Neuromuscular Junction Blockers

• Neuromuscular Junction Blockers prevent muscle contraction and allow for surgical procedures without cardiorespiratory depression

Objectives

• Compare and contrast the mechanisms of action for both competitive and depolarizing neuromuscular junction blockers
• List the therapeutic uses of neuromuscular blockers
• Compare the duration of action of neuromuscular junction blockers types
• Describe potential drug interactions of neuromuscular junction blockers
• Describe toxicities of neuromuscular junction blockers
• Compare d-tubocurarine and succinylcholine regarding inhibition of cholinesterases
• Discuss the pathophysiological basis of muscle spasms along with classes of agents that promote skeletal muscle relaxation
• Discuss the mechanism of action and toxicities of drugs that treat muscle spasms

Neuromuscular Junction

• NMJ blockers facilitate adequate muscle relaxation during surgery
• NMJ blockers do not produce cardiorespiratory depression that can occur during deep anesthesia

Neuronal Activation of Skeletal Muscle Contraction

• Acetylcholine activates nicotinic receptors.
• Influx of Na+ through nicotinic receptors depolarizes the membrane; voltage-gated Na+ and L-type voltage-gated Ca2+ channels then open
• Ca2+ activates ryanodine receptors on the sarcoplasmic membrane
• Open ryanodine receptors allow the release of Ca2+.
• Ca2+ then induces actin-myosin cross-linking, which results in muscle contraction

Curare

• Tubocurarine is isolated from the South American vine chondrodendron tomentosum

Chemical Structures

• NMJ blockers have structural variations, but generally have two quaternary nitrogen groups

Depolarizing Blockers

• Succinylcholine is a depolarizing blocker that results from two Ach molecules joining and acting as a cholinergic agonist

Mechanism of Action: Competitive Blockers

• Competitive blockers include tubocurarine, pancuronium, mivacurium and atracurium
• Competitive blockers compete with acetylcholine for the postjunctional nicotinic receptors.
• Neuromuscular transmission has a large safety margin, about 75% of receptors must be blocked before inhibition occurs
• Blockers are antagonized and readily reversed by anticholinesterase agents, for example, neostigmine

Competitive Blockers Effects

• Competitive blockers have no direct effect on resting membrane potential
• Instead, competitive blockers prevent the endplate potential from reaching threshold and generating an action potential

Depolarizing Blockers

• Succinylcholine and nicotine are examples of depolarizing blockers
• Depolarizing agents contain acetylcholine esterase inhibitors

Phase I (Depolarization)

• The first phase of depolarization includes muscle fasciculations
• Nicotinic receptors open but maintain depolarization during phase I
• Na+ channels inactivate, causing refractoriness in phase I
• Anticholinesterase agents worsen pure Phase I depolarizing block

Depolarizing Blockers Phase II (Desensitization)

• Prolonged depolarization causes membrane repolarization, but also desensitization.
• Nicotinic receptors inactivate allowing muscle to repolarize
• Na+ channels de-inactivate.
• Inactivated nicotinic receptors do not respond, which reduces available receptors
• Adding Ach with acetylcholine esterase inhibitors reverse blockade, activating available receptors

Genetic Variants of Plasma Cholinesterase

• A prolonged NMJ block can develop in patients with genetic variant of plasma cholinesterase
• Dibucaine number measures the ability to metabolize succinylcholine
• Dibucaine inhibits normal butyrylcholinesterase enzyme by 80% but abnormal enzyme by 20%

Monitoring Skeletal Muscle Relaxation

• Train-of-four (TOF) pattern applies four stimuli at 2 Hz
• TOF ratio measures the strength of the fourth contraction divided by that of the first

Monitoring NMJ Blockade

• TOF between 0.15-0.25 provides adequate surgical relaxation
• TOF of > 0.9 allows for safe extubation and recovery after surgery

Competitive NMJ Blockers

• Competitive NMJ blockers are generally highly polar quaternary nitrogen
• Must be administered via parenteral route
• Steroidal muscle relaxants are metabolized to 3-hydroxy metabolites in the liver
• These will accumulate with prolonged use, in ICU settings
• Common adverse effect: respiratory depression
• No CNS effects occur because of the quaternary nitrogen

Tubocurarine

• Weak autonomic ganglionic blockade can induce hypotension
• Histamine release can induce hypotension and bronchospasm; can pretreat with antihistamine

