General Mechanism of Action
The fundamental mechanism of anticholinesterase drugs is the inhibition of the enzyme acetylcholinesterase (AChE). This enzyme normally ensures the rapid breakdown of acetylcholine in the synaptic cleft. By blocking AChE, these drugs cause an accumulation of the body's own (endogenous) acetylcholine.
It is important to understand that these medications do not directly stimulate receptors themselves. All observed pharmacological effects are the result of excessive activity of the body's natural neurotransmitter. The drugs merely create conditions for its prolonged action.
Effects on Muscarinic (M) Receptors
The accumulation of acetylcholine leads to typical effects of parasympathetic nervous system stimulation:
- Eyes: Miosis (marked pupillary constriction) and accommodation spasm.
- Cardiovascular System: Bradycardia develops and cardiac output drops. However, blood pressure decreases only slightly because vascular $M_3$ receptors are extrasynaptic, and the neurotransmitter accumulated in synapses rarely reaches them.
- Smooth Muscle: Tone of the bronchi, urinary bladder, and gastrointestinal motility increases.
- Exocrine Glands: Pronounced hypersecretion is observed.
Effects on Nicotinic (N) Receptors
Effects on skeletal muscle are among the most clinically significant for this group. The drugs facilitate neuromuscular transmission, leading to a substantial increase in skeletal muscle tone.
At therapeutic doses, autonomic ganglion stimulation is weak. However, at toxic doses, the picture changes: powerful stimulation of N-receptors occurs in sympathetic ganglia, carotid bodies, and adrenal chromaffin cells. Clinically, this manifests as paradoxical tachycardia and a sharp rise in blood pressure, which override the initial parasympathetic effects.
Classification and Chemical Structure
Anticholinesterase drugs are divided into two major groups based on the type of bond formed with the enzyme: reversible and irreversible agents.
Reversible agents are classified according to the structure of their 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 penetrate the CNS across the blood-brain barrier). Exert a stimulating effect on the brain. Examples: galantamine hydrobromide, physostigmine, rivastigmine, donepezil.
Interaction with Active Sites of the Enzyme
Acetylcholinesterase has two key sites: an anionic site (with a carboxyl group) and an esteratic site (with an OH group).
Many drugs (e.g., carbamates) act similarly to acetylcholine by binding to both sites. However, unlike physiological deacetylation, which takes fractions of a millisecond, the hydrolysis of carbamates results in carbamoylation of the esteratic site. This covalent bond is much stronger, and its hydrolysis can take from 30 minutes to several hours, shutting down the enzyme for a prolonged period.
Other agents, such as edrophonium, form only weak electrostatic and hydrogen bonds with the anionic site, providing a very short duration of action (5–10 minutes).