Neuromuscular Blocking Agents (NMBAs)

• Neuromuscular blocking agents (NMBAs), also called paralytics or muscle relaxants, induce skeletal muscle weakness or paralysis, inhibiting movement
• These agents act at the neuromuscular junction by disrupting acetylcholine (Ach) activity

Key Terms and Definitions

• Acetylcholinesterase (AchE): Enzyme that breaks down acetylcholine (Ach) at the synaptic cleft, enabling transmission of the next nerve impulse
• Amnestic properties: Ability to cause total or partial memory loss
• Aspiration: Accidental inhalation of food, fluids, or gastric contents into the lungs
• Fasciculation: Involuntary contractions or twitching of muscle fibers
• Myasthenia gravis: Autoimmune neuromuscular disorder with chronic muscle fatigue
• Nerve cell (neuron): Basic unit of the nervous system for transmitting electrical impulses
• Neuromuscular blocking agents (NMBAs): Substances interfering with neural transmission between motor neurons and skeletal muscles
• Neurotransmitter: Chemical released from a nerve ending to transmit impulses
• Nosocomial pneumonia: Pneumonia acquired in a health care setting
• Sedation: Production of a restful state of mind, often drug-induced, to relieve anxiety
• Somatic motor neurons: Part of the nervous system controlling voluntary muscles
• Status asthmaticus: Asthma exacerbation unresponsive to standard treatment
• Status epilepticus: Continuous seizure activity for at least 30 minutes without full recovery

Indications and Uses of NMBAs

• Facilitating intubation
• During surgery
• Enhancing ventilator synchrony
• Reducing intracranial pressure (ICP)
• Reducing O2 consumption
• Terminating status epilepticus and tetanus
• Facilitating procedures and studies
• Keeping patients immobile

Physiology of the Neuromuscular Junction

• CNS: Brain and spinal cord
• PNS:
  • Somatic motor nervous system (skeletal, voluntary control)
  • Autonomic nervous system (involuntary control)
• Rapid sequence intubation (RSI) requires quick airway security and minimized aspiration, indicated for patients with acute respiratory failure where a paralytic agent is administered after sedation
• Neuron:
  • Cell body
  • Axons
  • Dendrites
• Neurotransmitter: Acetylcholine mediates nerve conduction in skeletal muscle and is broken down by acetylcholinesterase (AChE)
• Depolarization: Action potential occurs
• Repolarization: Membrane potential returns to baseline

Blocking Muscle Contraction

• Competitive inhibition: Nondepolarizing agents
• Prolonged occupation and persistent binding: Depolarizing agents

Nondepolarizing Agents

• Competitive inhibition that blocks acetylcholine receptors without activating them
• Affect postsynaptic cholinergic receptors at the neuromuscular junction
• Compete against endogenous acetylcholine
• The effect is dose-related
• Acetylcholinesterase inhibitors (neostigmine) can reverse blockade

Pharmacokinetics of Nondepolarizing Agents

• Chemically resemble acetylcholine
• Poorly lipophilic, so poorly absorbed in the GI tract and must be given IV
• Onset of paralysis and duration of action vary and are dose-dependent
• Longer duration than depolarizing agents
• Duration can be increased by advanced age, hepatic or renal failure
• Even when normal conduction returns, 75% of receptors may still be occupied by the blocker, meaning additional doses may appear more potent
• d-Tubocurarine and doxacurium: Minimally metabolized, 60% excreted by kidneys and the remainder in bile
• Pancuronium: Some hepatic metabolism
• Atracurium and cisatracurium: Partly inactivated by spontaneous degradation by pH and temperature (Hofmann degradation), making them optimal choices for patients with hepatic or renal failure
• Vecuronium: Primarily hepatic metabolism
• Mivacurium: One of the shortest-acting (10–20 minutes) and is eliminated by plasma cholinesterase

Nondepolarizing Agents (cont’d) •Adverse effects and hazards ◦Cardiovascular effects: ◦Vagolytic effect  tachycardia, increase in mean arterial pressure ◦Pancuronium has the greatest potential to cause cardiovascular side effects ◦Histamine release ◦Cause histamine release from mast cells  hypotension, reflex tachycardia, bronchospasm ◦Inadequate ventilation ◦Paralysis of diaphragm and intercostals Depolarizing Agents •Shorter acting than nondepolarizing agents •No agents that reverse their blockade •Only agent is succinylcholine •Paralysis in 60–90 seconds that lasts from 10 to 15 minutes •Ideal for patients requiring intubation