Mivacurium

• Mivacurium has a short duration; metabolized by pseudocholinesterase
• Mivacurium can induce histamine release, causing hypotension, bronchospasm

Atracurium

• Atracurium exerts an intermediate-acting isoquinoline non-depolarizing muscle relaxant effect
• Spontaneous Hofmann elimination produces laudanosine
• Laudanosine is slowly metabolized by the liver
• Laudanosine enters the brain and may cause seizures at high concentrations
• Hypotension results from histamine release
• Arecurium is no longer in widespread clinical use

Cisatracurium

• Cisatracurium is an isomer of atracurium
• Cisatracurium has intermediate-acting isoquinoline non-depolarizing muscle relaxant effects
• Cisatracurium has fewer adverse effects than atracurium
• Cisatracurium causes less histamine release and produces less laudanosine
• Cisatracurium is less dependent on hepatic inactivation
• Cisatracurium is favored in renal/hepatic impairment due to rapid nonenzymatic degradation in the blood.
• Cisatracurium has replaced atracurium in clinical practice

Pancuronium

• It is a long-acting steroid muscle relaxant
• Can cause tachycardia due to antimuscarinic effects
• Primarily renal excretion
• Less commonly used due to its longer duration

Vecuronium and Rocuronium

• Preferred for their rapid onset and intermediate duration
• Excreted through biliary excretion/hepatic metabolism
• Duration may prolong with impaired liver function
• Minimal cardiovascular effects
• No histamine release or autonomic ganglia effects
• Suitable for various surgical procedures

Sugammadex (Bridion)

• NMJ blocker antagonist
• Binds steroidal rocuronium and vecuronium, reduces plasma concentration, and reverses the effects of neuromuscular blockers
• Excreted unchanged in urine
• Prolonged elimination in renal insufficiency
• Can cause anaphylaxis (0.3% at 16 mg/kg dose) or hypersensitivity reactions such as nausea, pruritus, urticaria
• Bradycardia and potential cardiac arrest
• Can cause coagulopathy, which causes transient elevated activated partial thromboplastin time and prothrombin time
• Binds steroidal drugs like progesterone-based contraceptives or selective estrogen receptor modulators like toremifene
• Can decrease efficacy of hormonal contraceptives; alternative contraception is recommended for 7 days

Depolarizing Blocker (Succinylcholine)

• Onset of action is in 20-40s
• Duration <10 min due to rapid metabolism by pseudocholinesterase; also depends on genetic variability
• Can induce respiratory depression
• No effects on the CNS due to quaternary nitrogen
• Can cause muscle soreness, hyperkalemia, especially with burns, neuromuscular disease, trauma
• Can decrease HR and contractility, stimulate muscarinic receptors; block with antimuscarinic
• Can cause increased intragastric pressure; risk of regurgitation, aspiration
• Can cause increased intraocular pressure
• Can induce malignant hyperthermia

Malignant Hyperthermia

• An autosomal dominant genetic disorder of skeletal muscle
• Abnormal Ca2+ channels in skeletal muscle
• Can be caused by exposure to inhalation anesthetics and depolarizing muscle relaxants like succinylcholine
• Involves abnormally large increase of Ca2+ within skeletal muscle
• Leads to rapid onset of severe muscle rigidity, hyperthermia, hyperkalemia, tachycardia, hypertension, acid-base imbalance with acidosis
• Rare but important cause of anesthetic morbidity and mortality, treat via dantrolene

Dantrolene Treatment

• Dantrolene blocks calcium release by interacting with ryanodine receptors
• Treat via measures to control body temperature

Drug Interactions

• Inhalation anesthetics: increase NMJ block
• Isoflurane > sevoflurane, desflurane, enflurane, halothane > N₂O
  • This causes CNS depression of motor cortex which decreases the release of acetylcholine
  • Anesthetics increase flow of NMJ blockers to muscle via vasodilation
  • Anesthetics decrease sensitivity of muscle to depolarization
• Antibiotics, especially aminoglycosides
  • NMJ block is increased, decreasing Ach release by blocking presynaptic Ca2+ channels
• Local anesthetics
  • Small doses enhance NMJ blockers by decreasing Ach release
  • High doses directly block the nicotinic channels

