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Acetylcholine appears in various chapters, from snake bites to the eating of poisonous fish, from myasthenia gravis following intoxication by tropanes (plant alkaloids) or insecticides, to muscle relaxation during surgical operations. The synthesis of acetylcholine takes place in the cytoplasm of the nerve endings. Acetylcoenzyme-A provides an acetyl group which is transferred to choline with the help of choline-acetyl transferase. Acetylcholine is a neurotransmitter. When an action potential reaches the nerve endings, acetylcholine is released into the synapse, diffuses across the synaptic cleft, binds with the post-synaptic receptor and depolarises the post-synaptic cell. To terminate the stimulation, acetylcholine which is free in the synaptic cleft is broken down by acetylcholine-esterase. The choline binds to a carrier and is returned to the pre-synaptic cell.
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Acetylcholine is an important neurotransmitter.
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Acetylcholine can bind to two types of receptors:
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The clinical effects of antagonists or agonists vary between substances depending on the activity on nicotine and muscarine receptors, the dose and method of administration, diffusion through the blood-brain barrier and whether the binding to the target is reversible or irreversible.
The skeletal muscles use acetylcholine at the neuromuscular junction. These nicotine receptors are stimulated by the alkaloid with the same name, from the tobacco plant. Paralysis may occur if the action of acetylcholine at the neuromuscular junction is reduced, or if there has been overstimulation for a long time. The release of acetylcholine from the pre-synaptic nerve cell may be prevented by various snake venoms (b -toxins) or by botulinum toxin. Myasthenia gravis patients have antibodies against the post-synaptic receptor, leading to muscle weakness. Some toxins contained in snake venoms cause a competitive inhibition at the post-synaptic receptor (a -toxins). Curare has the same mechanism of action. Curare is the name for a number of substances which are obtained from plants such as Chondrodendron tomentosum (Menispermaceae) and others. Tubocurarine gets its name from the fact that it was transported in bamboo stems. Curare-derived products have application as muscle relaxants during surgery. Clinically, poisoning by curare is characterised by flaccid paralysis, which is reversible by administering an acetylcholinesterase such as neostigmine.
The three major natural cholinomimetic alkaloids which are active upon muscarine receptors are pilocarpine, muscarine and arecoline. Arecoline is an important constituent of betel, the seeds of Areca catechu. The seed is chewed by many people, together with chalk and the leaves of Piper betel, a pepper plant. Pilocarpine is a functional acetylcholine analogue. This molecule was discovered in 1875 in leaves from Pilocarpus microphyllus and related species of South American shrubs (called jaborandi) belonging to the Rutaceae. The substance produces miosis and salivation. It is still used in the treatment of glaucoma if it is administered as topical eyedrops. It is also sometimes used to induce sweating in the diagnosis of mucoviscidosis and in sicca syndrome (dry mouth). Muscarine is a substance obtained from the fly agaric Amanita muscaria. The concentration of muscarine in the fungus is quite low, however, and its toxicity is chiefly caused by other substances. The fungi Inocybe and Clitocybe contain a much higher concentration of muscarine.
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If the enzyme acetylcholinesterase is inhibited, the breakdown of acetylcholine is slowed down. Examples are neostigmine, physostigmine, pyridostigmine, edrophonium, various insecticides such as malathion and nerve gases such as sarin. Neostigmine is an anticholinesterase and is prepared synthetically. It is used in the treatment of cobra bites, to end curare-induced muscle paralysis after surgery, in post-operative bladder atonia and paralytic ileus. It can also be used for the diagnosis of myasthenia gravis since it leads to a brief improvement. Pyridostigmine is used in the maintenance treatment of myasthenia gravis. It is closely related chemically to physostigmine. Physostigmine was discovered originally in a plant, Physostigma venenosum (Fabaceae) also known as the Calabar bean. The use of this plant in the traditional jurisdiction of the Efik people in Nigeria led to many deaths in their region and was forbidden by law by the British authorities in the nineteenth century. Suspects were forced to eat several poisonous seeds to prove their innocence. Physostigmine penetrates the blood brain barrier and affects the central nervous system. Later, due to its capacity to induce miosis it had a place in the treatment of acute narrow angle glaucoma. It is also used in the treatment of atropine intoxication.
Pralidoxime (2-PAM, Protopam®) reduces the binding of an organophosphate to cholinesterase and is able to reactivate an inactive enzyme. It is used as an antidote in intoxication by organophosphate insecticides. About 1-2 grams IV pralidoxime are given, followed by an infusion of 200-400 mg/hr. Obidoxime has the same action. Organophosphates and nerve gases such as sarin initially stimulate the muscles but ultimately lead to depression and paralysis.
The action of the parasympathetic nervous system can be weakened by blocking the post-synaptic receptor. Atropine is the typical example of an anticholinergic active upon the muscarine receptors. Atropine is not active at the neuromuscular junction. It is prepared from Atropa belladonna (Solanaceae). The name "belladonna" refers to the mydriasis which is considered to make women’s eyes attractive. Atropa refers to the one of the Greek Fates who cuts through the thread of life. Nowadays the derivative homatropine is often used to obtain enlargement of the pupils (e.g. for ophthalmoscopy). Related molecules are found in Datura stramonium (thornapple), Hyoscyamus niger (henbane) and Scopolia carniolica. Datura stramonium or thornapple also known as Jimson weed. This refers to an incident in 1676, in Jamestown, Virginia, when a number of British soldiers were accidentally poisoned by this plant ("jimson" being a corruption of "Jamestown"). Hyoscine is also named scopolamine. N-butylhyoscine is a derivative of hyoscyamine. They are used as spasmolytics. Intoxication with atropine is characterised by mydriasis, dry warm skin and dry mucosa, increased body temperature, tachycardia, restlessness, convulsions, respiratory failure and coma followed by death. As well as activated charcoal and general supportive measures, physostigmine can be used as an antidote (see above). For adults 0.5-2 mg are injected IM or IV.
