2.

3-03
August 14, 2013
Frederick C. Loyola, M.D. CNS Pharmacology II:
"It is requisite for the relaxation of the mind that we make use, from time to time, of Skeletal Muscle Relaxants
playful deeds and jokes." –Saint Thomas Aquinas

SECTION PAGE NEUROMUSCULAR BLOCKERS

I. Overview of Skeletal Muscle Relaxants 1
II. Neuromuscular Blockers 1 MATURE NM RECEPTOR
A. General
1. Chemistry 1
2. Pharmacokinetics 1
3. Pharmacodynamics 1-2
4. Clinical Uses 2
B. Nondepolarizing Neuromuscular
Blockers
1. Chemistry 2
2. Pharmacokinetics 2-3
3. Pharmacodynamics 3
4. Clinical Pharmacology 3
5. Reversal 3
C. Depolarizing Neuromuscular Blockers
1. Chemistry 3
2. Pharmacokinetics 3  2 alpha (α) peptides
3. Pharmacodynamics 3-4  1 beta (β) peptide
4. Clinical Pharmacology 4  1 gamma (γ) peptide
5. Adverse Effects 4  1 delta (δ) peptide
D. Train-of-Four Monitoring 5  Acetylcholine binding sites – pockets at α-β and α-δ
E. Drug Interactions 5
 Mechanisms in blockade of end plate function:
III. Spasmolytics o Nondepolarizing blockers (d-tubocurarine)
A. Overview 5-6  Pharmacologic blockade of acetylcholine
B. Diazepam 6  Nicotinic receptor antagonist
C. Baclofen 6 o Depolarizing blockers (succinylcholine)
D. Tizanidine 6  Excess of depolarizing agonist
E. Other Centrally Acting Spasmolytics 6  Nicotinic receptor agonist
F. Dantrolene 6-7
G. Botulinum Toxin 7 GENERAL
H. Treatment for Acute Local Muscle Spasms 7
CHEMISTRY
IV. Review Questions 7
 Structurally similar to acetylcholine
TRANSMASTER'S NOTE  Presence of 1 or 2 quaternary nitrogens  result in poor
References: Katzung 10th and 12th, lecture lipid solubility  limited CNS entry
 Highly polar compounds
 Italic – lecture-based or transmaster's notes
 * in drug name – not discussed in lecture PHARMACOKINETICS
 Highly ionized
OVERVIEW OF SKELETAL MUSCLE RELAXANTS  Do not readily cross cell membranes

1. NEUROMUSCULAR BLOCKERS PHARMACODYNAMICS

 Interfere with neuromuscular end plate transmission
 Lack central nervous system activity
 Used in surgical procedures and ICU settings to
produce muscle paralysis
 Used as adjuncts during general anesthesia to:
o Facilitate tracheal intubation
o Optimize surgical conditions while ensuring
adequate ventilation

2. SPASMOLYTICS
 Reduce spasticity in neurologic conditions
 "Centrally-acting" muscle relaxants
 Used primarily to treat:
o Chronic back pain
o Fibromyalgic conditions
 Dantrolene
o No CNS effects
o Used in treating malignant hyperthermia

Martin Page 1 of 7
 CNS Pharmacology II: Skeletal Muscle Relaxants

Based on the previous figure, nondepolarizing blockers NONDEPOLARIZING NEUROMUSCULAR BLOCKERS

(e.g. d-tubocurarine, bottom left) block the NM receptor
and prevent channel opening (closed state) while CHEMISTRY
depolarizing blockers (e.g. succinylcholine, bottom right)  Bulky, semi-rigid ring system
both block the Nm receptor and channel in open state, o Conceal double-acetylcholine structure
preventing normal channel closure.  Acetylcholine-like fragments
 Major families
CLINICAL USES o Isoquinoline derivatives (-ine, -curium)
o Steroid derivatives (-curonium)
1. SURGICAL RELAXATION
 Facilitates intracavitary surgery
 Especially important in: ISOQUINOLINE STEROID-BASED
o Intra-abdominal procedures d-tubocurarine Pancuronium
o Intra-thoracic procedures Atracurium Pipecuronium
Cisatracurium Rocuronium
2. TRACHEAL INTUBATION Mivacurium Vecuronium
 Relaxation of pharyngeal and laryngeal muscles 
facilitate laryngoscopy and ET tube placement PHARMACOKINETICS
 Distribution
3. CONTROL OF VENTILATION o Phases
 Provide adequate gas exchange  Rapid initial distribution phase
 Prevent atelectasis  Slow elimination phase
 Elimination half-life correlates with duration of action
4. TREATMENT OF CONVULSIONS o Shorter in short-acting drugs eliminated via liver
 Attenuate peripheral manifestations of convulsions in: o Longer in long-acting drugs eliminated via kidneys
o Status epilepticus
o Local anesthetic toxicity

