Gout and Hyperuricemia

Question 1

Describe the pathophysiology of gouty attacks

Answer 1

Phagocytes attempt to phagocytose urate crystals → fail and get lysed → release factors that recruit more phagocytic cells via a positive feedback loop

Factors like cytokines, PG and free radicals → severe inflammation and pain

Neutrophil lysis → release of lysosomal enzymes → tissue injury and inflammation

Question 2

What are the 3 classes of drugs used for gouty arthritis?

Answer 2

Anti-inflammatory and analgesic - NSAIDs, Glucocorticoids

Reduces leukocyte migration into joints - Colchicine

Question 3

What are the 2 classes of drugs used for ULT?

Answer 3

Xanthine oxidase inhibitors - Allopurinol, febuxostat
Uricosuric agents - probebecid

Question 4

Why shouldn’t ULT be initiated when the patient is having a gout attack?

Answer 4

Dramatically lowering serum urate levels during an attack → increases gradient between joints and the plasma → increases mobilisation of crystals out of the joints

Crystals are stable within joints and are largely protected from immune cells, but as they mobilise out, they’re increasingly recognised by immune cells and result in the mounting of an immune response, therefore worsening the acute attack

Uricosuric agents push uric acid out of the kidneys, and during an attack mobilisation already pushes uric acid crystals out of the kidneys → increases rate of kidney stone formation

Question 5

How do NSAIDs help in a gout attack?

Answer 5

inhibit production of prostaglandins and urate crystal phagocytosis

Question 6

Where are NSAIDs contraindicated?

Answer 6

concurrent use with low-dose aspirin and salicylates (anti-uricosuric actions)

Question 7

How can prednisolone be administered?

Answer 7

PO or IA

Question 8

What are the 4 mechanisms of action of colchicine?

Answer 8

• Binds to tubulin
• Prevents tubulin polymerisation into microtubules
• Inhibits leukocyte migration and phagocytosis
• Inhibits leukotriene B3 and prostaglandin production

Question 9

What are the side effects of colchicine

Answer 9

diarrhea, nausea and vomiting, abdominal pain, muscle weakness, unusual bleeding, pale lips and change in urine amount

Question 10

What is the dose limiting side effect of colchicine and why?

Answer 10

GI SE
colchicine can prevent cell division and the GI tract contains the most rapidly dividing cells

Question 11

XOIs come with a risk of SCAR. What are the 3 risk factors of developing SCAR?

Answer 11

renal impiarment (CrCl < 60)
thiazide therapy
HLA-B*5801

Question 12

What are side effects of XOIs?

Answer 12

skin rask, nausea, vomiting, diarrhea, fever, sore throat, stomach pain, dark urine, jaundice

Question 13

What are the 3 MOAs of probenecid?

Answer 13

1. inhibits proximal tubule anion transport
2. inhibits uric acid re-absorption
3. increases uric acid excretion

Question 14

What should patients be counselled on while on probenecid therapy?

Answer 14

take plenty of fluids to minimise renal stone formation

alkalines (eg. potassium citrate) may be administered to keep the urine pH above 6.0

Question 15

What are side effects of probenecid?

Answer 15

nausea and vomiting, painful urination, lower back pain, allergic reactions, rash

Question 16

Describe the process of normal purine metabolism

Answer 16

Glutamine and PRPP undergo de novo synthesis into nucleic acids in the body → break down into G and A → breaks down into hypoxanthine

G, A and hypoxanthine can undergo the “salvage pathway” → reform nucleic acids

Hypoxanthine → xanthine (by xanthine oxidase) → uric acid (by XO) → excreted 65% in the urine and 35% in the GI (degraded by intestinal flora)

Question 17

Differentiate between primary and secondary gout

Answer 17

• Primary gout → inborn errors of metabolism
• Secondary gout → conditions that increase cell turnover and purine generation

Question 18

Hyperuricemia can be caused by increased purine biosynthesis or decreased uric acid clearance.

What are causes from increased purine synthesis? (EPFD)

Answer 18

excessive ethanol, dietary purine, fructose or use of cytotoxic drugs

Question 19

Hyperuricemia can be caused by increased purine biosynthesis or decreased uric acid clearance.

