RNFA MASTER STUDY GUIDE-NOTES #11
Neuromuscular blockers - correct answer Tubocurarine Atracurium Cisatracurium
Mivacurium Rocuronium Pancuronium Vecuronium Succinylcholine
Ache inhibitors - correct answer Neostigmine Edrophonium
Muscarinic Antagonists - correct answer Glycopyrrolate
Spasmolytics - correct answer Dantrolene Diazepam Baclofen Tizanidine Gabapentin
Progabide Glycine Idrocilamide Riluzole Dantrolene Botulinum toxin Cyclobenzaprine
Neuromuscular blockers. - correct answer Used during surgical procedures and in
intensive care units to cause paralysis.
NONDEPOLARIZING BLOCKERS - correct answer • They are competitive antagonists.
In small clinical doses they act predominantly at the nicotinic receptor site by competing
with acetylcholine. Their action can be overcome by increasing the concentration of
acetylcholine in the synaptic cleft; this can be achieved, for example, by administration
of acetylcholinesterase inhibitors such as neostigmine or edrophonium.
Anaesthesiologists use this strategy to shorten the duration of the neuromuscular
blockade.
• In larger doses, nondepolarizing blockers also enter the pore of the ion channel to
cause a more intense motor blockade. This further weakens neuromuscular
transmission and diminishes the ability of acetylcholinesterase inhibitors to antagonize
the action of nondepolarizing blockers.
• Nondepolarizing blockers may also block prejunctional sodium channels. As a result,
they reduce the release of acetylcholine at the nerve ending.
• During anesthesia, the IV administration of a nondepolarizing blocker first causes
motor weakness; ultimately, skeletal muscles become totally flaccid and inexcitable to
stimulation. Larger muscles (e.g. Those of the trunk) are more resistant to block and
recover more rapidly than smaller ones (e.g. Muscles of the hand).
DEPOLARIZING BLOCKERS - correct answer Succinylcholine is the only depolarizing
neuromuscular blocker used clinically in the USA. Succinylcholine remains popular
because it is the only ultrarapid onset/ultrashort duration neuromuscular blocker
available.
• Succinylcholine binds to the nicotinic receptor and acts like acetylcholine to cause
depolarization of the end plate. This in turn spreads and depolarizes adjacent
membranes, causing transient fasciculations, especially in chest and abdomen, though
general anesthesia and prior administration of a small dose of a nondepolarizing muscle
relaxant tends to attenuate them. Succinylcholine is not metabolized effectively at the
,synapse, therefore the membrane remains depolarized and unresponsive to additional
impulses. A flaccid paralysis results. This is called Phase I block, or depolarization
block. Phase I block is augmented, not reversed, by acetylcholinesterase inhibitors.
• The onset of neuromuscular blockade is very rapid, usually within 1 minute. Because
of its rapid hydrolysis by plasma butyrylcholinesterase (pseudocholinesterase), duration
of neuromuscular block is 5-10 minutes.
• With a single large dose, repeated doses, or prolonged continued infusion of
succinylcholine (30-60 minutes) the membrane repolarizes; despite this repolarization,
the membrane can't be depolarized again because it is desensitized.
The channels behave as if they are in a prolonged closed state. This is called phase II
block or desensitization block. Phase II block may be reversed by acetylcholinesterase
inhibitors.
PHARMACOKINETICS OF NEUROMUSCULAR BLOCKERS - correct answer • All
neuromuscular blocking agents contain one or two quaternary ammonium
Groups, which makes them highly polar and very poorly soluble in lipid.
• Neuromuscular blockers are inactive if given by mouth. They are always given IV or
IM. They penetrate membranes very poorly and do not enter cells or cross the blood-
brain barrier.
NON-DEPOLARIZING BLOCKERS - correct answer Highly ionized. They don't cross
membranes well and have limited volume of distribution of 80-140 ml/Kg -not much
larger than blood volume.
They have durations of action that range from 20 to 90 minutes, which can be extended
by supplemental dosing.
Non-depolarizing blockers can be classified into: long-, intermediate-, and short-acting.
SHORT-ACTING
Mivacurium
INTERMEDIATE-ACTING
Atracurium
Rocuronium
Cisatracurium
Vecuronium
LONG-ACTING
Tubocurarine
Pancuronium
METABOLISM - correct answer The duration of neuromuscular blockade produced by
nondepolarizing relaxants is strongly correlated with the elimination half-life.
