Pharmacology of Skeletal Muscle Relaxants

Introduction

Skeletal muscle relaxants are a diverse group of medications that act on the central nervous system (CNS) or directly on skeletal muscles to reduce muscle tone and alleviate symptoms such as muscle spasms, pain, and hyperreflexia (Katzung & Trevor, 2021). These drugs are commonly used in various clinical settings, including anaesthesia, neurology, and pain management. In this article, we will delve into the pharmacology of skeletal muscle relaxants, discussing their classification, mechanisms of action, pharmacokinetics, clinical uses, adverse effects, and drug interactions.

Classification of Skeletal Muscle Relaxants

Skeletal muscle relaxants can be broadly classified into two categories: centrally acting agents and peripherally acting agents (Brunton, Hilal-Dandan, & Knollmann, 2018).

Centrally Acting Muscle Relaxants

Centrally acting muscle relaxants work by inhibiting the transmission of nerve impulses in the CNS, particularly in the spinal cord. This group includes:

1. Benzodiazepines (e.g., diazepam)
2. Baclofen
3. Tizanidine
4. Cyclobenzaprine
5. Methocarbamol
6. Carisoprodol

Peripherally Acting Muscle Relaxants

1. Dantrolene
2. Botulinum Toxin
3. Neuromuscular Blocking Agents

Neuromuscular blocking agents (NMBAs) are a group of peripherally acting muscle relaxants that act at the neuromuscular junction to cause paralysis. They are primarily used during surgical procedures to facilitate endotracheal intubation and optimize surgical conditions (Katzung & Trevor, 2021). NMBAs can be classified into two categories based on their mechanism of action: depolarizing and non-depolarizing blockers.

1. Depolarizing agents (e.g., succinylcholine)
2. Non-depolarizing agents (e.g., rocuronium, vecuronium, and cisatracurium)

Mechanisms of Action

Centrally Acting Muscle Relaxants

1. Benzodiazepines: These drugs enhance the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS. By binding to the GABA-A receptor, benzodiazepines increase the frequency of chloride channel opening, leading to hyperpolarization of the postsynaptic membrane and reduced neuronal excitability (Katzung & Trevor, 2021).
2. Baclofen: Baclofen is a GABA-B receptor agonist that inhibits the release of excitatory neurotransmitters, such as glutamate and substance P, in the spinal cord. This results in reduced synaptic transmission and muscle tone (Brunton et al., 2018).
3. Tizanidine: Tizanidine is an alpha-2 adrenergic receptor agonist that reduces muscle spasticity by inhibiting the release of excitatory amino acids in the spinal cord (Katzung & Trevor, 2021).
4. Cyclobenzaprine: Cyclobenzaprine is structurally similar to tricyclic antidepressants and acts centrally by reducing tonic somatic motor activity, possibly through antagonism of 5-HT2 receptors (Brunton et al., 2018).
5. Methocarbamol and Carisoprodol: The exact mechanisms of action for these drugs are not well understood, but they are thought to act centrally by depressing spinal polysynaptic reflexes (Katzung & Trevor, 2021).

Peripherally Acting Muscle Relaxants

1. Dantrolene: It is a unique muscle relaxant that acts directly on skeletal muscle by inhibiting the release of calcium from the sarcoplasmic reticulum (Katzung & Trevor, 2021). This action reduces the excitation-contraction coupling and leads to muscle relaxation.
2. Botulinum toxin: It is a neurotoxin produced by the bacterium Clostridium botulinum. It acts by inhibiting the release of acetylcholine at the neuromuscular junction, leading to flaccid paralysis (Brunton et al., 2018).
3. Depolarizing agents: Succinylcholine is the only depolarizing agent currently in clinical use. It is a structurally modified form of acetylcholine (ACh) with a longer duration of action. When administered intravenously, succinylcholine rapidly binds to nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction, mimicking the action of ACh (Katzung & Trevor, 2021). This leads to the opening of ion channels and an influx of sodium ions, causing sustained depolarization of the postsynaptic membrane. Initially, this depolarization results in brief muscle fasciculations, which are visible contractions of the skeletal muscles. However, as the depolarization persists, the postsynaptic membrane becomes refractory to further stimulation, leading to a state of flaccid paralysis (Brunton et al., 2018). Succinylcholine has a rapid onset of action (30-60 seconds) and a short duration of action (5-10 minutes) due to its rapid hydrolysis by plasma cholinesterase.
4. Non-depolarizing agents: Non-depolarizing agents, also known as competitive neuromuscular blocking agents, act by competing with ACh for binding to nAChRs at the neuromuscular junction. These drugs have a higher affinity for the receptors than ACh but do not activate them, thereby preventing depolarization and muscle contraction (Katzung & Trevor, 2021). Non-depolarizing agents can be further classified into two subgroups based on their chemical structure: benzylisoquinolinium compounds (e.g., atracurium, cisatracurium) and aminosteroid compounds (e.g., rocuronium, vecuronium). The onset and duration of action of non-depolarizing agents vary depending on their potency and physicochemical properties. For example, rocuronium has a rapid onset (1-2 minutes) and an intermediate duration (30-60 minutes), making it suitable for rapid sequence induction of anaesthesia (Brunton et al., 2018). On the other hand, cisatracurium has a slower onset (3-5 minutes) but a longer duration of action (60-90 minutes), making it useful for prolonged surgical procedures.

