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NEUROMUSCULAR BLOCKING AGENTS (NMBAs)

MD Anaesthesiology Exam Notes

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1. HISTORY AND CLINICAL RELEVANCE

• 1942: Harold Griffith and Johnson first described d-tubocurarine (dTc) as safe for surgical muscle relaxation.
• 1954: Beecher and Todd reported a sixfold increase in mortality with dTc use - attributed to residual block, lack of monitoring, and failure to reverse.
• 1952: Succinylcholine introduced by Thesleff and Foldes - rapid onset and ultrashort duration revolutionized anesthetic practice.
• Key principle (Beecher & Todd, 1954): "Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia." - Morgan & Mikhail, Ch. 11

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2. NEUROMUSCULAR JUNCTION - ANATOMY AND PHYSIOLOGY

Structure

• Motor neuron terminal separated from muscle membrane by a 20-nm synaptic cleft.
• Action potential in the motor nerve terminal triggers an influx of calcium ions through voltage-gated channels.
• Calcium causes fusion of acetylcholine (ACh)-containing vesicles with the presynaptic membrane.
• Each vesicle contains ~10,000 molecules of ACh - this constitutes one quantum.

Nicotinic ACh Receptors (nAChR)

• Each postsynaptic receptor has two α subunits, each with an ACh binding site.
• Both α sites must be occupied by ACh for the channel to open.
• One α site blocked by a nondepolarizing agent = receptor inactivated (competitive antagonism).

Signal at NMJ

• ACh binding opens the ion channel → Na+ influx, K+ efflux → end plate potential (EPP).
• EPP exceeds threshold → propagated action potential → muscle contraction.
• ACh rapidly hydrolyzed by acetylcholinesterase (AChE) at the junctional folds.
• Miller's Anesthesia 10e, Ch. 24

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3. CLASSIFICATION OF NMBAs

A. By Mechanism

B. By Chemical Class

C. By Duration of Action

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4. DEPOLARIZING AGENT - SUCCINYLCHOLINE

Structure

• Two joined ACh molecules → acts as ACh receptor agonist.
• Only available depolarizing NMBA in clinical use.

Mechanism

1. Binds to both α subunits of the nAChR → sustained depolarization (the end plate stays depolarized).
2. Phase I block (depolarizing block): Persistent depolarization prevents repolarization and further ACh action.
3. Phase II block (desensitization/dual block): With repeat/large doses, the receptor becomes desensitized despite persistent drug occupancy - clinically resembles nondepolarizing block and can be reversed with anticholinesterases.

Features of Phase I vs Phase II Block

Pharmacokinetics

• NOT metabolized by AChE - diffuses away from the NMJ and is hydrolyzed in plasma/liver by pseudocholinesterase (butyrylcholinesterase/plasma cholinesterase).
• Onset: 30-60 seconds IV.
• Duration: 5-10 minutes (ultra-short).
• IV dose: Adults 1.0-1.5 mg/kg; Children 2 mg/kg; Neonates/infants 3 mg/kg (larger ECF volume = larger Vd).
• IM dose (pediatric emergency): 4 mg/kg, onset 3-4 min.

Pseudocholinesterase (Dibucaine Number)

• Normal dibucaine number: 80 (80% inhibition of plasma cholinesterase by dibucaine).
• Heterozygous atypical enzyme: Dibucaine number 40-60, duration doubled or tripled.
• Homozygous atypical enzyme: Dibucaine number 20, duration 4-8 hours (scoline apnea).
• Incidence of homozygous atypical: 1 in 3,000 patients.
• Low enzyme states: Pregnancy, liver disease, malnutrition, malignancy, anticholinesterases - prolong blockade but dibucaine number remains normal. - Morgan & Mikhail, Ch. 11

Side Effects of Succinylcholine

1. Hyperkalemia

• Normal muscle releases K+ to raise serum K+ by 0.5 mEq/L - usually insignificant.
• Pathological hyperkalemia (>5 mEq/L rise): Burns, massive trauma, denervation injuries (spinal cord injury, stroke), prolonged immobilization, myopathies, rhabdomyolysis.
• Hyperkalemia NOT seen in first 24 hours after acute injury - upregulation of extrajunctional fetal nAChRs begins after 24-48 hours.
• Peaked T waves on ECG → bradycardia → cardiac arrest.

