Mechanisms of vascular reactions
The decrease in blood pressure upon intravenous administration of acetylcholine is a complex physiological process. Its key feature is that the drug acts not directly on smooth muscle, but on the vascular endothelium.
Endothelial cell membranes contain $M_3$-cholinergic receptors. Their stimulation triggers the release of endothelium-derived relaxing factor — nitric oxide (NO). It is this factor that penetrates the smooth muscle cells of the vascular wall and causes their relaxation. An important nuance for differential diagnosis: if the endothelium were absent, direct stimulation of smooth muscle $M_3$-receptors would lead to vasoconstriction. However, under normal physiological conditions, endothelium-dependent relaxation always predominates.
The effect of denervation on drug action
The efficacy of pharmacological action on a denervated organ (for example, when studying the circular muscle of the eye) strictly depends on whether the drug has a direct or indirect mechanism of action.
- Indirect mimetics (anticholinesterase agents: neostigmine, physostigmine, armine). Their task is to inhibit the enzyme acetylcholinesterase to prevent the breakdown of the endogenous mediator. But upon denervation, the nerve impulse is absent, and acetylcholine is not released. Consequently, there is nothing to protect from breakdown, and the effect of drug administration is completely absent.
- Direct M-cholinomimetics (pilocarpine, as well as carbachol, which has a direct component). They bind to receptors independently. On a denervated organ, their effect is preserved: they are able to cause persistent pupillary constriction (miosis). In some cases, denervation hypersensitivity of receptors to such agonists is even observed.
Interaction and differences in action spectra
The main difference between M-cholinomimetics and anticholinesterase agents lies in their effect on skeletal musculature. Skeletal muscles are controlled via $N_M$-cholinergic receptors in neuromuscular synapses.
M-cholinomimetics act extremely selectively: only on M-receptors of smooth muscles, glands, the heart, and the endothelium. They do not affect skeletal muscles. Anticholinesterase agents, on the other hand, increase the overall concentration of acetylcholine, which stimulates both types of receptors (M and N), leading to facilitation of neuromuscular transmission and an increase in skeletal muscle tone.
This difference is clearly demonstrated in the pharmacological antagonism of neostigmine and atropine. Atropine is a blocker of M-cholinergic receptors only. It successfully eliminates neostigmine-induced bronchospasm, bradycardia, miosis, and glandular hypersecretion. However, atropine cannot eliminate the increase in skeletal muscle tone, as this process proceeds via N-cholinergic receptors which are uncontrolled by it.
Paradoxical pressor effect
A classic example of an interaction that changes the sign of a reaction is the combination of acetylcholine and atropine. Under normal conditions, acetylcholine lowers blood pressure. However, if atropine is administered beforehand, thereby blocking M-cholinergic receptors, subsequent administration of acetylcholine will lead to an increase in blood pressure.
The mechanism of this phenomenon lies in the activation of free N-cholinergic receptors (nicotinic). With M-receptors blocked, acetylcholine actively excites:
- Sympathetic ganglia (stimulating postganglionic sympathetic fibers).
- The adrenal medulla (provoking a massive release of adrenaline and noradrenaline).
As a result, a powerful pressor response occurs.
Clinical application: BBB permeability and selectivity
The choice of a cholinotropic drug for the therapy of specific pathologies relies on its ability to cross the blood-brain barrier (BBB) and its selectivity for receptor subtypes.
- Alzheimer's disease: Central-acting agents capable of penetrating the BBB and replenishing the acetylcholine deficit in the brain are required (donepezil, rivastigmine, galantamine). Peripheral-acting drugs (quaternary ammonium compounds: neostigmine, edrophonium, pyridostigmine) poorly penetrate the barrier and are not used.
- Motion sickness (kinetosis): Scopolamine easily crosses the BBB. It blocks M-cholinergic receptors of the vestibular nuclei and the vomiting center, exerting a pronounced antiemetic effect in sea and air sickness.
- Gastroenterology: Pirenzepine selectively blocks $M_1$-cholinergic receptors (gastric intramural ganglia and enterochromaffin-like cells), suppressing hydrochloric acid secretion more strongly than non-selective atropine. Selectivity provides a better safety profile: common adverse effects (dry mouth, tachycardia) are significantly less pronounced.
Briefly: answers to topical questions
What systemic adverse effects does the non-selective M-cholinoblocker atropine cause?
The non-selective M-cholinoblocker atropine causes a number of systemic adverse effects due to its low selectivity of action. The main undesirable reactions include:
- Xerostomia — dry mouth.
- Mydriasis — dilation of the pupils.
- Cycloplegia (paralysis of accommodation) — impaired near vision.
- Tachycardia — increased heart rate.
- Urinary retention — an atropine-like effect associated with the blockade of peripheral receptors.
Which drugs belong to peripherally acting muscle relaxants that block Nm-cholinergic receptors?
Peripherally acting muscle relaxants that block skeletal muscle Nm-cholinergic receptors include non-depolarizing and depolarizing drugs. Non-depolarizing agents are divided into two classes:
- Benzylisoquinolines — tubocurarine, atracurium besylate, cisatracurium besylate, mivacurium chloride.
- Aminosteroids — pancuronium bromide, pipecuronium bromide, vecuronium bromide, rocuronium bromide.
The group of depolarizing muscle relaxants includes:
- Succinylcholine (suxamethonium) — the only depolarizing muscle relaxant currently used in clinical practice.
To remember the paradoxical effect of acetylcholine against the background of atropine, imagine: "The doors for relaxation (endothelial M-receptors) are locked by atropine. Acetylcholine has no choice but to ring the spare bell (ganglionic and adrenal N-receptors), causing an adrenaline storm and a pressure surge."
Class and exam questions
Why do anticholinesterase agents not work on an eye with a severed nerve?
The target of these drugs is the enzyme that destroys the mediator released from the nerve terminal. During denervation, there is no impulse, the mediator is not released, so inhibitors have nothing to "protect" from destruction.
Will atropine relieve muscle cramps in case of anticholinesterase agent overdose?
No, it will not relieve it. Atropine exclusively blocks M-cholinergic receptors, whereas muscle tone is regulated via N-cholinergic receptors of neuromuscular synapses, which atropine does not affect.
What is the key advantage of pirenzepine over atropine in the treatment of ulcers?
Pirenzepine selectively blocks only gastric M1-cholinergic receptors, effectively lowering acidity without causing the severe systemic adverse effects of atropine (tachycardia, pronounced dry mouth).
What else to study on this topic
- Mechanism of release of endothelium-derived relaxing factor (NO)
- Pathogenesis of denervation receptor hypersensitivity
- Pharmacokinetics of quaternary ammonium compounds
- The role of M-cholinergic receptor subtypes in the regulation of gastrointestinal functions
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