West Visayas State University – College of Medicine – Batch 2020

Block XX
Module 6 Muscle Relaxants
Lecture 6
05/ 15/ 19
Mark David Arbizo, MD

TOPIC OUTLINE IDEAL MUSCLE RELAXANT

I. Introduction • Fast onset
A. Clinical Uses • Short duration / easily reversible
B. Complications
II. Muscle Contractions
• Minimal side effects
A. Morphology • Minimal systemic complications
B. Physiology • Inactive metabolites
III. Pharmacology
A. Classifications
B. Mechanism of Action II. MUSCLE CONTRACTIONS
C. Characteristics A. MORPHOLOGY
D. Pharmacology • Corticospinal Tracts
IV. Reversal Agents Course of electrical signals
A. Mechanism of Action Ventral horns of the spinal cord
B. Characteristics
V. Sample Cases Contains the cell bodies and axons
Review Questions • Cell Bodies
References Receive and integrate information from the central
nervous system
LECTURER BOOK REFERENCE OLD TRANS
• Axons
Conduit of the impulse from the cell bodies to the
distal organ
OBJECTIVES
• Three main aims of anesthesia:
Relieve anxiety: Sedatives
Relieve pain: Analgesia
Immobility: Neuromuscular Blocking Agents
(Muscle Relaxants)

I. INTRODUCTION
A. CLINICAL USES
• Improve conditions for tracheal intubation
• Improve surgical working conditions
neurosurgery, ophthalmologic surgery (very
dangerous if patient moves)
• Facilitate mechanical ventilation at the OR/ICU

B. COMPLICATIONS
• Residual neuromuscular blockade
Airway obstruction
Attenuation of the hypoxic ventilatory response
(patient deeply inhales in response to low O2.
Muscle paralysis impairs skeletal muscles of
respiration, thereby rendering the patient unable to
inspire deeply)
Oxygen desaturation, patient compromise
• Increased incidence of awareness during general
anesthesia
you will not be able to know when the GA wears
off and the patient is conscious since the patient is
still paralyzed) Figure 1. Corticospinal Tract.

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MD 3 Tobias, Toledo, Valdez
 B. PHYSIOLOGY
• Under resting conditions, the electrical potential of the
inside of a nerve cell is negative (-90 mV).
• Depolarization
Signal/stimulation
Sodium channels open and allow sodium ions to
enter the cell
Na influx is faster than K efflux
• Cascade/series of depolarization of the next segment
Propagation of an electric impulse or action
potential
1. Electrical signal depolarizes the nerve terminal
2. Opening of voltage-gated Ca2+ channels
3. Release of acetylcholine into the synaptic cleft
4. Binding of two molecules of acetylcholine to 2
alpha subunits of nAchRs
5. Conformational change in the nAchRs that opens
the ligand-gated channels
6. Na and Ca2+ influx, K efflux
7. Depolarization of the muscle membrane leading to
muscle contraction
8. Acetylcholinesterases hydrolyze acetylcholine to
acetic acid and choline
9. Repolarization

NICOTINIC ACETYLCHOLINE RECEPTORS

(NACHRS)

Figure 2. This is a cross-sectional view of a muscle bundle, which

contains the Fascicles. Inside the Fascicles, Motor Units are located.
The motor unit is the functional contractile unit and is composed of a
single myelinated alpha motor neuron and all muscle fibers that
receive innervation from this single neuron. The terminal portion of the
axon is a specialized structure, the synapse, designed for the
production and release of acetylcholine. The neuromuscular junction
(NMJ) is composed of the presynaptic motor neuron terminal, the
postsynaptic muscle surface, and a synaptic cleft (gap) that contains
the enzyme acetylcholinesterase.

Figure 4. NACHRS Subunits

Figure 3. The NMJ has a highly ordered mechanism that converts the
electrical signal of the motor nerve (the action potential) into a
chemical signal (effected by the release of acetylcholine, which in turn
is converted into an electrical event (muscle membrane
depolarization), leading to a mechanical response (muscle
contraction). Nicotinic muscle-type Ach receptors (muscle-type
nAChRs) are located in folds of the postsynaptic muscle membrane in
very high concentrations.
• Subunits:
2 alpha
─ Binding sites for the acetylcholine,
succinylcholine and NMBA
Delta & Epsilon
─ Stabilize the closed state of the receptor
Beta
• The function of nAChR endplates depends on five
subunit proteins that combine to form the pentameric
unit consisting of two alpha subunits in association with
single beta, delta, and epsilon subunits.
• These subunits form a transmembrane pore as well as
the extracellular binding pockets for acetylcholine and

