Continuing Education Activity
Neostigmine is a water-soluble, ionized compound that reversibly inhibits acetylcholinesterase and is an FDA-approved agent for reversing non-depolarizing neuromuscular blockade after surgery. This drug demonstrates a short duration of action, minimal penetration across the blood-brain barrier, and targeted activity at neuromuscular junctions. Adverse effects associated with neostigmine administration include bradycardia, hypersalivation, bronchoconstriction, and increased gastrointestinal motility, whereas contraindications include mechanical obstruction of the gastrointestinal or urinary tract. This activity addresses indications, mechanism of action, adverse effects, contraindications, pharmacokinetics, dosing, relevant drug interactions, and adverse effect profiles within a clinical framework.
Administration in anesthesiology settings relies on careful dosing based on the extent of neuromuscular blockade and patient comorbidities. Participants will review optimal monitoring strategies to detect bradycardia and other cholinergic symptoms, preserving patient safety during perioperative care. Collaboration among anesthesiologists, surgeons, nurses, and pharmacists supports the effective use of neostigmine in diverse clinical scenarios.
Objectives:
Evaluate the mechanism of action of neostigmine.
Identify the FDA-approved indications and off-label uses of neostigmine.
Screen patients for contraindications and potential risks associated with neostigmine.
Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from neostigmine therapy.
Indications
Neostigmine is an ionized water-soluble compound that reversibly inhibits the enzyme acetylcholinesterase.
FDA-Approved Indications
Neostigmine is FDA-approved to reverse the effects of non-depolarizing neuromuscular blocking agents. This drug is primarily administered to patients undergoing surgery requiring muscle relaxation. After the administration of neostigmine, the concentration of acetylcholine in the neuromuscular junction is increased, allowing muscles to contract with full strength, and patients can breathe spontaneously and protect their airways safely after anesthesia is no longer required.[1][2][3]
Off-Label Uses
Acute colonic pseudo-obstruction (ACPO), or Ogilvie syndrome, is an acute colon dilation without a mechanical or anatomic cause. While neostigmine is not FDA-approved for ACPO, it is often used off-label after conservative treatments fail to improve symptoms. However, it should be considered cautiously in this context, particularly for patients with cardiac conditions, such as symptomatic first-degree heart block or a permanent pacemaker.[4][5] According to the American Society for Gastrointestinal Endoscopy guidelines, pharmacologic therapy with neostigmine is recommended for patients with ACPO who are not candidates for conservative treatment, have failed conservative treatment for 72 hours, or are at risk for perforation, provided there are no contraindications to its use. Appropriate cardiovascular monitoring should be performed during treatment. If a patient does not respond to the first dose of neostigmine, a second dose may be considered.[6] According to the American Society of Colon and Rectal Surgeons Clinical Practice Guidelines, neostigmine is recommended when ACPO fails to resolve with conservative management. In cases of persistent ACPO, where mechanical obstruction or perforation are absent, nonoperative management with neostigmine is generally considered the next step in treatment.[7] The neostigmine test is sometimes used to diagnose myasthenia gravis and has shown high diagnostic value.[8] Neostigmine may be used as an alternative diagnostic test in seronegative patients with normal electrodiagnostic results and helps assess neuromuscular function in cases where standard tests are inconclusive.[9]
Mechanism of Action
Acetylcholine is a neurotransmitter that is synthesized, stored, and released by the end of motor nerve terminals. Acetylcholinesterase is an enzyme that hydrolyzes acetylcholine into choline and acetic acid in the neuromuscular junction, and neostigmine belongs to the acetylcholinesterase inhibitor class. Neostigmine is an oxy-diaphoretic inhibitor of acetylcholinesterase; it binds and inhibits the enzyme via acid-transferring or binding to the enzyme's anionic site to create a covalent bond. This allows acetylcholine to build up at the neuromuscular junction and overcome the competitive inhibition of nondepolarizing blocking drugs. Acetylcholinesterase inhibitors such as neostigmine accelerate the reversal of nondepolarizing neuromuscular blockade of nicotinic receptors in the neuromuscular junction at the end of surgery. Because neostigmine is a quaternary ammonium compound, it does not penetrate the blood-brain barrier.[10][11][12]
Pharmacokinetics
Absorption: Neostigmine is typically administered via intravenous injection, ensuring complete bioavailability.
