Gout and Hyperuricemia Flashcards
Describe the pathophysiology of gouty attacks
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
What are the 3 classes of drugs used for gouty arthritis?
Anti-inflammatory and analgesic - NSAIDs, Glucocorticoids
Reduces leukocyte migration into joints - Colchicine
What are the 2 classes of drugs used for ULT?
Xanthine oxidase inhibitors - Allopurinol, febuxostat
Uricosuric agents - probebecid
Why shouldn’t ULT be initiated when the patient is having a gout attack?
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
How do NSAIDs help in a gout attack?
inhibit production of prostaglandins and urate crystal phagocytosis
Where are NSAIDs contraindicated?
concurrent use with low-dose aspirin and salicylates (anti-uricosuric actions)
How can prednisolone be administered?
PO or IA
What are the 4 mechanisms of action of colchicine?
- Binds to tubulin
- Prevents tubulin polymerisation into microtubules
- Inhibits leukocyte migration and phagocytosis
- Inhibits leukotriene B3 and prostaglandin production
What are the side effects of colchicine
diarrhea, nausea and vomiting, abdominal pain, muscle weakness, unusual bleeding, pale lips and change in urine amount
What is the dose limiting side effect of colchicine and why?
GI SE
colchicine can prevent cell division and the GI tract contains the most rapidly dividing cells
XOIs come with a risk of SCAR. What are the 3 risk factors of developing SCAR?
renal impiarment (CrCl < 60)
thiazide therapy
HLA-B*5801
What are side effects of XOIs?
skin rask, nausea, vomiting, diarrhea, fever, sore throat, stomach pain, dark urine, jaundice
What are the 3 MOAs of probenecid?
- inhibits proximal tubule anion transport
- inhibits uric acid re-absorption
- increases uric acid excretion
What should patients be counselled on while on probenecid therapy?
take plenty of fluids to minimise renal stone formation
alkalines (eg. potassium citrate) may be administered to keep the urine pH above 6.0
What are side effects of probenecid?
nausea and vomiting, painful urination, lower back pain, allergic reactions, rash
Describe the process of normal purine metabolism
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)
Differentiate between primary and secondary gout
- Primary gout → inborn errors of metabolism
- Secondary gout → conditions that increase cell turnover and purine generation
Hyperuricemia can be caused by increased purine biosynthesis or decreased uric acid clearance.
What are causes from increased purine synthesis? (EPFD)
excessive ethanol, dietary purine, fructose or use of cytotoxic drugs
Hyperuricemia can be caused by increased purine biosynthesis or decreased uric acid clearance.
What are causes from decreased purine excretion? (SPELLED CLN)
salt restriction
pyrazinamide
ethanol
levodopa
laxative abuse
ethambutol
diuretics
ciclosporin
low-dose salicylates
nicotinic acid
How is gout diagnosed?
presence of MSU crystals in the synovial fluid (detected from joint aspirate) or in tissue sections of tophaceous deposits
What does pseudogout refer to?
absence of uric acid crystals in joint aspirate
When should treatment for acute flares be initiated?
as soon as possible (within 24h)
How is colchicine (for acute flares) dosed?
(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
Which combination of drugs should not be given during an acute attack?
NSAIDs should not be given together with steroids
How can corticosteroids be given during an acute attack?
PO (or IA if patient cannot take orally)
How should ULT be started if a patient is currently having flare?
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
Why should colchicine be used with caution in patients with renal or hepatic toxicity?
increased risk of toxicity including myopathy, neuropathy and pancytopenia
How should allopurinol be dosed?
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
How should febuxostat be dosed?
Initiate: ≤ 40mg/day
Maintenance: up to 80mg/day
How should probenecid be dosed?
Initiate: 250mg BD every week, then 500mg BD
Titrate: by 500mg every 4 weeks
Maintenance: ≤ 2g a day
State the contraindication and 2 areas of caution for probenecid
CI: pts with urolithiasis,
Caution: risk of hemolytic anemia in G6PD patients, not recommended in CrCl < 50ml/min
What are the notable drug interactions with allopurinol? (4 broad classes)
- Increases risk of bone marrow suppression → 6-mercaptopurine, azathioprine, cyclophosphamide
- Increase HS rxn or allopurinol toxicity → ACEi, loop diuretics, thiazides, ampicillin, amozicillin
- Allopurinol increases the adverse effects of → pegloticase
- Monitor treatment as allopurinol increases concentrations of → carbamazepine, warfarin, theophylline
How should colchicine, PO coxibs and PO corticosteroids be dosed for ULT PROPHYLAXIS and how long should it be started for?
- 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
What are 4 NPM counselling points?
limit alcohol intake
limit purine rich foods
limit high-fructose corn syrup
manage weight (due to association with obesity)
What are some purine rich foods?
asparagus, cauliflower, mushroom, red meat, anchovies (ikan bilis), seafood (herring, prawn, fish roe, mussels, scallops), durian, peanuts and organ meat (eg. liver)
Which diuretic should not be used in gout?
hydrochlorothiazide (decreases urate excretion)
Which antihypertensives are preferred in gout patients?
ACEis like enalapril and captopril
ARBs like losartan
have uricosuric effects (ECL)
