Urates and tumour lysis syndrome Flashcards
Objective of treatment for gout? Pharmacological treatment of acute gout and physiology
Objective: relieve pain, swelling, inflammation and immobility of joint. Treatment does not affect uric acid levels
NSAIDs - traditionally indomethacin, however, all NSAIDs can be used
Colchicine - binds tubulin and inhibits microtubule polymerisation
- inhibits activation and migration of neutrophils into the joint
- reduces phagocytosis and inflammatory process
- NOT an analgesic, does not affect uric acid production/excretion
Corticosteroids - anti inflammatory, MOA complex but reduces phospholipase A2 and release of arachidonic acid. Leads to reduced levels of prostaglandins and leukotrienes e.g. prednisolone
Diuretics and uric acid. How (2)?
Diuretics may reduce uric acid excretion
= increase uric acid levels
Do so by…
- competing with uric acid for transport by OAT1 (reduce excretion)
- increasing uric acid transport by URAT1 (increase reuptake)
Drug interactions with allopurinol?
Compounds metabolised by xanthine oxidase - 6-mercaptopurine and azathioprine.
With allopurinol, serum levels through the roof
Tumour lysis syndrome and the kidneys. Treatment (2)
Hyperuricaemia = uric acid stones in renal tubules and subsequent blockage
Calcium phosphate crystals can also form in renal tubules
Together = renal failure
Treatment:
1 allopurinol
- may be used prophylactically (before chemotherapy) to prevent tumour lysis syndrome
- not the drug of choice in established tumour lysis syndrome as it does not breakdown uric acid already formed
2 rasburicase
recombinant uricase (urate oxidase) enzyme
- moa: catalyses enzymatic oxidation of uric acid into allantoin = reduces uric acid levels
- injection not orally
- may be used prophylactically and/or to treat established disease
Ongoing treatment of gout? Without treatment?
Without treatment, majority will experience second attack within 6 months to 2 years
Treatment:
Patient education and lifestyle change
- weight reduction, exercise
- reduced purine intake
- reduced alcohol intake
Pharmacological
- block production of uric acid e.g. allopurinol, febuxostat
- increase urinary excretion of uric acid e.g. probenecid
What is an acute attack of gout? Pathological underpinning and process? Joint involvement? Left untreated?
When conc. of uric acid in serum exceeds its solubility, urate crystals deposited in joints.
An acute attack of gout occurs when neutrophils infiltrate into the joint and phagocytose the monosodium urate crystals
= inflammatory reaction
- release of pro inflammatory and pain producing mediators such as cytokines, prostaglandins and vasoactive peptides
End result: very painful, inflamed, immobile and swollen joint
Usually confined to 1 joint (most often in metatarsophalangeal joint in big toe).
Untreated: resolve over 1-2 weeks
Treated: NSAIDs, colchicine and corticosteroids
Gout and eostrogen?
Oestrogen increases renal excretion of uric acid by reducing tubular reabsorption by an effect on URAT1 and GLUT9
Uncommon in premenopausal women. Incidence increases after menopause
Allopurinol and febuxostat MOA. Effect (2). Administration.
Both inhibit xanthine oxidase enzyme which produces uric acid
1 Inhibit uric acid production = reduce both serum and urine levels of uric acid
- prevent formation of uric acid stones and nephropathy
2 dissolution of uric acid deposits - reduction in tophi and joint improvement
Initiation of these medications may precipitate an acute attack of gout - mobilisation of urate from tissue deposits
- always administer initially with either an NSAID or colchicine
- maintain dual therapy for 3 months
Explain drug interaction of colchicine and P-glycoprotein.
P-glycoprotein: moves compounds out of cells.
Inhibitors: increase serum levels + produce toxicity e.g. clarithromycin
Inducers: decrease serum levels + reduce efficacy e.g. rifampicin
How does alcohol increase uric acid?
Breakdown of alochol to acetyl CoA requires ATP breakdown therefore increasing uric acid production
What is uric acid? How is it excreted? Name 2 uric acid transporters in the kidney for reabsorption? Normal levels for males compared to females?
End product of purine metabolism
Excretion:
70% kidneys
30% faeces
Glut9 and Urat1
Levels higher in males than females
What drug increases urinary excretion of uric acid? MOA
Probenecid, uricosuric agent
moa = inhibits reabsorption of uric acid in renal tubule by URAT1
- increases conc. urine, therefore, may cause renal uric acid stones
reduces/stops future attacks of gout
may precipitate acute attack of gout when first commenced (initiate with colchicine or NSAID)
Side effects of Colchicines (2)
Drug interactions (2)
Also used to treat? (2)
Side effects
1 abdominal pain, vomiting, nausea, vomiting
2 bone marrow and respiratory depression
Drug interactions
1 P0glycoprotein and/or CYP3A4 inhibitors e.g. clarithromycin, erythromycin, digoxin, diltiazem, verapamil
Treats pericarditis and myocarditis
Symptoms of hyperuricaemia?
Acute gout, recurrent attacks, chronic gouty arthritis (majority will not get acute gout)
Development of tophi (deposition of urate crystals in tissues) and tophaceous gout which result in joint damage/destruction
renal stones/impairment
increased CVD risk?
What is tumour lysis syndrome? Caused by? Can result in (3 - biochemistry)?
Intracellular contents of lysed cells being released into extracellular space and blood
Caused by rapid breakdown of cells which can occur following the initiation of cancer therapy
Can result in…
1 hyperkalaemia and hyperphosphataemia from release of potassium and phosphate following cell breakdown
2 hypocalcaemia is a consequence of hyperphosphataemia as calcium phosphate can precipitate in soft tissues and renal tubules
3 hyperuricaemia when purines, those in nucleic acids, are released from lysed cells and converted to uric acid
What affect does testosterone have on uric acid?
Increases renal reabsorption of uric acid but an effect on URAT1