Distribution: Neostigmine exhibits a protein binding range of 15% to 25% to human serum albumin. The volume of distribution (Vd) is reported to be between 0.12 and 1.4 L/kg following intravenous administration.
Metabolism: Neostigmine undergoes hydrolysis by cholinesterase and hepatic metabolism primarily via microsomal enzymes.[13]
Elimination: Neostigmine is primarily excreted renally, and its elimination half-life varies according to age and ranges from 24 to 113 minutes.
Administration
Available Dosage Forms and Strengths
Neostigmine is available as 5 mg/10 mL and 10 mg/10 mL intravenous solutions and as 3 mg/3 mL and 5 mg/5 mL prefilled syringes. This medication is primarily used to reverse nondepolarizing neuromuscular blockade after surgery via slow intravenous injection and for myasthenia gravis via intramuscular or subcutaneous injections.
Adult Dosage
A peripheral nerve stimulator should be utilized to determine when neostigmine therapy should be initiated and when subsequent doses should be administered. Neostigmine should be administered when the first twitch response of a peripheral nerve stimulator is greater than 10% of the baseline or when a second twitch is present. The drug is administered intravenously as a bolus. The typical intravenous dosage ranges from 0.03 mg/kg to 0.07 mg/kg (up to 5 mg), with the higher dose for first twitch responses that are close to but not substantially greater than 10%. The peak effect (antagonism) occurs between 7 and 10 minutes, and the duration of action lasts approximately 55 to 75 minutes. Neostigmine is typically administered with an antimuscarinic agent like glycopyrrolate or atropine to attenuate the parasympathomimetic activity at other non-muscular acetylcholine receptor sites.[14][15]
Specific Patient Populations
Hepatic impairment: The pharmacokinetics of neostigmine in patients with hepatic impairment have not been studied. Caution is advised, as neostigmine is metabolized by liver microsomal enzymes, and its concentration may increase impaired hepatic function.
Renal impairment: Neostigmine's elimination half-life is prolonged in patients with renal dysfunction, with an average of 104.7 minutes in transplant patients and 181 minutes in anephric patients.
Pregnancy considerations: No adequate or well-controlled studies of neostigmine in pregnant women exist. The available data are limited, and it is unknown whether the drug can cause fetal harm. Neostigmine may cause uterine irritability and induce premature labor if administered near term. Therefore, neostigmine should be used during pregnancy only if needed.
Breastfeeding considerations: Limited clinical data suggest that neostigmine may be acceptable during breastfeeding when treating myasthenia gravis, though pyridostigmine is generally preferred. Clinicians must monitor the newborn, as abdominal cramps following breastfeeding have been reported. Due to its short half-life, single doses of neostigmine used to reverse neuromuscular blockade after surgery are unlikely to cause significant or lasting effects on the breastfed infant.[12]
Pediatric patients: Neostigmine is considered the drug of choice for routine practice in reversing neuromuscular blocking agents in the pediatric population. This is due to an excellent final recovery from a blockade compared to edrophonium. The elimination half-life of neostigmine is shorter in children, but distribution volumes are similar in infants, young children, and adults. As in adults, the speed of onset of antagonism is dependent on the degree of neuromuscular blockade at that time; however, the dose requirements are slightly less in children when compared to adults. If the pediatric patient has a "train-of-four" response with fade, a dose of 20 μg/kg of neostigmine, followed by 10 to 20 μg/kg of atropine or 5 to 10 μg/kg of glycopyrrolate is sufficient to achieve reversal of neuromuscular blockade and return of adequate muscle strength.
