Neostigmine

Drug Name

  • Generic Name: Neostigmine Methylsulfate
  • Pronunciation: nee-oh-stig-meen
  • Common Brand Names (US): Bloxiverz®
Doctor loading Neostigmine

Drug Class

  • Pharmacologic Class: Acetylcholinesterase Inhibitor (Reversible)
  • Therapeutic Class: Neuromuscular Blockade Reversal Agent (Antidote)
  • Chemical Class: Quaternary Ammonium Compound

Mechanism of Action (MOA)

Neostigmine is a reversible inhibitor of acetylcholinesterase (AChE), the enzyme responsible for breaking down acetylcholine (ACh) in the synaptic cleft. By inhibiting AChE, neostigmine increases the concentration of ACh. This increased ACh competitively displaces non-depolarizing neuromuscular blocking agents (e.g., rocuronium, vecuronium) from nicotinic receptors at the motor end-plate, restoring neuromuscular transmission.

Pharmacokinetics

  • Onset: Relatively rapid onset of action after IV administration, typically within 3-5 minutes.
  • Distribution: Being a quaternary ammonium compound, it is polar and does not readily cross the blood-brain barrier.
  • Metabolism: Partially metabolized by plasma cholinesterases.
  • Excretion: Primarily excreted unchanged by the kidneys. The duration of action is approximately 30-60 minutes but can be significantly prolonged in patients with renal failure.

 

Pharmacodynamics

Pharmacodynamics describes the drug's effects on the body, which are mediated by the excess acetylcholine at both nicotinic and muscarinic receptors:

  • Nicotinic Effects (Desired): Reversal of non-depolarizing neuromuscular blockade, leading to restored skeletal muscle strength.
  • Muscarinic Effects (Undesired Side Effects):
    • Cardiovascular: Bradycardia (via vagal stimulation), potential for hypotension.
    • Pulmonary: Bronchoconstriction and increased bronchial secretions.
    • Gastrointestinal: Increased GI motility and secretions.
    • Other: Increased salivation, lacrimation, sweating, and urination. (This is the classic SLUDGE syndrome).

Dosing & Administration

  • Route: Intravenous (IV).
  • IV Dosing (for NMB reversal):
    • Dose: 0.04 - 0.07 mg/kg (up to a maximum of 5 mg).
    • Administration: Must be co-administered with an anticholinergic agent (glycopyrrolate 0.2 mg or atropine 0.4-0.8 mg IV) to block the muscarinic side effects. The anticholinergic is often given immediately before or simultaneously with neostigmine.
  • Administration Note: Dose should be reduced in patients with renal impairment. It should be administered slowly to minimize bradycardic effects.

Clinical Uses / Indications

  • Reversal of Non-Depolarizing Neuromuscular Blockade: This is its primary and almost exclusive use in anesthesia.
  • Treatment of Myasthenia Gravis: (Less common intraoperatively, more of a chronic therapy).
  • Treatment of Postoperative Ileus or Urinary Retention: (Rare, off-label uses).

Contraindications

  • Absolute:
    • Known hypersensitivity to neostigmine or bromides.
    • Mechanical obstruction of the intestinal or urinary tract.
  • Relative:
    • Peritonitis.
    • Uncontrolled bronchial asthma or COPD (risk of bronchospasm).
    • Bradycardia or AV block.
    • Severe cardiovascular disease.

Adverse Effects / Side Effects

  • Cardiovascular: Profound bradycardia, heart block, hypotension.
  • Pulmonary: Bronchospasm, bronchorrhea (excessive secretions).
  • Gastrointestinal: Abdominal cramps, nausea, vomiting, diarrhea.
  • Other: Increased salivation, lacrimation, sweating, muscle fasciculations (at high doses).

Drug Interactions

  • Anticholinergics: (Glycopyrrolate, Atropine) - Intentionally co-administered to block muscarinic side effects.
  • Depolarizing Neuromuscular Blockers: (Succinylcholine) - Prolongs the duration of action of succinylcholine by inhibiting its metabolism.
  • Beta-Blockers: Can have an additive effect, leading to profound bradycardia.
  • Aminoglycoside Antibiotics: (e.g., gentamicin) - Can have additive neuromuscular blocking effects, making reversal more difficult.

Monitoring Parameters

  • Peripheral Nerve Stimulator (PNS): Mandatory. Objective evidence of reversal (e.g., a Train-of-Four (TOF) ratio ≥ 0.9) is required before administering neostigmine and before extubation.
  • Standard Anesthesia Monitoring: Continuous ECG (for bradyarrhythmias), NIBP (for hypotension), SpO2, and EtCO2 (for adequate ventilation and to detect bronchospasm).
  • Clinical Assessment: Observe for adequate tidal volume, sustained head lift (>5 seconds), and strong hand grip.

Key Considerations for the Anesthesia Provider

  • Never Reverse Blind: The PNS is your guide. Administering neostigmine to a patient with no neuromuscular blockade or a very deep block is ineffective and dangerous.
  • Always Use an Anticholinergic: Forgetting the glycopyrrolate or atropine can lead to severe bradycardia and asystole. Glycopyrrolate is often preferred due to its more potent antisialogogue effect and lack of central nervous system effects.
  • Renal Failure is a Red Flag: Dose must be reduced. Accumulation can lead to prolonged cholinergic effects and a "recurarization" phenomenon.
  • Reversal is Not Instant: Allow 5-10 minutes after administration for the full effect to peak before assessing for extubation criteria.
  • Consider the "Rule of 4s": A general (though not infallible) guideline: 4 twitches on the PNS, a TOF ratio > 0.9, a head lift of 5 seconds, and a tidal volume of 4-5 mL/kg are good indicators of adequate reversal.

Summary / "Bottom Line"

Neostigmine is the standard acetylcholinesterase inhibitor used to reverse non-depolarizing neuromuscular blockade. Its use is critically dependent on objective monitoring with a peripheral nerve stimulator and mandatory co-administration with an anticholinergic to prevent life-threatening muscarinic side effects like bradycardia and bronchospasm. Dose adjustment is essential in renal failure.

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