Signal transduction mechanism
Muscarinic receptors belong to metabotropic receptors, meaning they are coupled with G proteins. There are five subtypes in total ($M_1$–$M_5$), of which the first three are the most studied.
Let us look at the cascade of reactions using cardiac $M_2$ receptors as an example:
- The substance binds to receptors on the cardiomyocyte membrane.
- The inhibitory $G_i$ protein is activated.
- The enzyme adenylyl cyclase is inhibited.
- Intracellular synthesis of cyclic adenosine monophosphate (cAMP) decreases.
- The activity of cAMP-dependent protein kinases drops.
- Protein phosphorylation is impaired, ultimately leading to the inhibition of cardiac function (bradycardia develops).
Muscarine and toadstool poisoning clinical picture
The prototype of the group is muscarine, an alkaloid found in poisonous mushrooms. It stimulates all muscarinic receptor subtypes, but due to its structure (quaternary nitrogen), it does not cross the blood-brain barrier (BBB) and does not affect the central nervous system. It is used exclusively in experimental pharmacology and toxicology.
The clinical picture of toadstool poisoning consists of two components:
- Peripheral effects (action of muscarine): pupil constriction (miosis) and accommodation spasm, profuse salivation and sweating, bradycardia and hypotension. Bronchospasm with mucus hypersecretion (sensation of suffocation) is typical, as well as spastic abdominal pain, vomiting, and diarrhea.
- Central effects (neurotoxicity): caused by other toxins in the mushroom (ibotenic acid, muscimol). They manifest as hyperthermia, seizures, myoclonus, and coma in severe cases.
Treatment: in addition to standard decontamination (gastric lavage, sorbents, laxatives), administration of the physiological antagonist — atropine — is mandatory.
Chemical classification
The ability of drugs to cross cellular barriers (including the BBB) directly depends on their chemical structure:
- Quaternary ammonium compounds (acetylcholine, muscarine). They carry a permanent positive charge, which is why they cross lipid membranes and the BBB very poorly.
- Tertiary ammonium compounds (aceclidine, pilocarpine). They lack a permanent charge, allowing them to cross histohematic barriers more easily.
Clinical use of synthetic drugs
Synthetic analogs are used in medical practice because they have a more predictable action and a better safety profile.
Aceclidine (Aceclidinum) Used topically in ophthalmology to lower intraocular pressure in glaucoma (effect lasts up to 6 hours, but may cause conjunctival irritation). Systemically (orally or parenterally), it is prescribed for intestinal and urinary bladder atony, as well as to increase uterine tone and stop postpartum hemorrhage. It is less toxic than pilocarpine.
Bethanechol (Bethanechol) Has a spectrum of resorptive action similar to aceclidine. The main indication is the relief of intestinal and urinary bladder atony.
Cevimeline (Cevimeline) An agonist predominantly of $M_3$ receptors (and partially $M_1$). The main effect is powerful stimulation of the salivary glands. It is prescribed for xerostomia (dry mouth), for example, in Sjögren's syndrome or after radiation therapy.
Contraindications and side effects
Overdose or systemic action of direct muscarinic agonists causes hypersalivation, diarrhea, drop in blood pressure, and smooth muscle spasms.
Based on their mechanism of action, the drugs are strictly contraindicated in:
- Bronchial asthma and COPD (they provoke bronchospasm).
- Angina pectoris and bradycardia (they suppress heart function).
- Peptic ulcer disease and hyperacid gastritis (they stimulate hydrochloric acid production).
- Pregnancy (they increase myometrial tone, creating a risk of miscarriage).
Briefly: answers to topical questions
In which organs and tissues are M1, M2, and M3 muscarinic receptors predominantly localized?
Muscarinic receptors are localized on the cells of target organs of the parasympathetic nervous system.
- M1 receptors are structures associated with the regulation of HCl secretion in the stomach.
- M2 receptors are membranes of cardiomyocytes in the heart.
- M3 receptors are smooth muscle cells of internal organs: bronchi, stomach, intestines, urinary bladder, biliary tract; they are also associated with the stimulation of salivary gland secretion.
Through what mechanism do direct muscarinic agonists reduce intraocular pressure in glaucoma?
The mechanism of intraocular pressure reduction depends on the form of glaucoma and is due to the improvement of aqueous humor outflow.
- Angle-closure glaucoma — pupil constriction (miosis) leads to thinning of the iris and opening of the anterior chamber angle, which provides access to the spaces of Fontana and the canal of Schlemm.
- Open-angle glaucoma — contraction of the ciliary muscle causes tension in the trabecular meshwork of the pectinate ligament, mechanically widening the spaces of Fontana and improving outflow through the trabecular meshwork.
The effects of muscarinic agonists are easy to remember by the rule "everything flows, everything narrows, everything slows down": the secretion of all glands increases (saliva, sweat, gastric juice), the smooth muscles of hollow organs and bronchi constrict, and the heart beats more slowly.
Class and exam questions
What is the main difference between tertiary and quaternary M-cholinomimetics?
Tertiary amines (e.g., aceclidine) do not carry a permanent ionic charge. This allows them to penetrate biological membranes much better compared to quaternary compounds.
Why is aceclidine used in obstetrics?
Aceclidine stimulates myometrial muscarinic receptors, increasing uterine tone. This property is used to stop uterine bleeding in the postpartum period.
What else to study on this topic
- Localization and physiological role of $M_1, M_3, M_4$, and $M_5$ receptors
- Mechanism of intraocular pressure reduction in glaucoma
- Differences between direct muscarinic agonists and anticholinesterase agents
- Pharmacological properties of the alkaloid arecoline and its effect on the central nervous system
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