Pharmacokinetics

Centrally Acting Muscle Relaxants

1. Benzodiazepines: Diazepam is rapidly absorbed orally, with peak plasma concentrations occurring within 1-2 hours. It is extensively metabolised in the liver by CYP enzymes and has a long elimination half-life of 20-50 hours (Brunton et al., 2018).
2. Baclofen: Baclofen is rapidly absorbed after oral administration, with peak plasma concentrations reached within 2-3 hours. It undergoes minimal hepatic metabolism and is primarily excreted unchanged in the urine. The elimination half-life is 3-4 hours (Katzung & Trevor, 2021).
3. Tizanidine: Tizanidine is rapidly absorbed, with peak plasma concentrations occurring within 1-2 hours. It undergoes extensive first-pass metabolism in the liver by CYP1A2 and has a short elimination half-life of 2-4 hours (Brunton et al., 2018).
4. Cyclobenzaprine: Cyclobenzaprine is well absorbed orally, with peak plasma concentrations reached within 3-8 hours. It is extensively metabolised in the liver by CYP3A4 and has an elimination half-life of 18-24 hours (Katzung & Trevor, 2021).
5. Methocarbamol and Carisoprodol: These drugs are rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. They are metabolised in the liver and have elimination half-lives of 1-2 hours and 2-3 hours, respectively (Brunton et al., 2018).

Peripherally Acting Muscle Relaxants

1. Dantrolene: It is poorly absorbed orally, with peak plasma concentrations occurring within 3-6 hours. It undergoes hepatic metabolism and has a half-life of 8-10 hours (Brunton et al., 2018).
2. Botulinum toxin: It is administered by local injection into the affected muscles, with effects lasting for 3-6 months (Katzung & Trevor, 2021).
3. Succinylcholine: Succinylcholine is rapidly hydrolyzed by plasma cholinesterase, with an ultra-short duration of action (5-10 minutes) (Katzung & Trevor, 2021).
4. Non-depolarizing agents: The onset and duration of action vary among different agents, depending on their potency and physicochemical properties. Rocuronium has a rapid onset (1-2 minutes) and an intermediate duration (30-60 minutes), while cisatracurium has a slower onset (3-5 minutes) and a longer duration (60-90 minutes) (Brunton et al., 2018).

Clinical Uses

Centrally Acting Muscle Relaxants

1. Benzodiazepines: Diazepam is used to treat muscle spasms associated with various conditions, such as spinal cord injuries, cerebral palsy, and multiple sclerosis (Katzung & Trevor, 2021).
2. Baclofen: Baclofen is primarily used to treat spasticity resulting from spinal cord injuries, multiple sclerosis, and other neurological disorders (Brunton et al., 2018).
3. Tizanidine: Tizanidine is used to manage spasticity associated with multiple sclerosis, spinal cord injuries, and stroke (Katzung & Trevor, 2021).
4. Cyclobenzaprine: Cyclobenzaprine is used as an adjunct to rest and physical therapy for short-term relief of muscle spasms associated with acute musculoskeletal conditions (Brunton et al., 2018).
5. Methocarbamol and Carisoprodol: These drugs are used for the short-term treatment of acute, painful musculoskeletal conditions (Katzung & Trevor, 2021).

Peripherally Acting Muscle Relaxants

1. Dantrolene: It is primarily used to treat malignant hyperthermia, a life-threatening condition triggered by exposure to volatile anaesthetics and succinylcholine (Katzung & Trevor, 2021). It is also used to manage spasticity associated with cerebral palsy, multiple sclerosis, and spinal cord injuries (Brunton et al., 2018).
2. Botulinum toxin: Therapeutic uses of botulinum toxin include the treatment of focal spasticity, cervical dystonia, blepharospasm, and spasmodic dysphonia (Brunton et al., 2018).
3. Succinylcholine: Succinylcholine is used for rapid sequence induction of anaesthesia and to facilitate tracheal intubation (Brunton et al., 2018).
4. Non-depolarizing agents: These drugs are used to provide muscle relaxation during surgical procedures and to facilitate mechanical ventilation in critically ill patients (Katzung & Trevor, 2021).

Adverse Effects

Centrally Acting Muscle Relaxants

1. Benzodiazepines: Common adverse effects include sedation, dizziness, ataxia, and memory impairment. Respiratory depression can occur at high doses or when combined with other CNS depressants (Brunton et al., 2018).
2. Baclofen: Adverse effects include drowsiness, dizziness, weakness, and confusion. Abrupt discontinuation can lead to withdrawal symptoms, such as seizures and hallucinations (Katzung & Trevor, 2021).
3. Tizanidine: Common side effects include dry mouth, drowsiness, dizziness, and hypotension (Brunton et al., 2018).
4. Cyclobenzaprine: Adverse effects include drowsiness, dry mouth, dizziness, and constipation (Katzung & Trevor, 2021).
5. Methocarbamol and Carisoprodol: These drugs can cause drowsiness, dizziness, and gastrointestinal disturbances. Carisoprodol has a potential for abuse and dependence (Brunton et al., 2018).

