2. outline
• Introduction
• History of neuromuscular block
• Uses of neuromuscular blocking agents
• Steps in neuromuscular transmission
• outline
3. 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
4. Uses of neuromuscular blocking agents
• By intravenous or systemic administration:
• Adjuvant in surgical anesthesia to obtain relaxation of skeletal
muscle
• “Balanced” anesthesia – to minimize anesthetic use without
compromising analgesia
• To assist in intubation (esp. succinylcholine)
• Corneal or retinal surgeries to obtain relaxation of extraocular
muscles (cisatracurium)
• Therapy of spastic disorders
• By topical administration:
• Mydriasis in birds (vecuronium)
5. Definition
• Definition/Introduction
• Neuromuscular blockade is frequently used in anesthesia to
facilitate endotracheal intubation, optimize surgical conditions,
and assist with mechanical ventilation in patients who have
reduced lung compliance
6. cont
• Neuromuscular blocking agents (NMBAs) come in two forms:
depolarizing neuromuscular blocking agents (e.g.,
succinylcholine) and nondepolarizing neuromuscular blocking
agents (e.g., rocuronium, vecuronium, atracurium,
cisatracurium, mivacurium). The class of NMBAs used for
achieving neuromuscular blockade must be selected carefully
based on patient factors, the type of procedure being
performed, and clinical indication.
7. depolarizing
• Depolarizing neuromuscular blockers: Succinylcholine is
the depolarizing neuromuscular blocker of choice. It is widely
used due to its rapid onset and short duration of action, making
it ideal for rapid sequence inductions. Its mechanism of action
involves binding to post-synaptic cholinergic receptors on the
motor endplate, which causes rapid depolarization,
fasciculation, and flaccid paralysis.
8. cont
• Usually, paralysis takes place approximately 1 minute after
administration and lasts approximately 7-12
minutes. Succinylcholine is metabolized by plasma
pseudocholinesterase. If the patient has pseudocholinesterase
deficiency, this can lead to prolonged neuromuscular blockade
that may require postoperative mechanical ventilation.
9. Non depolarizing
• Nondepolarizing neuromuscular blockers: Nondepolarizing
neuromuscular blockers can be divided into two classes based
on their chemical structure: steroidal (e.g., rocuronium,
vecuronium, pancuronium) or benzylisoquinolinium (e.g.,
mivacurium, atracurium, cisatracurium)
10. cont
• Nondepolarizing neuromuscular blockers are competitive
acetylcholine (ACh) antagonists that bind directly to nicotinic
receptors on the postsynaptic membrane, thus blocking the
binding of ACh so the motor endplate cannot depolarize. This
leads to muscle paralysis.
• Monitoring neuromuscular blockade: Train-of-four (TOF)
stimulation is the most common method utilized to monitor the
extent of neuromuscular blockade. It consists of four
consecutive 2 Hz stimuli to a chosen muscle group, and the
respective number of twitches evoked, also known as train-of-
four count (TOFC provides information on the patient’s
recovery from neuromuscular blockade.
•
11. cont
• The train-of-four ratio (TOFR) is determined by dividing the
amplitude of the fourth twitch to the amplitude of the first
twitch. If the TOFR is <0.9, this indicates residual
neuromuscular blockade and necessitates the use of a reversal
agent. Reversal of neuromuscular blockade is commonly
achieved with neostigmine, an anticholinesterase, and
glycopyrrolate. However, sugammadex can also be used as a
reversal agent if a steroidal NMBA was used.
12. Adverse effects
• Issues of Concern
• Adverse Effects: Succinylcholine use should be avoided in
patients with severe hyperkalemia, significant burns,
denervating disease, and a history of malignant
hyperthermia. Nondepolarizing neuromuscular blockers may
cause histamine release associated with hemodynamic
instability. Slowing the infusion rate or pre-treating with
antihistamines can reduce the incidence
13. interations
• Drug Interactions
• Antimicrobials - Aminoglycosides, tetracyclines, polymyxins,
and clindamycin can potentiate neuromuscular blockade.