2. Cardiovascular Effects

• Stimulates all cholinergic autonomic receptors (muscarinic and nicotinic).
• First dose: Bradycardia (muscarinic), especially in children (vagal dominant) and with repeat dosing.
• Pretreat with atropine (especially before second dose in children) - Barash, Ch.
• Sinus arrest may follow second dose.
• Some sympathomimetic effects can also occur.

3. Intraocular Pressure (IOP)

• Increases IOP by 5-10 mmHg (tonic contraction of extraocular muscles, choroidal vasodilation).
• Use cautiously in open globe injury; though risk of vitreous extrusion is debated.

4. Intragastric Pressure

• Raises intragastric pressure - however this is offset by simultaneous increase in lower esophageal sphincter pressure, so risk of aspiration is minimal in healthy patients.

5. Intracranial Pressure (ICP)

• May transiently increase ICP - but prevention of laryngoscopy-related hypertension and hypoxia from a failed airway outweighs this risk.
• Use with adequate anesthetic depth/lidocaine for ICP-sensitive patients.

6. Myalgias

• Postoperative myalgia (POMs) in young ambulatory patients, especially women.
• Prevented by pretreatment with small dose of nondepolarizing agent (defasciculation dose = 10-15% of intubating dose, given 3-5 min before succinylcholine).

7. Fasciculations

• Caused by synchronous discharge of motor units during Phase I depolarization.
• Defasciculation prevents myalgias and reduces IOP/ICP rise.

8. Malignant Hyperthermia (MH)

• Succinylcholine is a known MH trigger in susceptible individuals.
• Avoid in known/suspected MH susceptibility.

9. Masseter Muscle Rigidity (MMR)

• Increased jaw tone after succinylcholine may indicate MH susceptibility.
• Isolated MMR without generalized rigidity may be a normal response in some children.

Contraindications to Succinylcholine

• Morgan & Mikhail, Ch. 11; Barash, Ch. 14

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5. NONDEPOLARIZING NMBAs

Mechanism

• Competitive antagonism at the postsynaptic α subunits of nAChR - block ACh binding.
• Presynaptic effects: Block presynaptic α3β2 receptors → reduce ACh mobilization and release → contributes to fade with TOF and tetanic stimulation.
• Single-twitch depression = mainly postjunctional.
• Fade = mainly prejunctional. - Miller's Anesthesia 10e

Key Pharmacological Principle: Potency vs. Onset

• Onset is inversely proportional to potency (lower molar potency = faster onset).
• Rocuronium has molar potency ~13% of vecuronium and ~9% of cisatracurium - hence faster onset.
• High-potency drugs require fewer molecules to occupy receptors; low-potency drugs have more molecules competing, buffering the receptor occupancy rate. - Miller's Anesthesia 10e, Ch. 24

ED95 (the dose causing 95% twitch suppression in 50% of subjects)

• Intubating dose = 2× ED95 (produces adequate intubating conditions).

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6. INDIVIDUAL NONDEPOLARIZING AGENTS

A. ROCURONIUM

B. VECURONIUM

C. PANCURONIUM

D. ATRACURIUM

• Hofmann elimination: pH and temperature-dependent. Hypothermia and acidosis slow it. - Morgan & Mikhail, Ch. 11

E. CISATRACURIUM

F. MIVACURIUM

G. d-TUBOCURARINE (dTc) - Historical

• First NMBA used clinically (1942).
• Histamine release, ganglion blockade → hypotension.
• Largely historical; rarely used.
• Eliminated primarily renally (~50%).

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7. PHARMACOKINETICS COMPARISON TABLE

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8. NEUROMUSCULAR MONITORING

Purpose

• Prevents overdose and residual block.
• Safe extubation requires TOF ratio ≥0.9.
• Quantitative monitoring is the ONLY reliable method of confirming adequate recovery. - Miller's Anesthesia 10e

Sites of Monitoring

• Adductor pollicis (thumb) - most commonly monitored.
• More centrally located muscles (laryngeal adductors, diaphragm, masseter) recover faster and are more resistant than adductor pollicis.
• Clinical implication: When adductor pollicis shows recovery, airway muscles have already recovered - monitoring at the thumb is conservative (safe).

