Allopurinol

Introduction Overview

Generic Name

allopurinol

Brand Name

Zyloprim

Dosage Form

Tablet

Drug Class

Antigout agents, Antihyperuricemic agents

Pharmacokinetics

Absorption: Allopurinol is rapidly absorbed after oral administration, with peak plasma concentrations typically reached within 1.5 hours. The oral bioavailability of allopurinol is approximately 80-90%, although this can be influenced by the presence of food which may reduce the rate but not the extent of absorption. Its rapid and nearly complete absorption allows for effective plasma concentrations following oral dosing.

Distribution: Allopurinol distributes widely into bodily tissues and fluids, including saliva, breast milk, and cerebrospinal fluid, reflecting its low protein binding (approximately 50%). The volume of distribution ranges between 1.6 and 2.3 L/kg. Notably, allopurinol crosses the placenta and may be detected in fetal tissues, and is also found in breast milk. Because of this distribution, it has the potential for systemic effects and requires cautious use in pregnancy and breastfeeding.

Metabolism: The primary metabolic pathway of allopurinol is conversion to oxypurinol (alloxanthine), its major active metabolite, through enzymatic oxidation by xanthine oxidase. Oxypurinol exhibits a longer half-life and contributes significantly to the drug's pharmacodynamic effect. Metabolism is not dependent on hepatic cytochrome P450 enzymes but involves aldehyde oxidase and other non-CYP pathways. Oxypurinol accumulates in patients with impaired renal function due to decreased clearance.

Elimination: Allopurinol and its active metabolite oxypurinol are primarily eliminated renally. Approximately 70% of an administered dose is recovered in the urine as metabolites within 24-72 hours. The elimination half-life of allopurinol is approximately 1 to 2 hours, while oxypurinol has a prolonged elimination half-life ranging from 18 to 30 hours, which accounts for the sustained pharmacologic effect. In patients with renal impairment, elimination is delayed, necessitating dose adjustments to prevent accumulation and toxicity. Hemodialysis can partially remove oxypurinol from plasma.

Dosage Forms

Available Dosage Forms:
- Oral tablet
Available strengths include:
- 100 mg tablet
- 300 mg tablet

Dosages for Adults and Adolescents:
- For gout management:
- Adults: Initial dose typically starts at 100 to 300 mg per day, administered once daily or divided into multiple doses. Dosage may be titrated as needed, with usual maximal doses not exceeding 800 mg per day.
- For hyperuricemia secondary to cancer therapies:
- Adults and children 11 years and older: 300 to 800 mg per day, dosage adjusted based on patient response.
- For pediatric patients:
- Children’s dose is determined by the healthcare professional. For hyperuricemia in children, dosing is often calculated based on body surface area, approximately 100 mg/m2 every 8 to 12 hours, not exceeding 800 mg per day.
- For prevention of recurrent kidney stones:
- Adults: 200 to 300 mg per day, administered once or divided doses.

Specific Patient Populations:
- Renal impairment: Dosage adjustments are critical to avoid oxypurinol accumulation and adverse effects; dose reduction or extension of dosing interval is recommended.
- Pediatric: Use and dosing must be carefully individualized by physicians, particularly in children undergoing chemotherapy.
- Geriatric: Limited specific data; dosing should be cautious and individualized due to potential for impaired renal function.

Mechanism Of Action

Allopurinol acts primarily as a selective inhibitor of xanthine oxidase, the enzymatic catalyst responsible for the oxidation of hypoxanthine to xanthine and subsequently xanthine to uric acid, the final oxidation product of purine metabolism. By inhibiting xanthine oxidase, allopurinol decreases the production and accumulation of uric acid in the blood and urine, thereby preventing gout attacks and uric acid nephropathy.

At the molecular level, allopurinol resembles a purine base and competitively binds to the molybdenum site of xanthine oxidase, preventing the catalytic conversion of hypoxanthine and xanthine to uric acid. Its metabolite, oxypurinol (alloxanthine), also contributes to xanthine oxidase inhibition with a longer half-life, sustained action, and similar binding characteristics.

The reduced uric acid levels decrease urate crystal formation in joints and tissues, alleviating gout symptoms and joint inflammation. Additionally, lowered serum urate lessens the risk of uric acid stone formation in kidneys.

In comparison to other antigout agents such as febuxostat (Uloric), which also inhibits xanthine oxidase but through a non-purine selective mechanism, allopurinol is often preferred due to extensive clinical experience and cost considerations. However, febuxostat may be used in patients intolerant to allopurinol. Studies have shown that allopurinol effectively reduces serum urate levels and decreases gout flares, thereby confirming its central role in hyperuricemia management.

Pharmacological Actions

Xanthine oxidase inhibitor reducing uric acid production
Antihyperuricemic agent lowering serum and urinary uric acid levels
Prevention and treatment of gout and gouty arthritis
Reduction in formation of uric acid kidney stones (calcium oxalate calculi)
Adjunct in management of hyperuricemia secondary to malignancy chemotherapy
Exhibits antioxidant properties by limiting reactive oxygen species generated during purine metabolism
Modulates inflammatory response by decreasing uric acid-induced neutrophil activation
Prolonged action through active metabolite oxypurinol
Improves renal function by reducing uric acid nephropathy in susceptible patients
Potentially stabilizes endothelial function through uric acid lowering
May reduce cardiovascular risk factors associated with hyperuricemia