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 other agonists (depolarizing neuromuscular-blocking Onset time
drugs) or antagonists (nondepolarizing neuromuscular- • Time to maximum blockade (disappearance of ST)
blocking drugs). • Directly proportional to potency (high potency, long
• In order for the conformational change to occur, 2 onset time)
molecules of Ach must attach to the 2 alpha subunits
of nAchRs. Duration
• On the other hand, an important function of the delta • Time from injection of NMBA to return to 25% twitch
and epsilon subunits is to stabilize this closed state. height
• 25% twitch height was chosen because rapid reversal
Table 1. Events Associated with Up-Regulation or Down- can normally be achieved at that level
Regulation of Nicotinic Acetylcholine Receptors (nAchRs)
nAchRs Up-Regulation nAchRs Down- Mechanism of Action (Depolarization Agent)
(Sensitive to Sch; Regulation (Resistant to 1. Binding of succinylcholine to alpha subunits of
Resistant to non- Sch; Sensitive to non- nAchRs
depolarizing agents) depolarizing agents) 2. Conformational change in the nAchRs that opens
Spinal cord injury Myasthenia gravis the ligand-gated channels
Cerebral vascular Anticholinesterase 3. Na and Ca2+ influx, K efflux
accident overdose 4. Depolarization of the muscle membrane leading to
muscle contraction
Thermal injury Organophosphate
5. Acetylcholinesterases cannot hydrolyze
poisoning
succinylcholine
Prolonged immobility 6. Neuromuscular blockade
Prolonged exposure to
neuromuscular-blocking Mechanisms of Neuromuscular Blockade
drugs • Desensitization
Multiple sclerosis Develops because Sch remains at the endplate
Guillain-Barre syndrome much longer
Depolarized post-junctional membrane cannot
III. PHARMACOLOGY respond to subsequent release of acetylcholine
Muscle paralysis starts at 75% occupancy of • Inactivation of Na channels
acetylcholine receptors Prevents the propagation of the action potential

Figure 5.
Figure 6. Neuromuscular Blocking Agents
C. NEUROMUSCULAR BLOCKING AGENTS (NMBA)
Potency
A. DEPOLARIZING NMBA
• Determined by constructing dose-response curve
Table 2. Succinylcholine
(Single Twitch Height)
Agent Succinylcholine
• ED 95 (effective dose) of a drug
Duration Ultrashort
• Half of the patients given with a particular NMBA based
Potency (ED 95 mg/kg) 0.25 – 3.0
on ED 95 will achieve 95% block of Single Twitch (ST),
Intubating Dose (mg/kg) 1.0 – 1.5
and half of the patients will achieve less than 95%
Onset Time (min) 1.0 – 1.5
block
Clinical Duration (min) 7 – 12
• Inversely proportional to the ED
Maintenance Dose N/A
• Small concentration of a drug produces muscle (mg/kg)
blockade Infusion Dose (ug/kg/min) Titrate to ST (single twitch)
muscle response

