Muscle relaxants Neuromuscular junction

Neuromuscular Nicotinic receptors are responsible for transmission at the neuromuscular junction. While briefly causing stimulation, this phase is rapidly obscured by desensitization and neuromuscular blockade. Thus, nicotine has muscle-relaxant effects. 

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. 

Low doses of nicotine stimulate respiration through activation of chemoreceptors in the aortic arch and carotid bodies, while high doses directly stimulate the respiratory centers. In toxic doses, nicotine depresses respiration by inhibiting the respiratory centers in the brainstem and by a complex action at the receptors at the neuromuscular junction of the respiratory muscles. At these neuromuscular receptors, nicotine appears to occupy the receptors, and the end plate is depolarized. After this, the muscle accommodates and relaxes. These central and peripheral effects paralyze the respiratory muscles. 

Skeletal muscle relaxants act peripherally at the neuromuscular junction or centrally in the cerebrospinal axis to reduce muscle tone. 

While most of the muscle relaxants exert their predominant actions at the post-junctional nicotinic receptors, many also have variable pre-junctional effects. Although pre-junctional receptors have not been demonstrated there is putative evidence for their existence. The pre-junctional mechanisms are supposed to be responsible for the development of fade in response to tetanic or train-of-four (TOP) stimulation following administration of non-depolarising neuromuscular blocking drugs. 

Some sedative-hypnotics, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone. 

Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order isoflurane (most) sevoflurane, desflurane, enflurane, and halothane and nitrous oxide (least) (Figure 27-9). The most important factors involved in this interaction are the following (1) nervous system depression at sites proximal to the neuromuscular junction (ie, central nervous system) (2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction and (3) decreased sensitivity of the postjunctional membrane to depolarization. 

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. 

Release. Certain drugs will increase synaptic activity by directly increasing the release of neurotransmitter from the presynaptic terminal. Amphetamines appear to exert their effects on the CNS primarily by increasing the presynaptic release of catecholamine neurotransmitters (e.g., norepinephrine). Conversely, other compounds may inhibit the synapse by directly decreasing the amount of transmitter released during each action potential. An example is botulinum toxin (Botox), which can be used as a skeletal muscle relaxant because of its ability to impair the release of acetylcholine from the skeletal neuromuscular junction (see Chapter 13). 

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. 

Magnesium sulfate Skeletal muscle spasms myositis Muscle relaxant effect may be caused by decreased excitability of the skeletal muscle membrane and decreased transmission at the neuromuscular junction 2°/o aqueous solution or ointment from positive pole 2°/o ointment... 

Cryotherapy Cold/ice packs Ice massage Cold bath Vapocoolant sprays Decreased pain, edema, and inflammation Muscle relaxation and decreased spasticity Anti-inflammatory steroids (glucocorticoids) nonsteroidal anti-inflammatory analgesics (aspirin and similar NSAIDs) Skeletal muscle relaxants Peripheral vasodilators may exacerbate acute local edema Nonselective cholinergic agonists may stimulate the neuromuscular junction Some forms of cryotherapy may produce local vasoconstriction that temporarily impedes diffusion of drugs to the site of inflammation... 

Local application Hot packs Paraffin Decreased muscle spasms Skeletal muscle relaxants Nonselective cholinergic agonists may stimulate the neuromuscular junction ... 

Matsuo S, Rao DB, Chaudry I, Foldes FF. Interaction of muscle relaxants and local anesthetics at the neuromuscular junction. Anesth Analg 1978 57(5) 580-7. 

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 main use of drugs at the neuromuscular junction is to relax muscle in anaesthesia, or to inhibit acetylcholinesterase in diseases where nicotinic receptor activation is reduced.e.g. myasthenia gravis. 

---