,Drugs that are excreted by the kidney typically have longer half-lives, leading to longer
durations of action.
Drugs eliminated by the liver tend to have shorter half-lives and durations of action.
Atracurium is inactivated by hydrolysis by non-specific plasma esterases and by a
spontaneous reaction (Hoffman elimination). Duration of neuromuscular block produced
by atracurium is not altered by the absence of renal function.
One of atracurium metabolites is laudanosine. Laudanosine may cause transient
hypotension and, in higher doses, seizures.
Cisatracurium, a stereoisomer of atracurium, undergoes Hoffman elimination to form
laudanosine. Because cisatracurium is more potent than atracurium and lower doses
are required, laudanosine concentrations following cisatracurium administration are
lower. Cisatracurium also causes less histamine release. Therefore, cisatracurium has
largely replaced atracurium in clinical practice.
Mivacurium has short duration of action. Hydrolysis by butyrylcholinesterase is the
primary mechanism for inactivation of mivacurium. Not dependent on liver or kidney.
Rocuronium has the most rapid onset among nondepolarizing blockers. Can be used as
alternative to succinylcholine for rapid sequence intubation.
DEPOLARIZING BLOCKERS - correct answer The extremely short duration of action of
succinylcholine (5-10 minutes) is due to its
Rapid hydrolysis by plasma (and hepatic) butyrylcholinesterase.
Neuromuscular blockade by succinylcholine (and mivacurium) may be prolonged in
patients with an abnormal variant of butyrylcholinesterase. Prolonged paralysis from
succinylcholine caused by abnormal butyrylcholinesterase should be treated with
continued mechanical ventilation until muscle function returns to normal.
Because of the rarity of these variants, butyrylcholinesterase testing is not routine
clinical procedure.
ADVERSE EFFECTS - correct answer ...
NON-DEPOLARIZING BLOCKERS - correct answer • Some benzylisoquinolines may
produce hypotension due to histamine release and ganglionic blockade.
• Some ammonio steroids may produce tachycardia due to blockade of muscarinic
receptors, which may lead to arrhythmias. These drugs should be used cautiously in
patients with cardiovascular disease.
HISTAMINE RELEASE - correct answer Tubocurarine, and to a lesser extent,
mivacurium and atracurium can produce
Hypotension as a result of histamine release. Tubocurarine is seldom used clinically at
this time.
, Clinical signs of histamine release are erythema at the face and upper chest, a transient
decrease in blood pressure, and an increase in heart rate.
More severe reactions of histamine release include bronchospasm and circulatory
collapse.
Antihistamines can counteract responses that follow histamine release, particularly if
given before the neuromuscular blocker.
GANGLION BLOCKADE - correct answer Tubocurarine may cause some blockade of
nicotinic receptors of the autonomic ganglia
And the adrenal medulla; this results in a fall in blood pressure and tachycardia.
BLOCKADE OF CARDIAC MUSCARINIC RECEPTORS - correct answer The
ammoniosteroid pancuronium causes moderate tachycardia due to blockade of cardiac
muscarinic receptors. The cardiovascular effects of pancuronium are usually not
considered to be a clinically relevant problem (see table below).
DEPOLARIZING BLOCKERS - correct answer Succinylcholine stimulates all autonomic
cholinoceptors: nicotinic receptors in both
Sympathetic and parasympathetic ganglia and muscarinic receptors in the heart.
HISTAMINE RELEASE
Succinylcholine has a slight tendency to release histamine.
BRADYCARDIA - correct answer Bradycardia may occur due to activation of muscarinic
receptors. It can be prevented by thiopental, atropine, ganglionic blockers and non-
depolarizing muscle relaxants.
MUSCLE PAIN - correct answer Important postoperative complaint. Due to damage
produced by the unsynchronized contractions of adjacent muscle fibers.
HYPERKALEMIA - correct answer Due to loss of tissue potassium during
depolarization. Risk of hyperkalemia is enhanced in patients with burns or muscle
trauma. Hyperkalemia may lead to cardiac arrest or circulatory collapse.
INCREASED INTRAOCULAR PRESSURE - correct answer Due to extraocular muscle
contractions. Despite this effect, the use of succinylcholine for eye operations is not
contraindicated unless the anterior chamber is to be opened.
INCREASED INTRAGASTRIC PRESSURE - correct answer In some patients, the
fasciculations caused by succinylcholine cause an increase in intragastric pressure.
This makes emesis more likely, with the potential hazard of aspiration of gastric
contents.