STEROID DERIVATIVES ISOQUINOLINE DERIVATIVES

 Metabolized into:
o 3-hydroxy metabolites ATRACURIUM
 Compared to parent drug:  Hofmann elimination
40-80% as potent o Exhaustive methylation
Longer half-life o Spontaneous chemodegradation into:
 Cause prolonged paralysis  Laudanosine
o 17-hydroxy metabolites Slowly metabolized in liver
o 3,17-dihydroxy metabolites Long elimination half-life of 150 minutes
Readily crosses blood-brain barrier
VECURONIUM AND ROCURONIUM  concentration  seizures and  in volatile
anesthetic requirement
 Intermediate-acting steroidal neuromuscular blockers
 Quaternary acid
 Elimination
o Depend more on:
 Biliary excretion CISATRACURIUM (NIMBEX)
 Hepatic metabolism  Potent stereoisomer of atracurium
 Commonly used clinically over long-acting ones  Less laudanosine formation
(pancuronium, pipecuronium)  Basically atracurium with less adverse effects

Martin Page 2 of 7

MIVACURIUM (MIVACRON)
 Shortest duration of action out of all nondepolarizing
neuromuscular blockers
o Duration of action prolonged in renal failure
 Has a slower onset than that of succinylcholine
o  dose to speed up onset – associated with profound
histamine release leading to:
 Hypotension
 Flushing
 Bronchospasm
 Rapidly cleared by plasma cholinesterase
PHARMACODYNAMICS
  frequency of Na+ channel opening at motor end plate
 progressive muscle paralysis
 Small doses
o Competes with acetylcholine at NM receptor site
(competitive inhibition)
 Large doses
o Can enter pores of ion channels  more intense
motor blockade  further weakens neuromuscular
transmission and diminishes antagonism by
cholinesterase inhibitors
 Blockade of prejunctional Na+ channels
o  acetylcholine mobilization at nerve ending
 Consequence of postsynaptic blockade
o Tetanic stimulation   acetylcholine released 
transient posttetanic facilitation (relief of blockade)
of twitch strength
d-TUBOCURARINE
 Prototype neuromuscular blocker
 Blocks ANS ganglia
 Releases histamine
 Causes hypotension
CLINICAL PHARMACOLOGY
 IV tubocurarine  initial motor weakness  skeletal
muscle flaccidity and inexcitability
 Large muscles (abdominal, paraspinous, diaphragm)
o Compared to small muscles (facial, foot, hand):
 More resistant to blockade
 Recover more rapidly
o Diaphragm
 Last muscle to be paralyzed
 First muscle to regain function
 Blockade lasts 45-60 minutes
 Onset of effect
PHARMACODYNAMICS
1. PHASE I BLOCK (DEPOLARIZING)
 Brief stimulation  fasciculation
 Succinylcholine
o Reacts with nicotinic receptors  channels open 
motor end plate depolarization  spread of AP 
contraction of motor units
o Depolarized membranes:
 Remain depolarized because of ineffective
metabolism of succinylcholine at end plate
Martin
CNS Pharmacology II: Skeletal Muscle Relaxants
o Determines how rapidly the trachea can be intubated
o Rocuronium
 Fastest onset among nondepolarizing blockers
(60-120 seconds)
REVERSAL OF NONDEPOLARIZING BLOCKADE
ACETYLCHOLINESTERASE INHIBITORS
NEOSTIGMINE AND PYRIDOSTIGMINE
 Inhibition of acetylcholinesterase   availability of
acetylcholine at motor end plate  blockade reversal
  acetylcholine release from nerve to a lesser extent
EDROPHONIUM
 Less effective than neostigmine in reversal of profound
neuromuscular blockade (significant in determining
recovery from residual block)
RESIDUAL BLOCK
Residual block is the remaining neuromuscular blockade
after completion of surgery and movement of patient to
receovery room. Unsuspecting residual block may result in
hypoventilation, leading to hypoxia and apnea, especially
if the patient received central depressants during recovery.
SUGAMMADEX*
 Modified γ-cyclodextran
 Forms complex with steroidal nondepolarizing blockers 
inactivation  urinary excretion
 Binds tightly to rocuronium on a 1:1 ratio
DEPOLARIZING NEUROMUSCULAR BLOCKERS
SUCCINYLCHOLINE (ANECTINE)
CHEMISTRY
 Single linear structure
 2 acetylcholine molecules linked end-to-end through
acetate methyl group
PHARMACOKINETICS
 Extremely short duration of action (5-10 minutes)
 Plasma cholinesterase
o Influences duration of action at motor end plate
o Succinylcholine  hydrolysis  succinylmonocholine 
succinic acid + choline
 Unresponsive to subsequent impulses
o Causes flaccid paralysis
o Block augmented by cholinesterase inhibitors
2. PHASE II BLOCK (DESENSITIZING)
 Succinylcholine
o Continued exposure   in initial motor end plate
depolarization  subsequent repolarization 
membrane cannot be depolarized
o Channel block
Page 3 of 7
 CNS Pharmacology II: Skeletal Muscle Relaxants

