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Neuromuscular Blocking Agents – Quick Reference

1. Definition

  • Peripheral skeletal muscle relaxants cause complete flaccid paralysis of all skeletal muscles by abolishing neurotransmission at the NMJ; they are also called neuromuscular blockers.

2. NMJ: types of cholinergic synapses

-NMJ operates via nicotinic receptors at the motor end plate (muscle-type nicotinic receptors).

  • Other peripheral cholinergic synapses use muscarinic receptors.

3. Structure and function of the NMJ I

  • NMJ components: α-motoneuron axon → nerve terminal → acetylcholine (ACh) release → synaptic cleft → nicotinic receptors on end plate → end plate potential (EPP) → Action potential in muscle.
  • End plate: motor end plate has nicotinic receptors and lacks voltage-gated Na⁺ channels.
  • Action potential propagation relies on voltage-gated Na⁺ channels and subsequent muscle fiber activation.
  • Nicotinic receptors: ionotropic, ligand-gated non-selective cation channels permeable to Na⁺, Ca²⁺, K⁺; two subtypes: muscular (NM) and neuronal (NN); prone to desensitization with sustained agonist exposure.

3. Structure and function of the NMJ II

  • Key elements: end plate potential (EPP), miniature end plate potential (MEPP) caused by spontaneous ACh release, and acetylcholinesterase (AChE) in cleft.
  • EPP amplitude ∝ amount of ACh released; if above threshold, an a.m.-all-or-none muscle action potential is evoked.

4. Important NMJ terms

  • Motor end plate: folded sarcolemma with nicotinic receptors but no voltage-gated Na⁺ channels.
  • End plate potential (EPP): local depolarization from ACh receptor activation; proportional to ACh release.
  • MEPP: spontaneous, small depolarization due to random ACh release.

5. Medical uses of NMJ blockers

  • Provide muscle relaxation to supplement general anesthesia (e.g., abdominal operations, bone reposition).
  • Short paralysis for tracheal intubation, joint reposition, ECT.
  • Facilitate artificial ventilation by turning off insufficient spontaneous breathing.
  • Symptomatic treatment of convulsions/rigidity in epilepsy, drug intoxications, tetanus when CNS-acting drugs fail.
  • Note: respiration may be paralyzed; patient must be sedated or lightly anesthetized.

6. Inhibitors of NMJ transmission (overview)

  • Prejunctional inhibitors: affect Ach synthesis, storage, or release; examples include:
    • Inhibitors of Ach synthesis: hemicholinium, triethylcholine
    • Inhibitors of vesicular Ach storage: vesamicol
    • Inhibitors of Ach release: aminoglycosides, Mg²⁺, botulinum toxin (local use, cosmetic/medical conditions; acts for months)
  • Postjunctional muscle relaxants:
    • Non-depolarizing: competitive antagonists of nicotinic NMJ receptors
    • Depolarizing: long-acting NMJ nicotinic receptor agonists

7. Non-depolarizing muscle relaxants: examples (benzyl-isoquinoline and others)

  • Benzyl-isoquinoline: d-tubocurarine (cis), atracurium, doxacurium, curare mixtures, metocurine, mivacurium.
  • Ammonio-steroidal: pancuronium, vecuronium, pipecuronium, rocuronium.

8. Pharmacodynamics of non-depolarizing relaxants

  • Mechanism: reversible competitive antagonism at post-junctional nicotinic receptors; high doses may block the ion channel portion.
  • Sequence of paralysis: external eye muscles → face → pharynx → extremities → trunk → respiratory muscles.
  • Recovery occurs in reverse order; post-recovery, contraction power may transiently drop due to junctional fatigue.
  • Reversal: with reversible acetylcholinesterase inhibitors (e.g., neostigmine). Co-administration of atropine mitigates muscarinic effects; sugammadex specifically binds steroidal relaxants in plasma.

9. Unwanted effects of non-depolarizing relaxants

  • Recurarization: recurrence of paralysis due to fatigue and faster decay of reversing agent than the relaxant.
  • Partial ganglionic block → hypotension, tachycardia (tubocurarine, metocurine, pancuronium).
  • Histamine release → bronchospasm, itching, hypotension (tubocurarine, metocurine, mivacurium, doxacurium, atracurium).
  • M2 receptor blockade → tachycardia (gallamine, pancuronium).
  • Laudanosine (atracurium metabolite) may provoke seizures after block ends.

10. Pharmacokinetics of non-depolarizing relaxants (general)

  • Hydrophilic, quaternary amines; not gut-absorbed; given IV; do not cross the blood–brain barrier.
  • Elimination routes: hepatic metabolism + biliary excretion; renal excretion; plasma/cholinesterase-mediated hydrolysis; Hofmann elimination.

