Neostigmine

Proserinum

For medical students2 min readUpdated 2026-10-10

Neostigmine is a synthetic, reversible anticholinesterase agent. The drug regulates peripheral nervous system functions by mimicking parasympathetic effects and potently stimulating skeletal muscle.

Drug ClassReversible acetylcholinesterase inhibitors

StructureQuaternary amine (poor blood-brain barrier penetration)

TargetAcetylcholinesterase and $N_M$ cholinergic receptors

FormulationsTablets, ampoules, powder for eye drops

Mechanism of Action

Acetylcholinesterase (AChE) has two active sites: an anionic site (containing a negatively charged glutamate carboxyl group) and an esterase site (containing a serine hydroxyl group). Neostigmine exhibits a dual mechanism of action at peripheral synapses:

Reversible AChE inhibition. As a carbamic acid ester (carbamate), the drug binds simultaneously to both active sites of the enzyme. Carbamylation occurs at the esterase site, forming a covalent bond with the carbamyl group. This bond is significantly stronger than the one formed with acetylcholine. Hydrolysis proceeds slowly, temporarily removing the enzyme from action, while the concentration of endogenous acetylcholine in the synaptic cleft rises sharply.
Direct stimulatory action. Neostigmine is capable of directly exciting skeletal muscle $N_M$ cholinergic receptors.

Pharmacological Effects

The clinical profile of neostigmine corresponds to marked parasympathetic nervous system excitation and stimulation of neuromuscular transmission.

Eye: Produces miosis (via contraction of the pupillary sphincter muscle) and decreased intraocular pressure (pupillary constriction opens the anterior chamber angle, improving fluid outflow through the spaces of Fontana into the canal of Schlemm). Accommodation spasm also develops: the ciliary muscle contracts, the suspensory ligaments relax, the lens curvature increases, and vision accommodates to the near point.
Cardiovascular system: Bradycardia and delayed atrioventricular conduction are observed.
Smooth muscle: Bronchial tone increases, gastrointestinal tone and motility are enhanced, and the contractile activity of the uterus and urinary bladder rises.
Exocrine glands: Secretion is enhanced.
Skeletal muscle: Neuromuscular transmission is facilitated, and muscle tone is increased.

Clinical Use and Administration

In modern practice, cholinergic drugs are rarely used as gastrointestinal motility stimulants (they increase tone but fail to provide adequate propulsive activity, yielding to $D_2$ receptor blockers). However, neostigmine is actively used for other indications.

Dosage Forms and Routes of Administration:

Oral: 0.015 g tablets. Prescribed as 0.015 g 2–3 times daily.
Parenteral: 0.05% solution in 1 ml ampoules. Administered subcutaneously at 0.0005 g. Administered intravenously at a dose of 0.015 g for reversal of neuromuscular blockade (decurarization) (after prior dilution in 15–20 ml of 0.9% NaCl solution).
Topical: Powder to prepare 0.5% eye drops. Instill 1–2 drops into the conjunctival sac.

Interaction with Atropine

Atropine is a competitive antagonist selective exclusively for muscarinic (M) cholinergic receptors. Its administration eliminates all neostigmine effects associated with the excitation of these receptors: bronchospasm, bradycardia, miosis, and glandular hypersecretion.

Important: Atropine does not reverse the increase in skeletal muscle tone caused by neostigmine, because this effect is mediated via $N_M$ cholinergic receptors, which atropine does not affect.

Pediatric Considerations

Neonates (up to 4 weeks of age) exhibit increased sensitivity to neostigmine. This is due to physiological immaturity of body systems:

Deficient hepatic enzyme systems (impaired metabolism).
Reduced renal excretory function.
Increased blood-brain barrier (BBB) permeability.
Underdevelopment of the nervous and endocrine systems.

Due to the high risk of toxicity, dosages of potent substances in pediatric practice are strictly regulated based on age and body weight.

Mnemonic

Neostigmine is "Acetylcholine squared" for muscles: it stimulates N-receptors directly and prevents the breakdown of the endogenous neurotransmitter.

Frequently asked questions

In which diseases and conditions is neostigmine indicated?

Neostigmine is indicated for conditions associated with impaired neuromuscular transmission and visceral atony.

Myasthenia gravis — for short-term increases in muscle strength.
Atony — treatment of intestinal and bladder atony, prevention of postoperative paresis.
Neurological disorders — muscular dystrophies, paralyses, sequelae of poliomyelitis and tick-borne encephalitis.
Psychiatry and toxicology — reversal of anticholinergic psychosis and delirium, antidote for atropine poisoning.
Anesthesiology — reversal of nondepolarizing neuromuscular blockade (decurarization).

What side effects can occur with neostigmine use?

Side effects may occur due to excessive cholinergic stimulation.

Gastrointestinal tract — abdominal discomfort and pain, diarrhea, hypersalivation.
Respiratory system and secretions — bronchospasm, rhinorrhea, bronchorrhea, glandular hypersecretion.
Cardiovascular system — bradycardia, hypotension.
Neuromuscular system — muscle twitching, cramps; higher doses may cause paradoxical muscle weakness.
Eyes — miosis.

Overdose may lead to a cholinergic crisis.

What are the contraindications for prescribing neostigmine?

General contraindications for neostigmine are not extensively detailed in the source texts.

Specific limitations and risks are noted:

in intensive care, neostigmine methylsulfate is listed among agents that provoke seizures, making administration contraindicated in certain contexts;
neostigmine methylsulfate and other cholinesterase inhibitors can trigger drug-induced epileptiform seizures in individuals without a history of epilepsy;
for pyridostigmine, contraindications are noted to be similar to neostigmine, though the specific contraindications are not explicitly listed.

What are the symptoms of neostigmine overdose (cholinergic crisis)?

Symptoms of neostigmine overdose manifest as a severe condition known as a cholinergic crisis.

Parasympathetic effects — sharp intensification of muscarinic stimulation symptoms.
Muscular disturbances — paradoxical worsening of muscle weakness and myasthenic symptoms.
Pathogenesis: excess acetylcholine causes persistent depolarization of the postsynaptic membrane. This results in a depolarizing block, leading to profound depression of neuromuscular transmission.

Why doesn't neostigmine have significant CNS effects?

Chemically, it is a synthetic compound possessing a quaternary nitrogen atom. Due to this charge, the molecule poorly crosses the blood-brain barrier, making the drug's effects predominantly peripheral.

Will atropine relieve muscle spasms caused by neostigmine overdose?

No. Atropine blocks only muscarinic receptors. Increased skeletal muscle tone is mediated by $N_M$ cholinergic receptors, so atropine will not affect this symptom.

What is the mechanism of intraocular pressure reduction with neostigmine eye drops?

The drug causes contraction of the pupillary sphincter muscle (miosis). The iris becomes thinner, leading to the opening of the iridocorneal angle and improved outflow of aqueous humor through the spaces of Fontana into the canal of Schlemm.

Go deeper

Competitive antagonism and principles of antidote therapy (using physostigmine and atropine as examples).
Biochemistry of acetylcholinesterase: anionic and esterase sites, carbamylation process.
Comparison of prokinetics ($D_2$ receptor blockers) and cholinergic GI motility stimulants.
Perinatal pharmacology: pharmacokinetic causes of increased drug sensitivity in neonates.
Substances affecting presynaptic processes: hemicholinium, vesamicol, botulinum toxin.