Neuromuscular Blocking Agents

M.7, W.3, L.13

Neuromuscular Junction (NMJ)

Neuromuscular blocking agents (NMBs) act at the neuromuscular junction, specifically on the nicotinic acetylcholine (ACh) receptor located on skeletal muscle

Normally:

1. a motor nerve action potential arrives at the NMJ

2. Acetylcholine is released

3. ACh binds nicotinc receptors

4. Sodium channels open → muscle depolarization

5. muscle contraction occurs

Mechanism of Action of NMBs

Neuromuscular blocking agents are:

• competitive antagonists at nicotinic ACh receptors

• large rigid molecules with quaternary ammonium groups

They prevent acetylcholine from binding to the receptor, therefore:

• end plate depolarization cannot occur

• transmission at the NMJ is blocked

• muscle contraction is prevented

About 80% of receptors must be blocked before transmission fails

Physiological Basis of Their Effects

Main Effect: Flaccid Paralysis

• Because skeletal muscle contraction depends on NMJ transmission, blockade causes:

  • loss of skeletal muscle contraction

  • flaccid paralysis

• Importantly:

  • the nerve still conducts impulses

  • the muscle can still respond to direct stimulation

  • only transmission across the NMJ is blocked

Respiratory Muscle Effects

different muscles have different sensitivities

• Respiratory Muscles

  • diaphragm and intercostals are relatively resistant

  • therefore:

    • last to become paralyzed

    • first to recover

• However:

  • airway control muscles are highly sensitive

  • patient may begin breathing before airway patency is restored

  • creates risk of airway obstruction

Consciousness and Pain Perception

• NMBs:

  • have no anesthetic effect

  • have no analgesic effect

  • does not affect consciousness

• Therefore:

  • patients must always be adequately anesthetized

  • otherwise they may be conscious but paralyzed

Physiological Basis of Side Effects

Hypotension

• Some NMBs can cause:

  • ganglion blockade

  • histamine release

• These effects cause

  • vasodilation

  • reduced blood pressure

Tachycardia

• some NMBs block muscarinic receptors:

  • reducing parasympathetic influence on the heart

  • increasing heart rate

Apnea

• because respiratory muscles are eventually paralyzed:

  • spontaneous ventilation stops

  • mechanical ventilation is required

• This is why NMBs are only used:

  • in anesthetized patients

  • with ventilatory support available

Reversal of Neuromuscular Blockade

Spontaneous Recovery

• as plasma drug concentration falls:

  • drug diffuses away from NMJ

  • enough receptors become available again

  • transmission resumes

Anticholinesterases

• Ex: neostigmine, edrophonium

• MOA

  • inhibit acetylcholinesterase

  • increase acetylcholine concentration

  • ACh competes with blocker at nicotinic receptors

  • neuromuscular transmission is restored

• Side effects

  • bronchoconstriction, bradycardia, salivation, urination/defecation

  • Antimuscarinic Drugs are given in addition to counter muscarinic side effects

    • ex: atropine

Sugammadex

• a chemical antagonist of rocuronium and vecuronium

• cyclodextrin molecule that surrounds the relaxant and inactivates it

• Advantages:

  • rapid reversal

  • no antimuscarinic required

Main Clinical Applications

• Facilitate endotracheal intubation

• Improve surgical access

• control ventilation during anesthesia

• ophthalmic surgery

Additional uses

• during deep general anesthesia

• alongside local anesthesia

• to improve surgical conditions without excessively deep anesthesia

Physicochemical Characteristics

Most NMBs are:

• large rigid molecules

• quaternary ammonium compounds

• permanently charged

Because they are highly ionized:

• they do not cross lipid membranes easily

• they cannot be absorbed orally

• they mainly extracellular

Influence on Route of Administration

Intravenous Administration

• Since NMBs cannot cross membranes efficiently

  • they must be given parenterally

  • in practice they are administered intravenously (IV)

• This allows:

  • rapid delivery to the NMJ

  • predictable onset

Examples of NMBs

Aminosteroids (“-onium)

• vecuronium

• rocuronium

• pancuronium

Benzylisoquinolines ("-curium”)

• atracurium

• cistacurium

• mivacurium

Overall Summary

NMB Agents:

• competitively block nicotinic ACh receptors at the skeletal NMJ

• prevent neuromuscular transmission

• cause flaccid paralysis without affecting consciousness or pain perception

• may cause hypotension, tachycardia, and apnea

• require mechanical ventilation and general anesthesia

• can be reversed spontaneously, with anticholinesterases, or chemically using sugammadex