General Mechanism of Action
The main principle of action of anticholinesterase agents is the inhibition of the enzyme acetylcholinesterase (AChE). This enzyme normally ensures the rapid breakdown of acetylcholine in the synaptic cleft. By blocking AChE, the drugs cause an accumulation of the body's own (endogenous) acetylcholine.
It is important to understand that the drugs of this group themselves do not stimulate receptors directly. All observed pharmacological effects are the result of excessive activity of the body's natural mediator. The drugs merely create conditions for its prolonged action.
Effect on M-cholinergic receptors
The accumulation of acetylcholine leads to typical effects of parasympathetic nervous system stimulation:
- Eyes: miosis (pronounced pupillary constriction) and accommodation spasm occur.
- Cardiovascular system: bradycardia develops and cardiac output drops. Meanwhile, blood pressure decreases only slightly. This is due to the fact that vascular $M_3$-cholinergic receptors are extrasynaptic, and the mediator accumulated in synapses hardly reaches them.
- Smooth muscles: the tone of the bronchi and urinary bladder increases, and gastrointestinal motility is enhanced.
- Exocrine glands: marked hypersecretion is observed.
Effect on N-cholinergic receptors
Effects on skeletal muscle are among the most clinically significant for this group. The drugs facilitate neuromuscular transmission, which leads to a substantial increase in skeletal muscle tone.
In therapeutic dosages, autonomic ganglion stimulation is mild. However, at toxic doses, the picture changes: there is powerful stimulation of N-cholinergic receptors in sympathetic ganglia, carotid bodies, and adrenal chromaffin cells. Clinically, this manifests as paradoxical tachycardia and a spike in blood pressure, which override the primary parasympathetic effects.
Classification and chemical structure
Anticholinesterase agents are divided into two large groups depending on the type of bond with the enzyme: reversible and irreversible action.
Reversible agents are classified according to the structure of the nitrogen atom:
- Quaternary ammonium compounds (permanently charged, polar, poorly cross the blood-brain barrier). Do not stimulate the CNS. Examples: neostigmine methylsulfate, pyridostigmine bromide, edrophonium.
- Tertiary ammonium compounds (less polar, readily cross the blood-brain barrier into the CNS). Exhibit stimulating effects on the brain. Examples: galantamine hydrobromide, physostigmine, rivastigmine, donepezil.
Interaction with active centers of the enzyme
Acetylcholinesterase has two key centers: the anionic center (with a carboxyl group) and the esteratic center (with an OH group).
Many drugs (e.g., carbamates) act similarly to acetylcholine by binding to both centers. However, unlike physiological deacetylation, which takes fractions of a millisecond, the hydrolysis of carbamates results in carbamoylation of the esteratic center. This covalent bond is much stronger, and its hydrolysis can take from 30 minutes to several hours, effectively shutting down the enzyme for a prolonged period.
Other agents, such as edrophonium, form only weak electrostatic and hydrogen bonds with the anionic center, providing a very short-lived effect (5–10 minutes).
Briefly: answers to topical questions
What symptoms occur during an overdose of anticholinesterase agents?
An overdose of anticholinesterase agents leads to a cholinergic crisis, manifested by M- and N-cholinergic effects.
Symptoms include:
- Gastrointestinal — discomfort, abdominal pain, diarrhea.
- Respiratory and secretory — rhinorrhea, bronchorrhea.
- Cardiovascular — decreased blood pressure.
- Muscular — muscle twitching, cramps, paradoxical worsening of muscle weakness due to the development of a depolarizing block and suppression of neuromuscular transmission.
What are the indications for the use of anticholinesterase agents?
Anticholinesterase agents are used to treat conditions requiring enhanced cholinergic transmission.
Indications include:
- Neuromuscular pathologies — myasthenia gravis (Myasthenia gravis), myasthenic crises, muscular dystrophies, movement disorders after injuries, paralyses.
- Neurological diseases — neuritis, polyneuritis, focal forms of tick-borne encephalitis.
- Cognitive disorders — dementias (including Alzheimer's disease and dementia with Lewy bodies).
- Smooth muscle atonia — postoperative atonia of the intestine and urinary bladder, labor weakness.
- Anesthesiology — decurarization (reversal of residual block from nondepolarizing muscle relaxants).
- Ophthalmology — angle-closure glaucoma.
What is used as an antidote in poisoning with anticholinesterase agents?
In poisoning with anticholinesterase agents, M-cholinoblockers and cholinesterase reactivators are used.
- M-cholinoblockers — atropine is the mainstay of emergency care. It competitively displaces acetylcholine from binding to receptors, eliminating symptoms of parasympathetic system overstimulation.
- Cholinesterase reactivators — restore the activity of the inhibited enzyme. They are effective in organophosphate (OP) poisoning, but are strictly contraindicated in poisoning with reversible agents (carbamates).
Class and exam questions
Why do anticholinesterase agents cause almost no drop in blood pressure?
Unlike direct M-cholinomimetics, anticholinesterase agents work only where endogenous acetylcholine is released. Vascular $M_3$-cholinergic receptors lack cholinergic innervation (extrasynaptic), so the mediator does not reach them.
What is the difference between tertiary and quaternary amines in this group?
Quaternary ammonium compounds are polar and do not cross the blood-brain barrier (e.g., neostigmine), thus having no central nervous system effects. Tertiary compounds are lipophilic, cross the barrier, and exert a central stimulating effect (e.g., galantamine).
What happens during an overdose of anticholinesterase agents?
In toxic doses, drugs begin to powerfully stimulate N-cholinergic receptors of sympathetic ganglia and the adrenal glands. This causes a paradoxical reaction — tachycardia and increased blood pressure, masking the expected parasympathetic action.
What else to study on this topic
- Mechanism of irreversible cholinesterase inhibition
- Use of anticholinesterase agents in Alzheimer's disease
- The role of butyrylcholinesterase in the body
- Organophosphate (OP) poisoning
- Cholinesterase reactivators and their mechanism
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