Skeletal Muscle Relaxants

Skeletal Muscle Relaxants

Learning Outcomes

• 9.1 Describe at least two ways in which skeletal muscles may be relaxed.

• 9.2 Describe peripherally acting muscle relaxants, including their mechanism of action.

• 9.3 Describe the major adverse effect on respiration associated with peripherally acting muscle relaxants.

• 9.4 Name the direct-acting skeletal muscle relaxant and describe its site of action.

• 9.5 Explain how centrally acting muscle relaxants (tranquilizers) relax skeletal muscles through a different mechanism of action than non-depolarizing blockers.

• 9.6 Identify which drugs are used in the chronic treatment of spastic muscle disorders.

Types of Skeletal Muscle Relaxants

• Centrally acting skeletal muscle relaxants (spasmolytics):

  • Drugs that block conduction to the spinal cord by acting on interneurons or descending pathways within the central nervous system. These can reduce muscle spasms and hyperreflexia.

• Peripheral skeletal muscle relaxants:

  • Inhibit contraction at the neuromuscular junction (NMJ) or within the contractile process. These agents directly affect muscle function, either by blocking nerve impulses or interfering with muscle fiber activity.

Somatic Efferent Pathway

• Somatic efferent innervation involves the spinal cord connecting to somatic effectors (skeletal muscles) via a myelinated fiber, ensuring rapid and direct control.

• The point of contact between the myelinated fiber and somatic effectors is labeled ACH (acetylcholine), where acetylcholine is released to stimulate muscle contraction.

Sites of Action of Skeletal Muscle Relaxants

• Centrally Acting Relaxants:

  • Baclofen, Carisoprodol, Diazepam, Methocarbamol, Orphenadrine, Tizanidine act on the upper region of the spinal cord, modulating neuronal activity to reduce muscle spasm.

• Neuromuscular Relaxants:

  • Depolarizing: Succinylcholine works by mimicking acetylcholine, causing prolonged depolarization and muscle paralysis.

  • Non-depolarizing: Curare, Cisatracurium, Pancuronium, Vecuronium competitively block acetylcholine receptors at the NMJ, preventing muscle contraction.

  • Botulinumtoxin A or B, abobotulinumtoxin A, incobotulinumtoxin A, onabotulinumtoxin A, rimabotulinumtoxin B act at the neuromuscular junction, inhibiting acetylcholine release and causing muscle paralysis.

• Direct-Acting Relaxant:

  • Dantrolene acts near the shoulder, directly on the muscle by interfering with calcium release from the sarcoplasmic reticulum, reducing muscle contraction.

Clinical indications for Skeletal Muscle Relaxants

• Spastic diseases such as multiple sclerosis and cerebral palsy, where muscle stiffness and spasms are common.

• Damaged spinal cord resulting in muscle spasticity and spasms.

• Overexertion of muscles causing strains, sprains, and muscle pain.

• Surgical procedures requiring muscle relaxation to facilitate the operation.

• Intubation to relax throat muscles

Peripherally Acting Relaxants

• Mechanism of action:

  • Neuromuscular blockers inhibit skeletal muscle contraction by interfering with nicotinic muscle receptors at the neuromuscular junction.

  • Types: Non-depolarizing (competitive antagonists) and depolarizing (agonists that cause prolonged depolarization).

  • Inhibition of ACH release: Prevents muscle contraction by reducing acetylcholine availability.

  • Botulinum toxin is used to relieve severe muscle spasticity and to improve facial appearance by paralyzing specific muscles.

• Route of administration:

  • Nm blockers are administered intravenously (IV) for rapid onset and precise control during surgical procedures.

  • Botulinum toxin A/B is administered intramuscularly (IM) or intradermally (ID) for localized effects in treating spasticity or cosmetic applications.

• Effects on cardiopulmonary systems:

  • Arrhythmias due to altered autonomic activity or electrolyte imbalances.

  • Bronchospasms resulting from histamine release or direct effects on bronchial smooth muscle.

Major Adverse Effects Associated with Peripheral NMB

• Respiratory paralysis requiring mechanical ventilation to maintain oxygenation.

