Neuromuscular Junction Blockers

• James Porter, Ph.D., created content on neuromuscular junction blockers

Objectives

• Compare and contrast the mechanisms of action for competitive and depolarizing neuromuscular junction blockers
• List the therapeutic uses of neuromuscular blockers
• Compare the duration of action of the two types of blockers
• Describe the drug interactions of each type of agent
• Describe the toxicity of each type of agent
• Compare d-tubocurarine and succinylcholine regarding reversal by cholinesterase inhibition
• Discuss the pathophysiological basis of muscle spasms and the classes of agents used to promote skeletal muscle relaxation
• Discuss the mechanism of action and toxicity of drugs that treat muscle spasms

Neuromuscular Junction (NMJ) Blockers Basics

• NMJ blockers facilitates adequate muscle relaxation for surgical procedures
• NMJ blockers can be used without causing cardiorespiratory depression, as can occur with deep anesthesia
• Acetylcholine activates nicotinic receptors, triggering muscle contraction
• Na+ influx through nicotinic receptors depolarizes the membrane
• This process opens voltage-gated Na+ and L-type voltage-gated Ca2+ channels
• Ca2+ activates ryanodine receptors on the sarcoplasmic membrane
• Ryanodine receptors then open, releasing more Ca2+
• Increased Ca2+ causes actin-myosin cross-linking, leading to muscle contraction

Curare

• Tubocurarine is isolated from the South American vine chondrodendron tomentosum

Chemical Structures of Blocking Drugs

• Most neuromuscular blockers have considerable structural variations
• They commonly feature two quaternary nitrogen groups
• Succinylcholine is a depolarizing blocker that consists of two acetylcholine molecules joined together and acts as a cholinergic agonist
• Tubocurarine contains an isoquinoline ring

Mechanism of Action: Competitive Blockers

• Competitive blockers include tubocurarine, pancuronium, mivacurium, and atracurium
• These agents compete with acetylcholine for postjunctional nicotinic receptors
• A large margin of safety exists for neuromuscular transmission
• About 75% of receptors must be blocked before inhibition can happen
• Effects are reversed by anticholinesterase agents like neostigmine
• Competitive blockers do not directly affect the resting membrane potential
• They prevent the endplate potential from reaching threshold and generating an action potential

Mechanism of Action: Depolarizing Blockers

• Succinylcholine (Anectine) and nicotine/acetylcholine with esterase inhibitors are depolarizing blockers
• Phase I (Depolarization) involves an initial period of muscle fasciculations
• Nicotinic receptors open, maintaining depolarization
• Na+ channels inactivate, causing refractoriness
• Cholinesterase agents worsen this Phase I block
• Phase II (Desensitization) occurs with prolonged exposure
• The membrane repolarizes but desensitizes
• Nicotinic receptors and Na+ channels inactivate
• Inactivated nicotinic receptors do not respond to Ach
• This causes a reduction in available nicotinic receptors
• Acetylcholinesterase inhibitors reverse the blockade by activating available nicotinic receptors

Genetic Variants Impacting NMJ Blockade

• Patients with an abnormal genetic variant of plasma cholinesterase exhibit a prolonged NMJ block
• Dibucaine number measures a patient’s ability to metabolize succinylcholine
• Dibucaine inhibits normal butyrylcholinesterase enzyme by 80%
• Dibucaine inhibits abnormal enzyme by 20%

Monitoring Neuromuscular Blockade and TOF Guidelines

• A train-of-four (TOF) pattern involves applying four stimuli are applied at 2 Hz
• TOF ratio (TOF-R) measures the strength of the fourth contraction divided by the first
• Guidelines
• TOF of 0.15-0.25 is surgical relaxation
• TOF of >0.9 is safe for extubation and recovery after surgery

Competitive NMJ Blockers

• They are highly polar compounds containing quaternary nitrogen
• Competitive NMJ Blockers must be administered parenterally
• Steroidal muscle relaxants in this class undergo metabolism to 3-hydroxy metabolites in the liver
• They can accumulate with prolonged use, especially in ICU settings
• Respiratory depression is a common adverse effect
• They do not cause CNS effects because they contain quaternary nitrogen