Depolarizing Agents (cont’d) •Mode of action ◦Depolarizes muscle membrane like acetylcholine ◦Resistant to AchE for a longer period ◦Causes fasciculations ◦Phase I block ◦Prolonged depolarization/flaccid paralysis ◦Phase II block ◦Resembles nondepolarizing block ◦Limits use in repeat doses

Depolarizing Agents (cont’d) •Metabolism ◦Rapid hydrolysis by plasma cholinesterase •Reversal ◦No agents available for reversal of succinylcholine

Depolarizing Agents (cont’d) •Adverse effects and hazards ◦Sympathomimetic response ◦Vagal response with repeat boluses ◦Seen more often in children ◦Muscle pain/soreness ◦Histamine release ◦Hyperkalemia ◦Increased intracranial, intraoptic, and intragastric pressure ◦Malignant hyperthermia

Depolarizing Agents (cont’d) •Sensitivity to succinylcholine ◦Metabolized by plasma cholinesterase (pseudocholinesterase) ◦Patients with abnormal or deficient pseudocholinesterase will not metabolize succinylcholine effectively ◦Prolonged recovery time and prolonged mechanical ventilation support

NMBAs and Mechanical Ventilation •Used to improve ventilation and oxygenation and to reduce pressure •Beneficial in: ◦Acute respiratory distress syndrome (ARDS) ◦Status asthmaticus ◦Inverse ratio ventilation and high-frequency oscillatory ventilation (HFOV) ◦Status epilepticus ◦Neuromuscular toxins ◦Tetanus

NMBAs and Mechanical Ventilation (cont’d) •Precautions and risks ◦Proper eye care ◦Suctioning ◦Proper sedation and analgesia ◦Aspiration/nosocomial pneumonia ◦Risk of prolonged skeletal muscle weakness ◦Decubitus ulcers ◦Deep venous thrombosis (DVT)

NMBAs and Mechanical Ventilation (cont’d) •Use of sedation and analgesia ◦Absolutely essential! ◦Monitor for tachycardia, hypertension, diaphoresis, and lacrimation ◦Analgesics ◦Fentanyl ◦Morphine ◦Amnestic sedatives ◦Propofol ◦Lorazepam ◦Midazolam

NMBAs and Mechanical Ventilation (cont’d) •Interactions with neuromuscular blocking agents ◦Inhaled anesthetics potentiate blockade ◦Aminoglycosides also produce NMBA ◦Agents antagonizing NMBA ◦Phenytoin ◦Azathioprine ◦Theophylline ◦Potentiate blockade ◦Acidosis ◦Hypokalemia ◦Hyponatremia ◦Hypocalcemia ◦Hypomagnesemia

NMBAs and Mechanical Ventilation (cont’d) •Choice of agents ◦Situation dependent ◦Factors: ◦Duration of procedure ◦Need for quick intubation ◦Adverse effects ◦Route of elimination ◦Drug interactions ◦Cost

Monitoring of Neuromuscular Blockade •Paralysis may mask clinical signs/symptoms •Ventilator malfunction must first be ruled out as the cause of agitation before initiating NMBA •Methods ◦Visual ◦Tactile ◦Electronic

Monitoring of Neuromuscular Blockade (cont’d) •Loss of muscle activity ◦Eyelids ◦Face ◦Neck ◦Extremities ◦Abdomen ◦Intercostals ◦Diaphragm •Return of muscle activity ◦Occurs in reverse order

Monitoring of Neuromuscular Blockade (cont’d) •Twitch monitoring •Train-of-four evaluation ◦2 Hz over 2 seconds ◦0 twitches = 100% blockade ◦1 twitch = 95% blockade ◦2 twitches = 90% blockade ◦3 twitches = 80% blockade ◦4 twitches = <75% blockade

Future of Neuromuscular Blocking Agents and Reversal •Gantacurium ◦Nondepolarizing ◦Rapid onset ◦Short-acting ◦Organ-independent inactivation ◦Less histamine release •Sugammadex ◦Inactivates and removes NMBA ◦Reverses rocuronium and vecuronium ◦Less effective on pancuronium, succinylcholine, and benzylisoquinoliniums