EpistemisAllopurinol
Allopurinol is the drug of choice for urate-lowering therapy in chronic gout and in the prevention of tumor lysis syndrome. Its action as a xanthine oxidase inhibitor depresses the production of plasma uric acid, but exposes the patient to severe immunologically mediated hypersensitivity dermal reactions.
Mechanism
💊 Common Business NamesZyloric, Allopurinol Kern, Allopur, Caplenal, Purinol, Bloxanth.
🔬 Pharmacological GroupXanthine oxidase enzyme inhibitor. Hypouricemic antigout. Analogue of purines.
Mechanism of Action
Allopurinol stably decreases de novo synthesis of uric acid by acting as a competitive substrate:
- Xanthine Oxidase (XO) Inhibition: Structurally, allopurinol is an analogue of the purine hypoxanthine. Upon binding to the enzymatic docking site of XO, it is initially converted by the enzyme itself into its main active metabolite: oxypurinol (or alloxanthin).
- Suicidal Inhibition of Oxipurinol: Oxypurinol coordinates strongly with the reduced molybdenum atom (valence +4) present in the active catalytic site of xanthine oxidase, pseudo-irreversibly blocking the subsequent conversion of hypoxanthine to xanthine, and of the latter to uric acid. As a direct result, serum concentrations of monosodium urate plummet, facilitating the progressive dissolution of articular tophi deposits and the remission of gout.
- Recycling of Purine Bases: When the new.
Pharmacokinetics
Key Pharmacokinetics
| Parameter | Quantitative Pharmacokinetic Profile |
|---|---|
| Routes of Administration | Exclusively by oral route (tablets). (Intravenous route reserved for pediatric oncology in specific tumor lysis). |
| Absorption | Rapid oral absorption in the upper duodenum; It has an absolute bioavailability of 67 - 90%. The time to reach the plasma peak (Tmax) of allopurinol is short: 1 - 1.5 hours. |
| Distribution and Protein Binding | No or negligible binding to plasma proteins (both for the parent allopurinol and for the active oxypurinol). Apparent volume of distribution (Vd): approximately 1.6 L/kg, widely distributed throughout the body's tissues and biological fluids. |
| Rapid Conversion Metabolism | It undergoes rapid hepatic metabolic conversion in vivo mediated by xanthine oxidase itself and to a lesser extent by aldehyde oxidase to give rise to the active metabolite with prolonged systemic retention: oxypurinol. |
| Excretion and Half-Life | Less than 10% of the parental allopurinol is excreted unchanged in the urine. Its biological clearance is marked by rapid biotransformation (t1/2 of allopurinol: 1.0 - 2.0 hours). For its part, active oxypurinol is eliminated by renal glomerular filtration, undergoing intense active tubular reabsorption mediated by anionic transporters. Elimination half-life (t1/2) of oxypurinol: extremely long, approximately 15.0 to 30.0 hours at steady state (doubling or tripling in nephropathies). |
Indicators and dose
Dosage and Adjustment
- Adults (Chronic Tophaceous Gout or Tumor Lysis Syndrome):
- Slow Escalation Protocol: Mandatory initiation at a low dose of 100 mg orally once a day to reduce the risk of inducing acute attacks and skin hypersensitivity.
- Progressively escalate in steps of 100 mg every 2 to 4 weeks according to periodic determinations of serum uric acid (titrate until reaching the therapeutic target of uricemia less than 6.0 mg/dL or 5.0 mg/dL in severe tophaceous gout).
- Usual Maintenance Dose: 300 mg to 600 mg per day. Absolute maximum daily dose: 800 mg/day under strict monitoring.
- Pediatrics: Not recommended for gout; reserved for chemotherapy tumor lysis in oncology at doses of 150 - 300 mg/day orally depending on total body weight and intravenous fluid count.
- Adjustment in Kidney Failure:
- Clcr 30-59 mL/min: Start at a maximum dose of 50 - 100 mg/day orally, and slowly escalate in steps less than 50 mg, without usually exceeding maintenance doses of 150 - 200 mg/day.
