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Neuromuscular-Blocking Drugs

Detailed view of a neuromuscular junction:
  1. Presynaptic terminal
  2. Sarcolemma
  3. Synaptic vesicle        
  4. Nicotinic acetylcholine receptor
  5. Mitochondrion
  1. Neuromuscular-blocking drugs
    1. Most neuromuscular blockers function by blocking transmission at the end plate of the neuromuscular junction.
    2. A nerve impulse arrives at the motor nerve terminal, initiating an influx of calcium ions which causes the exocytosis of synaptic vesicles containing acetylcholine.
    3. Acetylcholine then diffuses across the synaptic cleft. It may be hydrolysed by Acetylcholine esterase (AchE) or bind to the nicotinic receptors located on the motor end plate.
    4. The binding of two acetylcholine molecules results in a conformational change in the receptor that opens the sodium-potassium channel of the nicotinic receptor.
    5. This allows Na+ and Ca2+ ions to enter the cell and K+ ions to leave the cell causing a depolarization of the end plate, resulting in muscle contraction.
    6. Following depolarization, the acetylcholine molecules are then removed from the end plate region and enzymatically hydrolysed by acetylcholinesterase.
  2. Normal end plate function can be blocked by two mechanisms.
    1. Nondepolarizing agents like tubocurarine block the agonist, acetylcholine, from binding nicotinic receptors and activating them, thereby preventing depolarization.
    2. Alternatively, depolarizing agents such as succinylcholine are nicotinic receptor agonists which mimic Ach, block muscle contraction by depolarizing to such an extent that it desensitizes the receptor and it can no longer initiate an action potential and cause muscle contraction.

Peripherally Acting:
Depolarizing (Noncompetitive) Non Depolarizing (competitive)
a. Suxamethonium/succinyl choline/scoline. a. Gallamine, d-TC
b. Decamethonium b. Atra/Meva - curium
  c. Ve/Pan/Ro - curonium
  1. Differences

  1. Muscle Relaxation Potentiating Agent
    1. Aminoglycoside
    2. Tetracycline Mnemonic = ATP
    3. Polypeptide antibiotics
    4. Antiarrhythmic (AA)
    5. Beta - Blockers (BB)
    6. Ca++ channel blockers (CC)
  2. Muscle relaxants: (Important Points to Remember)
    1. Sequence of onset – eyes and digits, trunk and abdomen, Intercostal muscle and diaphragm.
    2. Recovery the same order
    3. fastest and shortest acting non depolarizing blocker- succinylcholine
    4. Fastest onset of action among non depolarizing group – Rapacuronium (1 min) 
    5. Second Fastest of action- Rocuronium (90 seconds)
    6. Shortest duration of action – Mivacurium/ Rapacuronium
    7. D.O.C. in renal dysfunction – Atracurium, Mivacurium, or Vecuronium (Low dose)
    8. D.O.C. in liver dysfunction – Atracurium, Mivacurium
    9. Hydrolysis in plasma – Atracurium (Hoffmann degradation; Non enzymatic self hydrolysis of muscle relaxant in the plasma), Mivacurium (By Pseudocholinesterase)
    10. Ganglion blocker – DTC > Metocurine
    11. Vagal blocker – Gallamine Pancuronium and Rocuronium – increased H.R.
    12. Histamine release – DTC > Metoc> Atrac > Miva. (Avoided in asthmatics)
    13. Doxacurium is devoid of side effects.
    14. Rapacuronium cause severe bronchospasm
    15. Laudanosine – Toxic metabolite of Atracurium cause CNS excitation.
    16. Liver metabolism – Pancuronium, Rocuronium, Rapa and Vecuronium
    17. Renal excretion – Gallamine, DTC and Metocurine

Important Points to remember

  1. Calcium channel blockers potentiate both competitive and depolarizing neuromuscular blockers. (MCQ)
  2. Adrenaline and other sympathomimetics reduce competitive block by increasing ACh release. (MCQ)
  3. Anticholinesterases (neostigmine) reverse the action of competitive blockers.
  4. Shortest acting non-depolarizing skeletal muscle relaxant is mivacurium. Its duration of action is 12-20 min. (MCQ)
  5. Shortest acting depolarizing skeletal muscle relaxant is succinylcholine. Its duration of action is 3-6 min. 
  6. In patients of myasthenia gravis, there is resistance to the muscle relaxant action of suxamethonium and decamethonium (depolarizing muscle relaxants) 
  7. In patients of myasthenia gravis, however, there is increased sensitivity to action of non-depolarizing muscle relaxants
  1. Neuro Muscular monitoring (Train of Four)
    • Train of four is best utilized for neuromuscular moni¬toring. In this four stimulus each of 2 Hz frequency are given for 2 seconds. 
    • The ratio of 4th recording (T4) to 1 st recording (T1) is taken. 
    • Normal ratio is 1. With depolarizers the amplitude of all 4 recordings decrease simultaneously while with non-depolarizers T4 decrease in proportion to T1. This is called as fading. Ratio of 0.3 is sufficient for most of surgeries while ratio of 0.7 is considered sufficient for reversal.
- Ulnar nerve is most commonly chosen (Adductor pollicis) 
  1. Mode of neuromuscular monitoring-
    1. Single twitch
    2. Double burst
    3. Tetanic stimulus
    4. Train of Four
Important: Adductor pollicis is employed for monitoring the beginning of blockade.
  1. Adductor pollicis makes sure that laryngeal, pharyngeal muscles have been blocked & intubation can be performed. The same applies at reversal. The sequence of reversal is the same (first to go, first to come)
    1. Absence of activity in orbicularis oculi means blockade in laryngeal muscle
    2. Diaphragm requires 90% of receptor occupation while 70-75% is sufficient for surgery
  2. Depolarizing relaxants
    1. Decamethonium - not used
    2. Suxamethonium (Succinyl choline)

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