Muscle relaxants

Muscle relaxants, also called, neuromuscular blockers or blocking agents, sometimes called peripheral muscle relaxants to separate them from the centrally acting muscle relaxants, is a group of drugs which inhibit the transmission from nerves to skeletal muscles, thereby paralysing them.

Muscle relaxants are used during surgery to induce muscle paralysis and relaxation to allow for easier intubation and ventilation of the patient during anaesthesia. These drugs do not cause anaesthesia, so anaesthetic drugs must be supplied as well, to prevent the patient from being completely immobilised but completely awake. Muscle relaxants are administered intravenously and act on all skeletal muscles, including the respiratory muscles. There are two types of neuromuscular blockers, non-depolarizing and depolarizing types.

They must be used with care in people with neuromuscular diseases like myasthenia gravis. Their effect can be monitored intraoperatively by train-of-four (TOF).

Compounds

Prejunctionally-acting agents	Non-depolarizing neuromuscular blockers	Depolarizing neuromuscular blockers	Drugs for reversal of neuromuscular blocking
Botulinum toxin	(Cis)atracurium	Suxamethonium (succinylcholine)	Sugammadex
Hemicholinium	Mivacurium		Neostigmine
Triethylcholine	Pancuronium
Vesamicol	Rocuronium
	Tubocurarine
	Vecuronium

Neuromuscular junction

The neuromuscular junction (NMJ) is the most important synapse. It’s the synapse between the nervous system and the skeletal muscle. More specifically, it’s the synapse between the axon of the alpha motor neuron in the anterior horn of the spinal cord and the skeletal muscle it innervates.An action potential travels down the axon of the alpha motor neuron, eventually reaching the presynaptic membrane, which becomes depolarized. This depolarization opens voltage-gated Ca2+ channels on the presynaptic membrane, which allows Ca2+ to flow into the end of the axon. This Ca2+ inflow triggers the release of acetylcholine from the presynaptic vesicles into the synaptic cleft.

The acetylcholine diffuses across the synaptic cleft and binds to the nicotinic acetylcholine receptors on the motor end plate. The nicotinic acetylcholine receptor is a non-selective cation channel, meaning that when acetylcholine binds to it, the ion channel will open and allow Na+ and K+ to enter the cell.

The influx of positive ions into the motor end plate causes an end plate potential (EPP) to form, which causes the threshold to be reached. This causes voltage-gated Na+ channel to open, which causes depolarization. This will initiate a series of events which eventually cause the muscle to contract.

After having bound to the nicotinic acetylcholine receptors and having caused the EPP, acetylcholine will eventually unbind from the receptor. The enzyme acetylcholinesterase, which exists in the synaptic cleft, will hydrolyse (break down) acetylcholine into acetate and choline. This “ends” the synaptic transmission. Choline is taken up by the presynaptic membrane which will reuse it to form more acetylcholine, getting ready for the next action potential to arrive.

Non-depolarising neuromuscular blockers

The non-depolarising muscle relaxants are competitive inhibitors of acetylcholine at the nicotinic acetylcholine receptor. Neostigmine and atropine can be used as an antidote for all of these. Vecuronium and rocuronium have a specific antidote called sugammadex.

The effect of this type of drug is called curarization (after the prototype drug, tubocurarine), and the process of reversing the effect is called decurarization.

Compounds

• Atracurium
• Cisatracurium
• Mivacurium
• Pancuronium
• Rocuronium
• Tubocurarine
• Vecuronium

Less important drugs in italic.

Indications

Non-depolarizing neuromuscular blockers are usually used for long-term skeletal muscle paralysis. The paralysis occurs within 1-5 minutes of parenteral administration. They last for 20-90 minutes, depending on the drug. They are all quaternary amines, meaning they are not well absorbed from the gut and they do not cross the blood-brain barrier.

The medical uses of neuromuscular blockers are the following:

The main medical use of neuromuscular blocker is to make endotracheal intubation easier and less risky. This is most frequently performed before induction of general anaesthesia, as general anaesthetics also stops the patient from breathing and protecting their own airways. They may also be used to make certain surgeries easier by reducing patient movement and muscle tone. Rocuronium has a fast onset of action and can be used for rapid sequence intubation.

Tubocurarine is a plant poison and is the “prototype” for most non-depolarizing neuromuscular blockers. It has a long duration of action. It causes significant ganglion blockade and histamine release, which makes it unfit for clinical practice.

Mechanism of action

The non-depolarizing neuromuscular blockers are competitive antagonists of the postsynaptic nicotinic acetylcholine receptors in the neuromuscular junction. In other words, they bind to the postsynaptic receptors that acetylcholine usually binds to and prevent acetylcholine from binding to it. This does so that the signal from the motoneuron is unable to cross the synaptic cleft, which prevents the muscle from depolarizing. Hence, the name non-depolarizing.

The sequence of paralysis is the external eye muscles, then the facial muscles, then the pharyngeal muscles, then the extremities, then trunk, and finally the respiratory muscles. The paralysis subsides in the reverse order.

Reversal

Decurarization can be accomplished by reversible cholinesterase inhibitors like neostigmine. These cholinesterase inhibitors allow acetylcholine to remain longer in the synaptic cleft, which gives them a larger opportunity to compete with the blocker drugs and eventually outcompete them.

Sugammadex is a drug that can bind to vecuronium and rocuronium in plasma to inhibit their effect, thereby decurarizing without the administration of cholinesterase inhibitors, making muscle relaxant reversal simpler. Sugammadex is expensive, however, and so is not widely used everywhere yet.

