Neuromuscular Junction (NMJ) Blockers

• Neuromuscular junction (NMJ) blockers induce muscle relaxation needed for surgical procedures.
• NMJ blockers do this without the cardiorespiratory depression of deep anesthesia.

Neuronal Activation of Skeletal Muscle Contraction

• Acetylcholine activates nicotinic receptors.
• Na+ influx through nicotinic receptors depolarizes the membrane.
• This opens voltage-gated Na+ channels and L-type voltage-gated Ca2+ channels.
• Ca2+ then activates ryanodine receptors on the sarcoplasmic membrane.
• Ryanodine receptors open, allowing Ca2+ to be released.
• Ca2+ causes actin-myosin crosslinking, leading to muscle contraction.

Curare

• Tubocurarine is isolated from the South American vine, chondrodendron tomentosum.

Chemical Structures

• Most neuromuscular blockers have two quaternary nitrogen groups.
• Succinylcholine consists of two acetylcholine molecules joined together.

Mechanism of Action: Competitive Blockers

• Competitive blockers include tubocurarine, pancuronium, mivacurium and atracurium.
• They compete with acetylcholine for postjunctional nicotinic receptors.
• A large margin of safety exists for neuromuscular transmission, and about 75% of receptors must be blocked before inhibition happens.
• These blockers are readily antagonized and reversed by anticholinesterase agents like neostigmine.
• Competitive blockers prevent the endplate potential from reaching threshold, thus preventing action potentials.
• Competitive blockers have no direct effect on resting membrane potential.

Mechanism of Action: Depolarizing Blockers

• Succinylcholine (Anectine) acts as a depolarizing blocker.
• Nicotine or acetylcholine can also act as depolarizing blockers when combined with acetylcholine esterase inhibitors.

Phase I (Depolarization)

• The first phase of depolarization starts with muscle fasciculations.
• Nicotinic receptors open and maintain depolarization, inactivating Na+ channels and causing refractoriness.
• Pure Phase I depolarizing block is worsened by anticholinesterase agents.

Phase II (Desensitization)

• In Phase II, the membrane repolarizes but becomes desensitized after prolonged depolarization.
• Nicotinic receptors inactivate, allowing the muscle to repolarize, accompanied by Na+ channel deactivation.
• Inactivated nicotinic receptors are unresponsive to acetylcholine, effectively reducing available nicotinic receptors.
• Acetylcholine esterase inhibitors can reverse the blockade by activating the remaining nicotinic receptors.

Genetic Variants of Plasma Cholinesterase

• Prolonged NMJ block may occur in patients with abnormal genetic variants of plasma cholinesterase.
• The dibucaine number indicates the patient's ability to metabolize succinylcholine.
• Dibucaine inhibits normal butyrylcholinesterase by 80% and abnormal enzyme by 20%.

Monitoring Skeletal Muscle Relaxation

• Train-of-four (TOF) patterns use four stimuli applied at 2 Hz.
• The TOF ratio (TOF-R) is the strength of the fourth contraction divided by the first.
• A TOF ratio between 0.15 and 0.25 indicates adequate surgical relaxation.
• A TOF ratio greater than 0.9 is safe for extubation and recovery.

Competitive NMJ Blockers

• Competitive NMJ blockers have highly polar quaternary nitrogen and must be administered parenterally.
• Steroidal muscle relaxants are metabolized to 3-hydroxy metabolites in the liver which accumulate with prolonged use, particularly in ICU settings.
• These blockers cause respiratory depression but have no CNS effects due to the quaternary nitrogen.
• Tubocurarine can cause hypotension, weak autonomic ganglionic blockade and histamine release leading to hypotension and bronchospasm; can be pretreated with antihistamine.

Other Competitive NMJ Blockers

• Mivacurium has a short duration, is metabolized by pseudocholinesterase, and induces histamine release.
• Atracurium is an intermediate-acting isoquinoline non-depolarizing muscle relaxant.
• Atracurium undergoes spontaneous Hofmann elimination, producing laudanosine, which is slowly metabolized, enters the brain, and can induce seizures at high concentrations as well as hypotension.
• Cisatracurium has fewer adverse effects than atracurium, less histamine release and produces less laudanosine, it is favored in renal or hepatic impairment due to rapid nonenzymatic degradation.
• Pancuronium is a long-acting steroid muscle relaxant that can cause tachycardia and is primarily renally excreted; it is less commonly used due to its longer duration.
• Vecuronium and rocuronium are preferred for their rapid onset and intermediate duration and are primarily cleared via biliary excretion or hepatic metabolism; they have minimal cardiovascular effects.

Sugammadex (Bridion)

• Sugammadex acts as an NMJ blocker antagonist that binds steroidal rocuronium and vecuronium which reduces their free plasma concentration and reverses their effects.
• It's excreted unchanged in urine with prolonged elimination in renal insufficiency.
• Adverse reactions include anaphylaxis, hypersensitivity reactions, bradycardia, potential cardiac arrest and transient coagulopathy.
• Sugammadex binds steroidal drugs like progesterone-based contraceptives and selective estrogen receptor modulators, decreasing the efficacy of contraceptives.

