← Back to Part 5

5.6 Neuromuscular Blocking Agents

Neuromuscular blockers interrupt transmission at the nicotinic receptors of the neuromuscular junction, producing skeletal muscle paralysis. They are essential for endotracheal intubation, mechanical ventilation, and surgical muscle relaxation.

Neuromuscular Junction Physiology

Normal Neuromuscular Transmission

1. Action potential arrives at motor nerve terminal

2. Voltage-gated Ca²⁺ channels open β†’ Ca²⁺ influx

3. Synaptic vesicles fuse with presynaptic membrane β†’ ACh release (quantal release)

4. ACh diffuses across synaptic cleft (~50 nm)

5. ACh binds to nicotinic receptors (N_M) on motor end plate

6. Receptor activation β†’ Na⁺ influx β†’ end-plate potential (EPP)

7. EPP β†’ muscle action potential β†’ excitation-contraction coupling

8. AChE rapidly hydrolyzes ACh (~1 ms) β†’ termination

Nicotinic Receptor at NMJ

Structure: Pentamer (α2βδγ in fetal; α2βδΡ in adult)

Activation: Requires ACh binding to both Ξ± subunits

Ion selectivity: Na⁺, K⁺ (depolarizes membrane)

Safety margin: Normal EPP far exceeds threshold β†’ blockade must be ~70-80% for clinical paralysis

Depolarizing Neuromuscular Blockers

Succinylcholine (Suxamethonium)

Structure: Two ACh molecules linked back-to-back

Mechanism: Nicotinic receptor agonist β†’ sustained depolarization β†’ inactivation of voltage-gated Na⁺ channels β†’ paralysis (Phase I block)

Metabolism: Plasma cholinesterase (butyrylcholinesterase) β†’ succinylmonocholine + choline

Duration: Ultra-short (5-10 minutes) - only NMB not reversed pharmacologically

Clinical Characteristics

Onset: Rapid (30-60 seconds) - fastest of all NMBs

Initial fasciculations: Muscle twitching before paralysis (ACh-like depolarization)

Use: Rapid sequence intubation (RSI), short procedures (<10 min), electroconvulsive therapy

Route: IV (1-1.5 mg/kg). Can give IM (3-4 mg/kg) but slower onset.

Adverse Effects

Hyperkalemia

Mechanism: Depolarization β†’ K⁺ release (~0.5 mEq/L increase normally)

Contraindications: Burns, crush injuries, denervation, prolonged immobilization, neuromuscular disease (↑ extrajunctional receptors β†’ massive K⁺ release β†’ cardiac arrest)

Malignant Hyperthermia (MH)

Trigger: Succinylcholine (also volatile anesthetics)

Pathophysiology: Genetic defect (RYR1 mutation) β†’ uncontrolled Ca²⁺ release from SR β†’ sustained muscle contraction, ↑↑ metabolism

Signs: ↑ CO2 production, ↑ temperature (>2Β°C/hour), muscle rigidity, tachycardia, hyperkalemia, rhabdomyolysis, acidosis

Treatment: Dantrolene (blocks RyR1 Ca²⁺ release), cooling, supportive care

Other Adverse Effects

  • β€’ Myalgia: Post-fasciculation pain (especially ambulatory patients)
  • β€’ ↑ Intragastric pressure: Aspiration risk (minimal clinical significance)
  • β€’ ↑ Intraocular pressure: Avoid in open globe injury
  • β€’ ↑ Intracranial pressure: Avoid in head trauma (controversial)
  • β€’ Bradycardia: Especially with repeat dosing (muscarinic effect)

Prolonged Paralysis

Causes: Plasma cholinesterase deficiency (genetic variants, pregnancy, liver disease, organophosphate exposure)

Genetics: Atypical enzyme (Asp70Gly mutation) - homozygotes have 2-3 hour paralysis

Management: Supportive ventilation until metabolism complete. Fresh frozen plasma (provides normal enzyme).

Non-Depolarizing Neuromuscular Blockers

Mechanism and Classification

Mechanism: Competitive antagonists at nicotinic receptors β†’ prevent ACh binding β†’ no depolarization

Chemical classes:

Benzylisoquinolinium Compounds

Atracurium, cisatracurium, mivacurium. Advantage: Hoffman elimination (non-organ dependent).