 Implicated in desensitization mechanism  Characteristics of blockade nearly identical to

 Channels behave as if they are in a prolonged those of nondepolarizing blockers
closed state ‒ Nonsustained twitch response
o Late phase II  Reversed by cholinesterase inhibitors

CLINICAL PHARMACOLOGY 3. INCREASED INTRAOCULAR PRESSURE

 IV succinylcholine  transient muscle fasciculations  Rapid onset of  IOP
over chest and abdomen within 30 seconds  paralysis o Peaks at 2-4 minutes
within 90 seconds  initial relaxation of arm, neck, and o Declines after 5 minutes
leg muscles  relaxation of respiratory muscles  Mechanisms
 Blockade lasts <10 minutes (because of rapid hydrolysis o Tonic contraction of myofibrils
of succinylcholine by plasma cholinesterase) o Transient dilation of ocular choroidal blood vessels

4. INCREASED INTRAGASTRIC PRESSURE

ADVERSE EFFECTS
 Succinylcholine-associated fasciculations   risk for
1. CARDIOVASCULAR EFFECTS regurgitation and aspiration of gastric contents
 Succinylcholine o More likely in patients with:
o Cardiac arrhythmias if given with halothane  Delayed gastric emptying
o Negative inotropic and chronotropic responses  Traumatic injury
 Attenuated by anticholinergics (atropine)  Esophageal dysfunction
o Transient bradycardia  Morbid obesity
2. HYPERKALEMIA 5. MYALGIAS (MUSCLE PAIN)
 Succinylcholine  Common post-operative complaint of:
o Induces release of K+ in patients with: o Heavily muscled patients
 Burns o Patients receiving large doses of succinylcholine
 Nerve damage  May be secondary to unsynchronized contractions
 Neuromuscular disorders of adjacent muscle fibers before onset of paralysis
 Closed head injury
 Trauma
 May result in cardiac arrest (rare)

Martin Page 4 of 7
 CNS Pharmacology II: Skeletal Muscle Relaxants

TRAIN-OF-FOUR (TOF) MONITORING ‒ Nervous system depression at sites

 Most commonly used peripheral nerve stimulation method
 Involves four successive supramaximal stimuli given at
intervals of 0.5 second (2 Hz)
o Stimulus  muscle contraction  counts as a "twitch"
 TOF ratio (TOF-R)
o Relative magnitude of fourth and first twitch
 Fade
o Pattern of decreased twitch intensity
 TOF changes in response to neuromuscular blockers
o Depolarizing blockade
 Same  in amplitude of all four twitches
 Fade connotes development of phase II block
o Nondepolarizing blockade
 Inversely proportional to degree of blockade
 Recovery –  fade  TOF-R approaches 1.0
proximal to neuromuscular junction
‒  muscle blood flow
‒  sensitivity of postjunctional membrane
to depolarization
 Isoflurane (most) > sevoflurane > desflurane
> enflurane > halothane > nitrous oxide
 Succinylcholine + volatile anesthetics
o Malignant hyperthermia (refer to Spasmolytics
– Dantrolene – Clinical Uses, p. 5)
2. ANTIBIOTICS
 P-type Ca2+ channel blockade  depression of evoked
acetylcholine release
 Aminoglycosides
o Enhancement of neuromuscular blockade