What are causes from decreased purine excretion? (SPELLED CLN)

Answer 19

salt restriction
pyrazinamide
ethanol
levodopa
laxative abuse
ethambutol
diuretics

ciclosporin
low-dose salicylates
nicotinic acid

Question 20

How is gout diagnosed?

Answer 20

presence of MSU crystals in the synovial fluid (detected from joint aspirate) or in tissue sections of tophaceous deposits

Question 21

What does pseudogout refer to?

Answer 21

absence of uric acid crystals in joint aspirate

Question 22

When should treatment for acute flares be initiated?

Answer 22

as soon as possible (within 24h)

Question 23

How is colchicine (for acute flares) dosed?

Answer 23

(1) One-off treatment with 1mg LD followed by 0.5mg one hour later
(2) 0.5mg two to three times per day, until the acute flares resolve

Max dose is 1.5mg a day

Question 24

Which combination of drugs should not be given during an acute attack?

Answer 24

NSAIDs should not be given together with steroids

Question 25

How can corticosteroids be given during an acute attack?

Answer 25

PO (or IA if patient cannot take orally)

Question 26

How should ULT be started if a patient is currently having flare?

Answer 26

If the patient is already on ULT, continue the ULT during the flare

If the patient is not already on it, do not initiate yet

possible to consider ULT without waiting for the flare to resolve to reduce the risk of patients not returning for treatment

Question 27

Why should colchicine be used with caution in patients with renal or hepatic toxicity?

Answer 27

increased risk of toxicity including myopathy, neuropathy and pancytopenia

Question 28

How should allopurinol be dosed?

Answer 28

Initiation: ≤ 100mg/day (start with lower doses ≤ 50mg/day in CKD stage 3 and above)
Titrate: 50-100mg increments every 2-8 weeks
Maintenance dose: > 300mg/day
Max dose: 800-900mg/day

Question 29

How should febuxostat be dosed?

Answer 29

Initiate: ≤ 40mg/day
Maintenance: up to 80mg/day

Question 30

How should probenecid be dosed?

Answer 30

Initiate: 250mg BD every week, then 500mg BD
Titrate: by 500mg every 4 weeks
Maintenance: ≤ 2g a day

Question 31

State the contraindication and 2 areas of caution for probenecid

Answer 31

CI: pts with urolithiasis,

Caution: risk of hemolytic anemia in G6PD patients, not recommended in CrCl < 50ml/min

Question 32

What are the notable drug interactions with allopurinol? (4 broad classes)

Answer 32

1. Increases risk of bone marrow suppression → 6-mercaptopurine, azathioprine, cyclophosphamide
2. Increase HS rxn or allopurinol toxicity → ACEi, loop diuretics, thiazides, ampicillin, amozicillin
3. Allopurinol increases the adverse effects of → pegloticase
4. Monitor treatment as allopurinol increases concentrations of → carbamazepine, warfarin, theophylline

Question 33

How should colchicine, PO coxibs and PO corticosteroids be dosed for ULT PROPHYLAXIS and how long should it be started for?

Answer 33

• Colchicine 0.5mg OD (first line)
• Low-dose PO NSAID or coxib (eg. celecoxib 200mg OD)
• Low-dose PO corticosteroid (eg. prednisolone 5-7.5mg per day)
• Prophylactic treatment should be continued for 3-6 months

Question 34

What are 4 NPM counselling points?

Answer 34

limit alcohol intake
limit purine rich foods
limit high-fructose corn syrup
manage weight (due to association with obesity)

Question 35

What are some purine rich foods?

Answer 35

asparagus, cauliflower, mushroom, red meat, anchovies (ikan bilis), seafood (herring, prawn, fish roe, mussels, scallops), durian, peanuts and organ meat (eg. liver)

Question 36

Which diuretic should not be used in gout?

Answer 36

hydrochlorothiazide (decreases urate excretion)

Question 37

Which antihypertensives are preferred in gout patients?

Answer 37

ACEis like enalapril and captopril
ARBs like losartan

have uricosuric effects (ECL)