- Clcr < 30 mL/min: Start at a dose of 50 mg every other day or 3 times a week, limiting maintenance to a minimum. Substitution with selective liver clearance alternatives such as Febuxostat is preferably recommended.
- Adjustment in Liver Failure: No systematic adjustment is required given the predominantly renal excretion of the active metabolite oxypurinol.
Security
Risk of Headache Induction and Paradoxical Gout Attacks of Onset
When allopurinol is introduced quickly and abruptly for the first time, a rapid drop in serum uric acid levels is caused. This breaks the homeostatic saturation balance and causes the accelerated mobilization and dissolution of the urate microcrystals previously deposited in the articular cartilage, releasing them freely into the synovial fluid. The exposed crystals are phagocytosed by macrophages, triggering a severe paradoxical gout attack. For this reason, allopurinol should never be started during an active acute gout attack (a minimum of 2 weeks must be waited after resolution), and its introduction must be necessarily associated with simultaneous prophylaxis with colchicine (0.5 mg/day) during the first 3 to 6 months.
Contraindications
- Absolute: Personal history of severe skin hypersensitivity reactions or allopurinol-induced hypersensitivity syndrome; Documented hypersensitivity to the active ingredient or its excipients.
- Relative: Presence of a risk genetic allele HLA-B*5801 (mainly in populations of Han Chinese, Thai or Korean origin, where the association with lethal skin reactions is close to 100%). Moderate to severe kidney failure.
Adverse Effects (ADR)
- Frequent / Tolerable: Transient nausea, mild gastric heartburn, moderate diarrhea, self-limited papulomacular skin rash, headache.
- Rare / Serious: Allopurinol Hypersensitivity Syndrome (AHS / DRESS) (severe hypersensitivity reaction characterized by high fever, generalized diffuse exfoliative skin rash, desquamation, extreme systemic eosinophilia, necrotizing vasculitis and fatal acute renal failure or liver necrosis; mortality rate of 20-30%); aplastic pancytopenia; Acute interstitial nephritis.
Critical Interaction with Azathioprine and 6-Mercaptopurine (6-MP)
Azathioprine is a cytostatic immunosuppressive drug that undergoes immediate intracellular conversion into its active analgesic and antimetabolite metabolite 6-mercaptopurine (6-MP). The main biological inactivation pathway of 6-mercaptopurine is directly catalyzed by the enzyme xanthine oxidase, generating inactive metabolites derived from urinary excretion. Co-administering allopurinol and inhibiting xanthine oxidase completely blocks the azathioprine/6-MP metabolic clearance pathway. This induces a massive intracellular accumulation of modified purine nucleotides that causes irreversible fulminant medullary aplasia with fatal pancytopenia. In case of mandatory coadministration, the dose of azathioprine or 6-MP should be immediately reduced to 25% of the usual standard dose (75% reduction) with weekly blood count controls.
Drug Interactions
- Ampicillin / Amoxicillin: Synergism of cutaneous dural immunological toxicity that very significantly increases the risk of maculopapular dermal eruption.
- Thiazide Diuretics (Hydrochlorothiazide): They compete for the renal tubular secretion of oxypurinol, delaying its plasma elimination and significantly increasing the risk of developing the feared allopurinol hypersensitivity syndrome.
- Warfarin: Allopurinol moderately prolongs the elimination half-life of oral anticoagulants by inhibiting their secondary hepatic metabolic oxidation.
Pregnancy and Breastfeeding
Classified in FDA Category C. It moderately crosses the placental barrier. Its systematic use is prohibited during pregnancy unless the indication is active refractory oncological tumor lysis and after weighing risks and benefits. Breastfeeding: Compatible with caution; It is excreted in low amounts in breast milk, but due to the long half-life of the active oxypurinol, the infant should be closely monitored for the presence of skin rashes or transient neutropenia.
Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.
- System
- Pain, Inflammation and Rheumatology
- Cluster
- Hypouricemic Enzymatic Action