SEPTEMBER 3, 2015

NEUROMUSCULAR BLOCKING
AGENTS & NARCOTICS
Steven Smith
Domini Crandon
Duncan Jackson

WHAT ARE
NEUROMUSCULAR
BLOCKING
AGENTS?

NEUROMUSCULAR BLOCKING AGENTS

Neuromuscular blocking agents (NMBAs)

interrupt transmission of nerve impulses
at the neuromuscular junction (NMJ) and
thereby produce paresis or paralysis of
skeletal muscles.

IF THE PATIENT IS
ANAESTHETIZED,
WHY PROVIDE
AGENTS TO PREVENT
MOVEMENT?

BRIEF HISTORY OF NEUROMUSCULAR

BLOCKING AGENTS IN ANAESTHESIA

They were first administered in 1942, when Griffith

and Johnson used Intocostrin to a patient
undergoing an appendectomy.
By 1946, it was appreciated that using drugs such
as curare in larger doses allowed the depth of the
anaesthesia to be lightened.
The use of NMBAs to improve conditions of tracheal
intubation, to provide immobility during surgery and
to facilitate mechanical ventilation evolved over
time.

HOW DO NMBAs
WORK?

THE NEUROMUSCULAR JUNCTION

1. An Action Potential (AP) is conducted down the somatic
motorneuron down to the synaptic knob.
2. The reversal in electrical polarity at the synaptic knob
causes an opening of voltage-gated Ca2+ channels
(Voltage gated calcium ion channels open and allow
calcium ions to flow inside due to the voltage change).
Calcium ions are very important for the release of
neurotransmitters and secretion of hormones by endocrine
cells.
3. Calcium flows into the synaptic knob and its this influx
that causes these vesicles to form and release/secrete
neurotransmitters. In other words, the entry of Ca 2+ into
the synaptic knob causes the exocytosis (secretion) of the
nerotransmitter Acetylcholine (ACh).
4. The ACh diffuses across the synaptic cleft and binds to
nicotinic ACh Receptor Site Proteins on the membrane of
the Skeletal Muscle Cell (Fiber). The first chemical they
discovered that affects this receptor site, happened to be
nicotine so thats why it got the name, nicotinic cholinergic
receptor.

THE NEUROMUSCULAR JUNCTION

5. Activation of the ACh Receptor Sites causes an opening
of ligand-gated Sodium Ion Channels.
6. Influx of sodium ions through channels result in endplate potential (EPP), and if this is large enough then the
AP is developed in the membrane, stimulating voltage
sensitive sodium channels
7. As the action potential spreads along the cell, it causes
the muscle cell to contract.
8. The ACh which is attached to the receptor site, is split
into acetate and choline by acetylcholinesterase (ACHase),
an enzyme of the skeletal muscle cell membrane.
9. The ligand-gated sodium ion channels close,
permitting the skeletal muscle cell to relax.

ACTION POTENTIAL PROPAGATION

WHAT ARE
FEATURES OF THE
IDEAL NMBA?

THE IDEAL NMBA

Non-depolarizing action
Rapid onset (within one circulation time)
Short duration, suitable for infusion
Rapid metabolism to inactive products
Antagonized by cholinesterase inhibitors
Actions confined to the NMJ
Not transferred across the placenta or blood-brain barrier
No local or systemic side effects
Compatibility with other drugs and solutions
Long shelf life without refrigeration
Cheap
Made by chemical synthesis
Sterilizable

WHAT ARE THE

TYPES OF NMBAs?

TYPES OF NMBAs

DEPOLARIZING AGENTS
SUCCINYLCHOLINE/SUXAMETHONIUM
CHLORIDE

NON-DEPOLARIZING AGENTS
d-TUBOCURARINE, PANCURONIUM, ATRACURIUM, ROCURONIUM, VECURONIUM,
MIVACURIUM

DEPOLARIZING AGENTS
Depolarizing NMBAs work by depolarizing the plasma membrane of the
muscle fiber, similar to acetylcholine. However, these agents are more
resistant to degradation by acetylcholinesterase, the enzyme responsible for
degrading acetylcholine, and can thus more persistently depolarize the
muscle fibers.
There are two phases to the depolarizing block. During phase I (depolarizing
phase), they cause muscular fasciculations (muscle twitches) while they are
depolarizing the muscle fibers. Eventually, after sufficient depolarization has
occurred, phase II (desensitizing phase) sets in and the muscle is no longer
responsive to acetylcholine released by the motoneurons. At this point, full
neuromuscular block has been achieved.

