Neuromuscular Junction Blocking Agents

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These compounds block impulses from motor neuron endings to skeletal muscle.

There are two suggested mechanisms of blocking nerve impulse transmission. One group of drugs, the typical representative and progenitor of which is tubocurarine, are called antidepolarizing drugs. By competitively binding with corresponding H-cholinore-ceptor regions, they counteract action of acetylcholine on the postsynaptic membranes, thus preventing its depolarizing action and excluding the possibility of exciting muscle fibers. It should be noted that because of minor differences in dosage causing necessary muscle relaxation and facilitating the development of paralysis of skeletal muscle, a slight overdose of muscle relaxant compounds can lead to serious damage of respiratory function and a sharp decline in blood pressure. Overdose is reversed by introducing anti-cholinesterase agents, which block acetylcholinesterase and elevate the concentration of acetylcholine in the synaptic chain, using artificial respiration with oxygen, and when necessary, using drugs that elevate arterial blood pressure (levarterenol).

Drugs of the other group, which is represented by succinylcholine, are referred to as depolarizing drugs. Compounds of this group cause initial activation (depolarization) of the receptor and subsequent prolonged, stable blockage, which leads to a delay in repolariza-tion and the inability to subsequently stimulate receptors, and in short, it disturbs the development of excitation from the nerve to the muscle. Unlike nondepolarizing agents, these drugs are not competitive antagonists, but on the contrary—they are more stable agonists than acetylcholine itself. Suitable antagonists of depolarizing agents are currently not available.

15.1.1 Antidepolarizing neuromuscular junction blockers

Initially, neuromuscular junction blockers were isolated from curare, the extract of which is produced from South American plants Strychnos and Chondodendron. Today, synthetic compounds as well as tubocurarine, an alkaloid isolated from curare, are used as antide-polarizing or curare-like drugs, which are called antidepolarizing or competitive blockers.

Tubocurarine and the majority of synthetic curare-like compounds contain two or more quaternary nitrogen atoms located approximately 1.0 ± 0.1 nm from each other, which is a necessary condition for this drug to bind with nicotinic cholinoreceptors.

These drugs are used in operations in which relaxation of skeletal muscle is required, in traumatology for repositioning broken bones, for resetting dislocations, and for tetanus. Interestingly, curare-like drugs relax muscles in a specific sequence. First, muscles of the face and neck relax, followed by the extremities and torso. Respiratory muscles and the diaphragm are last to relax, which leads to a discontinuation of respiration. Compounds of this group include tubocurarine, metocurine, gallamine, pancuronium, vecuronium, and atracurium.

Tubocurarine: Tubocurarine, 7 ',12' -dihydroxy-6,6' -dimethoxy-2,2,2',2' -tetramethyl-tubocuraranium dichloride (15.1.1), is synthesized from an aqueous extract of the Chondodendron plant [1-6].

Methods of synthesis of tubocurarine have been proposed [7,8].

Tubocurarine is used mainly in anesthesiology as a myorelaxant, causing prolonged muscle relaxation during an operation. Small doses are successful at causing temporary relaxation of skeletal muscle without any vital change of primary body functions. It is used particularly in endotracheal intubation or orthopedic surgery for repositioning fractures, resetting compound dislocations, and so on. The main synonyms are tubarine and curarine.

Metocurine: Metocurine, 6,6' ,7' ,12'-tetramethoxy-2,2,2' ,2' -tetramethyltubocuraranium dichloride (15.1.2), is synthesized by methylating two hydroxyl groups of tubocurarine with methylchloride [9].

Metocurine is used for the same indications as tubocurarine. A synonym of this drug is metubine.

Gallamine: Gallamine, 1,2,3-ira-(2-triethylaminoethoxy)benzene triiodide (15.1.4), is synthesized from pyrogallol, the hydroxyl groups of which are esterified by 2-diethyl-aminoethylchloride in the presence of sodium amide. The resulting 1,2,3-ins-(2-triethy-laminoethoxy)benzene (15.1.3) is further alkylated at all three nitrogen atoms by ethyliodide, giving gallamine (15.1.4) [10,11].

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