RCP 110 Chapter 18 - Skeletal Muscle Relaxants and Neuromuscular Blockade

• Skeletal Muscle Relaxants are also known as Neuromuscular Blocking Agents (NMBAs).
• NMBAs are drugs which cause skeletal muscle weakness or paralysis.
• NMBAs can be either nondepolarizing or depolarizing agents.
• Administered intravenously, NMBAs elicit a response in muscles that is dose-related.

Uses of NMBAs

• NMBAs aid intubation and can be used during surgery.
• These agents enhance ventilator synchrony, and reduce intracranial pressure (ICP).
• NMBAs reduce O2 consumption and terminate status epilepticus and tetanus.
• These relaxants facilitate medical procedures/studies and keep patients immobile.

Physiology of the Neuromuscular Junction

• The CNS consists of the brain and spinal cord.
• The PNS includes the somatic motor nervous system which controls skeletal muscles via voluntary control.
• The PNS also consists of the autonomic nervous system which regulates involuntary control.

Neuron and Neurotransmitter

• A neuron consists of a cell body, axons, and dendrites.
• Transmission of nerve conduction in skeletal muscle is chemically mediated by acetylcholine.
• Acetylcholine is broken down by acetylcholinesterase (AChE).

Depolarization and Repolarization

• Depolarization causes an action potential to occur.
• During Repolarization the membrane potential returns to baseline.

Blocking Muscle Contraction

• Muscle contraction can be blocked in two ways
• The first is competitive inhibition, using nondepolarizing agents
• The second is prolonged occupation and persistent binding, using depolarizing agents

Nondepolarizing Agents

• Nondepolarizing Agents cause competitive inhibition.
• Nondepolarizing Agents block acetylcholine receptors without activating them.

Mode of Action

• Nondepolarizing agents affect postsynaptic cholinergic receptors at the neuromuscular junction.
• These compete against endogenous acetylcholine and the effect is dose related.
• Acetylcholinesterase inhibitors like Neostigmine can reverse blockade.
• Nondepolarizers occupy but do not activate acetylcholine receptors, preventing acetylcholine from occupying receptors and causing muscle contraction to fail.
• Released acetylcholine is rapidly metabolized by membrane cholinesterase.
• Nondepolarizers also bind to prejunctional acetylcholine receptors and modify acetylcholine release.

Pharmacokinetics of Nondepolarizing Agents

• Nondepolarizing agents chemically resemble acetylcholine but are poorly lipophilic.
• They are poorly absorbed in the GI tract, requiring IV administration.
• Paralysis onset and action duration vary widely and depend on the dosage.
• Nondepolarizing agents last longer than depolarizing agents.
• Their duration can be prolonged by advanced age, and hepatic or renal failure.

Metabolism of Nondepolarizing Agents

• When normal conduction returns, 75% of receptors might still be occupied by a blocker, additional boluses may seem more potent.
• d-Tubocurarine and doxacurium are minimally metabolized, with 60% excreted by the kidneys and the remainder in bile
• Pancuronium undergoes some hepatic metabolism.
• Atracurium and cisatracurium are partly inactivated by spontaneous degradation by pH and temperature called Hofmann degradation, and are ideal for patients with hepatic or renal failure.
• Vecuronium undergoes primary hepatic metabolism.
• Mivacurium is one of the shortest acting, lasting 10–20 minutes, and is eliminated by plasma cholinesterase.

Adverse Effects and Hazards

• Cardiovascular effects potentially include a vagolytic effect, leading to tachycardia and increased mean arterial pressure.
• Pancuronium poses the greatest risk for cardiovascular side effects.
• Histamine release can cause hypotension, reflex tachycardia, and bronchospasm upon release from mast cells.
• These agents can cause Inadequate ventilation potentially leading to paralysis of the diaphragm and intercostals.

Reversal of Nondepolarizing Blockade

• Reversal can be achieved using an indirect-acting agent.
• Cholinesterase inhibitors can be used to produce the desired effect, inhibiting cholinesterase, breaking down acetylcholine
• Allows more acetylcholine at the junction to displace the blocker.
• Examples of agents include neostigmine, edrophonium, and pyridostigmine.

