A Textbook of Clinical Pharmacology and Therapeutics

but is an agonist. It causes depolarization and initial

uncoordinated contractions (‘fasciculation’), followed

by block.

All muscle relaxants are highly charged molecules and do not
readily pass through plasma membranes into cells. They are
usually administered intravenously and are distributed through-
out the body by blood flow and diffusion. Changes in muscle
blood flow or cardiac output can thus alter the speed of onset
of neuromuscular blockade. At the end of a procedure, the
concentration of relaxant at the end-plate decreases as the
drug diffuses down a concentration gradient into the plasma.
At this point, the effect of non-depolarizing drugs can be
reversed by the injection of an anticholinesterase, such as
neostigmine, which increases the amount of acetylcholine at
the end-plate by preventing its breakdown by acetyl-
cholinesterase.Atropineorglycopyrronium bromideis admin-
istered before neostigmine, to prevent the parasympathetic
effects of acetylcholine by blocking muscarinic receptors.
Respiratory acidosis, myasthenic syndromes and several
drugs (including some β-adrenoceptor blockers, aminoglyco-
sides,furosemide, volatile anaesthetics and some tetracyclines)
potentiate neuromuscular blockade. The muscle relaxants
have poor penetration of the placental barrier, and normal
doses do not affect the fetus or cross the blood–brain barrier.

NON-DEPOLARIZING AGENTS

Pancuroniumhas a peak effect at three to four minutes fol-

lowing an intubating dose, and duration of action of 60–90

minutes. It is partly metabolized by the liver, but 60% is elim-

inated unchanged by the kidneys, so patients with reduced

renal or hepatic function show reduced elimination and pro-

longed neuromuscular blockade. Pancuroniumhas a direct

vagolytic effect, as well as sympathomimetic effects, which

can cause tachycardia and slight hypertension. This may prove

useful when it is used in cardiovascularly compromised patients.

Vecuroniumhas an onset of action within three minutes,

following an intubating dose. The duration of action is

approximately 30 minutes, and can usually be reversed by

anticholinesterases after only 15–20 minutes. It has little or no

effect on heart rate and blood pressure, and does not liberate

histamine.Vecuroniumundergoes hepatic de-acetylation and

the kidneys excrete 30% of the drug.

Rocuronium bromideis a steroid muscle relaxant. Good

intubating conditions are achieved within 60–90 seconds.

Rocuronium bromidehas the most rapid onset of any non-

depolarizing muscle relaxant, and is only slightly slower than

suxamethonium. Its duration of action is 30–45 minutes, but it

is otherwise similar to vecuronium.

Atracuriumis a non-depolarizing muscle relaxant with a

rapid onset time (2.0–2.5 minutes) and duration of 20–25 min-

utes. Histamine release may cause flushing of the face and

chest, local wheal and flare at the site of injection and, more

rarely, bronchospasm and hypotension. Atracuriumdoes not

accumulate and hence continuous infusion is popular in

intensive care to facilitate intermittent positive pressure venti-

lation (IPPV). During long surgical cases it can provide stable

and readily reversible muscle relaxation. It is unique in that it

is inactivated spontaneously at body temperature and pH by

Hoffman elimination, a chemical process that requires neither

hepatic metabolism nor renal excretion. This makes it the

agent of choice for use in patients with significant hepatic and

renal impairment. Cisatracurium, a stereoisomer of atracurium,

has the advantage of causing less histamine release.

Mivacuriumhas an onset time and propensity for hista-

mine release similar to atracurium. Because it is metabolized

Nerve

ACh

Agonists

(suxamethonium)

Nicotinic

receptor

Muscle

Motor endplate

depolarization

Competitive

antagonists

(vecuronium,

atracurium,

pancuronium,

etc.)

− +

Figure 24.3:Mode of action of muscle relaxants.

Key points

Muscle relaxants in anaesthesia

• Neuromuscular blocking drugs:
  
  
  • non-depolarizing (e.g. atracurium);
  
  
  • depolarizing (e.g. suxamethonium).
  
  
  
  


• Used to:
  
  
  • facilitate tracheal intubation;
  
  
  • relax muscles of the abdomen and diaphragm
    during surgery.
  
  
  
  


• Following administration, respiration must be assisted
  or controlled until the effects have subsided.

Key points

Non-depolarizing muscle relaxants

• These compete with acetylcholine at the neuromuscular
  junction.


• Action is reversed by anticholinesterases (e.g.
  neostigmine) (note that atropine or glycopyrrolate is
  required to prevent dangerous bradycardia and
  hypersalivation).


• They may cause histamine release.


• Allergic cross-reactivity has been reported.


• There is a prolonged effect in myasthenia gravis and
  hypothermia.


• Examples include atracurium, vecuronium and
  pancuronium (longer duration of action).

MUSCLERELAXANTS 151