Table of Contents
Skeletal muscle relaxants: drugs indicated during surgery/intubation to induce muscle relaxation/paralysis and for painful conditions due to muscle spasticity.
Depolarizing relaxants: relaxation of muscles achieved by persistent depolarization of the receptors at the end plate of skeletal muscle fibres (succinylcholine).
Non-depolarizing relaxants: relaxation of muscles achieved by antagonistic action on the nicotinic receptors at the end plate of skeletal muscle fibres (rocuronium).
Spasmolytics: relieve the painful conditions that arouse due to muscle contractions (dantrolene).
Classification of Skeletal Muscle Relaxants
- Short-acting: rocuronium
- Intermediate-acting: pancuronium, pipecuronium
- Long-acting: tubocurarine
- Acute use: Cyclobenzaprine
- Chronic use:
- via CNS: baclofen, diazepam, tizanidine
- on muscle (direct-acting): dantrolene
Mechanism of Action of Skeletal Muscle Relaxants
In order to understand the mechanism of action of skeletal muscle relaxants, it is important to first understand how the skeletal muscle contracts.
Muscle contraction is mediated by signals from the motor axons of the nervous system. At the neuromuscular junction, acetylcholine is released from presynaptic terminal and binds to the nicotinic receptors on the motor end plate to generate an end-plate potential (EPP).
Important: end-plate potential (EPP) is produced due to influx of Na+ ions.
The end-plate potential initiates the process of muscle contraction by depolarization of muscle fibres.
Always remember: Muscle relaxants act at the motor neuron end plate (please see the illustration).
Muscle relaxation can be medically induced by blocking the transmission at the level of the end plate. It is used during surgery, intubation and mechanical ventilation. Drugs used for this purpose are amines and are similar in structure to ACh in order to interact with nicotinic receptors. There are of two types: non-depolarizing and depolarizing.
Non-depolarizing neuromuscular blockers are antagonists of nicotinic receptors and do not cause depolarization of the skeletal muscle. These drugs are also called competitive blockers because they compete with ACh for binding at neuromuscular junctions.
A typical member of this group of neuromuscular blocking agent is tubocurarine. The action of these drugs can be surpassed with agents that have a higher affinity for nicotinic receptors or by increasing the levels of agonists (ACh) at the end plate (by usage of cholinesterase inhibitors).
Depolarizing neuromuscular blockers are agonists of the nicotinic receptors. There is only one drug used clinically for the purpose of muscle relaxation that acts through depolarization of skeletal muscle – succinylcholine. It causes persistent depolarization of the muscle.
After the muscle is depolarized, contraction is impossible. Because of the initial depolarization, fasciculations can be seen at the beginning of succinylcholine administration.
The process of depolarization by succinylcholine occurs in two phases:
Phase 1 starts with opening of sodium channels attached with the nicotinic receptors resulting in depolarization of receptor. This causes transient twitching of muscle.
Phase 2 includes continuous binding of the depolarizing agent to the receptor, which makes it incapable of transmitting impulses. When this continues, gradual repolarization of the sodium channel takes place thus blocking it and resulting in resistance to depolarization and flaccid paralysis.
Muscle relaxation can be induced by agents called spasmolytics, which act on the central nervous system. Spasmolytics made for chronic use (baclofen, diazepam, and tizanidine) are active in the spinal cord and they work at the level of primary spinal motor neuron.
Baclofen is GABAB agonist and it causes hyperpolarization of the membrane.
Diazepam interacts with GABAA receptors and facilitates inhibition.
Tizanidine has α2 agonist function. It is indicated in spasticity caused by neurological disorders such as multiple sclerosis and spinal cord injury.
Dantrolene acts on the ryanodine receptor (RyR1) channel. Dantrolene is relatively selective for skeletal muscle as cardiac and smooth muscles are almost unaffected by this drug. It is also used in treatment of malignant hyperthermia – a state caused by sudden and massive release of calcium from skeletal muscle. This disorder is extremely rare, but usually caused by general anesthesia. It is administered via IV route (1 mg/kg repeated as required).
Agents used for acute muscle relaxation are usually administered when muscle is injured. Cyclobenzaprine is a prototype of this group. The mechanism of action of this drug is not fully understood, but it is believed that it disturbs the maintenance of skeletal muscle tone. It can be administered orally.
Pharmacology of Neuromuscular Blocking Agents
Non-depolarizing neuromuscular blocking agents are always given parenterally. Their polarity insures they do not cross the blood-brain barrier. This is why they have to be used after the administration of sedatives in general anesthesia protocols.
