Curare neuromuscular junction

Curare-like muscle relaxants act by blocking acetylcholine receptor sites, thus eliminating transmission of nerve impulses at the neuromuscular junction. There are two acetylcholine-like groupings in the molecules, and the drugs, therefore, probably span and block several receptor sites. The neurotransmitter acetylcholine is also a quaternary ammonium compound. The natural material present in curare is tubocurarine, a complex alkaloid that is a mono-quaternary salt. Under physiological conditions, the tertiary amine will be almost completely protonated (see Section 4.9), and the compound will similarly possess two positively charged centres. 

Neuromuscular blockade Neurotoxicity can occur. Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on the neuromuscular junction. 

ACh receptors are destroyed by endocytosis via coated pits and proteolysis in lysosomes. In myasthenia gravis, the receptors are crosslinked by antireceptor antibodies, which facilitate the rate-limiting endocytosis step receptor destmction occurs in less than half the normal time, resulting in net receptor loss. The chronic disease is characterized clinically by such muscular weakness and abnormal fatigue that patients cannot even keep their eyes open. Acetylcholinesterase inhibitors increase the ACh concentration and excitation of the neuromuscular junction, resulting in increased strength and endurance. As expected, AChE inhibitors are also potent curare antidotes because the increased ACh levels displace the blocker more readily. 

The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents... 

The major therapeutic uses of the cholinomimetics are for diseases of the eye (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and very rarely, the heart (certain atrial arrhythmias). Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage. Several newer cholinesterase inhibitors are being used to treat patients with Alzheimer s disease. 

The curare alkaloids, which are constituents of arrow poisons used by South American Indians, are complex bases which usually contain one or more quaternary centers. They act at the neuromuscular junction, preventing muscles from responding to nerve impulses or to acetylcholine, and they are used to secure muscular relaxation during surgery. 

ANTAGONIZING ACETYLCHOLINE Curare, found in a resinous extract of the plants Chondrodendrott tomentosum and Strychnos toxifera from the Orinoco and Amazon basins in South America, is an antagonist at nicotinic acetylcholine receptors. Curare does not cross the blood—brain barrier, and therefore its actions are expressed only outside of the brain at the neuromuscular junction where neurons control muscles. Curare is extremely lethal for one simple reason—it blocks the nicotinic receptors located on the diaphragm therefore, death from curare results from asphyxiation. Imagine you ve been shot by a curare-tipped arrow you d be awake, fully aware of having been shot, yet completely unable to move, speak, or, ultimately, breathe. 

Drugs discussed in this chapter are used to decrease muscle excitability and contraction via an effect at the spinal cord level, at the neuromuscular junction, or within the muscle cell itself. Some texts also classify neuromuscular junction blockers such as curare and succinylcholine as skeletal muscle relaxants. However, these drugs are more appropriately classified as skeletal muscle paralytics because they eliminate muscle contraction by blocking transmission at the myoneural synapse. This type of skeletal muscle paralysis is used primarily during general anesthesia using neuromuscular blockers as an adjunct in surgery was discussed in Chapter 11. Skeletal muscle relaxants do not typically prevent muscle contraction they only attempt to normalize muscle excitability to decrease pain and improve motor function. 

The pharmacological properties of P-erythroidine and its dihydro derivative are very similar to those of d-tubocurarine and therefore need not be described in any detail. The two compounds differ from curare in three important respects, namely, less potent paralytic action on neuromuscular junctions, briefer duration of paralysis, and oral efficacy. Indeed, gastrointestinal absorption of the alkaloids is so rapid and complete that the difference between effective oral and subcutaneous doses is rather small. Dihydro-P-erythroidine is longer acting than P-erythroidine and about six times as active. Similar to curare, P-erythroidine and its dihydro derivative are antagonized at the neuromyal junction by anticholinesterases such as neostigmine. 

B Curarization (blocking acetylcholine action at the neuromuscular junction) C Application of hexamethonium (ganglia protection)... 

The effects of curare develop rapidly after it enters the body. Victims develop rapid weakness of voluntary muscles followed by paralysis, respiratory failure, and death. The cause is a blockade of nicotinic cholinergic receptors at the neuromuscular junctions in skeletal muscle. Unlike botulinum toxin, release of acetylcholine by the cholinergic nerve terminals is not affected. When curare is present, however, the acetylcholine that is released cannot bind to the receptors because they are reversibly occupied by the curare. As a consequence, nerve-muscle communication fails and paralysis ensues. 

The development and use of muscle relaxants, to allow a reduction in the level of anesthesia during surgery, follows entirely from studies of South American arrow poisons (44)and particularly from the isolation by King (45) of pure D-tubocurarine (29) in the 1930s, from tube curare. Another of the South American blowpipe poisons, calabash curare, was used for similar purposes and developed (46,47), to give alcuronium (30) from the alkaloid C-toxiferine 1 (31). Both types of curare paralyze skeletal muscle by a similar mechanism, antagonizing the effect of acetylcholine at the neuromuscular junction (48). 

The po.ssible existence of a junction between muscle and nerve was suggested as early as 1856, when Claude Bernard ob.servcd that the site of action of curare was neither the nerve nor the muscle. Since that lime, it has been agreed that ACh mediates transmission at the neuromuscular junction by a sequence of events described above in this chapter. The neuromuscular junction consists of the axon impinging onto a specialised area of the mu.scle known as the muscle end plate. The axon is covered with a myelin sheath, containing the nodes of Ranvier, but is bare at the ending. The nerve terminal is separated from the end plate by a gap of 200 A. The subsynaptic membrane of the end plate contains the cholincigic receptor, the ion-conducting channels (which are opened under the influence of ACh), and AChE. 

Protein components of the venom of the banded krait (Bungarus multicinctus). Two major components a- and (3-bungarotoxins. ct-Bungarotoxin binds irreversibly to ACh receptor causing neuromuscular blockade and muscle paralysis similar to effects of curare, p-Bungarotoxin contains several components prevents ACh release at skeletal neuromuscular junction. Crude venom LD50 SC mouse, 0.16 mg/kg bw. 

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