12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Magnesium prevents seizures in patients with preeclampsia and controls seizures in patients with eclampsia by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Magnesium has a depressant effect on the central nervous system [see Drug Interactions (7)]. Magnesium acts peripherally to produce vasodilation.
With intravenous administration of magnesium sulfate the onset of anticonvulsant action is immediate and lasts about 30 minutes. The estimated magnesium concentration (above baseline) required to elicit half-maximum effect (EC50) on systolic and diastolic blood pressure in pregnant women with preeclampsia that received intravenous magnesium sulfate therapy was reported to be 1.5 and 1.8 mEq per liter (1.9 and 2.2 mg per dL), respectively, in a published study. Effective anticonvulsant serum concentrations range from 2.5 to 7.5 mEq per liter.
Drug Interaction Studies
The following information is based upon published case reports and clinical studies that could not be confirmed by an adequately controlled study, but still warrant consideration given the potential risks involved [see Drug Interactions (7)].
Neuromuscular Blocking Agents:
Potentiation and prolongation of neuromuscular blockade requiring modification of the neuromuscular blocking agent dosage and/or increased reversal agent requirements were reported in preeclamptic women who received magnesium sulfate treatment who underwent subsequent surgery (for example, caesarian section) with anesthesia that included either a depolarizing (d-tubocurarine, succinylcholine) or nondepolarizing neuromuscular blocking agent (vecuronium, rocuronium).
Narcotics and/or Propofol:
Potentiation and prolongation of analgesic and/or sedative effects as well as a reduced requirement for an intravenous narcotic (fentanyl, sufentanil, tramadol), intrathecal narcotic (fentanyl), and/or intravenous propofol was reported in magnesium sulfate treated patients who required surgery or intensive care that also included narcotic and/or propofol therapy.
Dihydropyridine Calcium Channel Blockers:
An exaggerated hypotensive response (blood pressure 80–93/49–60 mm Hg) was reported in preeclamptic women who received oral nifedipine in addition to magnesium sulfate treatment. Blood pressure returned to previous levels within approximately 30 minutes with supportive care.
Approximately 1 to 2% of total body magnesium is located in the extracellular fluid space. Magnesium is 30% bound to albumin.
The average half-life and systemic clearance of magnesium sulfate in preeclamptic women is approximately 4 to 5 hours and 4 to 5 liters per hour, respectively.
Patients with Renal Impairment:
Plasma magnesium concentrations of 7 to 12.3 mEq per liter (8.6 to 15.1 mg per dL) were reported in preeclamptic women with a urine output less than 100 mL per 4 hours that received 20 grams of magnesium sulfate intravenously over 2 to 8 hours in a published study [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].