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 Elimination Route / Plasma cholinesterase Due to depolarization or sustained muscular
Metablism (pseudocholinesterases / contractions
butyrylcholinesterases) • Increases Intracranial Pressure
Active Metabolites None Succinylcholine may increase intracranial pressure
Side Effects Myalgia, Laryngoscopy and tracheal intubation with
bradycardia/systole, inadequate anesthesia or muscle relaxation are
anaphylaxis likely to increase intracranial pressure even more
Contraindications Hyperakalemia, than succinylcholine
malignant • Increase IOP
hyperthermia, burn, Ach Intraocular pressure increases by 5 to 15 mmHg
receptor upregulation,
Recommended to avoid succinylcholine in open-
pseudocholinesterase
eye injuries
deficiency
Factors of inadequate anesthesia, elevated
Comments Fastest onset, most reliable
systemic blood pressure, and insufficient
NMBA for rapid tracheal
neuromuscular blockade during laryngoscopy and
intubation
tracheal intubation might increase intraocular
pressure more than succinylcholine
Succinylcholine
• Increases Intragastric Pressure
Only needs to occupy ½ of the acetylcholine
Lower esophageal sphincter tone is also increased
receptors to produce neuromuscular blockade, even
Thus, there is no increase in the risk of aspiration
if the other ½ is occupied by acetylcholine.
from the use of Sch
• Cardiac Dysrhythmias
Sinus bradycardia, junctional rhythm, and even
B. NON-DEPOLARIZING AGENTS
sinus arrest
Mimics the effects of acetylcholine at the cardiac
muscarinic cholinergic receptors
Tachycardia, hypertension
Mimics the effects of acetylcholine at the
autonomic nervous system ganglia
• Hyperkalemia
Channels remain open, maintaining efflux of K
from the cell
Serum K increases by approximately 0.5 mEq/L
Patients with pre-existing hyperkalemia (CKD
patients) do not have a greater increase in
Figure 6. Non-depolarizing Agents
potassium levels
Only INTERMEDIATE ACTING drugs are available
─ But the absolute level might reach the toxic
in the market
range
• Mechanism of Action (Non-Depolarizing Agent)
Severe hyperkalemia, occasionally leading to
1. Binds competitively to alpha subunits of nAchRs
cardiac arrest
2. No conformational change in the nAchRs ligand-
─ Has been described in patients with major
gated channels
denervation injuries, spinal cord transection,
3. No Na and Ca2+ influx, K efflux
peripheral denervation, stroke, trauma,
4. No depolarization of the muscle membrane
extensive burns, and prolonged immobility with
leading to muscle contraction
disease
5. Paralysis
• Muscle Pains
Common 24 to 48 hours after succinylcholine
d-TUBOCURARINE
administration
• 1st NMBA to undergo clinical investigation
Incidence is variable (1.5% to 89% of patients
• Long duration of action
receiving succinylcholine)
• Excreted in kidney and bile
Due to sustained muscular contractions
• Long duration and CVS effects have restricted its use
• Fasciculations
Prevalence is high (60% to 90%) after the rapid
injection of succinylcholine, especially in muscular
adults

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Table 3. Aminosteroids High doses of rocuronium can be used in place of
Agent Vecuronium Rocuronium succinylcholine
Duration Intermediate Intermediate
Potency (ED 95 0.05 0.3 Table 4.
mg/kg) Agent Pancuronium Pipecuronium
Intubating Dose 0.1 0.6 Duration Long Ultralong
(mg/kg) Potency (ED 95 0.07 0.45
Onset Time (min) 3–4 1.5 – 3 mg/kg)
Clinical Duration 25 – 50 30 – 70 Intubating Dose 0.1 0.1
(min) (mg/kg)
Maintenance 0.01 0.1 Onset Time (min) 2–4 4–6
Dose (mg/kg) Clinical Duration 60 – 120 80 – 140
Infusion Dose 1–2 5 – 12 (min)
(ug/kg/min) Maintenance 0.02 0.01
Elimination Renal (10-50%); Renal 30%; Dose (mg/kg)
Route/Metabolism Hepatic (30- Hepatic 70% Infusion Dose 20 – 40 (not N/A (not
50%) (ug/kg/min) recommended) recommended)
Active Metabolites 3-desacetyl- 17-desacetyl- Elimination Renal (40-70%); Renal (45% -
vecuronium rocuronium Route/Metabolism Hepatic (20%) 60%);
(60% potency) (minimal, 20% Unchanged
Can cause potency) 40%
prolonged Active Metabolites 3-OH- 3-desacetyl
paralysis pancuronium; metabolite (50%
Side Effects Vagal blockade Minimal 17-OH- potency)
with large doses pancuronium
Contraindications None None Side Effects Vagal block Minimal
Comments Not for Pain on (tachycardia);
prolonged ICU injection, catecholamine
administration reversible by release
(myopathy), Sugammadex Contraindications Short surgical Short surgical
reversible by procedures procedures
Sugammadex Comments Significant Can be
accumulation; reversed by
VECURONIUM prone to residual Sugammadex
• Onset is slower blockade
• Duration of action is governed by redistribution (hepatic
uptake) PANCURONIUM
• Potent metabolite 3-desacetyl-vecuronium (60% active • Slow onset limits its usefulness in Rapid sequence
of the parent drug) intubation
• Prolonged paralysis, myopathy • Long-acting drug
• No CVS effects after average doses, vagal blockade • Clearance is decreased in renal and hepatic failure
after large doses • Metabolized to 3-OH-pancuronium (50% NMB activity
• No histamine release of the parent compound)
Residual blockade
ROCURONIUM • Vagolytic effect at the post-ganglionic nerve terminals
• Fastest onset among Aminosteroidal NMBA Result of blocking the muscarinic receptors
Drug of choice for rapid sequence intubation if Tachycardia, hypertension, increased CO
Succinylcholine is contraindicated • No histamine release
• Duration of action is governed by redistribution (hepatic • Not available in the market
uptake)
High hepatic uptake decreases the plasma
concentration after an injection
• No hemodynamic changes
• No histamine release
• Major drawback is the long duration of action