Tubocurarine

• Causes a weak autonomic ganglionic blockade resulting in hypotension
• Induces histamine release, also causing hypotension and bronchospasm
• Can pre-treat with antihistamines

Mivacurium

• Has a very short duration and is metabolized by pseudocholinesterase
• It induces histamine release which can causes hypotension and bronchospasm

Atracurium

• An intermediate-acting isoquinoline non-depolarizing muscle relaxant
• Undergoes spontaneous Hofmann elimination, producing laudanosine
• Laudanosine is slowly metabolized by the liver
• Laudanosine enters the brain
• Laudanosine may cause seizures at high concentrations
• Can cause hypotension due to histamine release
• It is no longer broadly used in clinical practice

Cisatracurium

• It is an isomer of atracurium
• An intermediate-acting isoquinoline non-depolarizing muscle relaxant
• Cisatracurium has fewer adverse effects compared to atracurium
• It causes less histamine release
• Produces less laudanosine
• Exhibits less dependence on hepatic inactivation
• It is favored in renal or hepatic impairment due to Hofmann elimination
• Has virtually replaced atracurium in clinical practice

Pancuronium

• It is a long-acting steroid muscle relaxant
• Causes tachycardia
• Primarily relies on renal excretion
• Less commonly used due to its longer duration of action

Vecuronium and Rocuronium

• They are preferred for rapid onset and intermediate duration
• Primarily undergo biliary excretion or hepatic metabolism
• If liver function is impaired, duration may be prolonged
• They cause minimal cardiovascular effects
• Are not associated with histamine release
• Have no effect on autonomic ganglia
• Suitable for various surgical procedures

Sugammadex (Bridion)

• It is an NMJ blocker antagonist
• Sugammadex binds steroidal rocuronium and vecuronium
• This helps in lowering free plasma concentration
• It reverses the effects of neuromuscular blockers faster
• It is excreted unchanged in urine
• Prolonged elimination may occur in renal insufficiency
• Adverse reactions include, anaphylaxis, hypersensitivity reactions, bradycardia, and coagulopathy
• Has drug interactions with steroidal drugs

Sugammadex Drug Interactions

• Sugammadex binds steroidal drugs
• Specifically progesterone-based contraceptives
• Selective estrogen receptor modulators like toremifene
• It can decrease efficacy of hormonal contraceptives
• It is generally recommended to use alternative contraception for 7 days post-administration

Depolarizing Blocker: Succinylcholine

• Depolarizing Blocker (Succinylcholine) onset occurs in 20-40 seconds
• Duration is less than 10 minutes
• Has rapid metabolism by pseudocholinesterase
• Is effected by genetic variability
• Adverse effects
• Respiratory depression and muscle soreness can occur
• No CNS effects due to its quaternary nitrogen,
• Hyperkalemia, especially with burns, neuromuscular disease, or trauma
• It decrease heart rate (HR) and contractility by stimulating muscarinic receptors
• Stimulates muscarinic receptors, which can be blocked with antimuscarinics
• Increased intragastric pressure (risk of regurgitation and aspiration)
• Increased intraocular pressure
• May cause malignant hyperthermia

Malignant Hyperthermia

• An autosomal dominant genetic disorder of skeletal muscle, marked by
• Abnormal Ca2+ channels (ryanodine receptors)
• Sensitivity/Exposure to potent inhalation anesthetics
• Depolarizing muscle relaxants like succinylcholine
• This causes and abnormally large increase in Ca2+ within skeletal muscle
• Causes rapid onset of severe muscle rigidity, hyperthermia, hyperkalemia, and tachycardia
• Also may cause hypertension and acid-base imbalance with acidosis
• Considered a rare but significant cause of anesthetic morbidity and mortality
• Treated with dantrolene, which blocks calcium release via ryanodine receptors in the sarcoplasmic reticulum
• Measures to control body temperature are needed

Drug Interactions - Inhalation Anesthetics

• Increase NMJ block
• Isoflurane increases NMJ block more than sevoflurane, desflurane, enflurane, and halothane, which > N2O

Inhalation Anesthetics Causes

• CNS depression of motor cortex
• Leads to decreased acetylcholine release
• Vasodilation increases NMJ blocker flow to muscles
• Decreased muscle sensitivity to depolarization

