Metamizole (Dipyrone)

Mechanism

💊 Common Business Names

Nolotil, Neo-Melubrin, Algifen, Metalgial, Dalmasin.

🔬 Pharmacological Group

Pyrazolone derivative. Analgesic, antipyretic and spasmolytic.

Mechanism of Action

Metamizole acts as a non-acidic prodrug that exerts multiorgan effects through central and peripheral routes:

• Inhibition of cyclooxygenases (weak peripheral, powerful central non-selective mechanism): Reduces COX activity by acting on the peroxidase catalytic site. As it does not bind competitively to the arachidonate site like classical acidic NSAIDs, it has excellent gastric tolerance and does not significantly alter systemic peripheral platelet function in an irreversible manner.
• Modulation of the Nitric Oxide-cGMP pathway at the peripheral level: Activates soluble guanylate cyclase and induces the synthesis of nitric oxide, causing depolarization and relaxation of smooth muscle cells. This supports its marked spasmolytic effect in renal and biliary colic.
• Blocking glutamate-induced hyperalgesia at the spinal level: Interferes with NMDA-type glutamate receptors and negatively regulates central nociceptive currents, exerting powerful temperature control in the hypothalamic thermoregulatory center.

Pharmacokinetics

Key Pharmacokinetics

Metamizole is a hydrophilic prodrug that undergoes immediate non-enzymatic chemical hydrolysis in the gastrointestinal tract before absorption:

Indicators and dose

Dosage and Adjustment

• Adults:
  • Oral Route: 575 mg to 1150 mg every 6 or 8 hours. Maximum recommended dose: 4000 mg/day (exceptionally up to 6000 mg/day in strict monitoring).
  • Intravenous / Intramuscular Route: 1000 mg to 2000 mg every 8 hours in slow diluted infusion.
• Pediatrics: Reserved for refractory febrile situations at doses of 10 - 15 mg/kg taken orally or intramuscularly, spaced every 6 or 8 hours. Not recommended for infants under 3 months or weighing less than 5 kg.
• Adjustment in Kidney Failure:
  • Cl_cr > 30 mL/min: No adjustment required for short-term therapies.
  • Cl_cr ≤ 30 mL/min: Reduce the daily cumulative dose by half or extend the intervals to every 12 hours, given the accumulation of active and inactive metabolites.
• Adjustment in Liver Failure: In moderate to severe liver failure, the dose should be reduced to 50% of the standard dose due to the alteration of the metabolic clearance rate of 4-MAA.

Security

Contraindications

• Absolute: Documented history of hypersensitivity or immunoallergic reactions to pyrazolones (propyphenazone, phenylbutazone, metamizole); acute intermittent porphyria (induction of the enzyme delta-aminolevulinate synthase); congenital glucose-6-phosphate dehydrogenase deficiency; bone marrow dysfunction or pre-existing blood dyscrasias (medullary aplasia, leukopenia, agranulocytosis).
• Relative: Pre-existing arterial hypotension or hemodynamic instability (risk of profound hypotension in rapid IV administration); analgesic-induced asthma or known intolerance to salicylates (bronchospasm reactions).

Adverse Effects (ADR)

• Frequent / Moderate: Arterial hypotension (especially due to rapid intravenous infusion); skin rashes, nausea, dry mouth.
• Rare / Serious: Agranulocytosis and aplastic anemia. Anaphylactic shock induced parenterally. Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN).
• Mechanism of Agranulocytosis: Immunoallergic type reaction (idiosyncratic Type B) where the metamizole metabolite acts as a hapten. The synthesis of antibodies directed against peripheral mature neutrophils and bone marrow precursors is induced, causing their immediate destruction. It has an associated mortality rate of close to 10% if neutropenic sepsis develops.

Safety Warning: Risk of Hypotension in Intravenous Use

Rapid direct intravenous administration of metamizole can induce a sudden reduction in peripheral vascular resistance without sympathetic reflex compensation, causing severe arterial hypotension and cardiovascular collapse regardless of the dose. To mitigate this risk, parenteral administration should be carried out exclusively by slow infusion diluted in at least 100 mL of physiological saline solution to pass in a time of no less than 20-30 minutes, with continuous monitoring of the patient's vital signs.

Drug Interactions

• Ciclosporine / Tacrolimus: Metamizole can induce a decrease in serum levels of cyclosporine by activation of its hepatic metabolism mediated by cytochromes, requiring analytical control of its serum concentrations.
• Acetylsalicylic acid (Aspirin): Co-administered with metamizole at analgesic doses, the latter can reduce the platelet inhibitory effect of aspirin by competing for access to the active site of platelet COX-1, compromising cardioprotection. It is recommended to space the administration of metamizole at least 30-60 minutes after taking low-dose aspirin.
• Methotrexate: Metamizole decreases the tubular excretion of methotrexate, increasing the risk of hematological toxicity of the latter.

Pregnancy and Breastfeeding

Avoid use during the first and second trimester due to lack of robust safety data and possible mild teratogenic risks. Absolutely contraindicated during the third trimester of pregnancy because, like classic NSAIDs, it interferes with native vasodilator prostaglandins and can cause premature constriction of the fetal ductus arteriosus (ductus arteriosus) and induce fetal renal dysfunction with associated oligohydramnios. Breastfeeding: Not recommended; The active metabolites are excreted in breast milk in significant quantities and their long-term effects on nursing infants are not defined.