Neuromuscular Blocking Agents- Free Version

A Brief Review of Neuromuscular Blocking Agents

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Skeletal Muscle relaxants

Classification

• Peripherally acting (Neuromuscular blockers)
  1. Pre synaptic neuromuscular blocker
     • Inhibit Ach synthesis: triethylacholine – hemicholinium
     • Inhibit Ach release: Mg, aminoglycosides, botulinum toxin
  2. Post synaptic neuromuscular blocker
     • Competitive (non depolarizing blockers):
       • d- tubocurarine
       • Gallamine
       • Atracurium
       • Pancuronium
       • Vecuronium
     • Depolarizing blockers: succinylcholine (suxamethonium)
• Centrally acting skeletal muscle relaxants
  1. Baclofen – Diazepam  
• Direct acting skeletal muscle relaxants
  1. Dantrolene

Mechanism of action

1. Non depolarizing relaxant drugs
   • All neuromuscular blocking agents used in USA except succinylcholine are classifies as non depolarizing agents
   • When small doses of nondepolarizing muscle relaxants are administered, they act predominantly at nicotinic receptor site by competing with acetylcholine
   • The least potent relaxant (eg. Rocuronium) have the fastest onset and the shortest duration of action
   • In large doses, nondepolarizing drugs enter the pore of ion channel to produce a more intense motor blockade. This action further weakens neuromuscular transmission and diminishes the ability of the cholinesterase inhibitor (eg. Neostigmine, edrophonium, pyridostigmine) to antagonize the effect of non depolarizing muscle relaxants.
   • They also block prejunctional sodium channels. As a result of this action, muscle relaxants interfere with the metabolization of acetylcholine at the nerve ending.
   • Both halothane and succinylcholine increase the intensity and duration of action of pancuronium. (1)

2. Depolarizing relaxant drugs
   1. Phase I block (depolarizing)
      • Succinylcholine is the only available depolarizing neuromuscular blocking drug. (2)
      • It produces a longer effect at the myoneural junction
      • It reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing contractions of muscle motor units.
      • Because succinylcholine is not metabolized at the synapse, the depolarized membranes remain depolarized and unresponsive to subsequent impulses
      • This is called Phase I (depolarizing) block, not reversed by cholinesterase inhibitors
   2. Phase II block (desensitizing)
      • With prolonged exposure to succinylcholine, initial end plate depolarization decreases and the membrane become repolarized
      • Despite this repolarization, the membrane cannot be easily depolarized again because it is desensitized
      • The channel block is more important than agonist action at the receptor in phase II of succinylcholine’s neuromuscular blocking action
      • Later in phase II, the characteristics of the blockade are nearly identical to those of a non depolarizing block (ie, a nonsustained twitch response to a titanic stimulus) with possible reversal by acetylcholinesterase inhibitors

• Succinylcholine produce reversible contracture of intrafusal fibers of the muscle spindle and leads to acceleration of the afferent discharge. (3)
• Another study by Martin Jeevendra and Duriex Marcel E found that: (4)

              1. Succinylcholine caused initial activation of the muscle AchR followed by desensitization

              2. At clinically relevant concentrations, succinylcholine has no stimulatory or inhibitory interactions                            with α3β2 (presynaptic) or α3β4 (ganglionic) AchRs

              3. High doses of succinylcholine caused inhibition of both α3β2 and α3β4 receptor. 

Pharmacokinetics of neuromuscular blocking drugs

• Succinylcholine has the fastest onset of action among all the muscle relaxants. (5)
• The elimination of succinylcholine appears to follow first order kinetics with linear relationship between intensity of the effect and logarithm of the dose. The rate of recovery is independent of dose for each age group. The rate of recovery is faster in children than in infants; the rate of recovery is faster in infants than in adults. The elimination rate constant for infabts was similar to that of children, but is dissimilar from those of adults. (6)

Drug

Elimination

Clearance (mL/kg/min)

Approximate duration of action (minutes)

Approximate potency relative to Tubocurarine

Atracurium

Spontaneous

6.6

20-35

1.5

Cisatracurium

Mostly spontaneous

5-6

25-44

1.5

Doxacurium

Kidney

2.7

> 35

6

Metocurine

Kidney (40%)

1.2

> 35

4

Mivacurium

Plasma ChE

(Butyrylcholinesterase)

70-95

10-20

4

Tubocurarine

Kidney (40%)

2.3-2.4

> 50

1

Pancuronium

Kidney (80%)

1.7-1.8

> 35

6

Pipecuronium

Kidney (60%) and liver

2.5-3.0

> 35

6

Rocuronium

Liver (75-90%) and kidney

2.9

20-35

0.8

Vecuronium

Liver (75-90%) and kidney

3-5.3

20-35

6

Succinylcholine

Plasma ChE (100%)

(Butyrylcholinesterase)

>100

0.4

Soutce: Bertram G. Katzung, Susan B. Masters and Anthony J. Trevor. Basic amd Clinical Pharmacology. 11th Edition. Chapter 27. Skeletal Muscle Rexants. Page 451-465.

Pharmacology of Neuromuscular blocking drugs

Drug

ED95a (mg/kg)

Intubating dose (mg/kg)

Onset timeb (s)

Clinical durationc(min)

Succinylcholine

0.3

1.0d

60

10

Benzylisoquinolone

Tubocurarine

0.5

0.5-0.6

220

80+

Atracurium

0.23

0.5

110

43

Mivacurium

0.08

0.15-0.2

170

16

Doxacurium

0.025

0.05

250

83

Cisatracurium

0.05

0.1

150

45

Aminosteroids

Pancuronium

0.07

0.1

220

75

Vecuronium

0.05

0.1

180

33

Pipecuronium

0.045

0.08

300

95

Rocuronium

0.3

0.6

75

33

Rapacuronium

1.2

1.5