Depolarizing Blocker: Succinylcholine

• Succinylcholine's onset is in 20-40 seconds, duration is less than 10 minutes, due to rapid metabolism by pseudocholinesterase and genetic variability.
• Succinylcholine causes respiratory depression, muscle soreness and hyperkalemia particularly with burns, neuromuscular disease, or trauma.
• It can decrease HR and contractility by stimulating muscarinic receptors, which can be blocked by antimuscarinics.
• Succinylcholine increases intragastric pressure, intraocular pressure and can trigger malignant hyperthermia.

Malignant Hyperthermia

• Malignant hyperthermia is an autosomal dominant genetic disorder where abnormal Ca2+ channels (ryanodine receptors) in skeletal muscle react to potent inhalation anesthetics and depolarizing muscle relaxants like succinylcholine.
• Exposure leads to an abnormally large increase in Ca2+ channels within skeletal muscle.
• The syndrome involves rapid onset of severe rigid muscles, hyperthermia, hyperkalemia, tachycardia, hypertension, and acid-base imbalance with acidosis.
• Dantrolene blocks calcium release from Ryanodine Receptors in the sarcoplasmic reticulum.

Drug Interactions

• Inhalation anesthetics increase the NMJ block: Isoflurane > sevoflurane, desflurane, enflurane, halothane > N2O
• Inhalation anesthetics cause CNS depression to the motor cortex which leads to less release of acetylcholine, vasodilation and decreased sensitivity of muscle to depolarization.
• Antibiotics, specifically aminoglycosides, elevate the NMJ block by decreasing Ach release via blocking presynaptic Ca2+ channels.
• Small doses of local anesthetics enhance NMJ blockers by decreasing Ach release, whereas high doses block nicotinic channels.

Other NM Blocking Drugs

• Preventive curarization, using small doses of nondepolarizing NMJ blockers before succinylcholine, prevents fasciculations and postoperative pain.
• It greatly increases the amount of succinylcholine needed, possibly causing postoperative weakness; this isn't widely used anymore.

Effects of Diseases and Aging

• Myasthenia gravis enhances the effect of NMJ blockers because there are fewer nicotinic receptors.
• Elderly patients older than 70 years also show an enhanced effect of NMJ blockers and decreased clearance,
• Individuals with severe burns, upper motor neuron disease, or prolonged immobilization are resistant to nondepolarizing blockers due to the upregulation of nicotinic receptors at NMJ.

Uses of NMJ Blockers

• NMJ blockers induce surgical relaxation.
• NMJ blockers can be used to control ventilation.
• NMJ blockers treat convulsions by blocking skeletal muscle contractions.

Spasmolytic Drugs

• Spasmolytic drugs are used to treat Spasticity.
• Spasticity includes increased tonic stretch reflexes, flexor muscle spasms and muscle weakness.
• Such drugs modify the stretch reflex arc by modifying skeletal muscle (dantrolene) and inhibiting motor neurons (diazepam, baclofen, tizanidine).

Spasmolytic Drugs: Diazepam

• Diazepam enhances GABAA receptor-mediated inhibition onto motor neurons in the spinal cord.
• Sedation is a common problem.

Spasmolytic Drugs: Baclofen

• Baclofen works by stimulating GABAB receptors, resulting in hyperpolarization of motor neurons and reduces the release of glutamate.
• It is as effective as diazepam and cause les sedation.
• Baclofen causes less reduction in overall muscle strength than dantrolene and intrathecal administration can control severe spasticity and muscle pain.

Spasmolytic Drugs: Tizanidine

• Tizanidine is an α2 receptor agonist related to clonidine that reduces spasticity with fewer cardiovascular effects.
• Tizanidine inhibits presynaptic glutamate release, enhances postsynaptic inhibition of motor neurons and inhibits nociceptive transmission.
• It causes less muscle weakness compared to other spasmolytics; common adverse effects include drowsiness, hypotension, dizziness and hepatotoxicity.

Spasmolytic Drugs: Gabapentin

• Gabapentin may work by increasing GABA levels, and presynaptically decreasing the release of glutamate by inhibiting presynaptic Ca2+ channels.
• It's renally excreted unchanged, does not induce hepatic enzymes, and does not alter plasma levels of other antiepileptics.
• Common side effects include sedation and movement disorders.
• Gabapentin is used as an adjunct treatment for partial and generalized tonic-clonic seizures, and pregabalin can treat neuropathic pain.

Spasmolytic Drugs: Dantrolene

• Dantrolene blocks ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum of skeletal muscle, preventing Ca2+ release, which is the treatment for malignant hyperthermia.
• Dantrolene can cause general muscle weakness, sedation and occasional hepatitis.

Spasmolytic Drugs: Botulinum Toxin A (Botox)

• Botulinum toxin A cleaves vesicular proteins inside motor neuron synaptic terminals which prevents the release of acetylocholine causing local muscle paralysis.
• Botulinum toxin A is applied to short-term wrinkle treatment, generalized spastic disorders and chronic migraines.
• Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever and pain.

Treatment of Acute Local Muscle Spasm

• Cyclobenzaprine (Flexeril) relieves acute muscle spasm caused by local tissue trauma or muscle strains, particularly lower back pain by working in the brain stem.
• Cyclobenzaprine is ineffective in muscle spasm from cerebral palsy or spinal injury, has strong antimuscarinic effects, and causes sedation and dry mouth.
• Carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol and orphenadrine are other muscle relaxants.