allopurinol

see also gout

• Originally synthesised as candidate for antineoplastic activity which it lacked but proved to be a substrate for & inhibitor of xanthine oxidase thus reducing uric acid production although it also inhibits uric acid renal excretion;
• Normally uric acid is the sole urinary purine, but in with allopurinol, purines are excreted in urine as hypoxanthine & xanthine as well which are more soluble;
• The lowered [uric acid]serum below its limit of solubility facilitates the dissolution of tophi & prevents development or progression of chronic gouty arthritis as well as preventing formation of uric acid stones & thus prevents nephropathy assoc. with gout;
• usually start at 200mg/d and gradually increase to 600mg/d.

• Well tolerated by most patients, most commonly HS reactions even after yrs Rx !;
• May induce incr. freq. ac. gout attacks initial months of Rx
  • → cover with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs);
  • → don't start allopurinol within 6wks of an acute attack
• Xanthine stones in kidney uncommon but esp. high uric acid producers → increase fluid intake to prevent;
  • see urolithiasis / renal stones / renal calculi
• Headache, drowsiness, N/V/D/gastric irrit., vertigo occas. but cont. Rx ;
• Pruritic rash, fever, malaise, myalgia in 3% but more likely if decr. renal function;

• severe cutaneous adverse reactions (SCARs)
  • eg. usually either Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS)
  • it seems 80% of patients at risk of these reactions have either HLA-A*34:02 or HLA-B*58:01 genes ¹⁾
  • carriage rate of HLA-B*58:01 is five times higher in U.S. Black individuals than in U.S. white individuals
    • hence, the American College of Rheumatology's conditional recommendation published in 2020 to perform HLA-B*58:01 screening before prescribing allopurinol to U.S. Asian and Black patients
  • the gene HLA-B*58:01 has long been used to screen patients in Southeast Asia - where it accounts for nearly all cases of severe cutaneous adverse reactions (SCARs)

• PH serious side effect; lactation; children (unless malig./inborn errors);
• Idiopathic haemochromatosis & their immed. relatives; 1st sign drug rash;

• impaired renal/hepatic function ⇒ risk of fatal exfoliative syndrome 1-6wk after starting Rx:
  • exfoliative rash
  • fever
  • hepatitis
  • renal failure
  • NB. this syndrome is more likely if pre-existing renal insufficiency or concomitant diuretics

• Azathioprine → decr. metab. azathioprine → decr. dose by 33%;
• Mercaptopurine → decr. metab. mercaptopurine → decr. dose by 25%;
• warfarin → decr. metab. warfarin → monitor INR carefully;
• Theophylline → decr. theoph. clearance → monitor [] & ? decr. dose;
• Thiazides → incr. serum [uric acid] → may need incr. allopurinol dose;
• Fe suppl. →