Peripherally Acting Muscle Relaxants

1. Dantrolene: Adverse effects include muscle weakness, sedation, diarrhea, and hepatotoxicity. Liver function should be monitored during long-term treatment (Katzung & Trevor, 2021).
2. Botulinum toxin: Adverse effects are usually localised and include pain at the injection site, muscle weakness, and rarely, systemic effects such as dysphagia and respiratory compromise (Katzung & Trevor, 2021). Botulinum toxin should be used cautiously in patients with neuromuscular disorders, as it may exacerbate muscle weakness (Brunton et al., 2018).
3. Succinylcholine: Adverse effects include malignant hyperthermia, hyperkalemia, and prolonged paralysis in patients with pseudocholinesterase deficiency (Katzung & Trevor, 2021).
4. Non-depolarizing agents: Common side effects include hypotension, tachycardia, and histamine release. Residual neuromuscular blockade can occur, leading to respiratory complications (Brunton et al., 2018).

Drug Interactions

Centrally Acting Muscle Relaxants

1. Benzodiazepines: Concomitant use with other CNS depressants, such as opioids, alcohol, and barbiturates, can potentiate sedation and respiratory depression (Katzung & Trevor, 2021).
2. Baclofen: Baclofen can enhance the effects of other CNS depressants and antihypertensive agents (Brunton et al., 2018).
3. Tizanidine: CYP1A2 inhibitors, such as ciprofloxacin and fluvoxamine, can increase tizanidine concentrations and the risk of adverse effects (Katzung & Trevor, 2021).
4. Cyclobenzaprine: CYP3A4 inhibitors, such as erythromycin and ketoconazole, can increase cyclobenzaprine concentrations (Brunton et al., 2018).
5. Methocarbamol and Carisoprodol: These drugs can enhance the effects of other CNS depressants (Katzung & Trevor, 2021).

Peripherally Acting Muscle Relaxants

1. Succinylcholine: Concomitant use with aminoglycoside antibiotics, lithium, or magnesium can potentiate neuromuscular blockade (Brunton et al., 2018).
2. Non-depolarizing agents: Aminoglycoside antibiotics, magnesium, and local anaesthetics can enhance neuromuscular blockade. Corticosteroids and certain antibiotics (e.g., clindamycin) can cause resistance to non-depolarizing agents (Katzung & Trevor, 2021).

Monitoring and Reversal of Neuromuscular Blockade

Monitoring the depth of neuromuscular blockade is essential to ensure adequate muscle relaxation during surgery and to prevent residual paralysis postoperatively (Brunton et al., 2018). The most common method of monitoring is the train-of-four (TOF) stimulation, which involves applying four supramaximal electrical stimuli to a peripheral nerve and assessing the muscle response (Katzung & Trevor, 2021). A TOF ratio (the amplitude of the fourth twitch compared to the first) of less than 0.9 indicates residual neuromuscular blockade and warrants the use of reversal agents (Brunton et al., 2018).

Reversal agents for non-depolarizing NMBAs include acetylcholinesterase inhibitors, such as neostigmine, and selective relaxant binding agents, such as sugammadex (Katzung & Trevor, 2021). Neostigmine inhibits the breakdown of acetylcholine, increasing its concentration at the neuromuscular junction and competitively displacing the non-depolarizing blocker. However, neostigmine can cause muscarinic side effects, such as bradycardia and increased secretions, necessitating co-administration with an anticholinergic agent like glycopyrrolate (Brunton et al., 2018).

Sugammadex is a novel reversal agent that selectively binds to and encapsulates the non-depolarizing blocker, particularly rocuronium, rendering it inactive (Katzung & Trevor, 2021). Sugammadex has a rapid onset of action and can reverse even deep levels of neuromuscular blockade without the muscarinic side effects associated with neostigmine (Brunton et al., 2018). However, sugammadex is more expensive than neostigmine and may not be readily available in all settings (Katzung & Trevor, 2021).

Conclusion

Skeletal muscle relaxants are essential drugs in the management of various conditions characterized by muscle spasms, spasticity, and hyperreflexia. Understanding the pharmacology of these agents, including their mechanisms of action, pharmacokinetics, clinical uses, adverse effects, and drug interactions, is crucial for their safe and effective use in clinical practice. Centrally acting muscle relaxants, such as benzodiazepines, baclofen, and tizanidine, act on the CNS to reduce muscle tone, while peripherally acting agents, such as succinylcholine and non-depolarizing NMBAs, act directly on skeletal muscles to produce muscle relaxation. Healthcare professionals should carefully consider the individual patient’s needs, comorbidities, and concomitant medications when selecting and dosing skeletal muscle relaxants to optimise therapeutic outcomes and minimise the risk of adverse effects.

References

Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (2018). Goodman & Gilman’s: The pharmacological basis of therapeutics (13th ed.). McGraw-Hill Education.

Katzung, B. G., & Trevor, A. J. (2021). Basic & clinical pharmacology (15th ed.). McGraw-Hill Education.