Neuromuscular Blockers

Neuromuscular blockers are skeletal muscle relaxant medications that block muscle contraction through a couple of mechanisms. Depolarizing neuromuscular blockers bind to nicotinic cholinergic receptors (nAChRs), locking the ion channel open. This results in an initial, persistent depolarization, followed by receptor desensitization to result in muscle relaxation and paralysis. Nondepolarizing neuromuscular blockers also bind to these same receptors; however, they act by keeping the channel closed to prevent depolarization. These agents are often used as an adjunct to general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts during surgery, and to facilitate endotracheal intubation. Since these medications also work on muscles associated with breathing, respiratory support should be employed. It is also important that adequate sedation is also given, since these agents do not have a sedative effect. Common adverse effects include anaphylaxis, bradycardia, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and prolonged paralysis. Physicians should also be aware of the potential for muscle fasciculations and hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia with succinylcholine.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Classification and Mechanism of Action

Classification

Neuromuscular blockers can be classified based on their mechanism of action.

  • Depolarizing neuromuscular junction (NMJ) blockers: succinylcholine
  • Nondepolarizing NMJ blockers:
    • Atracurium
    • Cisatracurium
    • Mivacurium
    • Pancuronium
    • Rocuronium
    • Tubocurarine
    • Vecuronium

Mechanism of action

Normal physiology:

  • Nicotinic cholinergic receptors (nAChRs) are ionotropic (ligand-gated receptors that are ion channels).
    • Evoke fast excitatory postsynaptic potential (EPSP)
    • Target for skeletal muscle relaxants 
  • N1 nAChR location: NMJ (end plate) on skeletal muscles innervated by the somatic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (SNS)
  • Activation of nAChRs by acetylcholine (ACh): 
    • Ion channel opens → net Na+ influx → fast EPSP 
    • Depolarization at postsynaptic membrane → action potential in muscle fiber → muscle contracts

Depolarizing neuromuscular blockers: 

  • Noncompetitively bind to the N1 nAChR and keep the ion channel open → Na+ influx → transient muscle contractions, followed by persistent depolarization of the end plate 
    • Phase I blockade
    • Associated with skeletal muscle fasciculations 
  • End plate eventually repolarizes, but N1 nAChR is desensitized → nondepolarizing blockade 
    • Phase II blockade
    • Associated with flaccid paralysis 
  • Succinylcholine is degraded by plasma pseudocholinesterase. 
  • Cholinesterase inhibitors do not reverse effects → may prolong depolarization due to plasma pseudocholinesterase inhibition 

Nondepolarizing neuromuscular blockers: 

  • Competitively block ACh from binding to the N1 nAChR and keep the ion channel closed → prevents muscle contraction 
  • Effects reversed by cholinesterase inhibitors (e.g., physostigmine, neostigmine)
Nondepolarizing blocker

Neuromuscular blockers bind to ionotropic N1 nicotinic cholinergic receptors (nAChRs) and can either close the ion channel (nondepolarizing blocker) or lock the ion channel in the open position (depolarizing blocker). The latter will result in a short period of transient muscle contraction before the channel becomes desensitized, resulting in muscle relaxation.

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Pharmacokinetics

Table: Pharmacokinetics of neuromuscular blocking agents
Medication Onset of action (min) Duration of action (min) Metabolism Excretion
Succinylcholine < 1 4–6 Plasma pseudocholinesterase Urine
Atracurium 2–3 20–35
  • Ester hydrolysis
  • Hofmann elimination*
Urine (minimal)
Cisatracurium 2–3 20–35 Hofmann elimination* Urine and bile
Pancuronium 2–3 60–100
  • Hepatic
  • Active metabolite
Urine and bile
Rocuronium 1–2 30
  • Hepatic (minimal)
  • Less active metabolite
Bile and urine
Vecuronium 3–5 45–65
  • Hepatic
  • Active metabolite
Bile and urine
*Hofmann elimination: the spontaneous degradation of a compound at physiologic body temperature and pH, allowing the compound to bypass renal and hepatic clearance

Indications

  • Induction of neuromuscular blockade for: 
    • Facilitation endotracheal intubation
    • Mechanical ventilation: 
      • Severe ventilator dyssynchrony despite sedation
      • Prevents spontaneous respiratory effort, which could have the potential for lung injury in certain circumstances
    • Adjunct to general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts during surgery
  • Note: Neuromuscular blockers do not have a sedative effect, so they should be given in conjunction with adequate sedation.