3. LOCAL ANESTHETICS AND ANTIARRHYTHMICS

TRAIN-OF-FOUR GRAPH
 Small doses – depress posttetanic potentiation
 Large doses – block neuromuscular transmission
 Higher doses – block ACh-induced muscle contractions

4. OTHER NEUROMUSCULAR BLOCKERS

 Nondepolarizing blockers
o Small doses  antagonize depolarizing effect
of succinylcholine   fasciculations

SPASMOLYTICS

STRETCH REFLEX ARC

In a train-of-four graph, fade denotes the pattern of
decreased amplitude (progressive shortening with each
line, like "wi-fi signal bars"). TOF ratio is the relative
magnitude of the fourth twitch compared to the first
twitch (the value of the former is divided by the latter). Fade
occurs with nondepolarizing blockers. Depolarizing
blockers decrease the amplitude of all twitches in phase
I blockade with no fade. Fade begins in phase II blockade.

TRANSMASTER'S NOTE
SIGNIFICANCE OF TOF IN RECOVERY

A TOF-R value of 0.7 traditionally indicates adequate

recovery from neuromuscular blockade. Still, the patient
should not be extubated (process of endotracheal tube
removal) until TOF-R value becomes 0.9, says Dr. Loyola.

DRUG INTERACTIONS
1. GENERAL ANESTHETICS
 Nondepolarizing blockers + volatile anesthetics
o Potentiation of neuromuscular blockade
 Dose-dependent
 Important factors involved:

Martin Page 5 of 7

SPASTICITY
 Characteristics
o  tonic stretch reflexes and flexor muscle spasms
o Muscle weakness
 Associated conditions
o Cerebral palsy
o Multiple sclerosis
o Stroke
 Mechanisms
o Involvement of stretch reflex arc and higher centers in
CNS (e.g. upper motor lesion)
o Damage to descending pathways in spinal cord 
hyperexcitability of alpha motoneurons
 Spasmolytics
o Modulate excitatory or inhibitory synapses  
hyperactivity of stretch reflex
  activity of Ia fibers that excite α motoneurons
 Enhance activity of inhibitory internuncial neurons
o Interfere directly with skeletal muscle (excitation-
contraction coupling)
DIAZEPAM (VALIUM)
 Acts at GABAA synapses  facilitates action of GABA 
 tonic output of primary spinal motor neurons
 Spasmolytic action partly mediated in spinal cord
o Somewhat effective in patients with cord transection
 Useful in muscle spasm of almost any origin
 Produces sedation at levels required to  muscle tone
BACLOFEN (LIORESAL)
 p-chlorophenyl-GABA
 Designed to be an orally active GABA-mimetic agent
 Compared to diazepam:
o Equally effective in reducing spasticity
o Produces less sedation
 Compared to dantrolene:
o Does not reduce overall muscle strength
PHARMACOKINETICS
 Rapid and complete absorption after oral administration
 Plasma half-life of 3-4 hours
MECHANISMS OF ACTION
 Activates GABAB receptors   K+ conductance 
hyperpolarization   Ca2+ influx  presynaptic inhibition
Martin
CNS Pharmacology II: Skeletal Muscle Relaxants
 Reduces release of excitatory neurotransmitters in
brain and spinal cord
 Reduces pain in patients with spasticity presumably by
inhibiting release of substance P (NK1) in spinal cord
ADVERSE EFFECTS
 Drowsiness
o  tolerance with chronic administration
TIZANIDINE (ZANAFLEX)*
 α2 adrenoceptor agonist
 Congener of clonidine (antihypertensive agent)
o 1/10 to 1/15 of antihypertensive properties of clonidine
 Findings in neurophysiologic studies
o Reinforces presynaptic and postsynaptic inhibition in
spinal cord
o Inhibits nociceptive transmission in dorsal horn
 Causes markedly less muscle weakness
ADVERSE EFFECTS
 Drowsiness
 Hypotension
 Dizziness
 Dry mouth
 Asthenia
 Hepatotoxicity
OTHER CENTRALLY-ACTING SPASMOLYTICS*
1. GABAPENTIN (Refer to 02.01-04 Antiepileptics)
 Shows considerable promise as spasmolytic agent in
patients with multiple sclerosis
2. PROGABIDE
 GABAA and GABAB agonist
 Converted to active metabolites including GABA
3. GLYCINE (Refer to 02.01-01 Central Neurotransmitters)
4. IDROCILAMIDE AND RILUZOLE
 Treatment for amyotrophic lateral sclerosis
 Inhibition of glutaminergic transmission   spasms
DANTROLENE (DANTRIUM)
 Hydantoin derivative
PHARMACOKINETICS
 Elimination half-life of 8 hours
MECHANISM OF ACTION
 Unique mechanisms
o Interferes with excitation-contraction coupling in
muscle fibers   skeletal muscle strength
o Binds to ryanodine receptor (RyR1)  blocks Ca2+
channel of SER  interferes with calcium release
 Rapidly-contracting motor units
o More sensitive to dantrolene
 No effect on cardiac and smooth muscle
o Ca2+ release from SER – mediated by ryanodine
receptor 2 (RyR2)
CLINICAL USES
 Malignant hyperthermia
o Rare autosomal dominant disorder
o Involves mutation of gene encoding for RyR1
o Triggered by various stimuli, particularly by:
 Volatile general anesthetics
‒ Halothane
Page 6 of 7
 CNS Pharmacology II: Skeletal Muscle Relaxants