• Malignant hyperthermia:

  • Drastic increase in body temperature, acidosis, electrolyte imbalance, and shock requiring immediate treatment with dantrolene.

• Drug interactions and incompatibility with anesthetics, antibiotics, and other medications.

Clinical Indications for Peripheral NMB

• Neuromuscular blockers:

  • Before and during surgeries to provide skeletal muscle relaxation and facilitate surgical procedures.

  • During electroconvulsive shock and tetanus therapies to prevent musculoskeletal injury.

  • To facilitate tracheal intubation by relaxing the muscles of the larynx and pharynx.

  • Bronchospasm or chronic obstructive pulmonary disorder in critically ill patients to improve ventilation and reduce respiratory distress.

• Botulinum toxin:

  • Cervical dystonia characterized by involuntary neck muscle contractions.

  • Blepharospasm involving involuntary eyelid movements.

  • Strabismus to correct eye misalignment.

  • Upper limb spasticity in patients with cerebral palsy or stroke.

  • Chronic migraine headache to reduce the frequency and severity of headaches.

  • Severe hyperhidrosis to decrease excessive sweating.

  • Urinary incontinence to relax bladder muscles.

  • Cosmetic nonsurgical procedures to reduce wrinkles and fine lines.

Direct-Acting Skeletal Muscle Relaxants

• Mechanism of action:

  • Dantrolene interferes with calcium ion release in the muscle fibers, inhibiting muscle contraction by blocking the ryanodine receptor.

• Clinical indication:

  • Dantrolene is used in the treatment of malignant hyperthermia and spastic conditions such as cerebral palsy and multiple sclerosis.

• Adverse effects:

  • Dizziness, vomiting, fatigue, and weakness.

  • Dantrolene has a potential for hepatotoxicity; liver function tests are necessary

• Contraindication:

  • Includes hepatitis, cirrhosis, and other hepatic diseases due to the risk of liver damage.

Centrally Acting Skeletal Muscle Relaxants (Spasmolytics)

• Mechanism of action:

  • Depress reflex impulse conduction within the spinal cord by acting on GABA receptors or other neurotransmitter systems.

  • Reduce the number of impulses available to produce muscle contraction by modulating neuronal activity.

  • Do not alter the function of the nicotinic-muscle receptors or the skeletal muscle fibers, but rather influence CNS pathways.

  • Benzodiazepines chlordiazepoxide and diazepam are used as tranquilizers to reduce anxiety and muscle tension.

• Specific drugs:

  • Baclofen and tizanidine reduce spasms in patients with multiple sclerosis by acting on GABA receptors and alpha-2 adrenergic receptors, respectively.

  • Spastic contraction results from overexertion, trauma, and nervous tension, which centrally acting relaxants help alleviate.

  • Administered orally or parenterally depending on the drug and the patient's condition.

• Adverse effects:

  • Blurred vision, lethargy, and decreased mental alertness.

  • Prolonged use of diazepam and chlordiazepoxide may lead to dependency, requiring careful monitoring and gradual withdrawal.

  • Larger doses can cause ataxia and hypotension.

  • Overdose can cause confusion, somnolence, depression of vital functions, coma, and death, necessitating immediate medical intervention.

Sites of Action of Centrally Acting Muscle Relaxants

• Motor neurons from skeletal muscle connect to the junction of the corticospinal pathway and inhibitory interneuron on the spinal cord.

• Baclofen and Tizanidine ($\alpha$ subscript 2) flow through GABA subscript B via two arrows labeled minus to Hyperpolarization.

• GABA and Baclofen from a nerve end pass through GABA subscript A and Benzodiazepines to Hyperpolarization.

• A downward arrow from Hyperpolarization is labeled Action potential; therefore, hyperpolarization prevents action potential.

Preferred Treatment for Selected Conditions

• Surgical relaxation:

  • Appropriate neuromuscular Nm receptor blocking drug, such as vecuronium, rocuronium, atracurium, mivacurium.

• Intubation:

  • Succinylcholine for rapid sequence intubation or rocuronium as an alternative.

