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NEUROMUSCULAR BLOCKING AGENTS
Keshore R. Bidasee, Ph.D. Durham Research Center 3047
Phone: 559-9018Email: [email protected]
Spring 2005
ADDITIONAL READING MATERIAL
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, p. 193-206, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition
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) Describe the pharmacodynamic and pharmacokinetic properties of neuromuscular blocking agents
(4) Identify precautions, contraindications, and drug-interactions associated with the use of neuromuscular blocking agents
Non-depolarizing blockers
(a) Isoquinoline Derivatives d-Tubocurarine (prototype) Atracurium (Tracrium)Mivacurium (Mivacron)
(b) Steroid DerivativesPancuronium (Pavulon))Vecuronium (Norcuron)Rucoronium (Zemuron)
Depolarizing blockersSuccinylcholine (Anetine)
Acetylcholinesterase inhibitorsNeostigmine (Prostigmin)Edrophonium (Tensilon,
Enlon)
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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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WE ARE INTERESTED IN DRUGS THAT
ACT ON NICOTINIC ACETYLCHOLINE
RECEPTORS (nAChR)
AND ALTER Na+ PERMEABILITY
These drugs bear structural resemblance to acetylcholine
bis-quaternaryaminosteroid
Mono-quaternaryaminosteroid
bis-quaternarybenzylisoquinoline
bis-quaternarybenzylisoquinoline
Blockade at the nAChR is accomplished by two ways
(1) Preventing depolarization
Drugs that do this are referred to as
non-depolarizing blockers - d-Tubocurarine (prototype)
(2) Excessive depolarization
Drugs that do this are referred to as
depolarizing blockers - Succinylcholine (prototype)
MECHANISM OF ACTION
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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
to cause blockade.
(3) Non-depolarizing agents can also block prejunctional
sodium channels and this interferes with ACh reuptake
at the nerve ending.
nAChRSODIUM CHANNELS
Gated channels
RESTING STATE:upper gate closedlower gate open
nAChR
AcetylcholineNon-depolarizingdrugs
There are two major classes of non-depolarizing agents
(a) isoquinoline derivatives
d-Tubocurarine is the prototype
Atracurium, Mivacurium and Doxacurium
(b) aminosteroids
– Pancuronium, Vecuronium, Rocuronium
Blockage by non-depolarizing blocker can be reversed
by administration of an acetylcholine esterase inhibitor
(neostigmine ann 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
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Depolarizing Blocking Agents(a) succinylcholine 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.
Depolarizing agents block in two steps
Phase II blockWith continuous exposure to succinylcholine, the initial
end plate depolarization decreases and the membrane
become repolarized. Despite this repolarization, the
membrane cannot easily be repolarized again, i.e.,
it is desensitized.
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Mechanism of Action of depolarizing blocker
nAChRSODIUM CHANNELS
Gated channels
RESTING STATE:upper gate closedlower gate open
DEPOLARIZATIONgates remains open
Blockage by depolarizing blocker cannot be
reversed by administration of an
acetylcholine esterase inhibitor.
MONITORING NEUROMUSCULAR FUNCTION
WHY BOTHER?
•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
TOF - four pulses are applied at 2Hz and the ratio of the strength ofthe fourth to that of the first is measured
The efficacy of block is usually assessed by stimulating a peripheral nerve and recording evoked contraction
–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
Non-depolarizing or competitive blockers areANTAGONISTS 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.
SUMMARIZE
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
Depolarizing blockers are AGONIST at the nicotinic acetylcholine receptors and there mechanism of action isjust a bit different
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Competitive Block
Depolarizing Block
Action atnicotinic receptorAntagonist Agonist
Effect ofneostigmine
Rate of recovery
Antagonize Augmented
10 - 60 min 4 - 8 min
Phase I Phase II
Antagoniz
>20 min
Initial excitatoryEffect on skeletalmuscle
None Fasciculation None
Comparison of depolarizing and non-depolarizing blockers
Neuromuscular blocking drugs (NMBs) are highly polar
and always administered intravenously by an
anesthesiologist. They are inactive when administered by
mouth.
PHARMACOKINETICS
Non-depolarizing agents
Rate of disappearance of non-depolarizing
agents from the blood is characterized by a rapid initial
distribution, followed by a slower elimination phase.
However, 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)
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Non-depolarizing agents can be eliminated
(1) Plasma cholinesterase (butrylcholinesterase)
(2) excreted by the kidney
(3) metabolized by the liver
(4) spontaneous breakdown (Hoffman elimination)
Atracurium is an isoquinoline NMB that is inactivated
mainly by spontaneous elimination (hydrolysis of ester
bond). One of the breakdown products is LAUDANOSINE
which does not possess neuromuscular blocking
properties. However, it is slowing metabolize by the liver
and can cross the blood-brain barrier. At high
concentrations (>17µg/ml), it can cause seizures.
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Atricurium is broken down spontaneously to for
laudanosine
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
Succinyl choline 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).
Depolarizing agents
The latter is metabolized by the liver to form choline and
succinic acid.
Succinylcholine Succinylmonocholine
Plasma
Cholinesterase
Liver Succinate +
Chloline
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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
(i) hypotension caused by
(ii) releases histamine from mast cells
(can be attenuated with antihistamines)
(iii) ganglion blockage
AMINOSTEROID TYPEPancuronium)
(i) can also block muscarinic acetylcholine receptors
(mACh) in the heart leading to tachycardia and slight
elevation in blood pressure
(ii) block reuptake of norepinephrine (not seen with
Vecronium)
(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 positiveinotropic and chronotrpoic responses
. low dosages can trigger negative inotropic and chronotrpoic responses
DEPOLARIZING BLOCKER
succinylcholine
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ISO
STE
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
E. Succinylcholine may precipitate a malignant hyperthermic crisis in genetically predisposed patients
C. Do not use succinylcholine in patients with atypicalplasma cholinesterase
D. Can increase intraoccular and intragrastric pressure
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Malignant Hyperthermia is a potentially fatal
pharmacogenetic disorder of skeletal muscle.
It is triggered in susceptible individuals by
exposure to commonly used volatile anesthetic
agents such as halothane, isoflurane,
sevoflurane, enflurane or depolarizing muscle
relaxants such as succinylcholine
Malignant Hyperthermia
• ↑ Ca++
• Depletion of high-energy phosphates
• Rapid metabolism• Rigor• Destruction of muscle
cell membrane
Cellular events in muscle
• Plasma – ↓ O2
– ↑ CO2
– ↑ Lactic acid– ↓ pH– ↑ K+
• Tachycardia• ↑ Rate and depth of
respiration• Muscle rigidity• ↑ Body temperature
Clinical Observations
Malignant Hyperthermia is triggered by
mutations on skeletal muscle
ryanodine receptor calcium release
channels
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DANTROLENE
• Given prior to surgery in patient know to carry the
gene (biopsy test)
– Avoid agents which will precipitate an attack
• Not used prophylactically
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 DonÕt use Dose No change in dose
High doses of antibiotics ↓ Dose ↓ Dose ↓ Dose
Malignant hyperthermia DonÕt use Use with caution Use with caution
Atypical plasmacholinesterase
DonÕt use Okay Okay