Skeletal Muscle Relaxants: Uses and Types

Uses of Skeletal Muscle Relaxants

• Skeletal muscle relaxants are used as an adjuvant in surgical anesthesia to achieve complete relaxation of skeletal muscle.
• They ease operative manipulations and endotracheal intubation.
• These relaxants counteract laryngospasm during barbiturate anesthesia and reduce the dosage of anesthetic agents.
• They shorten the post-anesthesia recovery period.
• Skeletal muscle relaxants treat cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, spinal injuries, trigeminal neuralgia, and malignant hyperthermia.
• These relaxants also treat muscle spasms of local origin, like spondylitis, sprains, and lumbago.

Peripheral Acting Muscle Relaxants

• Peripheral acting muscle relaxants act at the neuromuscular junction (NMJ) and fall into two categories.
• Non-depolarizing (competitive blockers) prevent access of ACh at the Nm receptor of the motor end plate, preventing depolarization.
• Long-acting non-depolarizing agents include pancuronium, doxacurium, and pipercuronium.
• Intermediate-acting non-depolarizing agents include vecuronium, atracurium, and rocuronium.
• Short-acting non-depolarizing agents include mivacurium and rapacuronium.
• Depolarizing agents act as agonists at ACh receptors; examples include succinylcholine (suxamethonium) and decamethonium.

Centrally Acting (Spasmolytic) Drugs

• These drugs have selective action in the cerebrospinal axis.
• Examples include carisoprodol, chlorzoxazone, chlormezanone, and methocarbamol.
• Diazepam and clonazepam act through GABAA receptors.
• Baclofen acts via GABAB receptors.
• Tizanidine is a central α2 agonist.
• Dantrolene acts directly by interfering with the release of calcium from the sarcoplasmic reticulum.

Mechanism of Skeletal Muscle Contraction

• The mechanism includes initiation of impulse, release of ACh, and activation of nicotinic receptors at the motor end plate.
• It also involves the opening of ion channels and the passage of Na+, leading to depolarization of the end plate and muscle contraction.

Mechanism of Action: Non-Depolarizing Agents

• At low doses, these drugs combine with nicotinic receptors and prevent acetylcholine binding, acting as competitive blockers.
• They prevent the depolarization of the endplate.
• These drugs inhibit muscle contraction and enhance the relaxation of skeletal muscles.
• Their action can be overcome by increasing the concentration of ACh in the synaptic gap via acetylcholinesterase enzyme inhibition (e.g., physostigmine, neostigmine).
• Anesthetists shorten the duration of the blockade and overcome overdosage using this method.
• At high doses, these drugs block ion channels of the end plate.
• This weakens transmission further and reduces the ability of acetylcholinesterase inhibitors to reverse the action.

Mode of Action and Pharmacokinetics

• All muscles are not equally sensitive to blockade.
• Small and rapidly contracting muscles are paralyzed first.
• Respiratory muscles are the last to be affected and the first to recover after surgery.
• These drugs are administered IV due to poor oral absorption as they remain ionized at physiological pH.
• They cross the blood-brain barrier poorly due to being poorly lipid soluble.
• They have limited Vd because they are highly ionized.
• Drugs excreted by the kidney have a longer duration of action (35-100 min).
• Drugs eliminated by the liver have an intermediate duration of action (25-50 min).
• Some drugs are inactivated spontaneously in plasma (Hoffman elimination).
• Others are inactivated by plasma cholinesterases, resulting in shorter action duration (15-20 min).
• Atracurium is degraded spontaneously in plasma by ester hydrolysis, releasing histamine and causing a fall in blood pressure, flushing, and severe bronchoconstriction; its metabolites can provoke seizures.
• Cisatracurium has similar pharmacokinetics but a better safety margin.

Drug Interactions and Adverse Effects

• Cholinesterase inhibitors like neostigmine, pyridostigmine, and edrophonium, if used with high doses, can cause depolarizing block due to elevated ACh concentration at the muscle end plate.
• Halothane, aminoglycosides, and calcium channel blockers act synergistically with these drugs.
• Adverse effects: reduction in arterial pressure (mainly due to ganglionic blockade), bronchospasm due to histamine release (e.g., with atracurium, tubocurarine, and mivacurium).
• Other adverse effects of skeletal muscle relaxants includes pancuronium blocking muscarinic receptors (causing tachycardia), hypoxia, and respiratory paralysis.

Depolarizing Agents Mechanism and Uses

• Depolarizing agents like Succinylcholine (Suxamethonium) act like ACh but persist at the synapse at high concentrations for a longer duration, constantly stimulating the receptor.
• They first open the Na+ channels, resulting in depolarization and transient twitching of the muscle, followed by continuous binding and receptor incapability of transmitting further impulses, leading to paralysis.
• Therapeutic uses include endotracheal intubation, bronchoscopy, laryngoscopy, and ECT (electroconvulsive shock therapy).

Pka (Pharmacokinetics) of Depolarizing Agents

• Administered IV and rapidly inactivated by plasma cholinesterases.
• Causes paralysis of skeletal muscle with the sequence of paralysis possibly differing from that of non-depolarizing agents, but respiratory muscles are paralyzed last.
• Produces a transient twitching of skeletal muscle before causing block.
• Causes maintained depolarization at the end plate, leading to loss of electrical excitability.
• Has a shorter duration of action (5-10 mins).
• It stimulates the ganglion (sympathetic and parasympathetic).
• Low doses produce negative ionotropic and chronotropic effects.
• Acts like ACh but diffuses slowly to the end plate, remaining long enough to cause depolarization and loss of electrical excitability.

