Neostigmine: Action as Cholinesterase Inhibitor

Neostigmine (brand names Neostig, Neostigmine and generics) is a peripherally acting cholinesterase inhibitor that has been established since the 1930s in anesthesia, emergency medicine and addiction medicine. In Germany, neostigmine is primarily used in two clinical settings: in anesthesia to antagonize non-depolarizing muscle relaxants such as rocuronium, vecuronium or cisatracurium, and in myasthenia gravis as parenteral acute therapy when oral pyridostigmine administration is not possible. Additionally, neostigmine is used for postoperative gastric intestinal atony, urinary retention following surgery, and in specialized indications.

Characteristic is the quaternary ammonium structure, which barely crosses the blood-brain barrier. Thus neostigmine acts predominantly peripherally and causes fewer central nervous system side effects than tertiary physostigmine. Parenteral administration with rapid onset of action makes neostigmine a valuable tool in acute medicine. Use should be in the hands of experienced anesthesiologists or internists, because cholinergic crises with bradycardia and bronchospasm are possible.

Mechanism of Action

Neostigmine reversibly inhibits the enzyme acetylcholinesterase in the synaptic cleft of the neuromuscular endplate and parasympathetic synapses. This increases acetylcholine concentration locally, which displaces the effect of non-depolarizing muscle relaxants (competitive antagonists at the nicotinic receptor). The motor endplate becomes reactivatable, and muscle function is restored.

At parasympathetic synapses, increased acetylcholine causes cholinergic stimulation: bradycardia, bronchospasm, hypersalivation, sweating, abdominal cramps, increased gastric-intestinal activity, pupil constriction. To control these side effects on the parasympathetic system, neostigmine in anesthesia is typically combined with an anticholinergic agent such as atropine or glycopyrronium.

Pharmacokinetically, neostigmine is poorly absorbed orally (approximately 1 to 2 percent), with parenteral administration being paramount. Half-life after intravenous administration is approximately 50 to 90 minutes. Metabolism occurs via non-specific plasma esterases and renal elimination. Renal insufficiency prolongs the duration of action.

Indications

• Antagonization of non-depolarizing muscle relaxants in anesthesia following general anesthesia with rocuronium, vecuronium, cisatracurium or mivacurium
• Myasthenia gravis, parenteral administration in case of dysphagia or myasthenic crisis as bridging therapy until intensive care measures take effect
• Postoperative bowel atony with absent peristalsis following abdominal surgery
• Postoperative urinary retention in patients without mechanical obstruction
• Adjuvant in pseudoobstruction (Ogilvie syndrome) in acute colonic pseudoobstruction
• Diagnostic test for suspected myasthenia gravis (rare today, as modern diagnostics are preferred)

Neostigmine is not suitable for oral long-term therapy of myasthenia gravis due to poor bioavailability. Here pyridostigmine is the drug of choice. With depolarizing muscle relaxants such as succinylcholine, neostigmine is not suitable because it may even prolong their action.

Dosage and Administration

Antagonization in anesthesia: 0.03 to 0.07 mg per kg body weight intravenously, in combination with atropine (0.015 to 0.02 mg per kg) or glycopyrronium (approximately 0.01 mg per kg) to control parasympathetic effects. Standard doses in adults are typically 1 to 5 mg neostigmine.

Myasthenia gravis parenteral: 0.5 to 2.5 mg subcutaneously or intramuscularly, in acute crisis also intravenously. Duration of action 2 to 4 hours.

Postoperative bowel atony: 0.5 mg subcutaneously or intramuscularly, repeat if necessary after 4 to 6 hours. Prerequisite: no mechanical obstruction.

Postoperative urinary retention: 0.5 mg subcutaneously, usually single administration with follow-up observation.

Pediatric: Use established in pediatric anesthesia, weight-adapted.

Renal insufficiency: With eGFR below 30 ml per minute, dose reduction and longer observation are required due to prolonged duration of action. Hepatic insufficiency: Generally no dose adjustment necessary.

