Skeletal muscle neuromuscular blockade

Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and nondepolarizing blockade (see Chapters 7 and 27). Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglion block. 

Toxic action is complex, involving both stimulation and blockade of autonomic ganglia and skeletal muscle neuromuscular junctions, as well as direct effects on the central nervous system. Paralysis and vascular collapse are prominent features of acute poisoning, but death is usually due to respiratory paralysis, which may ensue promptly after the first symptoms of poisoning. Nicotine is not an inhibitor of cholinesterase enzyme. 

Skeletal muscles -neuromuscular junction Contraction, when the effect is prolonged it leads to a depolarisation blockade resulting in a flaccid paralysis Muscle relaxation in surgery... 

Paralysis usually is reserved for cases in whom sedation alone does not improve the effectiveness of mechanical ventilation. Neuromuscular blockers may lead to prolonged skeletal muscle weakness and should be avoided if possible. Patients requiring neuromuscular blockade are to be monitored and intermittent boluses should be utilized. 

Skeletal muscle Phrenic nerve/diaphragm Neuromuscular blockade... 

Two precautions should be kept in mind Neuromuscular blocking drugs inhibit, concentration-dependently, all skeletal muscles including those necessary for respiration. If these muscles are paralyzed by these drugs artificial respiration must be applied since central or peripheral nerve stimulation, for example with analeptics are useless. Furthermore is it important to realize that the individual subjected to a efficient neuro-muscular blockade is fully conscious and aware of any pain although completely unable to express discomfort. 

Edery96 studied the effects of V on neuromuscular blockade Induced by ethyl pyrophosphate or neostigmine methylsulfate in the cat, finding only an Insignificant effect. The skeletal muscle responses to both direct and Indirect excitation were altered by V In the absence of any other active chemical. The effect of V on the response of indirectly stimulated muscle to d-tubocurarlne was an Increase In the blockade of neuromuscular transmission similar to that of the salts of 2-PAM and of III. 

This type of response may be caused by several mechanisms. For instance, the muscle relaxation induced by succinylcholine, discussed in more detail in chapter 7, is due to blockade of neuromuscular transmission. Alternatively, acetylcholine antagonists such as tubocurarine may compete for the receptor site at the skeletal muscle end plate, leading to paralysis of the skeletal muscle. Botulinum toxin binds to nerve terminals and prevents the release of acetylcholine the muscle behaves as if denervated, and there is paralysis. This will be discussed in more detail in chapter 7. 

Dimethylphenylpiperazinium stimulates the autonomic ganglia, tetraethylammonium and hexamethonium block the autonomic ganglia, phenyltrimethylammonium stimulates skeletal motor muscle end plates, decamethonium produces neuromuscular blockade, and zZ-tubocurarine blocks both the autonomic ganglia and the motor fiber end plates. 

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. 

Skeletal muscle relaxants fall into three major categories those that reduce spasticity, those that cause neuromuscular blockade and those that work at the cellular level. Spasmolytic agents (e.g. metho-carbamol, guaifenesin) act centrally whereas neuromuscular blockers (e.g. succinylcholine (suxamethonium), pancuronium, atracurium) act at the neuromuscular end plate to produce muscular relaxation. Dantrolene falls into the third category and acts within the muscle cell itself to produce relaxation. 

In severe overdosage, CNS depression, circulatory collapse, and hypotension may occur. Coma and skeletal muscle paralysis may also occur followed by death due to respiratory failure. Acute overdosage with quaternary ammonium antimuscarinics may produce a curariform neuromuscular block and ganglionic blockade manifested as respiratory paralysis. 

Coniine acts on the autonomic ganglia to produce initial stimulation of skeletal muscle followed by neuromuscular blockade. The actions of coniine are similar to those of nicotine but produce paralysis of greater numbers of central nervous system (CNS) and skeletal muscle nerve endings. 

Neuromuscular blockade—may enhance effects of skeletal muscle relaxants. 

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. 

Neuromuscular blockade—may enhance effects of skeletal muscle relaxants. Contact dermatitis (neomycin). 

Historically, Bernard (1851, 1856) demonstrated that curare (from arrow poisons used by South American Indians) blocked nerve impulse transmission at the junction of the nerve and skeletal muscle. It was later shown that many alkaloids, such as morphine, atropine, nicotine, and even strychnine and brucine (the latter two normally causing convulsions), will become muscle relaxants when quaternized by methylation. It soon became apparent that a great many quaternary ammonium compounds qualitatively share the ability to produce neuromuscular blockade. In fact, the onium ion need not be a nitrogen atom. Thus sulfonium (/ 3S+), phosphonium (/ 3P+), and arsonium (/ 3As+) ions have been shown to be curariform , although of lesser activity than ammonium ions. 

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