Neuromuscular Junction Blockers

• Neuromuscular junction blockers are used to induce adequate muscle relaxation for surgical procedures, without the cardiorespiratory depression seen in deep anesthesia

Neuronal Activation of Skeletal Muscle Contraction

• Acetylcholine activates nicotinic receptors, triggering an influx of Na+ that depolarizes the membrane
• Depolarization opens voltage-gated Na+ and L-type voltage-gated Ca2+ channels
• Ca2+ activates ryanodine receptors on the sarcoplasmic membrane, leading to the release of more Ca2+
• The increase in Ca2+ leads to actin-myosin cross-linking and muscle contraction

Curare and Tubocurarine

• Tubocurarine is isolated from the South America vine chondrodendron tomentosum

Chemical Structures of Neuromuscular Blockers

• Most neuromuscular blockers have two quaternary nitrogen groups - some feature an isoquinoline ring

Depolarizing Blockers

• Succinylcholine is a depolarizing blocker comprised of two molecules of Acetylcholine joined together acting as a cholinergic agonist

Mechanism of Action: Competitive Blockers

• Competitive blockers like Tubocurarine, Pancuronium, Mivacurium and Atracurium compete with acetylcholine for postjunctional nicotinic receptors
• A large margin of safety exists for neuromuscular transmission, where about 75% of the receptors must be blocked before inhibition occurs
• Competitive blockers can be readily antagonized and reversed by anticholinesterase agents like neostigmine

Competitive Blockers Action

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

Depolarizing Blockers: Action

• Succinylcholine, also know as Anectine, mimics nicotine or acetylcholine in conjunction with acetylcholinesterase inhibitors
• Depolarization Phase I involves initial muscle fasciculations due to open nicotinic receptors that maintain depolarization
• Na+ channels inactivate, causing refractoriness, and the depolarizing block is made worse by anticholinesterase agents
• Phase II (desensitization) occurs with prolonged depolarization, where the membrane repolarizes but is desensitized
• Nicotinic receptors inactivate, allowing muscle to repolarize, and Na+ channels de-inactivate
• Increasing Ach with acetylcholinesterase inhibitors can reverse Phase II blockade

Dibucaine Number and Genetic Variants of Plasma Cholinesterase

• Dibucaine number measures the patient's ability to metabolize succinylcholine
• Dibucaine inhibits normal butyrylcholinesterase enzyme by 80% but inhibits abnormal enzyme by 20%
• Prolonged NMJ block can occur in individuals with abnormal genetic variants of plasma cholinesterase

Monitoring Muscle Relaxation

• Train-of-four (TOF) pattern involves applying four stimuli at 2 Hz
• TOF ratio (TOF-R) is the strength of the fourth contraction divided by that of the first

TOF Guidelines for NMJ Blockade

• TOF ratio of 0.15 - 0.25 indicates adequate surgical relaxation
• TOF ratio of greater than 0.9 indicates it is safe for extubation and recovery after surgery

Properties of Competitive NMJ Blockers

• Competitive NMJ blockers are highly polar with quaternary nitrogen and must be administered parentally
• Steroidal muscle relaxants get metabolized to 3-hydroxy metabolites in the liver and accumulate with prolonged use, especially in ICU settings
• Adverse effects include respiratory depression with no direct CNS effect due to quaternary nitrogen

Tubocurarine specific effects

• Weak autonomic ganglionic blockade resulting in hypotension
• Histamine release, leading to hypotension and bronchospasm; pretreatment with antihistamine may be necessary

Mivacurium

• Mivacurium has a very short duration of action because it is metabolized by pseudocholinesterase and induces histamine release leading to hypotension and bronchospasm

Atracurium

• Atracurium is an intermediate-acting isoquinoline non-depolarizing muscle relaxant
• It undergoes spontaneous Hofmann elimination to produce laudanosine, which is slowly metabolized by the liver and may cause seizures at high concentrations
• Can also cause hypotension due to histamine release, but is no longer in widespread clinical use

Cisatracurium

• Cisatracurium is an isomer of atracurium and as such is an intermediate-acting isoquinoline non-depolarizing muscle relaxant with fewer adverse effects than Atracurium
• Cisatracurium has less histamine release, produces less laudanosine, is less dependent on hepatic inactivation, and is favored in renal or hepatic impairment situations given its rapid nonenzymatic degradation in the blood
• It has virtually replaced atracurium in clinical practice.

