Allopurinol

Allopurinol is a structural analog of the natural purine base, hypoxanthine. It is considered to be one of the most effective drugs used to decrease urate levels and is approved by the FDA for management of gout, calcium oxalate stones and cancer therapy-induced hyperuricemia. It is also recommended as a part of urate-lowering therapies in chronic persistent gouty arthritis, tophaceous gout, uric acid urolithiasis.

Pharmacological class: Xanthine Oxidase Inhibitors

• Gout
• Cancer therapy-induced hyperuricemia or tumour lysis syndrome
• Calcium oxalate stones 

Allopurinol acts by inhibiting xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid. It leads to reduced production of uric acid, resulting in a decrease of urate levels and relief of symptoms associated with gout such as painful tophi, joint pain, inflammation, redness, decreased range of motion, and swelling.

Usual Adult Dose for Gout

• 200 to 300 mg/day- mild gout patients
• 400 to 600 mg/day- moderate to severe gout tophaceous gout
• 700 to 800 mg/day- severe gout conditions.
• The maximal recommended dose for patients with normal renal function 800 mg/day

Usual Adult Dose for prevention of uric acid nephropathy during the therapy of neoplastic disease

• 600 to 800 mg/day for 2 or 3 days

Usual Adult Dose for management of recurrent calcium oxalate stones

• 200 to 300 mg/day as a single equivalent or in divided doses 

Absorption: Approximately 90% of the drug is absorbed from the gastrointestinal tract. Peak plasma levels normally occur at 1.5 hours post-dose for allopurinol. Maximum plasma levels observed after one oral dose of 300 mg of allopurinol are 3 mcg/mL.

Volume of distribution (V_d):  Allopurinol is a substrate for enzyme xanthine oxidase, present in the cytoplasm of endothelial cells of capillaries and highest activity in the liver and intestinal lining. Human studies for tissue concentrations of allopurinol have not been reported, but in animal studies, it has been found to reach highest levels in blood, liver, intestine and heart, and lowest in the brain and lung tissues.  

Protein binding: Allopurinol is negligibly bound to plasma proteins

Metabolism: Allopurinol is rapidly metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), an inhibitor of xanthine oxidase enzyme. It is converted to their respective ribonucleotides by the purine salvage pathway. The effect of these ribonucleotides related to the hypouricemic action of allopurinol in humans is not fully elucidated.

Route of elimination: Approximately 80% of orally ingested allopurinol is excreted in the urine, and 20% of ingested allopurinol is excreted in the faeces.

Half-life: The plasma half-life of allopurinol is 1-2 hrs due to rapid renal clearance

Clearance: Allopurinol and its metabolites are mainly eliminated by the kidney; therefore, the dose should be reduced as the drug can accumulate in patients with renal failure. A daily dosage of 200 mg allopurinol is suitable in case of creatinine clearance of 10 to 20 mL/min whereas the daily dosage should not be higher than 100 mg in case of creatinine clearance less than 10 mL/min.

• It is contraindicated in patients with a hypersensitivity to allopurinol or those who have previously developed a severe reaction to this drug
• It is contraindicated in patients with impaired renal function as it may increase the persisting renal abnormalities
• It is contraindicated in nursing mothers and children (except in those with hyperuricemia secondary to malignancy)

• The addition of uricosuric agents such as probenecid or large doses of salicylate may reduce the extent of inhibition of xanthine oxidase by allopurinol or oxypurinol and also increases the renal clearance of oxypurinol
• Allopurinol prolongs the half-life of anticoagulant, dicumarol; therefore the use of allopurinol along with anticoagulant therapy should be considered
• Concomitant administration of chlorpropamide with allopurinol can increase the recognized risk of prolonged hypoglycemic activity of chlorpropamide when the renal function is reduced
• Allopurinol can increase the plasma half-life and concentration of vidarabine and cyclosporin respectively leading to enhanced toxic effects
• The metabolism of theophylline metabolism is inhibited in the presence of  relatively high doses of allopurinol (300 mg b.i.d.) under experimental conditions
• Coadministration of Ampicillin/Amoxicillin with allopurinol can increase the frequency of skin rash 

