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 trace the reaction cascade 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 (development of bradycardia).
Muscarine and Mushroom Poisoning
The prototype of the group is muscarine, an alkaloid found in poisonous mushrooms. It excites 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.
Amanita mushroom poisoning consists of two components:
- Peripheral effects (muscarine action): pupillary constriction (miosis) and accommodation spasm, profuse salivation and sweating, bradycardia, and hypotension. Bronchospasm with mucus hypersecretion (sensation of suffocation) is characteristic, along with spasmodic abdominal pain, vomiting, and diarrhea.
- Central effects (neurotoxicity): caused by other fungal toxins (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, and therefore cross lipid membranes and the BBB very poorly.
- Tertiary ammonium compounds (aceclidine, pilocarpine). They lack a permanent charge, allowing them to penetrate histohematogenous barriers more easily.
Clinical Application of Synthetic Agents
Synthetic analogs are used in medical practice because they possess more predictable action and a better safety profile.
Aceclidine (Aceclidinum) Used topically in ophthalmology to lower intraocular pressure in glaucoma (effects last 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 systemic activity profile similar to aceclidine. The main indication is the relief of intestinal and urinary bladder atony.
Cevimeline (Cevimeline) A predominantly $M_3$ receptor agonist (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 post-radiation therapy.
Contraindications and Adverse Effects
Overdose or systemic effects of m-cholinomimetics cause hypersalivation, diarrhea, drop in blood pressure, and smooth muscle spasms.
Based on their mechanism of action, these drugs are strictly contraindicated in:
- Bronchial asthma and COPD (provoke bronchospasm).
- Angina pectoris and bradycardia (suppress cardiac function).
- Peptic ulcer disease and hyperacid gastritis (stimulate hydrochloric acid production).
- Pregnancy (increase myometrial tone, creating a risk of miscarriage).