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Table 5. Benzylisoquinolinium Increased protein binding
Agent Atracurium Cisatracurium Upregulation of receptors, causing resistance of
Duration Intermediate Intermediate the muscle end-plate
Potency (ED 95 0.25 0.05
mg/kg) CISATRACURIUM
Intubating Dose 0.5 0.15 – 0.2 • Potent isomer of Atracurium
(mg/kg) • Longer onset time
Onset Time (min) 3-5 4–7 In order to shorten onset time, intubating dose is
Clinical Duration 30 - 45 35 – 50 increased
(min) Dose is still well below the threshold of histamine
Maintenance 0.1 0.01 release
Dose (mg/kg) Duration of action is prolonged
Infusion Dose 10 - 20 1–3
No adjustment in dose in the elderly and pediatric
(ug/kg/min)
patients
Elimination Renal (10%); Hofmann
• Dose must be increased in burn patients
Route/Metabolism Hofmann (30%); (30%); Ester
Ester Hydrolysis Hydrolysis Increased protein binding
(60%) (60%) Upregulation of receptors, causing resistance of
Active Metabolites none None the muscle end-plate
Side Effects Histamine None;
release; Histamine Table 6. Comparison of Mivacurium and Doxacurium
Laudanosine and release at high Agent Mivacurium Doxacurium
Acrylates dose
production Duration Short Ultralong
Contraindications Hemodynamically None Potency (ED 95 0.08 0.02 – 0.033
unstable patients mg/kg)
due to Histamine Intubating Dose 0.2 0.05 – 0.08
release (mg/kg)
Comments Organ Minimal Onset Time (min) 3-4 3 – 10
independent Histamine,
Laudanosine, Clinical Duration 15 - 20 80 – 160
and Acrylates (min)
levels Maintenance Dose 0.1 0.01
(mg/kg)
ATRACURIUM / CISATRACURIUM Infusion Dose 5-8 n/a (not
• Organ independent metabolism (ug/kg/min) recommended)
• Degraded via 2 metabolic pathways: Elimination Route/ Plasma Hepatic/Renal
Hofmann reaction (1/3) Metabolism Cholinesterase
─ Non-enzymatic degradation dependent on Active Metabolites none None
Temperature and pH Side Effects Histamine release None
Ester Hydrolysis (2/3) Contraindication Pseudocholinester None
• End products: ase deficiency
Comments Reversal by No accumulation;
Laudanosine
Cholinesterase no cardiac effects
─ Causing seizures in animals inhibitors at high doses
─ No deleterious effects have been established in
humans MIVACURIUM
Acrylates • Short duration of action
─ Have been shown to inhibit human cell Hydrolyzed by Plasma Cholinesterases
production in vitro • Onset time is long
─ Requires high concentration and exposure to • Associated with histamine release
obtain clinical effects • In Burn patients:
can be given safely to patients with renal disease Upregulation of receptors
Decreased number of Plasma cholinesterases
ATRACURIUM Net effect is either normal or enhanced blockade
• Associated with histamine release • Not available in the Philippines
use cautiously in asthmatic patients
• No adjustment in dose in the elderly and pediatric DOXACURIUM
patients • Potent
• Dose must be increased in burn patients
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• Long-acting
• Limited clinical use due to slow onset and long duration
of action
• Not available in the Philippines
IV. REVERSAL AGENTS
• Unimpaired muscle strength
Breathe normally
Cough forcefully
Swallow
Maintain patent airway
In most circumstances, all efforts should be made to
ensure that the patient leaves the operating room
with unimpaired muscle strength. Specifically,
respiratory and upper airway muscles must function
normally so the patient can breathe, cough, swallow
secretions, and keep his or her airway patent.
NEOSTIGMINE
Acetylcholinesterase inhibitor
DO NOT GIVE THIS FOR SUCCINYLCHOLINE!
• Inhibits Acetylcholinesterases at all Cholinergic
synapses (both Nicotinic and Muscarinic)
• Increases Acetylcholine concentration at the
neuromuscular junction (Nicotinic synapse)
• Increases the Acetylcholine concentration at the
