3. Neuromuscular Blocking Agents
• Competitive antagonists bind to N receptors
• Competitively block Ach binding
• Reduce the frequency of channel opening
– Neither duration nor conductance
• Increasing concentrations of Tubocurarine
– Progressively diminishes amplitude of excitatory EPP
– Block the channel in a non-competitive fashion
4. Neuromuscular Blocking Agents
• Depolarizing agents (e.g. Succinylcholine- SCh)
• Open the channel similarly to Ach
– Depolarize the membrane
• Persist at the junction for longer duration
– Longer-lasting depolarization
– Gives brief period of repetitive excitation
• May cause fasciculations
– Followed by block of transmission & flaccid paralysis
• Phase-I block
5. Neuromuscular Blocking Agents
• Phase-I block gets transitioned to non-depolarizing phase-II block
– Under clinical conditions
– Increasing concentrations of Succinylcholine
– Over time
Phase-I block
• Rapid onset; due to persistent depolarization of muscle end plate
• Features of classical depolarization blockade
• Depolarization declines shortly afterwards
• Repolarization occurs gradually
6. Neuromuscular Blocking Agents
Phase-II block
• Slow onset; due to desensitization of receptors to Ach
• Normally only phase-I block is seen in humans
• Phase-II seen in high dose/continuous infusion of SCh
• Produced readily in patients with atypical/deficient pseudocholinesterase
7. Actions of Neuromuscular Blocking Agents
Skeletal muscles
• IV non-depolarizing agents rapidly produce muscle weakness
– Followed by flaccid paralysis
• Small fast-response muscles affected first
• Fasciculations last a few seconds
– Not seen in well-anesthetized patients
• Apnoea generally occurs within 45-90 sec
– Lasts for 2-5 min
8. Actions of Neuromuscular Blocking Agents
Autonomic ganglia
• Some degree of ganglionic blockade
– Receptors are NN rather than NM
• D-Tubocurarine (D-TC) has maximum
• Newer drugs practically devoid
• SCh may cause ganglionic stimulation
Histamine release
• D-TC releases histamine from mast cells
• Due to its bulky cationic structure
9. Actions of Neuromuscular Blocking Agents
Cardiovascular system
• D-TC produces significant fall in BP
– Ganglionic blockade
– Histamine release
– Reduced venous return
• Due to paralysis of respiratory and limb muscles
• Heart rate may increase due to vagal ganglionic blockade
• Newer non-depolarizing drugs have negligible effect
10. Actions of Neuromuscular Blocking Agents
Cardiovascular system
• SCh causes bradycardia initially
– Activates vagal ganglia
• Then tachycardia and rise in BP
– Stimulation of sympathetic ganglia
• BP occasionally falls due to muscarinic action
11. Actions of Neuromuscular Blocking Agents
GI tract
• Ganglion blockade may enhance post-op paralytic ileus
CNS
• All neuromuscular blockers are 4O ammonium compounds
• IV administration has no central effects
• D-TC applied to brain cortex produces Strychnine-like effects
12. Succinylcholine (SCh)
• Most commonly used muscle relaxant for passing tracheal tube
• Rapid, complete, predictable paralysis
– Spontaneous recovery in about 5 min
• Occasionally used as IV infusion for longer action
• Should be avoided in younger children unless absolutely necessary
– Higher risk of hyperkalemia and cardiac arrhythmia
• Increases the risk of regurgitation and aspiration of gastric contents
– In GERD patients and obese people (esp with full stomach)
13. Pancuronium
• Synthetic steroidal compound
• About 5× more potent and longer-acting than D-TC
• Little ganglionic blockade; good CV stability
• Lower histamine-releasing potential
• Rapid IV injection may cause rise in BP & tachycardia
– Vagal blockade
– NA release
• Now restricted to prolonged operations (esp neurosurgery)
– Longer duration of action, needs reversal
14. Vencuronium
• Close congener to Pancuronium
• Shorter duration of action
– Rapid distribution and metabolism
• Recovery is generally spontaneous
– May need Neostigmine reversal
• CV stability is still better
– Tachycardia sometimes occurs
• Most commonly used drug for routine surgeries & in ICUs
15. Toxicity of Neuromuscular Blockers
• Respiratory paralysis and prolonged apnea
• Flushing is common with D-TC
• Fall in BP & CV collapse can occur
– Especially in hypovolemic patients
– Less likely with newer drugs
• Cardiac arrhythmias and arrests esp with SCh
• Precipitation of symptoms of asthma due to histamine release
• Post-op muscle soreness & myalgia may occur with SCh
• Malignant hyperthermia with SCh
– In patients given with fluorinated anesthetics
16. Directly Acting Muscle Relaxants
Dantrolene
• Acts on RyR1 Ca++ channels in SR of skeletal muscle
• Prevents Ca++-induced Ca++ release through these channels
• Interferes release of Ca++ for excitation and contraction
• Fast-contracting muscles affected more
• Cardiac muscles and smooth muscles affected little
– Have RyR2 channels
• Oral 25-100 mg QID reduces spasticity in various disorders
• Also reduces voluntary power: use limited in bedridden patients
17. Directly Acting Muscle Relaxants
Dantrolene
• IV 1 mg/kg (repeated as needed)
• Drug of choice for malignant hyperthermia
– It’s due to persistent release of Ca++ from SR
– Induced by fluorinated anesthetics and SCh
• In genetically susceptible patients with abnormal RyR1
Quinine
• Increases refractory period, reduces excitability of motor end plate
• Decreases muscle tone in myotonia congenia
• 200-300 mg at bedtime may abolish nocturnal leg cramps