SUCCINYLCHOLINE/SUXAMETHONIUM
CHLORIDE
Structure

Preparation

2 acetylcholine molecules joined by a methyl group

(diacetylcholine)

Clear solution containing 50 mg/ml. Should be stored at 4 degrees C

Administration

Metabolism

IV= 1-2mg/kg (1.5 if precruarized)

IM=3mg/kg (emergency)

Plasma cholinesterases

Onset

30-60s

Duration

5-10min

Indications
Rapid intubation of trachea
Modification of fits after electroconvulsive therapy

Contraindications

Recent burn (OK within 24 hours)

10-100 days after Spinal cord trauma causing paraplegia
Severe muscle trauma
h/o malignant hyperthermia
Hyperkalemia
Atypical cholinesterase activity/muscle disease

SUCCINYLCHOLINE/SUXAMETHONIUM
CHLORIDE
Fasciculation

Muscarinic action

Myalgia
Masseter spasm (esp children 8-12)
Intragastric pressure
ICP
IOP
serum potassium
N.B. Precurarization can help (not so much with

Bradycardia (only in children)

Salivation
N.B. Pre-treat with atropine to avoid

K)

Others

Allergic reaction
Phase II block
Prolonged paralysis (atypical cholinesterase activity)
Malignant hyperthermia

NON-DEPOLARIZING AGENTS

MOA:
Competitive antagonists at nicotinic ACh receptors on the motor endplate
Do not produce initial fasciculation
Block pre-synaptic autoreceptors
Inhibits further ACh release during repetitive stimulation
Causes tetanic fade
>75% blockade for failure of muscle contraction

NON-DEPOLARIZING AGENTS

Indications:
Optimize intubating conditions (midline vocal cords and facilitate mouth opening;
reduce coughing, gagging)
Prevent fasciculations and other complications from succinylcholine when a
small amount is administered prior (precurarization)
Optimize surgical conditions
Optimize conditions for mechanical ventilation (reduce bucking, coughing, breath
stacking)
Types of adverse effects:
Histamine release
Cardiovascular effects (muscarinic blockade)
Autonomic ganglion blockade
Anaphylaxis

Classification of Non-Depolarizing Agents

By structure:
Isoquinoline
derivatives:
d-Tubocurarine
Atracurium
Cisatracurium
Mivacurium
Steroid derivatives:
Pancuronium
Vecuronium
Rocuronium

By duration of action:
Short-acting:
Mivacurium
Intermediate-acting:
Atracurium
Cisatracurium
Rocuronium
Vecuronium
Long-acting:
d-Tubocurarine
Pancuronium

Long-Acting Non-Depolarizing Agents

d-Tubocurarine:

Structure
Elimination
Naturally occuring monoquaternary alkaloid
Kidneys (80%)
Derived from Chondrodendron tomentosum bark Bile (20%)
Administration

Side Effects

Intubating dose = 0.50.6 mg/kg

Hypotension +/- compensatory tachycardia

Bronchoconstriction
Increased salivary secretions

Onset
Duration

23 min
12 hrs

Notes
Prototype
No longer used (histamine release and
ganglion blockade)

Long-Acting Non-Depolarizing Agents

Pancuronium:
Structure

Elimination

Bisquaternary steroid derivative

Kidneys (85%)
Hepatic deacetylation (15%)

Administration

Side Effects and Interactions

Intubating dose = 0.1 mg/kg

Moderate tachycardia
Slightly inhibits plasma cholinesterases (potentiates succinylcholine
and mivacurium)

Onset

35 min

Duration
1.52 hrs
Notes
Longest duration of action
Does not stimulate histamine release
Suitable for asthmatics

Intermediate-Acting Non-Depolarizing Agents

Atracurium:
Structure

Elimination

Bisquaternary isoquinoline derivative

Hoffman elimination
Ester hydrolysis in plasma

Administration

Side Effects

Intubating dose = 0.5 mg/kg

Onset

23 min

Duration
2035 min
Notes
Not metabolized by liver or kidneys
Suitable for hepatic and renal disease

Transient hypotension (histamine release)

Bronchospasm
Cutaneous flushing
Anaphylaxis

Intermediate-Acting Non-Depolarizing Agents

Rocuronium:
Structure

Elimination

Monoquaternary steroid derivative

Bile (>70%)
Kidneys (<10%)

Administration
Intubating dose = 0.61.0 mg/kg

Side Effects
Anaphylaxis

Onset

6090 sec

Duration

3045 min

Notes
Fastest onset of non-depolarizing NMBAs
Can be used in rapid sequence induction
No significant histamine release or CV effects
Excreted unchanged by liver and kidneys
Caution in hepatic and renal disease

Intermediate-Acting Non-Depolarizing Agents

Vecuronium:
Structure

Elimination

Monoquaternary steroid derivative

Hepatic deacetylation (75%)

Kidneys (25%)

Administration
Intubating dose = 0.1 mg/kg
Onset
23 min

Side Effects
Prolonged paralysis (active metabolites)

Duration

4560 min

Notes
No significant histamine release or CV effects
Metabolism in liver produces active
metabolites
Accumulates after repeat doses in renal
disease

Short-Acting Non-Depolarizing Agents

Mivacurium:
Structure

Elimination

Bisquaternary isoquinoline derivative

Plasma cholinesterases

Administration
Intubating dose = 0.2 mg/kg

Side Effects
Transient hypotension (histamine release)
Bronchospasm
Cutaneous flushing
Prolonged paralysis (plasma cholinesterase deficiency)