• Inhaled anesthetics can potentiate neuromuscular blockade
when used with nondepolarizing NMBAs.
• Anti-seizure drugs - Chronic treatment with anti-seizure
medications can make a patient resistant to nondepolarizing
NMBAs.
14. • Lithium can potentiate neuromuscular blockade in both
depolarizing and nondepolarizing NMBAs.
• Local anesthetics can potentiate neuromuscular blockade in
both depolarizing and nondepolarizing NMBAs.
20. Competitive neuromuscular
blocking agents
• d-tubocurarine - slight hypotension; histamine (HA)
release (problem in asthma); limited use.
• Gallamine triethiodide (Flaxedil) - tachycardia; no HA
release; crosses placental barrier.
• Alcuronium chloride (Alloferin) - similar to curare, shorter
lasting; slight hypotension and tachycardia.
• Pancuronium bromide (Pavulon) - long-acting; slight
tachycardia and hypertension.
• Atracurium besylate (Tracrium) - intermediate-acting; safe
in liver and kidney disease; bradycardia may result during
surgical manipulations, esp ophthal-mologic, ENT, or
laparoscopy (treat with atropine or glycopyrrolate);
precipitates in alkaline pH; can cause HA release at higher
doses. Probably most used in veterinary medicine.
21. Competitive neuromuscular
blocking agents
• Cisatracurium besylate (Nimbex) - one of 10 isomers of
atracurium; 3X potency; immediate onset of action; used
in ophthalmologic surgeries.
• Vecuronium bromide (Noncuron) - intermediate-acting;
lack of CV or HA-releasing effects; drug of choice when
CV stability required; mydriasis in birds.
• Doxacurium chloride (Nuromax) - long-lasting, most
potent agent known; minimal CV or HA-releasing effects;
not currently used in veterinary medicine.
22. Effect of competitive blocking
agents on skeletal muscle
• First: motor
weakness
• Then flaccid motor
paralysis
• Sequence of paralysis
• Small, rapidly moving
muscles first
• Then large muscle
masses
• Then toes, jaw, eyes,
ears, limbs, neck and
trunk.
• Finally, intercostal
muscles and
diaphragm paralyzed
24. Effect of competitive blockers on
cardiovascular system
• Decreased blood pressure - due to histamine release
• Increased heart rate (baroreceptor reflex)
25. Competitive blockers contd.
• Onset of action -
slow
• Duration of action -
short initially, with
residual effect
• (Cumulative with
repeated doses)
• Poorly absorbed from GI
tract
• Termination of action:
hepatic metabolism/
renal excretion.
• Accumulation may occur
in patients with renal
insufficiency
26. Competitive blockers cont’d.
• Action enhanced or potentiated by:
• Acidosis
• Aminoglycoside antibiotics (inhibition of ACh release…membrane
stabilization)
• Volatile anesthetics (membrane stabilizers)
27. Competitive blockers cont’d.
• Action antagonized by cholinesterase inhibitors (neostigmine,
edrophonium), tetanic stimulation
• Coagulability of blood decreased (due to release of heparin
from mast cells)
30. Depolarizing neuromuscular
blocking agents
• Succinylcholine (suxamethonium; Scoline) - rapid and
short-lasting block, used to facilitate intubation (mostly in
humans); used illegally in bow hunting. In an emergency
can be given IM, but slower and less predictable action.
Can cause bradycardia (prevent with atropine),
hyperkalemia, anaphylaxis, or malignant hyperthermia in
genetically predisposed subjects. Dogs, cattle, sheep
sensitive; horses and pigs less so. Initial response (Phase I
block) is depolarizing block; with time becomes Phase II
block, similar to non-depolarizing blocking drugs.
• Rocuronium bromide (Zemuron) - succinylcholine
alternative developed for human use.
• Mivacurium chloride (Micacron) - succinylcholine
alternative developed for human use.