Therapeutic Or Clinical Uses

Prevention and management of gout and gouty arthritis
Treatment of hyperuricemia associated with cancer chemotherapy to prevent tumor lysis syndrome
Prevention of recurrent uric acid kidney stones (calcium oxalate calculi) in patients with hyperuricosuria
Management of gout in patients with elevated serum urate concentrations
Adjunctive therapy to reduce uric acid levels in patients with renal impairment and hyperuricemia
Used to minimize acute gout flares during initiation of uric acid-lowering therapy (often combined with colchicine or NSAIDs)
Prevention of uric acid nephropathy and renal failure in high-risk patients
Chronic management of hyperuricemia to maintain serum urate within target range
Off-label uses include treatment of Lesch-Nyhan syndrome symptoms by reducing uric acid
Used in tumor lysis syndrome prophylaxis to decrease uric acid burden

Side Or Adverse Effects

Ankle, knee, or great toe joint pain and stiffness
Skin rash including flat lesions or raised lesions
Serious hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Gastrointestinal disturbances such as nausea, vomiting, and stomach pain
Rare hematologic abnormalities including leukopenia, thrombocytopenia, and bleeding tendency
Hepatotoxicity presenting as elevated liver enzymes, jaundice
Allergic reactions including itching, hives, and swelling
Fatigue, dizziness, drowsiness, and headache
Rare neurological effects including seizures, confusion, and hallucinations
Renal impairment or acute kidney injury especially in predisposed patients
Changes in taste and metallic taste in the mouth
Photosensitivity and various skin discolorations
Respiratory symptoms such as cough or difficulty breathing
Swelling of face, extremities, or lymph nodes

Precautions

Inform the physician about any allergy to allopurinol or other medicines
Use cautiously in patients with renal impairment due to risk of accumulation and toxicity
Monitor liver function tests periodically during treatment
Baseline and periodic blood counts should be obtained to detect hematologic abnormalities
Avoid abrupt discontinuation during acute gout attacks; continue therapy under medical supervision
Exercise caution when used concomitantly with azathioprine or mercaptopurine due to increased toxicity risk
Use with caution in patients with bone marrow disorders
Be aware of potential severe cutaneous adverse reactions — discontinue at first sign of rash
Patients should be advised to maintain adequate hydration to reduce kidney stone risk
Dose adjustments recommended in elderly patients with poor renal function
Advise patients that initial treatment may precipitate gout flares; prophylactic measures may be required
Evaluate all concomitant medications to avoid interactions
Avoid use during pregnancy unless benefits outweigh risks
Caution advised if breastfeeding; potential risks to infant are unknown
Educate patients about signs of hypersensitivity and instruct immediate reporting

Warnings

Risk of severe hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Potential for life-threatening liver injury; monitor symptoms such as jaundice or dark urine
May cause bone marrow suppression leading to infection or bleeding
Increased risk of gout attacks during initiation of therapy; continue treatment and manage flares appropriately
Use caution in patients with pre-existing renal or hepatic disease
May cause drowsiness or dizziness; avoid driving or hazardous activities until response is known
Potentially severe skin reactions may require immediate drug discontinuation
Use caution with concomitant use of warfarin and other anticoagulants due to bleeding risk
May exacerbate existing cardiovascular conditions through uric acid changes
Avoid using alongside didanosine as contraindicated due to increased risk of toxicity
Monitor closely in patients with multiple comorbidities such as diabetes and hypertension
Ensure adequate patient hydration to prevent renal complications
Warning against use without proper renal function monitoring
Use only under prescription and supervision due to potential serious adverse effects
Potential interaction with chemotherapeutic agents requiring dose modifications

Contraindication

Known hypersensitivity or allergy to allopurinol or any component of the formulation
Concomitant use with didanosine due to increased risk of toxicity
History of severe hypersensitivity reaction or severe cutaneous adverse reactions to allopurinol
Patients with previous Stevens-Johnson syndrome or toxic epidermal necrolysis induced by allopurinol
Severe renal impairment without appropriate dose adjustment
Use cautiously in patients with active liver disease
Use contraindicated if patient has current acute gout attack without appropriate anti-inflammatory prophylaxis
Patients with known hypersensitivity to xanthine oxidase inhibitors
Use contraindicated in patients with concomitant mercaptopurine or azathioprine unless dose is adjusted
Concurrent use of capecitabine or fluorouracil without medical supervision

Drug Interactions

Didanosine – concomitant use contraindicated due to increased toxicity risk
Azathioprine – allopurinol increases azathioprine plasma levels increasing risk of bone marrow suppression
Mercaptopurine – similar interaction as azathioprine; dosage adjustment required
Warfarin – possible increased anticoagulant effect leading to bleeding risk
Captopril and enalapril – increased risk of hypersensitivity reactions and decreased renal function
Fluorouracil and capecitabine – potential increased toxicity when used together
Methotrexate – increased risk of bone marrow suppression
Pegloticase – co-administration may provoke severe reactions; use with caution
Aluminum hydroxide – may decrease absorption of allopurinol
Cyclosporine – increased risk of nephrotoxicity
Vidarabine – risk of increased toxicity with combined use
Phenprocoumon – potential for altered anticoagulant effect requiring monitoring
Levoketoconazole – co-administration requires monitoring due to metabolism interactions
Tegafur – possible increased toxicity when combined
Drugs affecting renal function may alter allopurinol elimination
Concurrent use with NSAIDs or colchicine recommended during initiation to manage gout flares

Preparations Of The Drug

Oral tablets for administration
Available in 100 mg and 300 mg strengths
Prescription-only medication
Packaged in bottles or blister packs suitable for oral dosing
Supplied as film-coated tablets to improve swallowing and stability
Storage at room temperature away from moisture and heat recommended
No injectable formulations commonly available under brand Zyloprim
Generic allopurinol formulations available in multiple preparations
Allopurinol used as active agent in all pharmaceutical preparations of Zyloprim
Available under various brand names internationally besides Zyloprim