Muscarinic synapses
• Side Effects:
Bradycardia / Bradyarrhythmias
Increased Salivation
Increased bowel motility
Increase in airway resistance (Bronchoconstriction)
• EFFECT ON SUCCINYLCHOLINE
Inhibition of Plasma Cholinesterases
─ Sustained Succinylcholine effect
─ Prolonged duration of action
use with caution in asthmatics because it increases
airway resistance
SUGAMMADEX
• FDA-approved Gamma-Cyclodectrin
• Selective relaxant binding agent (SRBA)-selective for
aminosteroidal agents
• eight-membered ring with a central cavity that perfectly
encapsulates the steroid nucleus of steroidal
intermediate-acting NMBAs (rocuronium>vecuronium
>>pancuronium/pipecuronium)
• has no affinity for any of the other depolarizing or
nondepolarizing NMBAs
Because Sugammadex does not bind to any known
receptor, it is devoid of major cardiovascular or other
side effects
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Figure 7.
• Rapidly binds all available unbound (free) rocuronium
molecules
• Concentration gradient that favors the movement of
steroidal NMBD molecules from the NMJ back into the
plasma
• This removal of NMBD from the NMJ results in a fast
recovery of neuromuscular function
V. SAMPLE CASES
1. 23/F, Asthmatic patient, with a known allergy to
seafoods. Patient was referred to Anesthesiologist for
Laparoscopic Surgery under General Anesthesia.
What is your muscle relaxant of choice?
A. Succinylcholine
B. Atracurium
C. Rocuronium
D. Cisatracurium
E. Vecuronium
2. 44/M patient with abdominal obstruction. Patient was
referred to Anesthesiologist for Exploratory Laparotomy
under General Anesthesia-Rapid Sequence
Induction/Intubation. What is your muscle relaxant of
choice?
A. Succinylcholine
B. Atracurium
C. Rocuronium
D. Cisatracurium
E. Vecuronium
3. 55/M patient with open eye injury was referred to
Anesthesiologist for Emergency Eye Surgery under
General Anesthesia-Rapid Sequence
Induction/Intubation because he had a full meal 2 prior
the injury. What is your muscle relaxant of choice?
A. Succinylcholine
B. Atracurium
C. Rocuronium
D. Cisatracurium
E. Vecuronium
4. 30/M, no co-morbid patient, stab wound victim was
referred to Anesthesiologist for Emergency Exploratory
Laparotomy under General Anesthesia-Rapid Sequence
Induction/Intubation. Minutes prior to admistration of
muscle relaxant, tachycardia and BP spikes were noted.
Patient is still moving despite giving Atracurium. What do
you think is happening?
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 Answers: 1F, 2A, 3C, 4rocuronium, 5D

REFERENCES
• Upclass notes
• Doctor’s lecture /ppt

The resident injected the wrong vial since dopamine vial

and the atracurium vial looks very similar.

What Muscle Relaxant will you give for the patient in

order to intubate?
Answer: None
If you are not sure that you can intubate the patient
intame before hypoxia sinks in, you can just give opiods
and intubate the patient awake to make sure.

REVIEW QUESTIONS
1. T/F. Under resting conditions, the electrical potential
of t the inside of a nerve cell is positive (+90 mV).
2. An ideal muscle relaxant is:
a. Fast onset
b. Irreversible
c. Several side effects
d. Multiple systemic complications
e. All of the above
3. An example of a depolarizing neuromuscular
blocking agent is:
a. Mivacurium
b. Doxacurium
c. Succinylcholine
d. Acetylcholine
4. What has the fastest onset among aminosteroidal
NMBA?
5. Effect of neostigmine on succinylcholine except:
a. Enhances plasma cholinesterases, thus
reducing the succinylcholine effect
b. Enhances plasma cholinesterases which
would prolong the duration of action
c. Inhibits plasma cholinesterases, thus
reducing the succinylcholine effect
d. Inhibits plasma cholinesterases which would
prolong the duration of action

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