Neuromuscular blockers - correct answer Tubocurarine Atracurium Cisatracurium
Mivacurium Rocuronium Pancuronium Vecuronium Succinylcholine
Ache inhibitors - correct answer Neostigmine Edrophonium
Muscarinic Antagonists - correct answer Glycopyrrolate
Spasmolytics - correct answer Dantrolene Diazepam Baclofen Tizanidine Gabapentin
Progabide Glycine Idrocilamide Riluzole Dantrolene Botulinum toxin Cyclobenzaprine
Neuromuscular blockers. - correct answer Used during surgical procedures and in
intensive care units to cause paralysis.
NONDEPOLARIZING BLOCKERS - correct answer • They are competitive antagonists.
In small clinical doses they act predominantly at the nicotinic receptor site by competing
with acetylcholine. Their action can be overcome by increasing the concentration of
acetylcholine in the synaptic cleft; this can be achieved, for example, by administration
of acetylcholinesterase inhibitors such as neostigmine or edrophonium.
Anaesthesiologists use this strategy to shorten the duration of the neuromuscular
blockade.
• In larger doses, nondepolarizing blockers also enter the pore of the ion channel to
cause a more intense motor blockade. This further weakens neuromuscular
transmission and diminishes the ability of acetylcholinesterase inhibitors to antagonize
the action of nondepolarizing blockers.
• Nondepolarizing blockers may also block prejunctional sodium channels. As a result,
they reduce the release of acetylcholine at the nerve ending.
• During anesthesia, the IV administration of a nondepolarizing blocker first causes
motor weakness; ultimately, skeletal muscles become totally flaccid and inexcitable to
stimulation. Larger muscles (e.g. Those of the trunk) are more resistant to block and
recover more rapidly than smaller ones (e.g. Muscles of the hand).
DEPOLARIZING BLOCKERS - correct answer Succinylcholine is the only depolarizing
neuromuscular blocker used clinically in the USA. Succinylcholine remains popular
because it is the only ultrarapid onset/ultrashort duration neuromuscular blocker
available.
• Succinylcholine binds to the nicotinic receptor and acts like acetylcholine to cause
depolarization of the end plate. This in turn spreads and depolarizes adjacent
membranes, causing transient fasciculations, especially in chest and abdomen, though
general anesthesia and prior administration of a small dose of a nondepolarizing muscle
relaxant tends to attenuate them. Succinylcholine is not metabolized effectively at the
,synapse, therefore the membrane remains depolarized and unresponsive to additional
impulses. A flaccid paralysis results. This is called Phase I block, or depolarization
block. Phase I block is augmented, not reversed, by acetylcholinesterase inhibitors.
• The onset of neuromuscular blockade is very rapid, usually within 1 minute. Because
of its rapid hydrolysis by plasma butyrylcholinesterase (pseudocholinesterase), duration
of neuromuscular block is 5-10 minutes.
• With a single large dose, repeated doses, or prolonged continued infusion of
succinylcholine (30-60 minutes) the membrane repolarizes; despite this repolarization,
the membrane can't be depolarized again because it is desensitized.
The channels behave as if they are in a prolonged closed state. This is called phase II
block or desensitization block. Phase II block may be reversed by acetylcholinesterase
inhibitors.
PHARMACOKINETICS OF NEUROMUSCULAR BLOCKERS - correct answer • All
neuromuscular blocking agents contain one or two quaternary ammonium
Groups, which makes them highly polar and very poorly soluble in lipid.
• Neuromuscular blockers are inactive if given by mouth. They are always given IV or
IM. They penetrate membranes very poorly and do not enter cells or cross the blood-
brain barrier.
NON-DEPOLARIZING BLOCKERS - correct answer Highly ionized. They don't cross
membranes well and have limited volume of distribution of 80-140 ml/Kg -not much
larger than blood volume.
They have durations of action that range from 20 to 90 minutes, which can be extended
by supplemental dosing.
Non-depolarizing blockers can be classified into: long-, intermediate-, and short-acting.
SHORT-ACTING
Mivacurium
INTERMEDIATE-ACTING
Atracurium
Rocuronium
Cisatracurium
Vecuronium
LONG-ACTING
Tubocurarine
Pancuronium
METABOLISM - correct answer The duration of neuromuscular blockade produced by
nondepolarizing relaxants is strongly correlated with the elimination half-life.
,Drugs that are excreted by the kidney typically have longer half-lives, leading to longer
durations of action.