Older patients: Older patients may have reduced renal function, potentially prolonging neostigmine's effects and slowing recovery from neuromuscular blockers. Extended monitoring is essential to ensure reversal.
Adverse Effects
Several adverse effects of neostigmine can affect multiple organ systems, most of which are related to the cholinergic adverse effects of the drug. Cardiac muscarinic effects include bradyarrhythmias like junctional escape rhythms, complete heart block, and asystole. One potentially life-threatening adverse effect of neostigmine is bronchoconstriction. Neostigmine and other anticholinesterase inhibitors can stimulate the muscarinic receptors in the airway smooth muscle, potentially leading to bronchospasm. Other adverse effects include increased secretions, miosis, nausea, and increased peristalsis.[16]
Most of these effects can be minimized by coadministering an anticholinergic drug with a similar onset time, such as glycopyrrolate for bronchospasm. During pregnancy, neostigmine can cross the placenta and cause fetal bradycardia. The simultaneous administration of atropine, which also crosses the placenta, should be considered for these patients. Another significant adverse effect of neostigmine and other anticholinesterase inhibitors is paradoxical anticholinesterase-associated muscle weakness. The clinical manifestations of muscle weakness include reduced upper airway dilator muscle tone, impairment of respiratory muscles like the diaphragm, and reductions in minute volume, which is the tidal volume multiplied by the respiratory rate.[16] One meta-analysis compared the effects of neostigmine and sugammadex for reversing neuromuscular blockade (NMB) in patients undergoing bariatric surgery. The results of this study revealed that neostigmine was associated with a higher risk of significant adverse effects, including postoperative residual curarization, postoperative nausea and vomiting, and cardiovascular complications, compared to sugammadex. These adverse events may increase the risk of postoperative complications, highlighting the need for careful monitoring.[17]
Drug-Drug Interactions
- Depolarizing muscle relaxants: Neostigmine should not be used to reverse the effects of depolarizing muscle relaxants, such as succinylcholine, as it may lead to a prolonged phase-1 block.
- Aminoglycosides: Aminoglycoside antibiotics, such as streptomycin, neomycin, and kanamycin, have nondepolarizing neuromuscular blocking effects. Simultaneous administration requires dosage adjustments and caution.
Contraindications
Absolute contraindications of neostigmine include hypersensitivity to neostigmine, peritonitis, and mechanical obstruction of the intestinal or urinary tract.[18] Neostigmine should also not be administered if absent twitching is observed on a peripheral nerve stimulator after administering a nondepolarizing neuromuscular blocking drug.
Warnings and Precautions
- Cardiovascular disease: Neostigmine administration may lead to arrhythmias, cardiac arrest, syncope, and hypotension, particularly in patients with recent acute coronary syndrome and preexisting coronary artery diseases.[19] Anticholinergic agents like atropine usually effectively address these complications.
- Cardiac arrhythmias: Neostigmine has been associated with bradycardia. An anticholinergic agent like atropine should be readily available.
- Hypersensitivity reactions: There have been reports of hypersensitivity reactions associated with the use of neostigmine, including anaphylaxis. Medical support measures should be readily available, including resuscitation equipment and medications.[20]
- Neuromuscular dysfunction: Large doses of neostigmine may cause neuromuscular dysfunction, particularly when the blockade is minimal. Reducing the dose of neostigmine may mitigate this risk.
- Cholinergic crisis: An overdose of neostigmine can lead to a cholinergic crisis, which can mimic symptoms of a myasthenic crisis, such as extreme muscle weakness. However, these conditions require different treatments. A cholinergic crisis requires immediate discontinuation of anticholinergics and administration of atropine.
