Download Neuromuscular Blockers

Neuromuscular Blocking Agents
• Dr. Ahmed Haki Ismael
Neuromuscular Blockers
• Competitive Antagonists of the Nicotinic
Receptor
e.g. curare (d-tubocurarine), vecuronium,
pancuronium, atracurium, etc…
• Depolarizing Blockers
e.g. succinylcholine, decamethonium
Key Concepts
•Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia
•Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to provide
immobility during surgery, and to facilitate mechanical ventilation.
•Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists.
•Depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away
from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme,
pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
butyrylcholinesterase).
•With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by
either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on
redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of
specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme
activity.
•Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom
blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a
very long blockade (eg, 4–6 h) following succinylcholine administration.
•Succinylcholine is considered contraindicated in the routine management of children and
adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with
undiagnosed myopathies
•Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise
serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline
potassium levels, a life-threatening potassium elevation is possible in patients with burn injury,
massive trauma, neurological disorders, and several other conditions
•Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and
their action is prolonged in patients with renal failure.
•Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature
by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate
and laudanosine) have no intrinsic neuromuscular blocking effects
•Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular
effects are caused by the combination of vagal blockade and catecholamine release from adrenergic
nerve endings
•Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged
neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy
metabolite, changing drug clearance, or the development of a polyneuropathy
•Rocuronium (0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s),
making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer
duration of action.
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Decamethonium
Depolarizing
Blockers
Succinylcholine
Vecuronium
Competitive
Blockers
D-tubocurarine
pancuronium
History of neuromuscular blocking agents
• Early 1800’s – curare
discovered in use by
South American Indians
as arrow poison
• 1932 – West employed
curare in patients with
tetanus and spastic
disorders
• 1942 – curare used for
muscular relaxation in
general anesthesia
• 1949 – gallamine
discovered as a
substitute for curare
• 1964 – more potent drug
pancuronium
synthesized
Curares -
Chondrodendron e Strychnos
Strychnos toxifera
West 1932
Milestones of Neuromuscular
Blockade in Anesthesia
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1942 introduction of dTc in anesthesia
1949 Succinylcholine, gallamine metocurine introduced
1958 Monitoring of NMF with nerve stimulators
1968 Pancuronium
1971 introduction of TOF
1982 Vecuronium,Pipecurium,atracurium
1992 Mivacurium
1994 Rocuronium
1996 Cisatracurium
2000 Rapacurium introduced and removed
Neuromuscular blockers differ
from each other in:
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Mechanism of action
Duration of action
Speed of onset and offset of action
Selectivity of action and safety margin
Adverse effects
Classification of Blockers
Agent
Pharmacological
Properties
Succinylcholine Ultrashort acting;
Depolarizing
Onset time Duration
(min)
(min)
1-1.5
6-8
Elimination
Plasma
cholinesterase
D-tubocurarine
Long duration;
Competitive
4-6
80-120
Renal and
liver
Atracurium
Intermediate duration;
Competitive
2-4
30-40
Plasma
cholinesterase
Mivacurium
Short duration;
Competitive
2-4
12-18
Plasma
cholinesterase
Pancuronium
Long duration;
Competitive
4-6
4-6
Renal and
liver
Rocuronium
Intermediate duration;
competitive
1-2
1-2
Renal and
liver
Site of Action of d-Tubocurarine
Nerve AP
Muscle AP
Left Leg
Muscle
Stimulation
Right Leg
Nerve
Stimulation
Right Leg Muscle Stimulation
Non-depolarizing Block
G: gallamine; TC: tubocurarine; NEO: neostigmine; S: succinylcholine.
Depolarizing Block
C10:
TC:
NEO:
S:
decamethonium
tubocurarine
neostigmine
succinylcholine
Comparison of Competitive and Depolarizing Blocking Agents
Competitive
Depolarizing
Effect of previous dtubocurarine
Additive
Effect of previous
decamethonium
None/antagonistic May be additive
Efect of cholinesterase
inhibitors
Reverse
Effect on motor end
plate
Elevated
Partial, persisting
threshold to Ach; depolarization
no depolarization
Initial excitatory effect
None
Effect of KCl or tetatnus Transient
on block
reversal
Antagonistic
No antagonism
Transient
fasciculations
No antagonism
Dual Block by Depolarizing Agents
NEO reversed
the blockade
by C10.
C10: decamethonium; NEO: neostigmine; TC: tubocurarine
Changing Nature of Neuromuscular Blockade
Depolarizing Blocker
Competitive Blocker
Competitive Blockade Noncompetitive Blockade
(desensitization)
(electrogenic Na pump)
(direct channel block)
Sequence of Paralysis
Fingers, orbit (small muscles)
limbs
Diaphragm
Trunk
neck
Intercostals
Recovery in Reverse
Other Effects of
Neuromuscular Blockers
• Action at Autonomic Ganglia
e.g. d-tubocurarine blocks,
succinylcholine may stimulate
newer agents have less ganglionic effects
• Histamine Release
e.g. d-tubocurarine
bronchospasm, bronchial and salivary
secretions
Adverse Effects/Toxicity
• Hypotension
• Decreased tone and motility in GI tract
• Depolarizing agents can cause increased K
efflux in patients with burns, trauma, or
denervation and lead to hyperkalemia
• Prolonged apnea (many reasons, check for
pseudochlinesterase genetic polymorphism)
• Malignant hyperthermia (succinylcholine +
halothane especially)
• Sinus bradycardia/junctional rhythm (with
succinylcholine)
% Change in Systolic BP with d-Tubocurarine
as a Function of Dose and Depth of Anesthesia
Increasing Dose
of d-tubocurarine
6 mg/m2
12 mg/m2
18
mg/m2
Systolic BP
Increasing Depth
(% Halothane)
0.25%
0.5%
0.75%
Systolic BP
Influence of Type of Anesthetic on Enhancement
of Neuromuscular Blockade By d-Tubocurarine
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Hemodynamic Effects of d-Tubocurarine and Pancuronium
HR
SVR
CO
MAP
Drug Interactions
• Cholinesterase Inhibitors (antagonize
competitive and enhance depolarizing)
• Inhalational Anesthetics (synergistic)
• Aminoglycoside Antibiotics (synergistic)
• Calcium Channel Blockers (synergistic)
Therapeutic Uses
• Adjuvant in surgical anesthesia
• Orthopedic procedures for alignment of
fractures
• To facilitate intubations – use one with a
short duration of action
• In electroshock treatment of psychiatric
disorders