Side effects

Because nicotinic receptors are found on autonomic ganglia as well (both parasympathetic and sympathetic), some of these drugs (like pancuronium) can have ganglion-blocking effects as well, causing side-effects like hypotension and tachycardia.

Some drugs belonging to this class are also highly basic (alkaline), which triggers histamine release, causing side-effects like bronchospasm, itching and hypotension. This is true for atracurium and mivacurium. Cisatracurium is similar to atracurium but doesn’t cause histamine release.

Vecuronium and rocuronium have fewest side effects.

Interactions

The effect of non-depolarizing muscle relaxants is increased by general anaesthetics, aminoglycosides and tetracycline, two classes of antibiotics. It is also increased in myasthenia gravis patients, as they have a lower number of functional nicotinic receptors.

The effect is decreased by cholinesterase inhibitors and by upper motoneuron lesions, as these cause the postsynaptic membrane to have more nicotinic receptors.

Pharmacokinetics

Most of these drugs are quaternary ammonium compounds and therefore poorly absorbed, but they're not used for oral administration anyway. Most are excreted by the kidneys.

• Short duration of action and fast onset
  • Mivacurium
  • Rocuronium
• Intermediate duration of action and intermediate onset
  • (Cis)atracurium
  • Vecuronium
• Long duration of action and slow onset
  • Pancuronium
  • Tubocurarine

Mivacurium and atracurium are mostly eliminated by enzymatic hydrolysis, mivacurium by butyrylcholinesterase in the plasma. Atracurium is broken down by spontaneous non-enzymatic hydrolysis in plasma, called Hofmann elimination.

Depolarizing neuromuscular blockers

Only one drug belongs to this category, suxamethonium, also called succinylcholine. It works in a very different manner than the non-depolarizing type. Suxamethonium is a strong nicotinic acetylcholine receptor agonist, thereby completely depolarising the muscle, preventing it from consciously depolarising. It also downregulates the number of acetylcholine receptors on the skeletal muscle.

Indications

Suxamethonium has the fastest onset of action of all the muscle relaxants, and the shortest duration of action (5-10 minutes). This makes it the best fit for so-called rapid sequence intubation, where intubation must occur quickly. It’s not often used for maintenance of muscle relaxation during surgery.

Mechanism of action

Suxamethonium is also called succinylcholine, and is, as the name implies, structurally similar to acetylcholine. This drug is actually a nicotinic receptor agonist, which causes the skeletal muscle to depolarize when it binds to the receptor. However, unlike acetylcholine, suxamethonium cannot be hydrolysed by acetylcholinesterase, only by butyrylcholinesterase, which is slower than acetylcholinesterase, meaning that when it binds to a receptor, it will stay bound for a long time.

By staying bound to the nicotinic receptor, the muscle cell will stay depolarized (-50mV membrane potential). This causes the voltage-gated Na+ channels to be unable to go back to the resting state, which makes the postsynaptic membrane unable to be excited, and the muscle unable to contract, causing paralysis! This is called the phase I block. This wave of depolarisation is visible on the patient as fasciculations, followed by flaccid paralysis.

If cholinesterase inhibitor were to be administered during the phase I block, the strength of the block will be increased, because succinylcholine will stay even longer. This has no clinical relevance but is useful to think about to understand the physiology.

There is also a phase II block, which only occurs when the suxamethonium treatment has lasted for a certain amount of time. The postsynaptic membrane slowly repolarizes as suxamethonium is unbound from the receptors and hydrolysed; however, the nicotinic receptors are now severely desensitized because the drug has been bound to them for so long. Densensitization means that the cell has removed many receptors from the membrane surface, so that very few receptors are now present. There are so few present that even if acetylcholine binds to the receptors is it not enough to cause depolarization.

In contrast to in phase I, administration of cholinesterase inhibitors will reverse the phase II block, because the inhibitors allow endogenous acetylcholine to stay for longer. When Ach can stay longer they compensate for the low number of receptors and cause depolarization.

Pharmacokinetics

Succinylcholine is hydrophilic, meaning it is poorly absorbed from the gut and does not enter the brain. The effect of succinylcholine is prolonged in people with genetic cholinesterase deficiency, in infants, in patients with liver damage, by cholinesterase inhibitors and by other drugs that are metabolized by butyrylcholinesterase.

Adverse effects

The excessive depolarization of muscles causes large efflux of potassium ions, potentially causing hyperkalaemia. Malignant hyperthermia, increased intragastric pressure and vomiting (caused by depolarization of muscles of the abdominal wall can also occur.

Malignant hyperthermia

Malignant hyperthermia is a genetic condition where the patient has a certain mutation in the gene for the ryanodine receptor, which causes enormous Ca2+ release from the sarcoplasmic reticulum in response to succinylcholine or inhaled general anaesthetics. It causes isotonic muscle contractions of all muscles in the body, which increases heat production. The increased energy need will cause a switch to anaerobic metabolism and therefore cause lactic acidosis. The muscle fibres can degenerate (rhabdomyolysis) which releases myoglobin into the blood, which can cause acute renal failure.

It is treated with dantrolene, a ryanodine receptor blocker, bicarbonate for the acidosis and physical cooling to prevent damage from the hyperthermia.

Prejunctionally acting muscle relaxants

Some drugs don’t directly affect the postsynaptic nicotinic receptors but instead the presynaptic release of acetylcholine. These include hemicholinium, triethylcholine and vesamicol, none of which have clinical relevance and probably aren’t important.

Botulinum toxin is used in cosmetic surgery, blepharospasm, strabismus, spasticity, hyperhidrosis and overactive bladder. The effect lasts for several months.