Patterns of Stimulation

TOF Interpretation

Block Types - Stimulation Patterns

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9. FACTORS AFFECTING NEUROMUSCULAR BLOCKADE

A. Diseases and Physiological States

B. Temperature and pH

C. Drug Interactions

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10. REVERSAL OF NEUROMUSCULAR BLOCKADE

A. Anticholinesterases (Cholinesterase Inhibitors)

• Ceiling effect: There is a maximum concentration of ACh achievable - neostigmine cannot reverse deep block.
• Neostigmine effective only from moderate to shallow block (TOF count ≥2, ideally TOF count 4 with fade).
• Must be combined with anticholinergic (atropine or glycopyrrolate) to block muscarinic side effects (bradycardia, hypersalivation, bowel motility).
  • Glycopyrrolate with neostigmine (slower onset - well matched).
  • Atropine with edrophonium (faster onset - well matched).

B. Sugammadex

• Only active against aminosteroids (rocuronium, vecuronium, pipecuronium).
• Does NOT reverse benzylisoquinoliniums (atracurium, cisatracurium) or succinylcholine.
• No ceiling effect (unlike neostigmine).
• Residual block after sugammadex still occurs (~1-5% of cases) - quantitative monitoring still required. - Miller's Anesthesia 10e, Ch. 24

• Bradycardia (rare but clinically significant case reports).
• Hypersensitivity reactions (rare).
• Recurrence of neuromuscular block (rare, e.g., if drug is administered too soon after rocuronium RSI dose).
• Does NOT need anticholinergics (no muscarinic effects).

• If re-paralysis needed after sugammadex reversal: Use a benzylisoquinolinium (atracurium/cisatracurium) as these are unaffected by sugammadex.
• Rocuronium can be re-administered but a waiting period of at least 24 hours is needed (or use a higher dose with monitoring).

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11. RESIDUAL NEUROMUSCULAR BLOCKADE (RNMB)

• 30-50% of patients can have TOF ratio <0.9 in PACU after neostigmine reversal in the absence of quantitative monitoring. - Miller's Anesthesia 10e
• TOF ratio <0.9 associated with:
  • Hypoxemic events.
  • Impaired hypoxic ventilatory response.
  • Upper airway obstruction.
  • Postoperative pulmonary complications.
  • Prolonged PACU stay.
• Quantitative monitoring (acceleromyography, mechanomyography, electromyography) is the ONLY reliable detection method.
• Clinical signs (head lift ×5 s, tongue protrusion, grip strength) unreliable below TOF 0.6-0.7.

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12. NEUROMUSCULAR BLOCKERS IN SPECIAL SITUATIONS

A. Rapid Sequence Induction (RSI)

• Succinylcholine 1.5 mg/kg remains gold standard (onset <60 s).
• Rocuronium 1.2 mg/kg is an acceptable alternative (onset 60-90 s) - Morgan & Mikhail, Ch. 11.
• With rocuronium RSI, sugammadex 16 mg/kg allows rapid reversal if "cannot intubate, cannot oxygenate."

B. "Cannot Intubate, Cannot Oxygenate" (CICO)

• If succinylcholine was used: spontaneous respiration will return in 5-10 min.
• If rocuronium (1.2 mg/kg) used: sugammadex 16 mg/kg reverses within 1-3 min.
• Do NOT rely on spontaneous return in a trauma/emergency context - proceed to FONA (front-of-neck airway). - Miller's Anesthesia 10e, Ch. 62

C. ICU Use

• Short-term infusions may facilitate ventilation in prone ARDS patients (cisatracurium preferred - no histamine, organ-independent, minimal laudanosine).
• Prolonged use should be avoided - risk of:
  • Critical illness myopathy.
  • Prolonged block after discontinuation (vecuronium 3-OH metabolite accumulation).
• Corticosteroids + prolonged vecuronium = myopathy in critically ill. - Barash, Ch. 7

D. Pediatrics (Barash, Ch. 14)

• Neonates/infants: larger ECF volume → larger Vd → higher dose of succinylcholine required (3 mg/kg IV, 4 mg/kg IM).
• NMJ is more sensitive to nondepolarizers in neonates (these two effects balance - mg/kg dose similar to adults).
• Succinylcholine in boys <8 years: risk of hyperkalemia and cardiac arrest in undiagnosed muscular dystrophy (~1:250,000, mortality 50%). Some centers restrict use.
• Pretreatment with atropine before succinylcholine in children (prevents vagal bradycardia from repeat dosing).

