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Skeletal Muscle Relaxants Pharmacology

Reading time: 8 minutes, 15 seconds

Skeletal muscle relaxants are drugs that cause a flaccid paralysis of skeletal musculature by binding to motor endplate cholinoceptors blocking neuromuscular transmission.

These agents are used as adjuncts to general anesthetics to help in ensuring that surgery is not disturbed by muscle contractions.

These drugs work by preventing acetylcholine from interacting with the postsynaptic receptors known as nicotinic receptors located on the motor end plate on the skeletal muscle membrane .

Classification of skeletal muscle relaxants

Skeletal muscle relaxants are classified into two main categories and named to based on what is thought to be their mechanism of action.

A. Central acting relaxants

These relaxants include:

  • Carisprodol
  • Baclofen
  • Chlorphenesin
  • Chlorzoxazone
  • Mefenesin
  • Methocarbamol
  • Tinazidine

They excert their action as a result of central nervous system depression.

B. Direct acting relaxants

An example is dantrolene sodium.

C. Neuromascular blocking agents

One can distinguish nondepolarizing from depolarizing muscle relaxants as to whether the receptor occupancy causes a blockade or an excitation of the endplate.

Skeletal muscle relaxants are divided into three categories:

  • Non-depolarizing (competitive) blocking agents
  • Depolarizing blocking agents
  • Miscellaneous blocking agents

Non-depolarizing neuromascular blockers

d-tubocurarine contains a quaternary nitrogen atom (N) and, at the opposite end of the molecule, a tertiary N that is protonated at physiological pH.

These two positively charged nitrogen atoms are common to all other muscle relaxants. In d-tubocularine.

Non-depolarizing neuromuascular blockers compete with acetylcholine and block its access to the postsynaptic receptor sites on the muscle but do not cause depolarization. These agents are also known to block presynaptic receptors that are responsible for facilitating the release of acetylcholine.

The time to maximum effect is between 1.5 -3 minutes and is relatively slow compared to depolarizing agents such as suxamethonium.

d-Tubocularine is used following suxamethonium to maintain muscle relaxation during surgery and to facilitate tracheal intubation in non-urgent situations.

d-Tubocurarine is administered through an intravenous  injection with an approximate dose of 10 mg.

The drug excerts its effects or works by binding to the endplate nicotinic cholinoceptors without exciting them therefore it acts as a competitive antagonist towards acetylcholine. This antagonist activity prevents the binding of released acetylcholine blocking neuromuscular transmission and muscular paralysis ensues within about 4 minutes.

The agent, d-Tubocurarine does not penetrate into the central nervous system. Therefore it may be associated with an interesting phenomena whereby a patient might experience motor paralysis and an inability to breathe, while he/she is fully conscious but unable to express anything. To prevent this, one must take care to eliminate consciousness by administering appropriate general anesthesia before giving a muscle relaxant.

The duration of action of a single dose is about 30 minutes.

Administration of an acetylcholinesterase inhibitor, such as pyridostigmine or neostigmine shortens the duration of action of d-tubocurarine.

By inhibiting acetylcholine breakdown, there is a rise in the concentration of acetylcholine released at the endplate.

Competitive “displacement” by ACh of d-tubocurarine from the receptor allows transmission to be restored.

Side effects of d-Tubocularine

Side effects of tubocularine result from a nonimmune mediated histamine release from mast cells, causing hypotension (low blood pressure), bronchospasm and urticaria.

Hypotension results due to ganglionic blockade by d-tubocurarine.

Pancuronium is a synthetic compound that is now commonly used. This agent does not cause histamine release or ganglionic blockade.

Pancuronium is approximately five times more potent than d-tubocurarine,and has a somewhat longer duration of action.

Pancuronium is associated with an increased heart rate and high blood pressure due to blockade of cardiac M2-cholinoceptors. Newer pancuronium congeners like vecuronium and pipecuronium do not cause tachycardia or hypertension.

Other nondepolarizing skeletal muscle relaxants include: alcuronium, a derivative of an alkaloid toxiferin; mivacurium, gallamine, rocuronium, and atracurium.

The latter agent is cleaved spontaneously and does not depend on hepatic or renal elimination.

These drugs work by competing with acetylcholine for receptors on the motor end plate. Therefore there effects can be reversed using anticholinesterases such as neostigmine and pyridostigmine.

This class of skeletal muscle relaxants has a longer duration of action than depolarizing blocking agents therefore making them to be the preferred choices for long surgical procedures.

Depolarizing blocking agents

Drugs under this category are suxamethonium and decamethonium.Succinylcholine is also known as succinyldicholine or suxamethonium, and is the clinically important drug.

Structurally, these agents resemble a double acetylcholine molecule. Suxamethonium works by acting as an agonist depolarizing the motor endplate nicotinic cholinoceptors just like acetylcholine, inhibiting its action and produces muscle relaxation.

Of importance to note is that, Suxamethonium is not hydrolyzed by acetylcholinesterase enzyme like in Acetylcholine. However,Suxamethonium is a substrate of nonspecific plasma cholinesterase known as serum cholinesterase.

