What is the mechanism of action of magnesium sulfate in preventing and treating seizures in a pregnant woman with pre‑eclampsia?

Mechanism of Action of Magnesium Sulfate in Pre-eclampsia

Magnesium sulfate prevents and treats eclamptic seizures through multiple mechanisms: it blocks neuromuscular transmission by decreasing acetylcholine release at the motor end-plate, produces cerebral and peripheral vasodilation to reduce vascular resistance, protects the blood-brain barrier to limit cerebral edema, and exerts central nervous system depression—though the precise mechanism remains multifactorial and not fully elucidated. 1, 2

Primary Anticonvulsant Mechanism

• Neuromuscular blockade: Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the motor nerve end-plate by the motor nerve impulse. 1

• Central nervous system depression: Magnesium exerts a depressant effect on the CNS, though it does not adversely affect the woman, fetus, or neonate when used as directed in eclampsia or pre-eclampsia. 1

• Therapeutic serum levels: Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/L, with normal plasma magnesium levels ranging from 1.5 to 2.5 mEq/L. 1

Vascular Mechanisms

• Peripheral vasodilation: Magnesium acts peripherally to produce vasodilation; with low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure by decreasing peripheral vascular resistance. 1, 2

• Cerebral vasodilation: Magnesium sulfate may relieve cerebral vasoconstriction, which is a key pathophysiologic feature of eclampsia, though it does not function as a primary antihypertensive agent (separate blood pressure control with labetalol, nifedipine, or hydralazine is required). 2, 3

Neuroprotective Mechanisms

• Blood-brain barrier protection: Magnesium sulfate may protect the blood-brain barrier and limit cerebral edema formation, which is critical in preventing the progression from severe pre-eclampsia to eclampsia. 2

• Calcium antagonism hypothesis: Magnesium may act by opposing calcium-dependent arterial constriction and may antagonize the increase in intracellular calcium concentration, though research shows magnesium does not substantially modulate serum ionized calcium levels during therapy. 4

Clinical Pharmacology

• Onset and duration: With IV administration the onset of anticonvulsant action is immediate and lasts about 30 minutes; following IM administration, onset occurs in about one hour and persists for three to four hours. 1

• Renal excretion: Magnesium is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration, making urine output monitoring (≥30 mL/hour) essential to prevent toxicity. 1, 3

Dose-Response Relationship and Toxicity

• Deep tendon reflex suppression: As plasma magnesium rises above 4 mEq/L, deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/L. 1

• Respiratory paralysis threshold: At plasma levels of approximately 10 mEq/L, respiratory paralysis may occur; respiratory rate should be maintained ≥12 breaths/minute during therapy. 1, 3

• Cardiac effects: Heart block may occur at plasma levels of 10 mEq/L or lower, and serum magnesium concentrations in excess of 12 mEq/L may be fatal. 1

• Calcium as antidote: The central and peripheral effects of magnesium poisoning are antagonized to some extent by IV administration of calcium. 1

Clinical Efficacy Evidence

• Eclampsia prevention: Magnesium sulphate more than halves the risk of eclampsia (RR 0.41,95% CI 0.29 to 0.58; NNTB 100) compared to placebo, with a non-significant reduction in maternal death (RR 0.54,95% CI 0.26 to 1.10). 5

• Superiority over other anticonvulsants: Magnesium sulphate reduced eclampsia compared to phenytoin (RR 0.08,95% CI 0.01 to 0.60) and nimodipine (RR 0.33,95% CI 0.14 to 0.77), establishing it as the gold-standard anticonvulsant for eclampsia. 5, 3

Important Clinical Caveats

• Not an antihypertensive: Magnesium sulfate does not control blood pressure and requires separate antihypertensive therapy (IV labetalol, oral nifedipine, or IV hydralazine) to achieve target BP <160/105-110 mmHg. 3, 6

• Calcium channel blocker interaction: Never combine magnesium sulfate with calcium channel blockers (especially IV or sublingual nifedipine) as this can cause severe myocardial depression and precipitous hypotension. 3, 6

• Multifactorial action: The specific mechanisms of action remain unclear, but the effect of magnesium sulfate in the prevention of eclampsia is likely multifactorial, involving vasodilation, blood-brain barrier protection, and central anticonvulsant action. 2