Mechanism of action and effects on muscles
The primary target of neostigmine is the enzyme acetylcholinesterase (AChE). The drug inhibits its activity, causing the neurotransmitter acetylcholine to accumulate in the synapses. At the skeletal muscle level, proserin has a dual mechanism of action: it not only preserves endogenous acetylcholine but also directly stimulates postsynaptic $N_M$-cholinergic receptors. This significantly facilitates neuromuscular transmission and increases muscle tone.
Pharmacological effects
The drug's action mimics profound excitation of the parasympathetic nervous system and affects many organs:
- Visual organs: causes pupillary constriction (miosis) due to contraction of the circular muscle of the iris. Lowers intraocular pressure by opening the anterior chamber angle and improving fluid outflow through the spaces of Fontana into the canal of Schlemm. Also causes spasm of accommodation: the ciliary muscle contracts, the suspensory ligament of Zinn relaxes, the lens becomes more convex, and the eye adjusts for near vision.
- Cardiovascular system: slows the heart rate (induces bradycardia) and impairs atrioventricular conduction.
- Smooth muscle: stimulates the tone and motility of the gastrointestinal tract, increases the contractile activity of the urinary bladder and uterus, and also increases bronchial tone.
- Glands: enhances the secretion of all exocrine glands.
Indications for use
In clinical practice, the drug is prescribed where it is critically necessary to enhance cholinergic transmission:
- Myasthenia gravis (Myasthenia gravis): in this severe autoimmune disease, antibodies destroy skeletal muscle $N_M$-receptors. The drug compensates for progressive muscle weakness. It is administered orally, subcutaneously, or intramuscularly (intravenously in life-threatening myasthenic crisis).
- Postoperative atony: helps "kickstart" bowel and bladder function after surgical interventions.
- Decurarization (reversal of residual blockade): administered intravenously to eliminate the effects of nondepolarizing (competitive) neuromuscular blockers.
- Closed-angle glaucoma: rarely used for this indication in modern practice.
Pharmacokinetic nuance: due to low oral bioavailability (incomplete absorption), the oral dose of proserin is 30 times higher than that used for injections.
Side effects and overdose
Excessive receptor stimulation leads to pronounced side effects. Symptoms of M-cholinergic receptor stimulation (hyperparasympathicotonia effects) include nausea, vomiting, diarrhea, profuse salivation (hypersalivation), bradycardia, blood pressure drop, and dangerous bronchospasm. To eliminate them, the M-cholinergic blocker atropine is used. Excessive stimulation of $N_M$-receptors manifests as muscle twitching (fasciculations).
The extreme degree of overdose is a cholinergic crisis. Excess neurotransmitter causes persistent depolarization of the postsynaptic membrane. A so-called depolarization block develops, and nerve impulse transmission ceases completely. As a result, muscle weakness paradoxically increases, myasthenic symptoms worsen, and the risk of respiratory arrest arises.
Contraindications
The drug is strictly contraindicated in conditions where vagal stimulation or a sharp increase in muscle tone is hazardous:
- CNS disorders: epilepsy, Parkinson's disease.
- Cardiovascular pathology: angina pectoris, any cardiac conduction disturbances.
- Respiratory system: bronchial asthma.
- Gastrointestinal tract: peptic ulcer disease of the stomach and duodenum.
To easily remember proserin's effects on smooth muscle, use the mnemonic "Spasm of tubes, tone of sacs": bronchi (tubes) constrict, while the intestines and bladder (sacs) actively contract.
Class and exam questions
Why does proserin have almost no effect on the central nervous system?
It is a polar hydrophilic compound with a quaternary nitrogen atom. This chemical structure prevents the drug from crossing the blood-brain barrier (BBB), restricting its action to the periphery.
Why is edrophonium used for the diagnosis of myasthenia gravis rather than proserin?
Edrophonium has an ultra-short duration of action (only 5–15 minutes). If a patient's muscle weakness is caused not by drug deficiency but by an overdose (cholinergic crisis), edrophonium will only temporarily worsen the muscle weakness, which is safe for the patient, unlike the longer-acting proserin.
What is the difference between neostigmine, pyridostigmine, and ambenonium?
They differ in duration of action. Neostigmine acts for 2–4 hours, pyridostigmine bromide for about 6 hours (while having fewer muscarinic side effects), and ambenonium chloride maintains activity for up to 10 hours.
What else to study on this topic
- Mechanism of development of depolarization block during excess acetylcholine in the synapse.
- Differential diagnosis of cholinergic and myasthenic crises using edrophonium.
- Comparative pharmacodynamics of pyridostigmine and ambenonium chloride in the treatment of myasthenia gravis.
- Interaction of neostigmine with curare-like nondepolarizing muscle relaxants.
- Pathogenesis of autoimmune damage to $N_M$-cholinergic receptors in Myasthenia gravis.
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