Allopurinol is widely prescribed as first line urate lowering therapy in gout patients. Serum uric acid  (sUA) levels are frequently not achieved due to percieved intolerability of doses above 300 mg. Studies related to the efficacy and safety of allopurinol at doses above 300 mg/day are limited. Evidences from a large open label, 6 month study (LASSO) indicated the sUA-lowering efficacy,  gout flare frequency and safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits.  A total of 1735 patients were enrolled and categorised in three categories: Category one (< 300 mg), Category two (300 mg) and Category three (> 300 mg). The results showed that allopurinol was well tolerated with low rates of treatment related adverse events (TEAEs) and discontinuation-related TEAEs. The most common TEAEs were diarrhea, upper respiratory tract infection, and arthralgia. Nephrolithiasis was also reported in 7 patients in the 300mg allopurinol category. The incidence of skin rash and allopurinol hypersensitivity syndrome (AHS) were low. Serious adverse events (SAEs) were observed in 51 patients. The various SAEs includes pneumonia, acute myocardial infarcation, cellulitis, diverticulitis, prostate cancer, gout, acute coronary syndrome, atrial fibrillation, atrial flutter, supraventricular tachycardia, and small intestinal obstruction.  Two patients in the 300-mg category and one patient in the < 300-mg category had an SAE with outcome of death, categorized respectively as sudden death, pulmonary embolism, and death due to natural causes.

Other common TEAEs associated with allopurinol withdrawal or study discontinuation were rash, diarrhea, increase in alanine aminotransferase and gamma glutamyl transferase. The overall incidence of MACE (CV death, nonfatal MI, and nonfatal stroke) was 0.58%, with an incidence rate of 1.42/100 patient-years (95% CI 0.68–2.61). The incidence of  non-MACE CV end points was 0.75%.  In conclusion, there were minor differences the incidence of TEAEs possibly related to allopurinol between the dosing categories (< 300 mg, 300 mg, and > 300 mg daily). The allopurinal doses were well tolerated without new safety signals emerging over 6 months.

• An increase in acute attacks of gout has been reported during the early stages of the administration, so maintenance doses of colchicine should be given when allopurinol administration is started
• Sufficient fluid intake is essential to yield a urinary output of at least 2 litres as it is desirable to reduce the risks of xanthine calculi
• Patients with impaired renal function should be monitored carefully during the early stages of administration. If increased abnormalities in renal function persist, the dose should be decreased or withdrawn
• The effect of allopurinol in nursing mothers and the pediatric population is unknown; therefore allopurinol should be administered with caution
• Allopurinol should not be used in patients with asymptomatic hyperuricemia

Gout: A cohort study was conducted by Li Wei et al. to study the impact of allopurinol on the urate levels and cardiovascular outcomes associated with gout. A total of 7135 patients aged ≥60 years with urate measurements between year 2000 and 2002 followed up until 2007 were included. Six thousand and forty-two patients refused to take urate-lowering therapy (ULT), and 45.9% of participants had urate concentrations ≤6 mg dl−1. Among 1035 participants administered with allopurinol, 44.7% reached target urate levels. No significant increase in risk of cardiovascular events was observed for allopurinol users as compared to non-ULT users and the non-ULT group with urate >6 mg dl−1. Cardiovascular events rates were  74.0  per 1000 person-years for the 100 mg group, 69.7  for the 200 mg group and 47.6  for the ≥300 mg group within allopurinol use cohort. High dose users had significant reductions in the risk of cardiovascular events and mortality as compared to patients administered with low dose allopurinol.  Less than 50% of patients receiving allopurinol reached urate concentrations. In conclusion, higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.

Calcium oxalate stones: A double blind study was conducted by Ettinger B et al. to examine the efficacy of allopurinol in the prevention of recurrent calcium oxalate calculi of the kidney. A total of sixty patients with hyperuricosuria and normocalciuria with a previous history of calculi were randomly categorised to receive either allopurinol (100 mg three times daily) or a placebo. The findings of study indicated a significant decrease in calculi in allopurinol group (81.2%) as compared to placebo (63.4%). The mean rate of calculous events was 0.26/patient/year in the placebo group and 0.12 in the allopurinol group. The comparison of treatment groups by actuarial analysis showed a significantly longer time before recurrence of calculi in allopurinol group. The study concludes that   allopurinol is effective in the prevention of calcium oxalate stones in patients with hyperuricosuria. 

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