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13. AUTONOMIC EFFECTS - SUMMARY TABLE

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14. KEY EXAM MNEMONICS AND HIGH-YIELD POINTS

HIGH-YIELD FACTS FOR MD ANAESTHESIA EXAMS

1. "Muscle relaxants do NOT guarantee consciousness, amnesia or analgesia" - Beecher & Todd (1954) - foundational principle.
2. Succinylcholine = 2 × ACh molecules joined together; mimics ACh as agonist.
3. Phase II block threshold: ~2-3 mg/kg cumulative succinylcholine; exhibits fade on TOF, can be reversed with neostigmine.
4. Hofmann elimination: pH ↓ + Temperature ↓ → slows degradation → prolonged atracurium/cisatracurium effect. Independent of liver/kidney.
5. Potency vs onset rule (Miller): Low potency drug = more molecules needed = more at receptor = faster onset. Rocuronium (low potency) → fast onset.
6. TOF ratio ≥0.90 for safe extubation. Quantitative monitoring only reliable method.
7. Sugammadex doses: 2 mg/kg (moderate), 4 mg/kg (deep), 16 mg/kg (immediate/RSI reversal).
8. Rocuronium RSI + Sugammadex 16 mg/kg = viable succinylcholine alternative in MH susceptibility, hyperkalemia, pseudocholinesterase deficiency.
9. Cisatracurium = preferred in ICU/organ failure (Hofmann, no histamine, less laudanosine, organ-independent).
10. Neostigmine has ceiling effect - cannot reverse deep block; TOF count ≥2 required.
11. Pancuronium = tachycardia + hypertension (vagolysis + catecholamine release) - avoid in ischemic heart disease.
12. Vecuronium + ICU long-term = prolonged block (3-desacetyl metabolite + polyneuropathy).
13. Hyperkalemia after succinylcholine does NOT occur in first 24h of injury (safe window for acute RSI in burns/denervation).
14. Dibucaine number 20 = homozygous atypical pseudocholinesterase = 4-8 hour succinylcholine apnea.
15. Chronic anticonvulsants → resistance to aminosteroids (shorter duration) - upregulation of ACh receptors.
16. Aminoglycosides potentiate block via presynaptic inhibition of ACh release.
17. Desflurane > sevoflurane > isoflurane in potentiating nondepolarizing NMBDs.
18. Neonates: Succinylcholine IV dose = 3 mg/kg (not 1-1.5 mg/kg as in adults) due to large ECF Vd.

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15. ILLUSTRATIVE CLINICAL SCENARIOS (Exam-Style)

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• Miller's Anesthesia, 2-Volume Set, 10e (ISBN 9780323935920) - Chapter 24: Neuromuscular Blocking Agents
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e (ISBN 9781975199074) - Chapters 7, 14
• Morgan & Mikhail's Clinical Anesthesiology, 7e (ISBN 9781260473797) - Chapter 11: Neuromuscular Blocking Agents

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What These Notes Cover

1. History - Griffith (1942), Beecher & Todd mortality data (1954)
2. NMJ Anatomy and Physiology - receptor subunits (adult α2βδε vs fetal α2βγδ), quantal ACh release
3. Classification - by mechanism, chemical class, duration
4. Succinylcholine in depth - mechanism, Phase I/II block, pseudocholinesterase/dibucaine number, all side effects (hyperkalemia, IOP, ICP, masseter rigidity, MH, myalgia, fasciculations), contraindications
5. Nondepolarizing agents - mechanism, potency-onset relationship (key Miller principle)
6. Individual drugs - rocuronium, vecuronium, pancuronium, atracurium, cisatracurium, mivacurium with full pharmacokinetic tables
7. Pharmacokinetics comparison table (exam-ready)
8. Neuromuscular monitoring - TOF, PTC, DBS, tetanus; TOF ≥0.9 standard
9. Factors affecting blockade - renal/hepatic/burns/aging/neonates, temperature, pH, drug interactions (volatile agents, antibiotics, anticonvulsants)
10. Reversal - neostigmine ceiling effect vs sugammadex doses (2/4/16 mg/kg)
11. Residual block - incidence (30-50%), clinical consequences, monitoring
12. Special situations - RSI, CICO management, ICU use, pediatrics
13. Autonomic effects table
14. 18 high-yield exam facts and mnemonics
15. Clinical exam scenarios with answers