Adverse Effects and Contraindications

Table: Adverse effects, precautions, contraindications, and drug interactions associated with neuromuscular blocking agents
Medication Adverse effects Precautions Contraindications Drug interactions
Succinylcholine
  • Respiratory arrest
  • Bradycardia
  • Hypotension
  • Hyperkalemia
  • Anaphylaxis
  • Malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia
  • Fasciculations
  • Postop myalgia
  • ↑ IOP
  • Tachyphylaxis
Atypical plasma cholinesterase gene → altered metabolism
  • During recovery following (risk of ↑ K+):
    • Major burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
    • Extensive trauma
    • Denervation of skeletal muscle or UMN injury
  • History of malignant hyperthermia
  • Skeletal muscle myopathy
  • Hypersensitivity
  • ↑ NMB activity:
    • Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides
    • Tetracyclines Tetracyclines Tetracyclines are a class of broad-spectrum antibiotics indicated for a wide variety of bacterial infections. These medications bind the 30S ribosomal subunit to inhibit protein synthesis of bacteria. Tetracyclines cover gram-positive and gram-negative organisms, as well as atypical bacteria such as chlamydia, mycoplasma, spirochetes, and even protozoa. Tetracyclines
    • Clindamycin
    • Amphotericin B
    • Vancomycin
    • Inhaled anesthetics Inhaled anesthetics Inhaled anesthetics are chemical compounds that can induce and maintain general anesthesia when delivered by inhalation. Inhaled anesthetics can be divided into 2 groups: volatile anesthetics and gases. Volatile anesthetics include halothane, isoflurane, desflurane, and sevoflurane. Inhaled Anesthetics
    • CCBs
    • Beta-blockers
    • Procainamide
    • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics
    • Steroids
    • Cyclophosphamide
    • Cyclosporine
    • Dantrolene
    • Mg
  • ↓ NMB activity:
    • Carbamazepine
    • Phenytoin
    • Ranitidine
    • Theophylline
Atracurium
  • Bradycardia
  • Hypotension
  • Respiratory arrest
  • Histamine release
  • Anaphylaxis
Resistance in burn or immobilized patients Hypersensitivity
Cisatracurium
  • Bradycardia
  • Respiratory arrest
  • Residual paralysis
  • Anaphylaxis
Pancuronium
  • Hypertension or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Tachycardia
  • Respiratory arrest
  • Histamine release
  • Anaphylaxis
Renal and hepatic impairment → reduced clearance
Rocuronium
  • Tachycardia
  • Hypertension or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Respiratory arrest
  • ↑ Vascular resistance
  • Anaphylaxis
  • Prolonged paralysis
  • Renal and hepatic impairment
  • Valvular disease or PH
Vecuronium
  • Respiratory arrest
  • Anaphylaxis
  • Prolonged paralysis
Renal and hepatic impairment
IOP: intraocular pressure
NMB: neuromuscular blocking
PH: pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
Postop: postoperative
UMN: upper motor neuron
CCB: calcium channel blocker

References

  1. Ishii, M, Kurachi, Y. (2006). Muscarinic acetylcholine receptors. Curr Pharm Des. 12(28), 3573–81. https://doi.org/10.2174/138161206778522056
  2. Wess, J. (2003). Novel insights into muscarinic acetylcholine receptor function using gene targeting technology. Trends Pharmacol Sci. 24(8), 414–20. https://doi.org/10.1016/S0165-6147(03)00195-0
  3. Olshansky, B, Sullivan, RM. (2013). Inappropriate sinus tachycardia. J Am Coll Cardiol. 61(8), 793–801. https://doi.org/10.1016/j.jacc.2012.07.074
  4. Greenberg, SB, Vender, J. (2013). The use of neuromuscular blocking agents in the ICU: Where are we now? Crit Care Med. 41(5), 1332–44. https://doi.org/10.1097/CCM.0b013e31828ce07c
  5. McCarthy, ML, Baum, CR. (2017). Centrally acting muscle relaxants. In Brent, J, et al. (Eds.), Critical Care Toxicology, 2e. Springer, Cham. https://doi.org/10.1007/978-3-319-17900-1_72
  6. Saguil, A. (2005). Evaluation of the patient with muscle weakness. Am Fam Physician. 71(7), 1327–36. https://www.aafp.org/afp/2005/0401/p1327.pdf
  7. Rosenbaum, P, et al. (2007). A report: The definition and classification of cerebral palsy. April 2006. Dev Med Child Neurol Suppl. 109, 8–14. https://pubmed.ncbi.nlm.nih.gov/17370477/ 
  8. Khanna, AK, et al. (2018). Respiratory depression in low acuity hospital settings: Seeking answers from the PRODIGY trial. J Crit Care. 47,80–87. https://doi.org/10.1016/j.jcrc.2018.06.014
  9. The 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. (2019). American Geriatrics Society 2019. Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 67(4), 674–694. https://doi.org/10.1111/jgs.15767
  10. Bittner, EA. (2021). Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects. In Finlay, G., and Crowley, M. (Eds.), UpToDate. Retrieved November 21, 2021, from https://www.uptodate.com/contents/neuromuscular-blocking-agents-in-critically-ill-patients-use-agent-selection-administration-and-adverse-effects

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