Drug Combinations

• Preventative curarization prior to succinylcholine:
  • Small doses of nondepolarizing NMJ blockers prevent fasciculations and postoperative pain
  • Does not undergo widespread use
  • Increases amount of succinylcholine needed; causes postoperative weakness

Effects of Diseases and Aging

• Diseases and aging influence the effect of NMJ blockers

Myasthenia Gravis

• Myasthenia gravis enhances the effect of NMJ blockers
• Myasthenia gravis is marked by decreased nicotinic receptors

Elderly

• In elderly populations (> 70 years old), there is enhanced effect of NMJ blockers
• This is due to decreased clearance of blockers

Burns

• In patients with burns, NMJ blockers effects are also reduced
• This occurs in severe burns/ upper motor neuron disease/ prolonged immobilization
• Resistance to nondepolarizing blockers is a result of upregulation of nicotinic receptors at NMJ

Uses of NMJ Blockers

• NMJ Blockers include surgical relaxation and control of ventilation and treatment of convulsions
• NMJ blockers act via mechanisms that blocks skeletal muscle contractions

Spasmolytic Drugs

• Spasmolytic drugs are used to treat spasticity; increased tonic stretch reflexes, flexor muscle spasms, and muscle weakness
• Spasmolytic Drugs modify the stretch reflex arc through modifying skeletal muscle of inhibiting motor neurons
• Dantrolene reduces excitation contraction
• Diazepam, baclofen and tizanidine inhibit motor neurons

Treatments to Prevent Contractions

• Diazepam, Baclofen and Tinzidine used to inhibit motor neurons to prevent contractions

Motor Neuron

• Diazepam enhances GABAA receptor, reducing stimulation to motor neuron of spinal cord
• Diazepam can cause sedation

Baclofen

• Baclofen stimulates GABAB receptors
• Baclofen hyperpolarizes motor neurons by activating K+ channels
• Baclofen reduces glutamate released from sensory fibers on motor neurons by inhibiting Ca2+ channels at synaptic terminals
• Baclofen is often just as, or more effective than diazepam, and less sedating
• Baclofen often causes a decreased reduction in muscle strength, relative to dantrolene
• Intrathecal administration can control spasticity and muscle pain

Tizanidine

• Tizanidine acts as a α2 receptor agonist and is related to clonidine
• Tizanidine reduces spasticity while producing less cardiovascular effects than clonidine
• Pre-synaptically and post-synaptically inhibits motor neurons
• Tizanidine decreases pre-synaptic glutamate release
• Tizanidine directly inhibits neurons that promote excitability
• Adverse effects drowsiness, hypotension (16-33%), dizziness, dry mouth, asthenia, hepatotoxicity
• Tizanidine withdrawal should be avoided to prevent rebound hypertension, tachycardia, spasm
• Effective for chronic migraine

Gabapentin

• Gabapentin works by increasing GABA production.
• Gabapentin presyanaptically decreases glutamate release
• Excreted renally and unchanged
• Does not induce hepatic enzymes and does not alter plasma levels of other antiepileptics!
• Adverse effects sedation and movement disorders, ataxia, nystagmus, tremor

Gabapentin Uses

• Adjunct treatment for partial and generalized tonic-clonic seizures
• Pregabalin used for neuropathic pain like painful diabetic neuropathy

Dantrolene

• Binds ryanodine receptor 1 on the skeletal sarcoplasmic reticulum to prevent Ca2+ release and excitation-contraction coupling
• Cardiac and smooth muscle minimally depressed due to different ryanodine receptors

Dantrolene Use

• Treat malignant hyperthermia
• Adverse effects include general muscle weakness, sedation, occasional hepatitis

Botulinum toxin

• Cleaves vesicular proteins inside motor neuron synaptic terminals to prevent acetylcholine and cause local muscle paralysis
• Used for wrinkles, spastic disorders, dystonia, incontinence, migraine
• Adverse effects respiratory tract infections, muscle weakness, incontinence, falls, fever, pain

Acute Muscle Spasm

• Cyclobenzaprine promotes acute muscle spasm relief from local tissue trauma or muscle strains, example back pain
• Works primarily in the stem to reduce tonic somatic motor activity
• Ineffective for spasm due to cerebral palsy/injury
• Causes strong antimuscarinic effects such as sedation and dry mouth
• Other treatments Carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, orphenadrine