Acetylcholine

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Acetylcholine, the first neurotransmitter discovered, was originally described as "Vagus Stuff" by Otto Loewi because of its ability to mimic the electrical stimulation of the vagus nerve. A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterase, but it is useful in some ophthalmological applications.

Chemistry

· Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the presence of a highly polar, charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood-brain barrier. A synonym of this drug is miochol.

Biochemistry

· Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain.

· The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Disease and Disorders

Myasthenia gravis

· The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor endplate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).

Pharmacology

· Blocking, hindering, or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor-ligand. Agonists increase the level of receptor activation, antagonists reduce it.

· Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery.

Nicotinic Receptor

· Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. When ACh interacts with a nicotinic ACh receptor, it opens a Na+ channel and Na+ ions flow into the membrane. This causes depolarization and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived. Curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.

Muscarinic Receptor

· Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.