Aminosteroid Compounds

Rocuronium, vecuronium, pancuronium. Note: Hepatic/renal elimination.

Individual Agents

Rocuronium

Onset: Rapid (60-90 sec at high dose) - closest to succinylcholine

Duration: Intermediate (30-40 min)

Use: RSI alternative to succinylcholine (when SCh contraindicated), general anesthesia

Reversal: Sugammadex (specific reversal agent, encapsulates rocuronium/vecuronium)

Vecuronium

Duration: Intermediate (30-40 min)

Advantage: No histamine release, minimal cardiovascular effects

Use: General anesthesia, ICU paralysis

Cisatracurium

Duration: Intermediate (40-60 min)

Elimination: Hoffman elimination (pH/temp dependent, organ-independent) β†’ ideal in renal/hepatic failure

Use: General anesthesia, ICU (preferred in organ failure)

Atracurium

Duration: Intermediate (30-40 min)

Elimination: Hoffman + ester hydrolysis (organ-independent)

Adverse: Histamine release (hypotension, bronchospasm), laudanosine metabolite (seizures at high doses)

Pancuronium

Duration: Long (60-90 min)

Cardiovascular: Vagolytic (↑ HR, ↑ BP) - blocks muscarinic M2 receptors

Use: Long surgeries. Less commonly used now (longer recovery).

Mivacurium

Duration: Short (15-20 min)

Metabolism: Plasma cholinesterase (like succinylcholine but non-depolarizing)

Use: Short procedures. Caution: Prolonged in cholinesterase deficiency.

Reversal of Non-Depolarizing Block

Acetylcholinesterase Inhibitors

Mechanism: ↑ ACh at NMJ β†’ overcomes competitive blockade

Neostigmine

Dose: 0.03-0.07 mg/kg IV (max 5 mg)

Always give with: Glycopyrrolate or atropine (prevent muscarinic side effects - bradycardia, salivation, bronchospasm)

Limitations: Cannot reverse deep block (requires some recovery first), ceiling effect

Edrophonium, Pyridostigmine

Less commonly used for reversal. Edrophonium shorter-acting, pyridostigmine longer-acting.

Sugammadex

Mechanism: Modified Ξ³-cyclodextrin that encapsulates aminosteroid NMBs (rocuronium, vecuronium) β†’ rapid reversal

Advantages: Reverses deep block, faster than neostigmine, no anticholinergic co-administration needed, no muscarinic side effects

Dose: 2-4 mg/kg (moderate block), 16 mg/kg (deep block, immediate reversal after rocuronium RSI)

Note: Does NOT reverse benzylisoquinolinium compounds (atracurium, cisatracurium). Only aminosteroids.

Monitoring Neuromuscular Blockade

Train-of-Four (TOF) Stimulation

Method: Four supramaximal electrical stimuli at 2 Hz β†’ measure response

TOF ratio: Height of 4th twitch / height of 1st twitch

  • β€’ TOF ratio > 0.9: Adequate recovery (safe extubation)
  • β€’ TOF ratio 0.7-0.9: Residual weakness (risk of respiratory complications)
  • β€’ TOF count 1-3: Partial blockade
  • β€’ TOF count 0: Deep blockade (no twitches)

Clinical Assessment

  • β€’ Sustained head lift (>5 seconds)
  • β€’ Sustained hand grip
  • β€’ Negative inspiratory force < -25 cmH2O
  • β€’ Vital capacity > 15 mL/kg
  • β€’ Normal tidal volume, respiratory rate

Drug Interactions

Potentiate NMB (Enhance Block)

  • β€’ Volatile anesthetics (isoflurane, sevoflurane, desflurane)
  • β€’ Aminoglycoside antibiotics (gentamicin, tobramycin)
  • β€’ Magnesium (↓ ACh release, ↓ muscle excitability)
  • β€’ Hypothermia, acidosis, hypocalcemia

Antagonize NMB (Reduce Block)

  • β€’ Chronic anticonvulsant therapy (phenytoin, carbamazepine)
  • β€’ Corticosteroids (chronic use)
  • β€’ Alkalosis, hypercalcemia
← 5.5 Adrenergic BlockersPart 6: CNS Pharmacology β†’