Monitoring
When administering neostigmine as a reversal agent, the duration of action of neuromuscular blocking agents must be considered. Administering neostigmine after a relative degree of spontaneous recovery of neuromuscular function is vital to prevent "recurarization," which can manifest as increased weakness in the postoperative recovery unit due to the lasting effect of the neuromuscular blocking drug. Up to 70% of acetylcholine receptors may still be blocked despite a peripheral nerve stimulator inducing an apparently normal "train-of-four" count. As mentioned above, neostigmine's action duration is prolonged in patients with renal impairment, as the kidneys excrete the drug. According to the American Society of Anesthesiologists (ASA) guidelines, quantitative neuromuscular monitoring of the adductor pollicis muscle is recommended to confirm that the train-of-four ratio has reached 0.9 or higher before extubation. Sugammadex is the preferred agent for reversing deep, moderate, or shallow neuromuscular blockades induced by rocuronium or vecuronium. However, neostigmine can be considered a reasonable alternative when the blockade is minimal.[21]
Various methods of using acetylcholinesterase reversal agents to reduce the risk of residual neuromuscular blockade depend on the train-of-four count (or ratio).
- Count is 1 (or no response): Do not administer neostigmine to reverse neuromuscular blockade. Wait until the count is greater than 1.
- Count is 2 or 3: Administer the appropriate dose of neostigmine (or another acetylcholinesterase inhibitor) and extubate when the train-of-four ratio is at least 0.9.
- Ratio is greater than 0.4: Administer a moderate dose of neostigmine and extubate when the train-of-four ratio is 0.9 or greater.
- Ratio is greater than 0.7: Avoid using neostigmine as the risk of anticholinesterase-induced muscle weakness is greater.
According to the American Society of Anesthesiologists (ASA) guidelines, quantitative neuromuscular monitoring of the adductor pollicis is recommended to confirm that the train-of-four ratio has reached 0.9 or higher before extubation. Sugammadex is the preferred agent for reversing deep, moderate, or shallow neuromuscular blockades induced by rocuronium or vecuronium. However, neostigmine can be considered when the blockade is minimal.[21]
Toxicity
Signs and Symptoms of OverdoseNeostigmine overdose may cause muscarinic symptoms such as nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia. A severe overdose can also cause a cholinergic crisis, which can cause muscle weakness and may result in death due to the involvement of respiratory muscles. Distinguishing between cholinergic and myasthenic crises is crucial, as their management differs.
Management of Overdose
If there is an overdose/toxicity of neostigmine, atropine should be administered immediately.[10][22] Overdose risk can be minimized by monitoring muscle twitch responses. If an overdose occurs, provide artificial ventilation if necessary and monitor cardiac function. In myasthenic crises, the management involves increasing the dose of anticholinesterase medications to improve muscle strength. Atropine may be administered to counteract muscarinic adverse effects, such as bradycardia, which can result from higher doses of anticholinesterase agents.[23] In a cholinergic crisis, all anticholinesterase medications should be immediately discontinued, and atropine should be administered to counteract the muscarinic effects of excessive acetylcholine. Ventilatory support may be required if respiratory function is severely impaired.
Enhancing Healthcare Team Outcomes
Neostigmine is primarily used by anesthesiologists, nurse anesthetists, emergency medicine physicians, and intensivists. The patient must be monitored after neostigmine is administered, as it can induce cholinergic adverse effects that can affect many organ systems. Besides bradycardia, a potentially life-threatening adverse effect of neostigmine is bronchoconstriction. ICU nurses and anesthesiologists should regularly monitor vital signs after administering neostigmine. When given to patients with myasthenia gravis, the lowest dose should be used and gradually titrated upwards, depending on the response. Pharmacists must advise the healthcare team on the appropriate use of neostigmine, monitor potential drug interactions, and assess dosing adjustments for patients with comorbidities to ensure safe and effective treatment. The neurologist and critical care physician should be consulted for the cholinergic crisis. An interprofessional team approach and communication among clinicians, specialists, pharmacists, and nurses are crucial to decreasing potential adverse effects and improving patient outcomes related to neostigmine.