NEUROMUSCULAR BLOCKING
AGENTS
Keshore R. Bidasee, Ph.D.
Durham Research Center 3047
Phone: 559-9018
Email: kbidasee@unmc.edu
2006
MINIQUIZ (Feb 17th, 2006)
FIRST FOUR LECTURES
MUSCLE RELAXANTS,
NEUROMUSCULAR BLOCKING AGENTS
GENERAL ANESTHETIC (2 LECTURE)
12 MULTIPLE CHOICE QUESTIONS
1 ASSAY QUESTION
CORRECTION
(6) Side Effects (METHOCARBAMOL)
(1) Most frequent:
- Drowsiness, loss of physical coordination, lightheadedness and dizziness
- Discoloration of urine
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DRUGS THAT AFFECT SKELETAL MUSCLE FUNCTION FALL
INTO TWO THERAPEUTIC GROUPS
(1) THOSE THAT ARE USED TO REDUCED SPASTICITY AND SPASMS
- “central acting” muscle relaxants also muscle-acting
(2) THOSE THAT ARE USED DURING SURGICAL PROCEDURES TO
INDUCE SKELETAL MUSCLE PARALYSIS - adjunct to general
anesthetics
MATERIAL SOURCES
Chapter 27, Skeletal Muscle Relaxants, Ronald Miller and
Betram Katzung, p. 428-446, in Katzung's Basic and Clinical
Pharmacology, 9th Edition, 2004
Chapter 9, Agents Acting at the Neuromuscular Junction and
Autonomic Ganglia, Palmer Taylor, in Goodman and Gilman's
The Pharmacological Basis of Therapeutics, 11th edition.
http://www.accessmedicine.com.library1.unmc.edu:2048/home.aspx
OBJECVTIVES OF THIS LECTURE
(1) Identify therapeutic strategies that could be use to block
conduction at the neuromuscular junction (NMJ)
(2) Differentiate between competitive (non-depolarizing)
blocking and depolarizing agents at the nicotinic
acetylcholine receptor receptor (AChR) in the NMJ
(3) Know pharmacodynamic and pharmacokinetic
properties of neuromuscular blocking agents
(4) Identify precautions, contraindications, and
drug-interactions associated with the use of
neuromuscular blocking agents
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DRUG LIST
Non-depolarizing blockers
Depolarizing blockers
Succinylcholine (Anetine)
(a) Isoquinoline Derivatives
d-Tubocurarine (prototype)
Atracurium (Tracrium)
Mivacurium (Mivacron)
Acetylcholinesterase
inhibitors
(b) Steroid Derivatives
Pancuronium (Pavulon))
Neostigmine (Prostigmin)
Edrophonium (Tensilon,
Vecuronium (Norcuron)
Enlon)
Rucoronium (Zemuron)
NEUROMUSCULAR BLOCKING DRUGS ARE ROUTINELY USED
(1) To prevent voluntary or reflex-induced muscle
contractions during surgical procedures
(2) To assist with artificial ventilation in unresponsive
patients (undergoing antiepileptic therapy)
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TO UNDERSTAND HOW
NEUROMUSCULAR BLOCKING
AGENTS WORK REQUIRE SOME
UNDERSTANDING OF
TRANSMISSION AT THE
NEUROMUSCULAR JUNCTION
SEQUENCE OF EVENTS:
(i) An action potential invading the end plate opens N-type
calcium channels
(ii) Ca2+ enters the terminus and cause the vesicles to fuse to the
membrane and release their content into the junctional cleft
(iii) The acetylcholine (ACh) molecules release bind with nicotinic
acetylcholine receptors (nACh receptors) and causes it to open
(iv) Opening of the nACh receptors results in the influx of Na+
ions into the muscle and depolarization
(v) Once the Ach unbinds, it is exposed to acetylcholinesterase
and is broken down
(vi) Most of the ACh released is not able to bind for a second time.
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WE ARE INTERESTED IN DRUGS THAT ACT ON
NICOTINIC ACETYLCHOLINE RECEPTORS
(nAChR) TO ALTER Na+ PERMEABILITY
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NEUROMUSCULAR BLOCKING AGENTS DO NOT
HAVE ANALGESIC PROPERTIES
These drugs bear structural resemblance to acetylcholine
bis-quaternary
aminosteroid
bis-quaternary
benzylisoquinoline
Mono-quaternary
aminosteroid
bis-quaternary
benzylisoquinoline
MECHANISM OF ACTION
Blockade at the nAChR can be accomplished in two
ways
(1) Pharmacological blockade of the physiologic agonist prevent depolarization
Drugs that do this are referred to as
non-depolarizing blockers - d-Tubocurarine (prototype)
(2) Excess of depolarization agonist
Drugs that do this are referred to as depolarizing
blockers - Succinylcholine (prototype)
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Non-depolarizing (competitive) blocking agents
(1) In low dosages and at low frequencies of stimulation,
they compete with acetylcholine for binding sites on
nAChR - competitive blockers or antagonists at nAChR
(2) In larger doses, some of these drugs enter the pore
(because of positive charge) to cause blockade.