Suxamethonium is degraded more slowly than acetylcholine. Due to this reason it remains in the synaptic cleft for longer, causing a longer endplate depolarization.

This depolarization initially triggers a propagated action potential in the surrounding muscle cell membrane, causing a contraction of the muscle fiber. This is why it is associated with fine muscle twitching known as fasciculations after an intravenous injection..

If the membrane is allowed to repolarize, then there is a triggering of a new action potential due to opening of voltage gated sodium-channes, allowing sodium ions to flow through the sarcolemma causing depolarization. These channels are then inactivated or automatically closed and the membrane potential returns to resting levels terminating the action potential.

Generation of a new action potential is usually impossible as long as the membrane potential remains incompletely repolarized, renewed opening of sodium channels.

If acetylcholine is released,a rapid breakdown by acetylcholinesterase allows repolarization of the endplate returning the sodium channel excitability in the adjacent sarcolemma.

With succinylcholine (Suxamethonium) there is a persistent depolarization of the motor endplate and adjoining membrane regions. But because the sodium channels remain inactivated, an action potential can’t be triggered in the adjacent membrane.

If the action potential fails, then the skeletal muscle fiber remains in a relaxed state.

This drug is often used at the start of anesthesia to facilitate intubation.It’s effect lasts only about 10 minutes.

The effect of depolarizing skeletal muscle relaxants cannot be counteracted by cholinesterase inhibitors. The effect of succynylcholine is prolonged in patients who have a genetic deficiency in pseudocholinesterase.

The drug is associated with an increased risk of cardiac arrythmia due to persistent depolarization of endplates associated with an efflux of potassium ion causing hyperkalemia (elevated serum potassium levels).

This agents are associated with increased Intraocular pressure therefore care must be taken during eye surgery.

Succinylcholine might evoke a persistent depolarization with development of a contracture and hyperkalemia in skeletal muscle fibers whose motor nerve has been severed,because acetylcholine receptors spread in a few days over the entire cell membrane. This effect are likely to occur in polytraumatized patients who are undergoing follow-up surgery.

Succynylcholine comes ready prepared in 50 mg/mL, 2 mL ampoules.

An adult dose is 1.5mg/kg administered intravenously. A short perioud of muscle twitching or fasculations occurs after injection as the muscle membrane is depolarized, followed by muscular paralysis in 40–60 seconds.

Recovery from its effects occurs spontaneously as suxamethonium is hydrolysed by the enzyme plasma pseudocholinesterase, and normal neuromuscular transmission is restored after 4–6 minutes.

Its rapid onsetor action makes it to be the drug of choice in facilitating tracheal intubation in a rapid sequence induction technique.

Suxamethonium has no direct effect on the cardiovascular, respiratory, or central nervous systems. Bradycardiaor slow heart rate occurs secondary to vagal stimulation  very large doses or repeated doses are administered. This secondary bradycardia is avoided by pretreatment with atropine.

Side effects of suxamethonium

  • Malignant hyperpyrexia in susceptible patients 
  • Increased intraocular pressure
  • Muscular pain around the limb girdles, 24 hours after administration in young adults
  • Anaphylaxis due to histamine release
  • Prolonged apnoea

A massive rise in serum potassium may provoke arrhythmias in patients with: burns after the burn denervation injury or in patients with muscle dystrophies, e.g. Duchenne’s crush injury

Miscellaneous blocking agents

Miscellaneous blocking agents such as botulinum A toxin and carbolonium prevent the release of acetylcholine at the motor end terminal.

Anticholinesterases inhibits the action of the enzyme acetylcholinesterase, leading to an increase in the concentration of acetylcholine within the synaptic cleft of the neuromuscular junction.

They are only used once there is return of at least two twitches on peripheral nerve stimulation using the train-of-four assessment. If used in the presence of more profound neuromuscular block there is an increased chance of residual muscle paralysis in the immediate postoperative period.

Skeletal muscle relaxant effect reversal

Anticholinesterases also increase the amount of acetylcholine within parasympathetic synapses, causing bradycardia, spasm of the bowel, bladder and bronchi,snd  increased bronchial secretions.

To prevent these muscarinic effects, anticholinesterases are administered with a suitable dose of an anti-muscarinic.

The most commonly used anticholinesterase is neostigmine with a fixed dose of 2.5 mg intravenously is used in adults whose  maximal effect is seen after approximately 5 min and lasts for 20–30 min. It is given concurrently with either atropine 1.2 mg or glycopyrrolate 0.5 mg.

Sugammadex is able to reverse any intensity of neuromuscular block that is induced by drugs of the aminosteroid group, such as vecuronium and rocuronium.

The dose needed, and time taken, for complete return of neuromuscular function vary depending on the intensity of the neuromuscular block to be reversed.

Sugammadex is a doughnut-shaped molecule that surrounds a molecule of neuromuscular blocker in the plasma, rendering it inactive.

Its use eliminated the need for, and unwanted side-effects of, both anticholinesterases and antimuscarinics when reversing residual neuromuscular block.


Post References

  • Revised on: 2021-07-10 03:48:21