31. Depolarizing blocking agents
Phase I block –
depolarizing block of
motor end-plate
Phase II block-
competitive block of
motor end-plate/
partially susceptible to
reversal by
cholinesterase
inhibitors
NS inhibition of SCh metabolism by AChE
32. Depolarizing agents cont’d.
• Effect on skeletal
muscle - fasciculation,
weakness, paralysis
• Effect on cardiovascular
system: increased blood
pressure, increased or
decreased heart rate (due
to stimulation of
parasympathetic and/or
sympathetic ganglia)
33. Depolarizing agents cont’d.
Onset of action - rapid
(1 minute)
Duration of action -
short; however may
revert to phase II block
Termination of action:
metabolized by plasma
pseudocholinesterase
and liver.
With SCh, initial
metabolite is
succinylmonocholine,
weaker, predominately
competitive blocking
action.
34. Depolarizing agents cont’d.
• Action enhanced or potentiated by neostigmine and
organophosphates (cholinesterase inhibitors), isoflurane.
• Undesirable side effects
• muscle fasciculation, hyperkalemia (important in patients with
congestive heart failure)
• Phase II block
35. Depolarizing agents cont’d.
• Undesirable side effects cont’d.
• May trigger malignant hyperthermia in genetically susceptible
patients (dyspnea, tremor and stiffness, extreme hyperthermia,
and rapid postmortem rigor mortis)
• Muscarinic actions at high doses
• Advantages - short duration of action, little histamine release
36. Centrally acting muscle relaxants
(spasmolytics)
• Used in defective neuronal control of muscle
activity – in Scottish terriers (Scotty cramp),
Dalmatians, and Labs
• Spasms associated with intervertebral disc
disease
• Spasms associated with tetanus or strychnine
toxicosis
• Adjunct to anesthesia for muscle relaxation
(guaifenesin)
• Do not abolish voluntary muscle control
40. Peripherally acting skeletal muscle
relaxants
• Dantrolene (Dantrium) - blocks release of
calcium from the sarcoplasmic reticulum
• No effect on cardiac or respiratory muscle
• Used to treat:
• urethral obstruction due to increased external
urethral tone (esp. sphincter)
• malignant hyperthermia
41. conclusion
• It is important to realize that muscle relaxation does not
ensure unconsciousness, amnesia, or analgesia.
• Depolarizing muscle relaxants act as acetylcholine (ACh)
receptor agonists, whereas non depolarizing muscle relaxants
function
• Because depolarizing muscle relaxants are not metabolized by
acetyl cholinesterase, they diffuse away from the
neuromuscular junction and are hydrolyzed in the plasma and
liver by another enzyme, pseudo cholinesterase (nonspecific
cholinesterase, plasma cholinesterase, or butyryl
cholinesterase)s.
42. • With the exception of mivacurium, non depolarizing agents
are not significantly metabolized by either acetyl
cholinesterase or pseudo cholinesterase. 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 acetyl cholinesterase enzyme activity.
• Muscle relaxants owe their paralytic properties to mimicry of
ACh. For example, succinylcholine consists of two joined ACh
molecules.
43. cont
• 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, 4-8 h) following
succinylcholine administration.
• Succinylcholine is considered contraindicated in the routine
management of children and adolescents because of the risk
of hyperkalemia, rhab domyolysis, and cardiac arrest in
children with undiagnosed myopathies.
44. cont
• 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.
45. cont
• Cirrhotic liver disease and chronic renal failure often result in
an increased volume of distribution and a lower plasma
concentration for a given dose of water-soluble drugs, such as
muscle relaxants. On the other hand, drugs dependent on
hepatic or renal excretion may demonstrate prolonged
clearance. Thus, depending on the drug, a greater initial
dose—but smaller maintenance doses—might be required in
these diseases.
• 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.
46. cont
• 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.
• image
• 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.
• image
47. cont
• 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.
• Skeletal muscle relaxation can be produced by deep
inhalational anesthesia, regional nerve block, or
neuromuscular blocking agents (commonly called muscle
relaxants). In 1942, Harold Griffith published the results of a
study using an extract of curare (a South American arrow
poison) during ..