(3) Non-depolarizing agents can also block pre-junctional
sodium channels and this interferes with ACh reuptake
at the nerve ending.
nAChR
nAChR
SODIUM CHANNELS
RESTING STATE:
upper gate closed
lower gate open
Acetylcholine
Non-depolarizing
Drugs bind and prevent
depolarization
Gated channels
There are two major classes of non-depolarizing agents
(a) Isoquinoline derivatives
d-Tubocurarine is the prototype
Atracurium, Mivacurium and Doxacurium
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(b) Aminosteroids
– Pancuronium, Vecuronium, Rocuronium
Blockage by non-depolarizing blocker can be reversed
by administration of an acetylcholine esterase inhibitor
(neostigmine and edrophonium)
Blockage of acetylcholine esterase results in a build up of
ACh at the end plate which can then compete with the drug
for binding site on the receptor
Depolarizing Blocking Agents
(a) Succinylcholine is only depolarizating agent
approved in USA
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Depolarizing agents block in two steps
Phase 1 block
(1) Succinylcholine binds to and activate or open the nicotinic
acetylcholine receptor (nAChR)
(2) Opening of the nAChR causes Na+ to enter the muscle and
this triggers a cascade of events that result in muscle
contraction.
(3) Because succinylcholine is not metabolized effectively by
acetylcholinesterase, the depolarized membrane remains
depolarized and unresponsive to additional impulses
(4) Since excitation-contraction coupling of the muscle requires
end plate repolarization (repriming) and repetitive firing to
maintain muscle tension, a flaccid paralysis results.
Phase II block
(i) With continuous exposure to succinylcholine, the initial
end plate depolarization decreases and the membrane
become repolarized.
(ii) Despite this repolarization, the membrane cannot
easily be repolarized again, i.e., it is desensitized.
Blockage by depolarizing blocker CANNOT BE reversed
by administration of an acetylcholine esterase inhibitor
(neostigmine and edrophonium)
Mechanism of Action of depolarizing blocker
nAChR
SODIUM CHANNELS
RESTING STATE:
upper gate closed
lower gate open
Gated channels
DEPOLARIZATION
gates remains open
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Katzung, Chapter 27
MONITORING NEUROMUSCULAR FUNCTION
•Wide inter-patient variability in dose requirements
•Differentiates type of block
•Allows careful titration to effect
•Allows assessment of readiness for reversal
•Allows assessment of adequacy of reversal
The efficacy of block is usually assessed by stimulating a
peripheral nerve and recording evoked contraction
TOF - four pulses are applied at 2Hz and the ratio of the strength of
the fourth to that of the first is measured
–Peripheral muscles are easily accessible
•Ulnar nerve-Adductor Pollicis similar to in vitro NM prep.
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Monitoring Neuromuscular
Function
TOF (Train of Four)
• TRAIN OF FOUR (TOF)
– Measures continued relaxation
– No control required
– Identifies phase II block
– Tolerable in awake patients
– Reliability? In visual /tactile
assessment
– measurement 0.7 of 0.9 or 1
SUMMARIZE
Non-depolarizing or competitive blockers are
ANTAGONISTS at the nicotinic acetylcholine receptors,
i.e., they bind but do not activate or open the channel
Blockage by competitive antagonist can be reversed
by administration of an acetylcholine esterase inhibitor.
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Depolarizing blockers are AGONIST at the nicotinic
acetylcholine receptors and there mechanism of action is
just a bit different
Succinylcholine is NOT metabolized by acetylcholine
esterase,
(a) persistent depolarization prevents new action
potential from occurring
(b) K+ leaves the muscle in an attempt to repolarize the
end plate
(c) as long a succinylcholine remains binding the
muscle will state in a state of flaccid paralysis
Comparison of depolarizing and non-depolarizing blockers
Competitive Depolarizing Block
Block
Phase I
Phase II
Action at
Antagonist Agonist
nicotinic receptor
Initial excitatory None
Effect on skeletal
muscle
Fasciculation None
Rate of recovery10 - 60 min 4 - 8 min
Effect of
neostigmine
>20 min
Antagonize AugmentedAntagoniz
PHARMACOKINETICS
ADMINISTRATION:
Neuromuscular blocking drugs (NMBs) are highly polar
and always administered intravenously by an
anesthesiologist. They are inactive when administered by
mouth.
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NON-DEPOLARIZING AGENTS
DISTRIBUTION:
(i) Rate of disappearance of non-depolarizing agents from
the blood is characterized by a rapid initial distribution,
followed by a slower elimination phase.
(ii) Because they are highly ionized they do not cross
membranes (blood brain barrier or the placenta) and have
limited volume of distribution (extracellular fluid volume)
ROUTE OF ELIMINATION:
Non-depolarizing agents
(1) Plasma cholinesterase (butrylcholinesterase)
(2) excreted by the kidney
(3) metabolized by the liver
(4) spontaneous breakdown (Hoffman elimination)
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(i)
Non-depolarizing NMBs that are excreted via the
kidney usually have long half live and long
duration of action (e.g., d-Tubocurarine,
Doxocurium, Pancuronium)
(ii) NMBs that depend bilary and hepatic metabolism
usually tend to have intermediate duration of
action (e.g., Vecuronium and Rucoronium)
Katzung
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ROUTE OF ELIMINATION:
(i)
Atracurium is an isoquinoline NMB that is inactivated
mainly by spontaneous elimination.
