It has a narrow therapeutic window.

Can result in a rare severe toxicity -> muscle damage, myelo-suppression, multiple organ failure

Do not describe if kidney or liver function is poor due to renal function.

DDIs - CYP3A4 & P-gp inhibitors

31
Q

What are the DDIs of colchicine?

A

CY3A4 & P-gp inhibitors:

Antibiotics (erythromycin, clarithromycin)

Ca2+ channel blockers - verapamil, diltiazem

Cyclosporin, grapefruit juice

32
Q

How has colchicine dosing changed?

A

It is now a low dose regimen

33
Q

What precautions are given to patients prescribed colchicine?

A

Patients are advised not to eat/drink grapefruit

To stop if they have any signs of Nausea, vomiting, and diarrhoea

Making sure patient understands these 2 points.

34
Q

How is chronic gout treated non-pharmacologically and pharmacologically?

A

Make lifestyle changes: Diet, alcohol and weight loss.

Drug therapy (Xanthine oxidase inhibitors, Uricase agents, Uricosuric agents)

35
Q

What is the aim of chronic gout treatment?

A

To reduce serum uric acid

36
Q

When should chronic gout be treated?

A

At the start of the first acute attack because this ensures better capture/compliance

37
Q

What is xanthine oxidase? What drug inhibits it?

A

The enzyme that converts hypoxanthine into xanthine and then into uric acid.

Allopurinol inhibits this pathway. (competitive inhibitor) then gets converted into alloxanthin/oxypurinol which non-competitively inhibits xanthine oxidise.

38
Q

How is allopurinol best prescribed due to method of absorbtion?

A

Well absorbed orally

39
Q

What is the half life of allopurinol?

A

2 - 3 hours but its metabolite is 18 - 30 hours so only needs to be taken once a day.

40
Q

How should allopurinol be prescribed?

A

Low does initially then increase by 100mg every 2 - 5/52 until SUA is 0.36mmol/L

Dose is maintained when target SUA is achieved.

Decrease doses in renal failure

Give prophylactic treatment (NSAIDs or colchicine) until target SUA is reached to prevent acute flares.

41
Q

What are the adverse effects of using allopurinol?

A

GI side effects

Drug reaction rash with eosinophilia and systemic symptoms (DRESS) and if rash is severe - Stevens johnson syndrome/TEN (SCAR) - it is rare but potentially fatal. Monitor carefully this can be avoided if started low dose.

42
Q

Who is at highest risk from adverse effects when using allopurinol?

A

East Asian with the IILA-B*5801 allele means very high risk. These people should be tested by PCR.

Instead give them febuxostat

43
Q

What are some dangerous drug interactions to consider with allopurinol use?

A

Mercaptopurine and azanthioprine

Allopurinol increases their side effects dramatically

44
Q

What is mercaptopurine?

A

Anti-metabolic chemotherapy agent that blocks DNA synthesis

45
Q

What is azathioprine?

A

Azathioprine is a pro -drug immunosuppressant

46
Q

What is febuxostat?

A

A non-purine selective inhibitor of XO.

Not a purine analogue

It is a replacement for allopurinol that is more expensive and only used in the people incapable of using allopurinol.

47
Q

Where is febuxostat metabolised?

A

Mainly in the liver making it useful in patients with renal impairment or those who do not respond to allopurinol

48
Q

What do uricosuric agents do?

A

Block urate re-uptake in the Proximal Tubule so this means patient must drink a lot of water.

49
Q

What blocks the effect of uricosuric agents?

A

Effect is blocked by low dose aspirin

50
Q

How should uricosuric agents be used?

A

Add to other therapies when SUA is too high.

51
Q

What are uricase agents?

A

Converts uric acid to allantoin which rapidly drops serum uric acid levels which makes it useful for removing tophi.

52
Q

Why can’t uricase agents be used for a long time?

A

IV only and short half life

Also issue with allergies

imed3003 (48 decks)

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