 Depolarizing neuromuscular blockers

‒ Succinylcholine 7. Cholinesterase degrades all of the following except:
o Triggering agents  sudden and prolonged Ca2+ release a. Atracurium
 massive muscle contraction   lactic acid and b. Mivacurium
hyperthermia c. Succinylcholine

ADVERSE EFFECTS 8. Fade is not seen in this type of neuromuscular blockade.

 Generalized muscle weakness a. Nondepolarizing block
 Sedation b. Phase I depolarizing block
 Hepatitis (occasional) c. Phase II depolarizing block

9. This muscle is the last muscle to undergo paralysis in

BOTULINUM TOXIN*
nondepolarizing blockade and the first to regain function.
CLINICAL USES a. Diaphragm
b. Latissimus dorsi
 Ophthalmic purposes
c. Rectus abdominis
 Relief of local muscle spasm
 Short-term treatment of aging-associated wrinkles
10. Most common method of assessing neuromuscular
 Generalized spastic disorders such as cerebral palsy
transmission:
a. Double burst stimulation
TREATMENT FOR ACUTE LOCAL MUSCLE SPASMS*
b. Single-twitch stimulation
 Centrally acting c. Train-of-four stimulation
o Carisoprodol
o Chlorphenesin 11. (Application of TOF) A recovering post-operative patient
o Chlorzoxazone who was given a nondepolarizing blocker was placed on
o Cyclobenzaprine TOF monitoring. Twitch amplitudes from first to fourth
 Prototype were as follows: 0.75, 0.7, 0.65, 0.6. Give the TOF ratio.
 Structurally related to tricylic antidepressants a. 0.80
 Inhibits muscle stretch reflex in spinal cord b. 0.87
(poorly understood mechanism) c. 0.93
 Produces antimuscarinic side effects
 Ineffective in treating muscle spasms due to 12. (Refer to #11) Based on the TOF ratio obtained, the
cerebral palsy or spinal cord injury patient can now be extubated.
 Adverse effects a. True
‒ Significant sedation b. False
‒ Confusion c. Can't decide
‒ Transient visual hallucination
o Metaxalone 13. GABAB-selective spasmolytic:
o Methocarbamol a. Baclofen
o Orphenadrine b. Gabapentin
c. Pregabide
REVIEW QUESTIONS
1. Not a class of neuromuscular blockers: 14. Major non-centrally-acting spasmolytic:
a. Cholinesterase inhibitors a. Baclofen
b. Depolarizing blockers b. Dantrolene
c. Isoquinoline derivatives c. Tizanidine
d. Steroid derivatives
15. Bonus: another name for succinylcholine.
2. Prototype nondepolarizing blocker: _______________
___________________________________
3. Prototype depolarizing blocker: _______________

4. All of the following are general chemical properties of

nondepolarizing blockers except:
a. Acetylcholine-like fragments
b. Linear structure
c. Semi-rigid ring system
d. None of the above

5. Most potent metabolite of steroid-based derivatives:

a. 3-hydroxy metabolite
b. 3,17-hydroxy metabolite
c. 10-hydroxy metabolite
d. 17-hydroxy metabolite

6. Products of Hofmann elimination:

a. Laudanosine
b. Quaternary acid
c. Both a and b

Martin Page 7 of 7