History

The earliest known use of muscle relaxant drugs dates back to the 16th century, when European explorers encountered natives of the Amazon Basin in South America using poison-tipped arrows that produced death by skeletal muscle paralysis. This poison, known today as curare, led to some of the earliest according to principles studies in pharmacology. Its active ingredient, tubocurarine, as well as many synthetic derivatives, played a significant role in scientific experiments to determine the function of acetylcholine in neuromuscular transmission. By 1943, neuromuscular blocking drugs became established while muscle relaxants in the practice of anesthesia and surgery.

Muscle relaxation and palsy can theoretically occur by interrupting function at several sites, including the central nervous system, myelinated somatic nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor close plate, and the muscle membrane or contractile apparatus. Most neuromuscular blockers function by the agency of blocking transmission at the end plate of the neuromuscular junction. Normally, a self-command impulse arrives at the motor nerve terminal, initiating an influx of calcium ions which causes the exocytosis of synaptic vesicles containing acetylcholine. Acetylcholine then diffuses across the synaptic cleft. It may be hydrolysed by Acetylcholine esterase (AchE) or bind to to the nicotinic receptors located on the motor expiration plate. The binding of two acetylcholine molecules results in a conformational change in the receptor that opens the sodium-potassium channel of the nicotinic receptor. This allows Na+ and Ca2+ ions to enter the cell and K+ ions to leave the cell causing a depolarization of the cessation plate, resulting in muscle contraction. Following depolarization, the acetylcholine molecules are then removed from the end plate province and enzymatically hydrolysed through acetylcholinesterase.

Normal end plate function be able to be blocked by two mechanisms. Nondepolarizing agents like tubocurarine block the agonist, acetylcholine, from binding nicotinic receptors and activating them, thereby preventing depolarization. Alternatively, depolarizing agents such as succinylcholine are nicotinic receptor agonists which minic Ach, block muscle contraction by depolarizing to such each extent that it desensitizes the receptor and it can not any longer initiate an action possible and cause muscle contraction.These neuromuscular blocking drugs are structurally similar to acetylcholine, the endogenous ligand, in manifold cases containing two acetylcholine molecules linked end-to-end by a severe carbon ring system, as in pancuronium..

Chemical diagram of pancuronium, end red lines indicating the two acetylcholine 'molecules' in the structure.

Spasmolytics

A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants. Black lines ending in arrow heads represent chemicals or actions that enhance the target of the lines. Blue lines ending in squares represent chemicals or actions that inhibition the target of the line. Click image to enlarge diagram.

The generation of the neuronal signals in motor neurons that cause muscle contractions are dependent on the balance of synaptic excitation and inhibition that the motor neuron receives. Spasmolytic agents generally act by either enhancing the condition of inhibition, or reducing the level of excitation. Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, similar of the same kind with GABA. Because they may act at the level of the cortex, brain stem or spinal cord, or all three areas, they have traditionally been referred to as 'centrally-acting' muscle relaxants. However, it is now known that not every agent in this class has CNS activity (e.g. dantrolene), so this name is inaccurate.

Because of the enhancement of inhibition in the CNS, most spasmolytic agents have the side-effects of sedation, drowsiness and may cause dependence with long term use. Several of these agents also have abuse potential, and their prescription is strictly controlled.

The benzodiazepines, such considered in the state of diazepam, interact with the GABAA receptor in the central nervous system. While it be able to be used in patients with muscle spasm of towards any origin, it produces sedation in greatest in quantity individuals at the doses required to model muscle tone.

Baclofen is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. It acts as a GABA agonist at GABAB receptors in the brain and spinal string, resulting in hyperpolarization of neurons expressing this receptor, most pleasing due to increased potassium ion conductance. Baclofen also inhibits neural function presynaptically, by reducing calcium ion influx, and in consequence of that reducing the let out of excitatory neurotransmitters in both the brain and spinal cord. It may also reduce pain in patients by inhibiting the release of substance P in the spinal cord as well.

Clonidine and other imidazoline compounds have also been shown to abate muscle spasms by their central of the nerves system activity. Tizanidine is perhaps the most thoroughly learned clonidine analog, and is an agonist at 2-adrenergic receptors, moreover reduces spasticity at doses that result in significantly less hypotension than clonidine. Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity. Furthermore, several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, by a different spectrum of adverse effects.