Pancuronium

• Pancuronium is a long-acting steroid muscle relaxant
• Can cause tachycardia due to antimuscarinic effects and is primarily renally excreted
• Less commonly used due to its longer duration

Vecuronium and Rocuronium

• Vecuronium and Rocuronium are intermediate-acting steroid muscle relaxants
• Preferred for their rapid onset and intermediate duration, they are primarily eliminated through biliary excretion or hepatic metabolism, and impaired liver function may prolong their duration
• They have minimal cardiovascular effects, and no histamine release or effect on autonomic ganglia
• Suitable for various surgical procedures

Sugammadex

• Sugammadex functions as an NMJ blocker antagonist by binding to steroidal rocuronium and vecuronium in order to lower free plasma concentrations and reverse the blockade.
• It gets excreted unchanged in urine and can have a prolonged elimination period in renal insufficiency
• Adverse reactions include anaphylaxis (0.3% at 16 mg/kg dose), hypersensitivity reactions, bradycardia and potential cardiac arrest, and coagulopathy through transient elevation of thromboplastin time.

Sugammadex Drug Interactions

• Binds to steroidal drugs, including progesterone-based contraceptives and selective estrogen receptor modulators like toremifene
• Can decrease the efficacy of hormonal contraceptives, and alternative contraception is advised for 7 days post-administration

Depolarizing Blocker: Succinylcholine

• It has a rapid onset of 20-40 seconds and a short duration of action of <10 minutes because of rapid metabolism by pseudocholinesterase
• Adverse effects include respiratory depression, muscle soreness, and hyperkalemia, especially with burns, trauma, and neuromuscular disease
• It acts with decreased HR and contractility, increased intragastric pressure, increased intraocular pressure, and may result in malignant hyperthermia

Malignant Hyperthermia

• Malignant Hyperthermia is an autosomal dominant genetic disorder of skeletal muscle
• It is characterized by abnormal Ca2+ channels within skeletal muscle
• Exposure to inhalation anesthetics and depolarizing muscle relaxants can trigger an abnormally large increase in Ca2+ within skeletal muscle
• A syndrome with rapid onset of severe muscle rigidity, hyperthermia, hyperkalemia, tachycardia, hypertension, and acid-base imbalance with acidosis appears

Malignant Hyperthermia Treatment

• Dantrolene is used to block calcium release through ryanodine receptors channels in the ER
• Temperature control is also vital
• Malignant Hyperthermia is a rare but devastating cause of morbidity and mortality

Inhalation Anesthetics Drug Interactions

• Results in an increased NMJ block
• Isoflurane produces the highest increase, followed by sevoflurane, desflurane, enflurane, halothane, and nitrous oxide
• Causes CNS depression, which leads to less presynaptic release of acetylcholine from motor cortex
• Also causes vasodilation, which causes increased blood flow to muscles with diluted blocker in the blood, as well as decreased sensitivity of muscle to depolarization

Antibiotics and Local Anesthetics Interactions

• Aminoglycosides cause increased NMJ block by decreasing ACh release by blocking presynaptic Ca2+ channels
• Small doses of local anesthetics can increase NMJ Block by decreasing Ach release
• High doses can directly block nicotinic channels

Other Neuromuscular Blocking Drugs

• Curarization is the act of administering preventive doses of non-depolarizing NMJ blockers prior to succinylcholine
• This can reduce fasciculations and postoperative pain from succinylcholine
• Doing results in a greatly increased amount of succinylcholine being needed and can cause postoperative weakness

