Rheumatology: Pharmacology - Anti-gout agents Flashcards
What is gout? List some of the clinical features
Metabolic disease characterised by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage
May also develop:
- Uric acid renal calculi
- Interstitial nephritis
- Tophi (subcutaneous deposits)
- Adverse CV outcomes
List seven classes of drugs used in gout, giving examples where relevant
- Colchicine
- NSAIDs (e.g. indomethacin)
- Uricosuric agents (e.g. probenecid, sulfinpyrazone)
- Corticosteroids
- Xanthine oxidase inhibitors (e.g. allopurinol, febuxostat)
- Pegloticase
- IL-1 antagonists
Describe the pathophysiology of gout
Urate crystals (end-product of purine metabolism) are phagocytosed by synoviocytes, which then release of inflammatory markers (prostaglandins, IL-1, lysosomal enzymes)
Neutrophils are attracted resulting in amplification of the inflammatory process
In later phases of the attack, macrophages ingest urate crystals and release more inflammatory mediators
What is the effect of colchicine in gout? What type of medication is colchicine?
Alkaloid medication
Relieves pain and inflammation of acute gout within 12-24hrs without alteration of urate metabolism or excretion, and without other analgesic effects
Also used for prevention of recurrence at lower doses
Which NSAID lowers serum uric acid?
Oxaprozin
Which three NSAIDs cannot be used to treat gout?
Aspirin
Salicylates
Tolmetin
What is the mechanism of action of colchicine?
Binds intracellular tubulin to prevent formation of microtubules, thereby inhibiting leukocyte migration and phagocytosis
Also inhibits LTB4 and IL-1B formation
Five clinical uses of colchicine
- Gout prophylaxis (most common)
- Acute gout
- Prevention of recurrent familial Mediterranean fever
- Prevention and treatment of pericarditis, pleurisy and coronary artery disease
- Mild beneficial effect in sarcoid arthritis and hepatic cirrhosis
Describe the pharmacokinetics of colchicine
Absorption: readily absorbed, peak levels within 2hrs, t1/2 = 9hrs
Excretion: metabolites excreted in GIT and urine
What is the dosage of colchicine used for gout prophylaxis vs treatment of acute flare?
Prophylaxis: 0.6mg 1-3x daily
Acute gout: 1.2mg followed by single 0.6mg dose
What is the potentially lethal dose of colchicine?
8mg
Narrow therapeutic index
List 10 adverse effects of colchicine
GI upset: diarrhoea (common), nausea, vomiting, abdo pain
Hepatic necrosis
Acute renal failure
DIC
Seizures
Rarely:
Hair loss
Bone marrow depression
Peripheral neuritis
Death
Describe the toxicity syndrome seen with colchicine
Burning throat pain
Bloody diarrhoea
Shock
Haematuria
Oliguria
May cause fatal ascending CNS depression
What is the treatment for colchicine toxicity?
Supportive
What is the mechanism of action of probenecid?
Prevents uric acid reabsorption in proximal tubule (inhibits both secretory and reabsorptive transporters but net effect is increased secretion)
Why should aspirin not be used in combination with probenecid for management of pain in acute gout flare?
Aspirin inhibits secretory transporters only
In combination with probenecid, which inhibits both secretory and reabsorptive transporters, net effect is increased reabsorption and therefore elevated serum uric acid
When is probenecid used in gout?
Prophylaxis only (can be started 2-3 weeks post acute flare)
What is the mechanism of action of allopurinol?
Xanthine oxidase inhibitor: decreases urate burden
When is allopurinol used in gout? What are some caveats to commencing allopurinol?
Used for prophylaxis only
Can precipitate gout so needs NSAID/colchicine cover for 6/12 post achieving target uric acid levels (<6mg/dL)
What uric acid level is targeted for prophylaxis of gout?
<6mg/dL
Describe the pharmacokinetics of allopurinol
Absorption: ~80% oral absorption, t1/2 = 1-2hrs, once daily dosing
Metabolism: by xanthine oxidase to alloxanthine (which still retains capacity to inhibit XO)
Two important medications interactions with allopurinol
Increases effect of chemotherapeutic purines and cyclophosphamide (should be dose reduced when given concomitantly)
Inhibits probenecid and oral anticoagulant metabolism
Five adverse effects of allopurinol
GI upset: nausea, vomiting, diarrhoea
Peripheral neuritis
Necrotising vasculitis
Bone marrow suppression
Aplastic anaemia