They can be metabolized by plasma cholinesterase, in liver or kidney. Typically, those eliminated by kidneys have the longest effect on muscles. Examples of these drugs are metocurine, pancuronium, pipecuronium, and tubocurarine. Their effect usually lasts for less than 35 minutes.
Mivacurium is metabolized by plasma cholinesterase, which ensures a shorter period of action (10-20 min). As patients with renal failure have lower levels of plasma cholinesterase, this drug will be active for longer periods of time in these patients.
Vecuronium (half life of 3.3-9 min) is mostly excreted from the body through the bile/feces. It has shorter duration of action (20-35 min). It is a drug of choice for patients with cardiovascular diseases.
Atracurium has dual metabolism (via kidney and liver). It is metabolized in the liver, but it also breaks down spontaneously, forming several different products. One of these metabolites is laudanosine (crosses BBB) and is known to cause seizures. For this reason, cisatracurium (a cis-isomer of atracurium) is used more often, as its breakdown produces less amount of laudanosine. Both of these are drug of choice for patients with renal or hepatic impairments.
Of depolarizing neuromuscular blocking agents, the only agent that is used clinically is succinylcholine. This drug is metabolized both in plasma and in the liver. Injection of succinylcholine IV results in redistribution of the drug and hydrolysis by pseudocholinesterase in liver and plasmas resulting in a short duration of action. Continuous infusion will produce longer duration of action. It is the most commonly used muscle relaxant during endotracheal intubation.
Important: off-label use of succinylcholine is to reduce the intensity of muscle contractions of electroconvulsive therapy (ECT).
Succinylcholine can interact with inhaled anaesthetics and cause malignant hyperthermia. Contraction of jaw muscles is the first sign seen in this condition.
Pharmacology of Spasmolytics
Spasmolytics for acute use
Prototype drug for this group is cyclobenzaprine. It is administered orally and has both sedative and antimuscarinic mechanism of action. Other drugs used in the relaxation of muscle spasm caused by muscle injury are metaxalone, methocarbamol, and orphenadrine. If spasm is caused by disorders such as cerebral palsy or injury of the motoneuron, none of these medications will be effective in the treatment.
Spasmolytics for chronic use
These agents are not similar to ACh both in structure and in the effect. Members of this group have different mechanisms of action and are suitable for treatment of chronic conditions that cause excessive muscle tonus.
Important: some of the muscle relaxants are also used in the management of back pain mostly in combination with NSAIDs.
Diazepam is a member of the benzodiazepine family; baclofen is a GABA agonist, tizanidine is a similar agent to clonidine, and dantrolene is the only agent in this group that acts peripherally (a direct-acting muscle relaxant). These drugs can be given orally.
Baclofen can also be given intrathecally. Botulinum toxin can also be used if severe spasm is causing pain or reduces function (contractions of orbicularis oculi). Drugs like gabapentin and pregabalin, usually used as antiseizure medications, have been shown to be effective in patients suffering from multiple sclerosis.
Adverse Effects and Toxicity of Skeletal Muscle Relaxants
Neuromuscular blocking agents
Neuromuscular blocking agents are administered to cause skeletal muscle paralysis/relaxation and make surgical procedures/intubation possible.
A common side effect of succinylcholine is muscle pain because it works by tiring out/depolarizing muscles; the pain can vary from mild pain to serious muscle damage.
During muscle contraction at the beginning of succinylcholine administration, regurgitation leading to asphyxiation is possible. Succinylcholine may also cause hyperkalemia.
Other side-effects of succinylcholine:
The action of muscle relaxant is potentiated by inhaled anesthetics. Isoflurane is especially known for this interaction. Specific interaction of succinylcholine is malignant hyperthermia. Trismus in any patient undergoing general anesthesia should be an alarming sign, as it can be the first sign of development of malignant hyperthermia.
Patients with myasthenia gravis and older patients are more responsive to neuromuscular blocking agents, and burn victims and patients with upper motor neuron damage are less responsive to neuromuscular blockade.
Non-depolarizing muscle relaxants such as tubocurarine and mivacurium cause histamine release. Side-effects are mostly related to histamine release (erythema of neck and torso) and mild/non-threatening in nature. Anaphylactic reactions are rare with muscle relaxants.
Pancuronium, alcuronium, and rocuronium have direct vagolytic actions.
Adverse Effects of Spasmolytics
Diazepam can cause sedation, hypotension, ataxia, and respiratory depression.
Baclofen causes drowsiness, slurred speech, hypotension, constipation and urinary retention.
Asthenia, drowsiness, hypotension and dry mouth are the major side effects of tizanidine.
Most common side-effects of dantrolene are drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea.
Cyclobenzaprine most commonly causes drowsiness, dizziness, headache and dry mouth.