Drugs eliminated by the liver tend to have shorter half-lives and durations of action.
Atracurium is inactivated by hydrolysis by non-specific plasma esterases and by a
spontaneous reaction (Hoffman elimination). Duration of neuromuscular block produced
by atracurium is not altered by the absence of renal function.
One of atracurium metabolites is laudanosine. Laudanosine may cause transient
hypotension and, in higher doses, seizures.
Cisatracurium, a stereoisomer of atracurium, undergoes Hoffman elimination to form
laudanosine. Because cisatracurium is more potent than atracurium and lower doses
are required, laudanosine concentrations following cisatracurium administration are
lower. Cisatracurium also causes less histamine release. Therefore, cisatracurium has
largely replaced atracurium in clinical practice.
Mivacurium has short duration of action. Hydrolysis by butyrylcholinesterase is the
primary mechanism for inactivation of mivacurium. Not dependent on liver or kidney.
Rocuronium has the most rapid onset among nondepolarizing blockers. Can be used as
alternative to succinylcholine for rapid sequence intubation.
DEPOLARIZING BLOCKERS - correct answer The extremely short duration of action of
succinylcholine (5-10 minutes) is due to its
Rapid hydrolysis by plasma (and hepatic) butyrylcholinesterase.
Neuromuscular blockade by succinylcholine (and mivacurium) may be prolonged in
patients with an abnormal variant of butyrylcholinesterase. Prolonged paralysis from
succinylcholine caused by abnormal butyrylcholinesterase should be treated with
continued mechanical ventilation until muscle function returns to normal.
Because of the rarity of these variants, butyrylcholinesterase testing is not routine
clinical procedure.
ADVERSE EFFECTS - correct answer ...
NON-DEPOLARIZING BLOCKERS - correct answer • Some benzylisoquinolines may
produce hypotension due to histamine release and ganglionic blockade.
• Some ammonio steroids may produce tachycardia due to blockade of muscarinic
receptors, which may lead to arrhythmias. These drugs should be used cautiously in
patients with cardiovascular disease.
HISTAMINE RELEASE - correct answer Tubocurarine, and to a lesser extent,
mivacurium and atracurium can produce
Hypotension as a result of histamine release. Tubocurarine is seldom used clinically at
this time.
, Clinical signs of histamine release are erythema at the face and upper chest, a transient
decrease in blood pressure, and an increase in heart rate.
More severe reactions of histamine release include bronchospasm and circulatory
collapse.
Antihistamines can counteract responses that follow histamine release, particularly if
given before the neuromuscular blocker.
GANGLION BLOCKADE - correct answer Tubocurarine may cause some blockade of
nicotinic receptors of the autonomic ganglia
And the adrenal medulla; this results in a fall in blood pressure and tachycardia.
BLOCKADE OF CARDIAC MUSCARINIC RECEPTORS - correct answer The
ammoniosteroid pancuronium causes moderate tachycardia due to blockade of cardiac
muscarinic receptors. The cardiovascular effects of pancuronium are usually not
considered to be a clinically relevant problem (see table below).
DEPOLARIZING BLOCKERS - correct answer Succinylcholine stimulates all autonomic
cholinoceptors: nicotinic receptors in both
Sympathetic and parasympathetic ganglia and muscarinic receptors in the heart.
HISTAMINE RELEASE
Succinylcholine has a slight tendency to release histamine.
BRADYCARDIA - correct answer Bradycardia may occur due to activation of muscarinic
receptors. It can be prevented by thiopental, atropine, ganglionic blockers and non-
depolarizing muscle relaxants.
MUSCLE PAIN - correct answer Important postoperative complaint. Due to damage
produced by the unsynchronized contractions of adjacent muscle fibers.
HYPERKALEMIA - correct answer Due to loss of tissue potassium during
depolarization. Risk of hyperkalemia is enhanced in patients with burns or muscle
trauma. Hyperkalemia may lead to cardiac arrest or circulatory collapse.
INCREASED INTRAOCULAR PRESSURE - correct answer Due to extraocular muscle
contractions. Despite this effect, the use of succinylcholine for eye operations is not
contraindicated unless the anterior chamber is to be opened.
INCREASED INTRAGASTRIC PRESSURE - correct answer In some patients, the
fasciculations caused by succinylcholine cause an increase in intragastric pressure.
This makes emesis more likely, with the potential hazard of aspiration of gastric
contents.
