Anticholinesterases // Pharmacology

The nervous system is composed of two divisions: the central nervous system, which includes the brain and the spinal cord, and the peripheral nervous system , which includes all the nerves that connect the central nervous system to the muscles and organs.
The peripheral nervous system is divided into the somatic nervous system which controls voluntary movement of our skeletal muscles and the autonomic nervous system which controls the involuntary activity of the smooth muscles and glands of our organs and is further divided into the sympathetic and parasympathetic nervous systems.
Preganglionic neurons of the parasympathetic division have their cell bodies in either the brain stem or the sacral spinal cord. Preganglionic axons project to a series of ganglia located near or in the effector organs.
All preganglionic neurons are cholinergic and release acetylcholine, which interacts at nicotinic receptors on the cell bodies of postganglionic neurons. Most postganglionic neurons of the parasympathetic division are also cholinergic.Receptors for Acetylcholine in the effector organs are muscarinic receptors rather than nicotinic receptors. Thus, Acetylcholine released from preganglionic neurons of the parasympathetic division activates nicotinic receptors, whereas Acetylcholine released from postganglionic neurons of the para- sympathetic division activates muscarinic receptors.
The nicotinic receptor is composed of five subunits and it functions as a ligand gated ion channel. Binding of acetylcholine molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell. The muscarinic receptor, on the other hand, is a membrane protein; upon stimulation by neurotransmitter, it causes the opening of ion channels indirectly, through a second messenger.
The signal at the postjunctional effector site is rapidly
terminated, because acetylcholinesterase cleaves acetylcholine
to choline and acetate in the synaptic cleft
Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine to acetate and choline and, thus, terminates its actions. It is located both pre and postsynaptically in the nerve terminal where it is membrane bound. Inhibitors of Acetylcholinesterase indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine produced endogenously at the cholinergic nerve endings. This results in the accumulation of Acetylcholine in the synaptic space. Therefore, these drugs can provoke a response at all cholinoceptors in the body, including both muscarinic and nicotinic receptors of the autonomic nervous system as well as at neuromuscular junctions and in the brain.
Examples of anticholinesterases include edrophonium, neostigmine, physostigmine, pyridostigmine, rivastigmine, galantamine, and donepezil.
Anticholinesterases are either organophosphates or carbamates. Organophosphates like parathion are often used as pesticides. The chemical weapon sarin gas also belongs to this group.
The most clinically used anticholinesterases are carbamates, and they are either tertiary or quaternary amines.
This is important because only the anticholinesterases with a tertiary structure can cross the blood brain barrier and enter the brain.
Edrophonium [ed-row-FOE-nee-um] is the prototype short acting acetylcholinesterase inhibitor. Edrophonium binds reversibly to the active center of acetylcholinesterase, preventing hydrolysis of acetylcholine. It is rapidly absorbed and has a short duration of action of 10 to 20 minutes due to rapid renal elimination. Edrophonium is a quaternary amine, and its actions are limited to the periphery. It is used in the diagnosis of myasthenia gravis,a disease where antibodies bind

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