Administration technique in anesthesia: Slow intravenous administration over approximately one minute, continuous ECG monitoring, atropine or glycopyrronium on hand, immediate intervention in case of bradycardia or bronchospasm.

Side Effects

Very common: Increased salivation, sweating, tearing, abdominal cramps, increased gastric-intestinal activity, pupil constriction.

Common: Bradycardia, nausea, vomiting, diarrhea, muscle fasciculations, tremor, headache.

Occasional to rare: Bronchospasm, especially in asthma, AV block, allergic skin reactions, hypotension, visual disturbances.

Cholinergic crisis: Overdose can cause paradoxical muscle weakness due to excess acetylcholine, similar to a myasthenic crisis. Clinically, additional strong cholinergic side effects are evident (abdominal cramps, salivation, pinpoint pupils, increased secretions). A cholinergic crisis requires intensive care treatment, possibly with atropine as an antidote.

In asthma: Bronchospasm possible. Query asthma history before use, have bronchodilators on hand.

In bradycardia and AV block: Exacerbation possible, therefore keep atropine or glycopyrronium on hand and carefully monitor patients with pre-existing cardiac disease.

Drug Interactions

• Atropine and glycopyrronium: Intended combination to control peripheral cholinergic side effects, standard in anesthesia.
• Anticholinergics (tricyclics, first-generation antihistamines, antispasmodics): Pharmacological antagonism, mutual weakening of effects.
• Aminoglycosides, tetracyclines, polymyxins, lithium, intravenous magnesium: Reduce neuromuscular transmission, may weaken neostigmine's antagonizing effect.
• Other cholinesterase inhibitors such as pyridostigmine: Additive effects, do not use in parallel in acute situations.
• Beta blockers and calcium antagonists: Additional bradycardia and cardiac conduction delays.
• Succinylcholine: If neostigmine residues remain unmetabolized, succinylcholine's duration of action may be prolonged.
• Inhalation anesthetics (sevoflurane, isoflurane, desflurane): Potentiate non-depolarizing muscle relaxant effects, complicating antagonization with neostigmine. Adequate recovery of neuromuscular function prior to antagonization is mandatory.

Special Precautions

Pregnancy: Possible when vitally indicated. In maternal myasthenia gravis, parenteral anticholinesterase antagonists such as atropine should be on hand before delivery. Lactation: No clinically relevant transfer to breast milk after single dose.

Children: Established in pediatric anesthesia, weight-adapted.

Before use in anesthesia: Confirm recovery of neuromuscular function (TOF ratio above 0.2 or train of four with two visible responses), atropine or glycopyrronium on hand, bronchodilator on hand.

In myasthenia gravis: Learn to distinguish between cholinergic and myasthenic crisis. The combination of both is very rare, clinically almost always clear by the presence or absence of peripheral cholinergic side effects.

Sugammadex as alternative: Sugammadex is a modern antagonist of rocuronium and vecuronium that binds directly to the muscle relaxant and inactivates it. It is faster acting than neostigmine and has no cholinergic side effects. For patients with asthma or bradycardia, sugammadex is a safer option, though more expensive and not suitable for all relaxants.

Lifestyle: In patients with myasthenia gravis, adequate sleep, avoidance of heat and physical exhaustion, early treatment of infections, and caution with medications that worsen the disease complement therapy.

Driving ability: After anesthesia and parenteral administration, reaction capability is impaired, individual assessment required in the postoperative phase.

You might also be interested in

• Pyridostigmine, oral peripheral cholinesterase inhibitor in myasthenia therapy
• Physostigmine, CNS-acting cholinesterase inhibitor as an antidote
• Sugammadex, modern antagonist of rocuronium and vecuronium
• Glycopyrronium, peripherally acting anticholinergic
• Scopolamine, anticholinergic agent in patches

Frequently Asked Questions

Sources

• Gelbe Liste, Neostigmine active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines on Anesthesia and Myasthenia Gravis
• German Society for Anesthesiology and Intensive Care Medicine