Adverse Effects of Depolarizing Agents

• Bradycardia occurs and can be stopped by atropine.
• Hyperkalemia presents in patients with trauma or burns.
• It may cause arrhythmia or cardiac arrest.
• Increases intraocular pressure due to contraction of extra-ocular muscles.
• Intragastric pressure increases which may lead to emesis and aspiration of gastric content.
• Malignant hyperthermia, a rare inherited condition caused by a mutation in the Ca2+ release channel of the sarcoplasmic reticulum, results in muscle spasms and a dramatic rise in body temperature is an issue.
  • This is treated by cooling the body and administering Dantrolene. -Note: Halothane also causes malignant hyperthermia.
• Prolonged paralysis results, due to factors reducing plasma cholinesterase activity.
• Other risk factors include genetic variants as abnormal cholinesterase severe deficiency, anti-cholinesterase drugs, neonates, and liver disease.

Key Muscle Relaxants

• Tubocurarine: Slow onset (5 min), long duration (1-2 hrs), causes hypotension (ganglionic block) and bronchoconstriction; a plant alkaloid, rarely used; alcuronium semi-synthetic is preferred.
• Pancuronium: Intermediate onset (2-3 min), long duration, causes mild tachycardia, no hypotension; better due to mild side effects; pipecuronium is an alternative.
• Vecuronium: Intermediate onset, intermediate duration (30-40 min), few side effects; widely used, causes prolonged paralysis due to active metabolite; rocuronium is similar in action but faster.
• Atracurium: Intermediate onset, intermediate duration (20-30 min), causes transient hypotension (histamine release); widely used; doxacurium is similar but stable in plasma, giving a long duration of action; cisatracurium, an isomer, will release less histamine.
• Mivacurium: Fast onset (2 min), short duration (15 min), causes transient hypotension (histamine release); new, similar to atracurium but is rapidly inactivated by plasma cholinesterases, longer-acting in liver disease and genetic cholinesterase deficiency.
• Suxamethonium: Fast onset, short duration (10 min), causes bradycardia and cardiac arrhythmia; acts by depolarization, nicotinic effect; paralysis is preceded by transient muscle fasciculation; used for brief procedures; rocuronium is similar in action.

Centrally Acting Muscle Relaxants (Spasmolytic Agents)

• Mephenesin group includes carisoprodol, chlorzoxazone, chlormezanone, and methocarbomol.
• Diazepam and clonazepam (benzodiazepines) act through GABAA receptors.
• Baclofen acts via GABAB receptors.
• Tizanidine is a central α2 agonist.

Mechanisms Underlying Spasticity

• Stretch reflex arc and higher centers in the CNS (i.e., upper motor neuron lesion) with damage in descending pathways in the spinal cord result in hyperexcitability of the alpha motor neurons in the spinal cord.

Basis of Pharmacotherapy for Spasticity

• Therapies alleviate some spasticity symptoms by modifying the stretch reflex arc.
• It can also be improved by directly interfering with skeletal muscle via excitation-contraction coupling.

Baclofen

• It acts via GABAB receptors.
• Causes hyperpolarization by increased K+ conductance, which reduces calcium influx and excitatory transmitter release in the brain and spinal cord.
• Reduces pain via inhibition of substance P in the spinal cord and has less sedative activity.
• Pka (Pharmacokinetics): Rapidly and completely absorbed orally, with a half-life of 3-4 hours; may increase seizures in epileptics; could prevent migraine.

Tizanidine

• It has significant α2-adrenoreceptor agonist effects.
• Reinforces both presynaptic and postsynaptic inhibition in the spinal cord.
• Inhibits nociceptive transmission in the spinal dorsal horn.

Dantrolene

• It acts directly and reduces skeletal muscle strength by interfering with excitation-contraction coupling in muscle fibers; it inhibits activator Ca2+ release from sarcoplasmic stores.
• Dantrolene treats malignant hyperthermia caused by depolarizing relaxants (e.g., suxamethonium).
• It can be administered orally or intravenously.
• Oral absorption is only 1/3, and its half-life is 8-9 hours.

Skeletal Muscle Relaxants

• These drugs are used for muscle relaxation during surgical procedures.
• Classification: Neuromuscular blockers, non-depolarizing blockers, isoquinolone derivatives (atracurium, cisatracurium, metocurine, mivacurium, tubocurarine), steroid derivatives (pancuronium, pipecuronium, rapacuronium, vecuronium), depolarizing blockers (e.g., succinylcholine).
• Spasmolytic agents treat muscular spasms (e.g., diazepam, lonazepam, dantrolene, baclofen, tizanidine, and botulinum toxin).

Mechanisms of Action

• Non-depolarizing blockers compete with ACh for nicotinic receptors in small doses; in larger doses, they enter the ion channel pore to cause a more intense blockade.
• Depolarizing blockers act in two phases: Phase 1 block depolarizes the motor end plate of nicotinic receptors, and Phase 2 block desensitizes the nicotinic receptors.
• Diazepam facilitates GABA-mediated presynaptic inhibition at GABAB receptor subtypes, and baclofen interferes with excitatory neurotransmitter release at GABAB receptors.
• Dantrolene interferes with excitation-contraction coupling in muscle fibers by acting in the sarcoplasmic reticulum in skeletal muscles.

Adverse Effects and Clinical Uses

• Adverse effects include hyperkalemia, increased intraocular pressure, increased intragastric pressure, muscle pains, and arrhythmia.
• Clinical uses involve muscle relaxation during surgical procedures, tracheal intubation, bronchoscopy, etc.
• Dantrolene treats malignant hyperthermia, and botulinum toxin manages cerebral palsy.