How disease states alter NMJ blockers

• Myasthenia gravis patients are more sensitive to the effects of NMJ blockers and have fewer nicotinic receptors at the NMJ
• Elderly patients > 70 years old have an enhanced effect of NMJ blockers and decreased clearance of blockers
• Patients with severe burns, upper motor neuron disease, and prolonged immobilization have resistance to nondepolarizing blockers due to the upregulation of nicotinic receptors at the NMJ

NMJ Blocker Uses:

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

Spasmolytic Drugs Definition

• Spasmolytic drugs act on spasticity, which is defined as increased tonic stretch reflexes, flexor muscle spasms, and muscle weakness

Spasmolytic Drugs Mechanism

• Spasmolytic drugs modify the stretch reflex arc by modifying skeletal muscle through reduced excitation-contraction coupling using dantrolene, or by inhibiting motor neurons using drugs like diazepam, baclofen, and tizanidine

Goal of Spasmolytic Drugs

• To inhibit motor neurons to prevent contraction of skeletal muscle

Diazepam

• Enhances GABAA receptor-mediated inhibition onto motor neurons in the spinal cord
• Sedation is a common issue

Baclofen

• Baclofen works by stimulating GABAB receptors
• Activation results in hyperpolarization of motor neurons by activating K+ channels, and reduces the release of glutamate from sensory fibers on motor neurons by inhibiting Ca2+ channels on synaptic terminals
• It is as effective as diazepam but less sedating
• Less reduction in overall muscle strength than dantrolene
• Intrathecal administration of Baclofen can control severe spasticity and muscle pain

Tizanidine (Zanaflex)

• Alpha-2 receptor agonist related to clonidine that reduces spasticity to a degree while producing less cardiovascular effects
• Works by presynaptic inhibition of glutamate release from sensory neurons onto motor neurons in the spinal cord, as well as postsynaptic inhibition of motor neurons by stimulation of K+ channels
• Inhibits nociceptive transmission
• Offers significantly less muscle weakness than other spasmolytics
• Common side effects include drowsiness, hypotension (16-33%), dizziness, dry mouth, asthenia, and hepatotoxicity
• Abrupt withdrawal is not advised and may result in rebound hypertension, tachycardia, and increased spasms
• Management of chronic migraine

Gabapentin (Neurontin)

• Gabapentin's mechanism raises GABA levels, perhaps by stimulating release, in addition to presynaptically decreasing release of glutamate by inhibiting presynaptic Ca2+ channels
• Gets renally excreted unchanged
• Does not induce hepatic enzymes or alter plasma levels of other antiepileptics
• Adverse effects include sedation and movement disorders such as ataxia, nystagmus, and tremor
• Used as an adjunct treatment for partial and generalized tonic-clonic seizures
• Pregabalin is useful to treat neuropathic pain

Dantrolene (Dantrium)

• Blocks ryanodine receptor 1 (RyR1) on the sarcoplasmic reticulum of skeletal muscle, which prevents Ca2+ release and excitation-contraction coupling
• Cardiac muscle and smooth muscle are minimally depressed due to different ryanodine receptors (RyR2)
• Used for malignant hyperthermia
• Side effects are general muscle weakness, sedation, and hepatitis

Botulinum toxin A (Botox)

• Botulinum toxin A Cleaves vesicular proteins (SNAP-25, synaptobrevin-2) inside motor neuron synaptic terminals to prevent the release of Ach triggering local muscle paralysis
• Used for short-term treatment of wrinkles around the eyes and mouth, treating generalized spastic disorders, also helps with dystonia, incontinence, and chronic migraine
• Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever, and pain

Treatment of Acute Local Muscle Spasm

• Cyclobenzaprine (Flexeril) promotes relief of acute muscle spasm caused by local tissue trauma or muscle strains
• It appears to primarily work in the brain stem to reduce tonic somatic motor activity and be ineffective in muscle spasm due to cerebral palsy or spinal injury
• Notably causes strong antimuscarinic effects, including sedation and dry mouth
• Alternatives are carisoprodol, chlorphenesin, Chlorzoxazone, metaxalone, methocarbamol and orphenadrine