Depolarizing Agents

• Depolarizing agents are shorter acting than nondepolarizing agents.
• No agents can reverse the effects of Depolarizing Agents.
• The only available agent is succinylcholine.
• Paralysis occurs in 60–90 seconds and lasts 10-15 minutes.
• Depolarizing Agents are ideal for patients who require intubation.
• Succinylcholine produces a depolarizing block by occupying and activating acetylcholine receptors.
• The process lets sodium enter and create an initial action potential.
• Continued occupancy stops repolarization and the next action potential from released acetylcholine.
• Activation of prejunctional acetylcholine receptors can modify how acetylcholine is released.

Mode of Action

• Depolarizing agents act by depolarizing the muscle membrane like acetylcholine.
• These agents are resistant to AchE for a longer period of time.
• They cause fasciculations.
• A Phase I block causes prolonged depolarization/flaccid paralysis.
• A Phase II block resembles nondepolarizing block and limits use in repeat doses.

Metabolism and Reversal

• Depolarizing agents undergo rapid hydrolysis by plasma cholinesterase.
• There are no agents available for reversal of succinylcholine.

Adverse Effects and Hazards

• Sympathomimetic response.
• Vagal response with repeat boluses is more often seen in children.
• These agents can cause muscle pain/soreness, histamine release, and hyperkalemia.
• Depolarizing Agents can cause increased intracranial, intraoptic, and intragastric pressure.
• Malignant hyperthermia is also a potential hazard.

Sensitivity to Succinylcholine

• Succinylcholine is metabolized by plasma cholinesterase (pseudocholinesterase).
• Patients with abnormal or deficient pseudocholinesterase will not metabolize succinylcholine effectively.
• This leads to prolonged recovery time and prolonged mechanical ventilation support.

NMBAs and Mechanical Ventilation

• NMBAs help improve ventilation and oxygenation, and reduce pressure.
• Beneficial in treating acute respiratory distress syndrome (ARDS) and status asthmaticus.
• Beneficial in inverse ratio ventilation and high-frequency oscillatory ventilation (HFOV).
• NMBAs can also benefit those with Status epilepticus, Neuromuscular toxins and Tetanus

Precautions and Risks

• Proper eye care and Suctioning
• Ensure Proper sedation and analgesia.
• These Agents can lead to Aspiration/nosocomial pneumonia and risk of prolonged skeletal muscle weakness.
• NMBAs can cause Decubitus ulcers and Deep venous thrombosis (DVT).

Use of Sedation and Analgesia

• Using Sedation and analgesia is absolutely essential!
• Key to monitor for tachycardia, hypertension, diaphoresis, and lacrimation.
• Analgesics include Fentanyl and Morphine
• Amnestic sedatives include Propofol, Lorazepam, and Midazolam.

Interactions with Neuromuscular Blocking Agents

• Inhaled anesthetics potentiate blockade, as do aminoglycosides.
• Agents antagonizing NMBA include Phenytoin, Azathioprine, and Theophylline.
• Blockade is Potentiated by Acidosis, Hypokalemia, Hyponatremia, Hypocalcemia, and Hypomagnesemia.

Choice of Agents

• The choice of agent is situation dependent.
• Factors to consider can include; the duration of procedure, need for quick intubation, adverse effects, route of elimination, drug interactions, and cost.

Monitoring Neuromuscular Blockade

• Paralysis may mask clinical signs/symptoms.
• Rule out Ventilator malfunction first as the cause of agitation before initiating NMBA.
• Include visual, tactile, and electronic methods.

Loss and Return of Muscle Activity

• Loss of muscle activity happens in this order; Eyelids, Face, Neck, Extremities, Abdomen, Intercostals, and Diaphragm.
• Return of muscle activity occurs in the reverse order.

Twitch Monitoring and Train-of-Four Evaluation

• 2 Hz over 2 seconds is the standard.
• 0 twitches = 100% blockade.
• 1 twitch = 95% blockade.
• 2 twitches = 90% blockade.
• 3 twitches = 80% blockade.
• 4 twitches = <75% blockade.