Mechanism of action
Acetylcholinesterase (AChE) has two active sites: anionic (containing a negatively charged glutamate carboxyl group) and esteratic (containing a serine OH group). Neostigmine exhibits a dual mechanism of action at peripheral synapses:
- Reversible inhibition of AChE. As a carbamic acid ester (carbamate), the drug binds simultaneously to both sites of the enzyme. Carbamoylation occurs at the esteratic site, forming a covalent bond with the carbamyl group. This bond is significantly stronger than the one formed by acetylcholine. Hydrolysis proceeds slowly, the enzyme is temporarily inactivated, and the concentration of endogenous acetylcholine in the synaptic cleft increases sharply.
- Direct stimulatory effect. Neostigmine is capable of directly exciting skeletal muscle $N_M$-receptors.
Pharmacological effects
The clinical presentation of neostigmine action corresponds to pronounced excitation of the parasympathetic nervous system and stimulation of neuromuscular transmission.
- Eye: miosis occurs (due to contraction of the circular muscle of the iris) along with decreased intraocular pressure (pupillary constriction opens the anterior chamber angle, improving fluid outflow through the spaces of Fontana into Schlemm's canal). Spasm of accommodation also develops: the ciliary muscle contracts, the suspensory ligament of lens relaxes, lens curvature increases—vision is focused on the near point.
- Cardiovascular system: bradycardia and slowing of 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 prescription
In modern practice, cholinergic drugs are rarely used as gastrointestinal motility stimulants (they increase tone but do not provide adequate propulsive activity, losing out 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 at 0.015 g 2–3 times a day.
- Parenteral: 0.05% solution in 1 ml ampoules. Subcutaneously administered 0.0005 g. Intravenously used at a dose of 0.015 g for decurarization (after prior dilution in 15–20 ml of 0.9% NaCl solution).
- Topical: powder for making 0.5% eye drops. Prescribed 1–2 drops into the conjunctival sac.
Interaction with atropine
Atropine is a competitive blocker exclusively of M-cholinergic receptors. Its administration eliminates all effects of neostigmine associated with the excitation of these receptors: bronchospasm, bradycardia, miosis, and glandular hypersecretion.
Important: Atropine does not eliminate 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 use
Neonates (under 4 weeks of age) exhibit increased sensitivity to neostigmine. This is due to the physiological immaturity of body systems:
- Insufficiency of hepatic enzyme systems (imperfect metabolism).
- Reduced renal excretory function.
- Increased permeability of the blood-brain barrier (BBB).
- Underdevelopment of the nervous and endocrine systems.
Due to the high risk of toxicity, the doses of potent substances for children are strictly regulated by the State Pharmacopoeia according to age and body weight.
Briefly: answers to topical questions
What diseases and conditions are indications for neostigmine?
The use of neostigmine is indicated for diseases associated with impaired neuromuscular transmission and atony of internal organs.
- Myasthenia gravis (myasthenia gravis) — for a short-term increase in muscle strength.
- Atony — treatment of intestinal and urinary bladder atony, prevention of postoperative paresis.
- Neurological pathologies — muscular dystrophies, paralyses, consequences of poliomyelitis and tick-borne encephalitis.
- Psychiatry and toxicology — management of anticholinergic psychosis and delirium, antidote in atropine poisoning.
- Anesthesiology — decurarization after the use of nondepolarizing muscle relaxants.
What side effects may occur with the use of neostigmine?
Side effects associated with cholinergic action may occur during neostigmine therapy.
- Gastrointestinal tract — abdominal discomfort and pain, diarrhea, hypersalivation.
- Respiratory system and secretion — bronchospasm, rhinorrhea, bronchorrhea, glandular hypersecretion.
- Cardiovascular system — bradycardia, decreased blood pressure.
- Neuromuscular system — muscle twitching, cramps; with dose escalation, a paradoxical increase in muscle weakness is possible.
- Visual organs — miosis.
Overdose may lead to a cholinergic crisis.
What are the contraindications for prescribing neostigmine?
The provided sources do not detail general contraindications for prescribing neostigmine.
Certain limitations and risks are noted:
- in the intensive care section, neostigmine methylsulfate is listed among agents that provoke seizures and whose administration is contraindicated;
- neostigmine methylsulfate and other cholinesterase inhibitors can cause drug-induced epileptiform seizures in individuals without a history of epilepsy;
- for pyridostigmine, it is indicated that its contraindications are similar to those of neostigmine, but the contraindications themselves are not disclosed in the source.
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 — a sharp intensification of M-cholinomimetic symptoms.
- Muscle disorders: a paradoxical increase in muscle weakness and myasthenic symptoms.
The pathogenesis of this condition lies in the fact that an excess of acetylcholine causes persistent depolarization of the postsynaptic membrane. As a result, a depolarization block develops, leading to profound inhibition of neuromuscular transmission.
Neostigmine is "acetylcholine squared" for muscles: it both stimulates $N$ receptors and prevents the destruction of the endogenous mediator.
Class and exam questions
Why does neostigmine not have a pronounced effect on the central nervous system?
Chemically, it is a synthetic compound with a quaternary nitrogen atom. Due to its charge, the molecule poorly crosses the blood-brain barrier, so the drug's action is predominantly peripheral.
Will atropine relieve muscle spasms caused by a neostigmine overdose?
No. Atropine blocks only muscarinic (M) cholinergic receptors. Skeletal muscle tone elevation is mediated by nicotinic ($N_M$) cholinergic receptors, so atropine will not affect this symptom.
What is the mechanism of intraocular pressure reduction when neostigmine is instilled?
The drug causes contraction of the circular muscle of the iris (miosis). The iris becomes thinner, which leads to the opening of the anterior chamber angle of the eye and improved outflow of intraocular fluid through the spaces of Fontana into the canal of Schlemm.
What else to study on this topic
- Competitive antagonism and principles of antidote therapy (using physostigmine and atropine as examples).
- Biochemistry of acetylcholinesterase: anionic and esteratic sites, carbamylation process.
- Comparison of prokinetics ($D_2$ receptor blockers) and cholinergic gastrointestinal motility stimulants.
- Perinatal pharmacology: pharmacokinetic causes of increased drug sensitivity in newborns.
- Substances affecting presynaptic processes: hemicholinium, vesamicol, botulinum toxin.
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