10a. Duration and elimination (selected agents)

  • d-tubocurarine: ~80–120 ext{ min}; kidney + liver elimination.
  • doxacurium: ~90–120 ext{ min}; kidney elimination.
  • atracurium (cisatracurium): ~30–60 ext{ min}; plasma esterase activity + Hofmann elimination.
  • mivacurium: ~10–20 ext{ min}; plasma cholinesterase.
  • pancuronium: ~120–180 ext{ min}; kidney elimination.
  • vecuronium: ~60–90 ext{ min}; liver elimination.
  • rocuronium: ~30–60 ext{ min}; liver and kidney; rapid onset (≈1–2 ext{ min}).
  • pipecuronium: ~80–100 ext{ min}; kidney + liver.

11. Interactions affecting non-depolarizing relaxants

  • Increased effect: general anesthetics, aminoglycosides, tetracyclines, quinidine, and myasthenia gravis (reduced functional receptor numbers).
  • Decreased effect/reversal: cholinesterase inhibitors (used for decurarization), burn injury, upper motor neuron lesions (extrajunctional receptors up-regulated).

12. The depolarizing muscle relaxant: suxamethonium (succinylcholine)

  • Mechanism: nicotinic receptor agonist resistant to acetylcholinesterase; cleaved by plasma cholinesterase.
  • Effects: sustained end-plate depolarization; initial fasciculations followed by depolarization block; then possible Phase II block with desensitization of receptors.
  • Onset/duration: very rapid onset; short duration (Phase I) ≈ 1–2 ext{ min} to follow-up infusion needed for longer procedures; total ~5–10 ext{ min} unless prolonged by deficiency or interactions.
  • Pharmacokinetics: hydrophilic; not gut-absorbed; hydrolyzed by pseudocholinesterase.
  • Special considerations: prolonged effect in pseudocholinesterase deficiency, preterm infants, liver disease; interactions with other drugs metabolized by cholinesterases.

13. Mechanism: depolarization block by suxamethonium

  • Phase I: sustained depolarization keeps Na⁺ channels in inactivated state; electrically unexcitable area around the junction; fasciculations occur before block.
  • Phase II: prolonged exposure leads to desensitization of nicotinic receptors; transmission may remain blocked even as depolarization declines.

14. Stages of action of depolarizing relaxants

  • Transient transmission with fasciculations.
  • Progressive block in a rostro-caudal sequence: arms → neck → legs → respiratory muscles → face → pharynx.
  • Phase I block: functional Na⁺ channel block due to depolarization.
  • Phase II block: desensitization of nicotinic receptors; may be partially overcome by cholinesterase inhibitors.

15. Pharmacokinetics of suxamethonium

  • Hydrophilic; not gut-absorbable; rapid plasma hydrolysis by pseudocholinesterase; very short T½; IV use for short procedures (≈5–10 ext{ min}).
  • Prolonged effect in cholinesterase deficiency or when co-administered with drugs metabolized by pseudocholinesterase or cholinesterase inhibitors.

16. Unwanted effects of suxamethonium

  • Myalgia/muscle pain; increased intragastric pressure; increased intraocular pressure due to extraocular muscle contraction; bradycardia; hyperkalemia (more with denervation or burns).
  • Malignant hyperthermia risk in genetically predisposed individuals.

17. Malignant hyperthermia

  • Triggered by certain inhaled anesthetics or suxamethonium in susceptible individuals.
  • Pathophysiology: mutation in ryanodine receptor → massive uncontrolled Ca²⁺ release from the sarcoplasmic reticulum.
  • Consequences: generalized muscle contraction, hyperthermia, lactic acidosis, myoglobinemia/uria, potential renal failure.
  • Treatment: dantrolene IV, bicarbonate, physical cooling; ryanodine receptor blockade reduces Ca²⁺ release.

18. Comparison of NMJ blockade types

  • Non-depolarizing (competitive): receptor blocked but not activated; membrane potential remains at rest; fasciculations do not occur; reversal by cholinesterase inhibitors.
  • Depolarizing Phase I: receptor activated and blocked during sustained depolarization; fasciculations present; reversal by cholinesterase inhibitors is not straightforward.
  • Depolarizing Phase II: receptor desensitization with partial or no response; reversal may occur with cholinesterase inhibitors in some cases.
  • Sequence: non-depolarizing blocks typically follow a predictable progression; depolarizing blocks produce an initial transient fasciculation period.
  • Block reversibility: non-depolarizing blocks can be reversed with acetylcholinesterase inhibitors (and sugammadex for steroidal agents); depolarizing blocks have limited reversal options.
  • Note: irreversible cholinesterase inhibitors would potentiate Ach and convert a non-depolarizing “block” into a depolarizing NMJ blocker.