(a)
One of the breakdown products is laudanosine
which does not possess neuromuscular blocking
properties
(b)
However, laudanosine can cross the blood-brain
barrier and at high concentrations, it can cause
seizures.
(c)
Cisatracurium (a stereoisomers of atricurium)
forms less laudanosine and releases less histamine
from tissues.
Atricurium is broken down spontaneously to for
laudanosine
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CLINICAL PHARMACOLOGY:
intravenous administration of non-depolarizing agents
will cause skeletal muscles to become totally flaccid and
inexcitable to stimulation.
In general, the larger muscles (those of the trunk) are
more resistance to block and recover more rapidly than
the smaller muscles (e.g., those of the hand). The
diaphragm is usually the last muscle to be paralyzed.
Rapidly moving muscles (eyes, fingers, toes)>limbs>trunk>diaphragm
• SENSITIVITY TO NMBDs’
–
–
–
–
–
–
–
Upper airway muscles
Masseter
Abdominal muscles
Peripheral limb muscles
Muscle of the larynx
Muscles of the face
Diaphragm
Increasing
resistance
DEPOLARIZING AGENTS
Succinylcholine has an extremely brief duration of action
(5-10 minutes) because it is rapidly hydrolyzed by plasma
cholinesterase (butrylcholinesterase/pseudocholinesterase)
to succinyl monocholine (small amount reaches the NMJ).
The latter is metabolized by the liver to form choline and
succinic acid.
Plasma
Succinylcholine
Succinylmonocholine
Cholinesterase
Liver
Succinate +
Chloline
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Plasma cholinesterase has an enomorous capacity to
hydrolyze succinylcholine at a rapid rate. Only a small
fraction of the injected dose reaches the NMJ
Since there are no cholinesterase at the end plate, blockade
by succinylcholine is terminated by diffusion
Neuromuscular blockade by succinylcholine can be
prolonged in patients with abnormal invariant of
plasma cholinesterase.
The “dibucaine number” is a test to determine the ability
of patients to metabolize succinylcholine (under standard
conditions, dibucaine inhibits normal enzyme 80% and
abnormal enzyme 20%)
ADVERSE EFFECTS
ISOQUINILONINE TYPE
d-Tubocurarine
(a) hypotension caused by
(i) releases histamine from mast cells
(can be attenuated with antihistamines)
(ii) ganglion blockage
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AMINOSTEROID TYPE (Pancuronium)
(a) Major : can also block muscarinic acetylcholine
receptors (mACh) in the heart leading to tachycardia
and slight elevation in blood pressure
(b) Minor: block reuptake of norepinephrine (not seen with
Vecronium)
SUCCINYLCHOLINE (depolarizing blocker)
(a) Children:
low dosages can stimulate muscarinic receptors in the
heart
(b) Adult:
high dosages can stimulate the nACh in the autonomic
ganglia and this can result in cardiac arrhythmias as well
as increases in blood pressure. Can also induce
positive inotropic and chronotrpoic responses
.
low dosages can trigger negative inotropic and
chronotropic responses
ISO
STE
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PRECAUTIONS, CONTRAINDICATIONS
A. Disease affecting muscle contraction where
(i) amount of acetylcholine released at the neuromuscular
junction is abnormal
example: amylotrophic lateral sclerosis
(ii) availability of acetylcholine receptors is abnormal
example: myasthenia gravis
B. Administration of succinylcholine can increases serum
potassium (hyperkalemia) in patients with recent burns
or muscular denervations
C. Do not use succinylcholine in patients with atypical
plasma cholinesterase
D. Can increase intraoccular and intragrastric pressure
E. Succinylcholine may precipitate a malignant
hyperthermic crisis in genetically predisposed patients
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DRUG-DRUG INTERACTIONS
Drugs which decrease muscle contraction can potentiate
the effects of neuromuscular blocking agents, e.g.,
(a) antibiotics – large doses particularly
aminoglycosides and polymyxins
(b) general anesthetics and barbiturates potentiate
(c) Quinidine
(d) Ca2+ channel blockers
Drugs that cause or promote desensitization of nAChR
•Volatile Anesthetics
•Antibiotics
•Cocaine
•Alcohols
•Barbiturates
•Agonists
•AChE Inhibitors
•Local Anesthetics
•Phenothiazines
•Phencyclidine
•Ca Channel Blockers
SUMMARY OF CONTRAINDICATIONS AND PRECAUTIONS:
Condition
Succinylcholine
d-Tubocurarine
Pancuronium
↓ Muscle contraction
↓ Dose
↓ Dose
↓ Dose
Recent burns
DonÕ
t use
Dose
No change in dose
High doses of antibiotics
↓ Dose
↓ Dose
↓ Dose
Malignant hyperthermia
DonÕ
t use
Use with caution
Use with caution
Atypical plasma
cholinesterase
DonÕ
t use
Okay
Okay
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