Last updated on January 10, 2019 at 19:36
|Prejunctionally-acting agents||Non-depolarizing neuromuscular blockers||Depolarizing neuromuscular blockers||Drugs for reversal of neuromuscular blocking|
Sometimes, we need to use drugs to paralyze skeletal muscles. This type of drug is used during surgery to induce muscle paralysis and relaxation. These drugs to not cause anaesthesia, so anaesthetic drugs must be supplied as well. They’re supplied parenterally, so they act on all skeletal muscles, including the respiratory muscles. There are two types of neuromuscular blockers, non-depolarizing and depolarizing types.
The neuromuscular junction is the synapse between the axons of motoneurons and the skeletal muscle. The presynaptic terminal is the end of the axon, the postsynaptic membrane is the membrane of the skeletal muscle. The synaptic cleft is the space in-between.
Action potentials are conducted down the motoneuron, which depolarizes the presynaptic terminal. This opens voltage-gates Ca2+-channels, causing the presynaptic terminal to take in Ca2+. The Ca2+ influx causes the presynaptic terminal to release pre-synthetized acetylcholine into the synaptic cleft by exocytosis. The molecules of acetylcholine diffuse to the nicotinic acetylcholine receptor on the postsynaptic membrane, which opens Na+ and K+ ion channels, which depolarizes the postsynaptic membrane.
Prejunctionally acting agents
Some drugs don’t directly affect the postsynaptic nicotinic receptors but instead the presynaptic release of acetylcholine.
Hemicholinium and triethylcholine inhibit the synthesis of acetylcholine.
Vesamicol inhibits the storage of acetylcholine
Aminoglycosides, Mg2+-ions and botulinum toxin all inhibit the release of acetylcholine from the presynaptic neuron. Botulinum toxin is used in cosmetic surgery, blepharospasm, strabismus, spasticity, hyperhidrosis and overactive bladder. The effect lasts for several months.
Non-depolarizing neuromuscular blockers
The non-depolarizing type of 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.
Non-depolarizing neuromuscular blockers are usually used for long-term motor paralysis. The paralysis occurs within 1-5 minutes of parenteral administration. They last for 20-90 minutes, depending on the drug. Most of them are metabolized by the liver. They are all quaternary amines, meaning they are not well absorbed from the gut and they do not cross the blood-brain barrier.
Pharmacodynamics of non-depolarizing neuromuscular blockers
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.
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. 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.
Certain non-depolarizing neuromuscular blockers have unwanted effects as well. Because nicotinic receptors are found on autonomic ganglia as well (both parasympathetic and sympathetic), these drugs 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.
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 (which are used to remove their effect) and by upper motoneuron lesions, as these cause the postsynaptic membrane to have more nicotinic receptors.
The medical uses of neuromuscular blockers are the following:
- To supplement general anaesthesia by providing muscle relaxation
- Short muscle paralysis required for intubation, joint reposition or electroconvulsive therapy
- To turn off insufficient spontaneous ventilation during artificial ventilation
- To treat symptoms of epilepsy, tetanus, drug intoxications etc
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.
Doxacurium also has a long duration of action. It is eliminated by the kidneys.
Atracurium is inactivated in blood plasma by spontaneous (non-enzymatic) hydrolysis. This hydrolysis is slower in acidosis and faster in alkalosis. It causes some histamine release. It can cause seizures and is therefore not used clinically anymore.
Cisatracurium is a stereoisomer of atacurium that causes less histamine release and has fewer side-effects than atacurium. Cisatacurium has replaced atacurium in clinical practice.
Mivacurium is short-acting (10-20 minutes) as it is rapidly hydrolysed by butyrylcholinesterase in blood plasma, has a slower onset than succinylcholine (mentioned further down), and produces moderate amounts of histamine. It is therefore not preferred.
Vecuronium and rocuronium are steroid-derivatives which cause little histamine-release and ganglion-blockade. They have intermediate duration of action (20-40 minutes) and are metabolized primarily by the liver. Rocuronium has a very fast onset (1-2 minutes).
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.
Pipecuronium and pancuronium are also steroid-derivatives but have long duration of action. They are metabolized by the kidney and the liver.
Depolarizing neuromuscular blockers
Only one drug belongs to this category, succinylcholine (or suxamethonium). It works in a very different manner than the non-depolarizing type. Succinylcholine is actually a nicotinic receptor agonist, which causes the skeletal muscle to depolarize when it binds to the receptor. However, unlike acetylcholine, succinylcholine cannot be hydrolysed by acetylcholinesterase, only by butyrylcholinesterase, meaning that when succinylcholine 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. When cholinesterase inhibitors are administered during the phase I block, the strength of the block will be increased, because succinylcholine will stay even longer.
The postsynaptic membrane slowly repolarizes as succinylcholine is unbound from the receptors and hydrolysed; however, the nicotinic receptors are now severely desensitized because succinylcholine has been bound to them for so long. Densensitization means that there 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.
This is called a phase II block and is only seen when the succinylcholine treatment has lasted for a certain amount of time. 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 can they compensate for the low number of receptors and cause depolarization.
Succinylcholine is hydrophilic, meaning it is poorly absorbed from the gut and does not enter the brain. It has a short duration (5-10 minutes), meaning it is mostly used for intubation and repositioning of muscles. Continuous infusion is needed for longer procedures.
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.
Succinylcholine can cause several unwanted effects, like muscle pain, increased intraocular pressure, vomiting due to increased intragastric pressure, bradycardia, hyperkalaemia, and most importantly, 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 general anaesthetics. It causes isotonic muscle contractions of all muscles in the body, which causes increased heat production. The increased energy need will cause a switch to anaerobic metabolism and therefore lactic acidosis. The muscle fibres can degenerate 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.
15. Muscarinic receptor antagonists
17. Agents acting on the biosynthesis, storage, release and elimination of catecholamines