• Relief of back or neck pain:

  • Carisoprodol and cyclobenzaprine for short term treatment, combined with physical therapy and non-pharmacological interventions. Metaxalone, methocarbamol, and orphenadrine are also used.

• Disorders associated with chronic spasticity:

  • Baclofen, dantrolene sodium, and tizanidine. Diazepam and clonazepam can also be used.

• Dystonias:

  • BTX products (Botulinum Toxin products), including abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.

• Malignant hyperthermia:

  • Dantrolene.

• Cosmetic nonsurgical rejuvenation procedures:

  • Botulinum toxin injection

Detailed Notes on Neuromuscular Blockers

Non-Depolarizing Neuromuscular Blockers

• Mechanism of Action:

  • Non-depolarizing neuromuscular blockers (NMBs) act as competitive antagonists of acetylcholine (ACh) at the nicotinic receptors on the motor endplate. By binding to these receptors, they prevent ACh from binding and initiating the depolarization necessary for muscle contraction.

  • These agents do not cause initial depolarization of the motor endplate. Instead, they maintain the membrane potential at its resting state, preventing muscle fiber excitation.

• Pharmacokinetics:

  • Typically administered intravenously due to poor oral absorption.

  • Distribution and elimination depend on factors such as renal and hepatic function.

  • Duration of action varies among different agents, influencing their clinical use.

• Adverse Effects:

  • Respiratory paralysis is a major concern, necessitating mechanical ventilation.

  • Cardiovascular effects can include changes in heart rate and blood pressure due to histamine release or autonomic ganglion blockade.

  • Allergic reactions, though rare, can occur.

• Specific Drugs:

  • Curare: A historically significant NMB, rarely used clinically due to its side effects.

  • Cisatracurium: A commonly used NMB with intermediate duration of action, undergoes Hoffman elimination, making it suitable for patients with renal or hepatic impairment.

  • Pancuronium: A long-acting NMB with vagolytic effects, increasing heart rate. Use is limited due to its prolonged duration of action and cardiovascular effects.

  • Vecuronium: An intermediate-acting NMB, commonly used in surgical procedures. Its effects can be reversed with anticholinesterase agents.

  • Atracurium: Similar to cisatracurium, undergoes Hoffman elimination. It may cause histamine release, leading to bronchospasm or hypotension in susceptible individuals.

  • Mivacurium: A short-acting NMB, also associated with histamine release. Its short duration makes it useful for brief procedures.

Depolarizing Neuromuscular Blockers

• Mechanism of Action:

  • Succinylcholine is the primary depolarizing NMB used clinically. It mimics ACh by binding to nicotinic receptors on the motor endplate, causing initial depolarization.

  • Unlike ACh, succinylcholine is not rapidly metabolized by acetylcholinesterase, resulting in prolonged depolarization of the motor endplate.

  • This sustained depolarization leads to an initial phase of muscle fasciculations (brief, uncoordinated muscle contractions) followed by paralysis.

• Pharmacokinetics:

  • Rapid onset and short duration of action due to rapid hydrolysis by plasma cholinesterase (pseudocholinesterase).

  • Metabolism by pseudocholinesterase results in succinic acid and choline, which are inactive.

• Adverse Effects:

  • Muscle Fasciculations: Initial muscle contractions can cause postoperative muscle pain.

  • Hyperkalemia: Succinylcholine can cause a significant release of potassium from muscle cells, posing a risk for patients with pre-existing hyperkalemia or certain neuromuscular disorders.

  • Malignant Hyperthermia: A rare but life-threatening reaction characterized by rapid increase in body temperature, muscle rigidity, and metabolic acidosis. It requires immediate treatment with dantrolene.

  • Bradycardia: Can occur due to stimulation of muscarinic receptors in the heart, particularly with repeated doses.

  • Increased Intragastric Pressure: May increase the risk of aspiration in susceptible individuals.

• Specific Drugs:

  • Succinylcholine: The only commonly used depolarizing NMB. It is used for rapid sequence intubation and other situations requiring quick muscle relaxation.

Table of Skeletal Muscle Relaxants