Mechanism of Action of Magnesium Sulfate
Magnesium sulfate works through multiple mechanisms including peripheral and cerebral vasodilation, blood-brain barrier protection, direct anticonvulsant effects via NMDA receptor antagonism, and reduction of neuroinflammation. 1
Primary Mechanisms
Anticonvulsant Action
- MgSO4 acts as a physiological antagonist at NMDA receptors in the central nervous system, blocking calcium influx and reducing neuronal excitability. 1
- The therapeutic concentration for seizure prevention in eclampsia is 1.8-3.0 mmol/L (4.3-7.2 mg/dL), which provides effective anticonvulsant activity without toxicity. 2
- MgSO4 reduces neuroinflammation by decreasing microglial activation—in preeclampsia models, microglial activation decreased from 35% to 6% with treatment, which directly lowers seizure threshold. 3
Vascular Effects
- MgSO4 causes peripheral vasodilation by acting as a calcium antagonist in vascular smooth muscle, reducing systemic vascular resistance and blood pressure. 1
- Cerebral vasodilation occurs through direct effects on cerebrovascular smooth muscle, potentially relieving vasospasm associated with severe preeclampsia. 1
- These vasodilatory effects help reduce the hypertensive crisis that characterizes severe preeclampsia and eclampsia. 1
Blood-Brain Barrier Protection
- MgSO4 may limit cerebral edema formation by protecting blood-brain barrier integrity, though this mechanism is less consistently demonstrated than its anticonvulsant effects. 1
- In animal models of severe preeclampsia, MgSO4 reversed seizure susceptibility and decreased neuroinflammation without necessarily affecting BBB permeability, suggesting neuroinflammation reduction is the primary protective mechanism. 3
Pharmacokinetic Principles
Distribution and Protein Binding
- After administration, approximately 40% of plasma magnesium is protein-bound, with the unbound magnesium ion diffusing into extravascular-extracellular space, bone, and across the placenta. 2
- The apparent volume of distribution reaches steady state between 3-4 hours after administration, ranging from 0.250 to 0.442 L/kg in pregnant women. 2
- MgSO4 follows a 2-compartment model with rapid distribution (alpha phase) followed by slower elimination (beta phase). 2
Elimination
- Magnesium is almost exclusively excreted renally, with 90% of the dose eliminated in urine during the first 24 hours after IV infusion. 2
- Renal impairment dramatically increases toxicity risk because excretion capacity is reduced—oliguria is a critical warning sign requiring immediate dose adjustment or discontinuation. 4, 5
Clinical Superiority Over Other Agents
Why MgSO4 is First-Line
- MgSO4 is superior to phenytoin and diazepam for preventing and controlling eclamptic seizures, with approximately 50% reduction in seizure risk demonstrated in multiple RCTs involving over 4,000 women. 4
- Benzodiazepines carry significant risks of respiratory depression in both mother and neonate, making them less suitable for peripartum use. 4
- The effectiveness of MgSO4 was demonstrated with 95% of eclamptic convulsions controlled with the initial dose, and an additional 2% controlled within 30 minutes. 6
Important Clinical Caveats
Drug Interactions
- Never combine MgSO4 with calcium channel blockers (especially IV or sublingual nifedipine) as this causes severe myocardial depression through additive calcium antagonism. 4
- MgSO4 may reduce antibiotic activity of streptomycin, tetracycline, and tobramycin when administered concurrently. 7
Monitoring for Toxicity
- Loss of patellar reflexes occurs at 3.5-5 mmol/L and is the first warning sign of impending toxicity. 2, 5
- Respiratory depression occurs at 4-5 mmol/L, with respiratory paralysis at 5-6.5 mmol/L. 5, 2
- Cardiac conduction alterations occur above 7.5 mmol/L, with cardiac arrest expected above 12.5 mmol/L. 2, 5
- Have calcium gluconate (10% solution, 15-30 mL IV over 2-5 minutes) or calcium chloride (10% solution, 5-10 mL IV) immediately available as a physiological antagonist to reverse magnesium toxicity. 8, 5