Drug Interactions - Anitbiotics and Local Anesthetics

• Aminoglycosides increase NMJ block by decreasing Ach release by blocking presynaptic Ca2+ channels
• Local anesthetics have variable effects:
• Small doses indirectly enhance the potency of NMJ blockers
• High doses directly block nicotinic receptors

Other Neuromuscular Blocking Drugs

• Preventive curarization prior to succinylcholine can be used -Small doses of nondepolarizing NMJ blockers prevent fasciculations and postoperative pain from succinylcholine -Greatly increases amount of succinylcholine needed causing postoperative weakness
  • It is no longer is widely used

Diseases, Aging, and NMJ Blockade

• Myasthenia gravis enhances the effect of NMJ blockers due to fewer nicotinic receptors
• The Elderly, >70 years old, also exhibit enhanced effect of NMJ blockers due to decreased clearance of drug
• Those with severe burns, upper motor neuron disease, or prolonged immobilization
• are resistant to nondepolarizing blockers
• exhibit upregulation of nicotinic receptors at the NMJ

Uses of NMJ Blockers

• Surgical relaxation
• Control of ventilation
• Treatment of convulsions by blocking skeletal muscle contractions

Spasmolytic Drugs

• These modify stretch reflex arc and are useful for spasticity
• Spasticity may present as increased tonic stretch reflexes, flexor muscle spasms and or muscle weakness
• Modify skeletal muscle by reducing excitation-contraction coupling (Dantrolene)
• Inhibit motor neurons through use of (diazepam, baclofen, tizanidine)

Spasmolytic Targets - Diazepam

• Enhances GABAA- mediated inhibition onto motor neurons in the spinal cord; causes sedation

Spasmolytic Targets - Baclofen

• Stimulates GABAB receptors
• Hyperpolarizes motor neurons by activating K+ channels -Reduces glutamate release from sensory fibers onto motor neurons by inhibiting Ca2+ channels on synaptic terminals
• As equally effective as diazepam but generates less sedation
• Causes less reduction in overall muscle strength compared to dantrolene
• Intrathecal administration helps control severe spasticity and muscle pain

Spasmolytic Targets - Tizanidine

• α2 receptor agonist related to clonidine
• Reduces spasticity while producing less cardiovascular effects than clonidine
• Decreases glutamate release from sensory neurons onto motor neurons in the spinal cord
• Increases motor neuron inhibition and inhibits nociceptive transmission
• Significantly less muscle weakness, versus other spasmolytics
• Causes drowsiness, hypotension, dizziness, dry mouth, asthenia, and hepatotoxicity
• Abrupt withdrawal can causes rebound hypertension, tachycardia, and increased spasms
• Effective for managing chronic migraine

Spasmolytic Targets - Gabapentin (Neurontin)

• Increases GABA levels perhaps by increasing GABA release
• Presynaptically lowers release of glutamate by inhibiting presynaptic Ca2+ channels
• Renally excreted unchanged
• Causes adverse effects which may include sedation or movement disorders
• An adjunct treatment for partial and generalized tonic-clonic seizures
• Pregabalin approved for neuropathic pain including painful diabetic neuropathy

Spasmolytic Targets - Dantrolene (Dantrium)

• Blocks ryanodine receptor 1 (RyR1) on skeletal muscle
• Prevents Ca2+ release and excitation-contraction coupling
• Minimally impacts cardiac and smooth muscle
• In contrast to skeletal muscle effects due to different ryanodine receptors (RyR2) in other muscle types Treats malignant hyperthermia

Spasmolytic Targets - Botulinum Toxin A (Botox)

• Cleaves vesicular proteins in motor neuron synaptic terminals
• Prevents the release of acetylcholine, causing local muscle paralysis
• Used for wrinkles, spastic disorders, treating dystonia, incontinence, and chronic migraine

Acute Local Muscle Spasm management - Cyclobenzaprine (Flexeril)

• The drug is promoted for pain relief of acute muscle spasm caused by local tissue trauma or muscle strains such as lower back pain from muscle spasm
• Works primarily in brain stem to reduce tonic somatic motor activity
• Ineffective in muscle spasm due to cerebral palsy or spinal injury
• Causes antimuscarinic effects like sedation and a dry mouth
• Carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, orphenadrine may also be used to treat muscle spasm