B6. Pharmacology of 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).
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.
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.
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.
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.