Onset
Duration
Notes

23 min
1025 min

Potentiated by atypical cholinesterase gene

and hepatic and renal disease

Factors Increasing Duration of Action

Drug interactions:
Prior administration of succinylcholine
Co-administration of inhalational agents (desflurane > sevoflurane >
isoflurane > halothane)
pH:
Metabolic and respiratory acidosis
Body temperature:
Hypothermia
Age:
Immature neonates and elderly
Electrolyte disturbance:
2+
Hypokalemia
and
decreased
ionized
Ca

Myasthenia gravis
Hepatic and renal disease

Reversal Agents

Given post-op to recover muscle contraction

Types:
Anticholinesterases (e.g. neostigmine, edrophonium)
Increase ACh by inhibiting acetylcholinesterase at the

NMJ
Cyclodextrins (e.g. sugammadex)
Binds steroidal drug to form an inactive complex in
plasma
Atropine may be co-administered to prevent
muscarinic side effects

NARCOTIC
ANALGESICS

NARCOTIC ANALGESICS
Opiates
Natural alkaloid (&/or semi-synthetic
derivative)
Obtained from opium poppy (Papaver
somniferum)
Bind to opioid receptors & produce
psychoactive effects
Opioids
Natural or synthetic
Exogenous (and/or Endogenous)

NARCOTIC ANALGESICS

NARCOTIC / OPIOID ANALGESICS

Treatment of moderate to severe pain
Mimic the actions of endogenous ligands resulting in the activation of pain-modulating (antinociceptive) systems
Analgesic effect mediated via opioid receptors located throughout CNS (esp. substantia
gelatinosa and peri-aqueductal grey)
(mu)
(kappa)

(delta)
ORL1
(, sigma)1

Evidence suggests that PCA may be superior to conventional methods (analgesic need
determined by clinicians) of treating pain in acute care setting

- Receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, with which some opioids also
interact.
1

Classification of Opioid Receptors

Analgesia
Supraspinal / spinal (1)
Spinal only (2)
Respiratory depression (2)
Euphoria
Miosis, constipation (marked)
Physical dependence (2)

Spinal analgesia
Miosis
Sedation
Dysphoria & hallucinations

spinal / supraspinal analgesia

Constipation (minimal)
Can also be proconvulsant

ORL1
Unlike other
receptors
naloxone is not
an antagonist

Dysphoria
Hallucinations
Cardiac
stimulation

Classification of Opioid Receptors

(International Union of Pharmacology, IUPHAR)

Receptor
(new
terminology)

Classical
terminology

Endogenous Ligand

Site

MOP

Mu; OP3

Endomorphin 1 and 2; metenkephalin; dynorphin A & B

Peripheral inflammation, pre- and

post-synaptic neurons in spinal
cord, periaqueductal grey matter,
limbic system, caudate putamen,
thalamus, cerebral cortex

KOP

Kappa; OP1

Dynorphin A & B;
-endorphin

Nucleus raphe magnus

(midbrain), hypothalamus, spinal
cord

DOP

Delta; OP2

Leu- and met-enkephalins; endorphin

Olf centres, cerebral cortex,

nucleus accumbens, caudate
putamen, spinal cord

NOP

Orphan; ORL-1

Nucleus raphe magnus, spinal

cord, afferent neurones

MOA Opioids

Analgesia is achieved predominantly by receptor:

K+ conductance (hyperpolarization of post-synaptic neurones)
Presynaptic inhibition of neurotransmitter release (substance P, dopamine, NE,
& ACh)
Ca2+ channel inactivation ( presynaptic neurotransmitter release)
Inhibition of adenylate cyclase
Pain impulse transmission is interrupted at the level of dorsal horn
Descending inhibitory impulses are accentuated

Pharmacodynamic Effects of Opioids

CNS
Sedation & Sleep
Mood (Euphoria, Dysphoria)
Miosis
Tolerance
Addiction

Respiratory
Ventilatory depression (esp. elderly,
neonates)
May cause increase in Cerebral blood flow
(if hypercapnic)

GIT
Nausea, vomiting
Biliary Colic

CVS
No significant effect if normotensive
Histamine-releasing opioids HR, SVR,
Partery
central sympathetic outflow
Other effects
Dependence & tolerance
Myoclonic jerks sedation & hallucinations
Urinary retention & urgency
Pruritus (esp. around nose)
Muscle rigidity
Thermoregulation impairment
Depression of immune system (long-term use)
Endocrine problems
Opioid-induced hyperalgesia*

Classification of Opioid Analgesics

Chemical Structure
Phenanthrenes, Phenylpiperidine, Diphenylpropylamines,
Benzomorphans

AGONISTS
morphine , meperidine (pethidine), methadone, fentanyl,
heroin, hydromorphone, oxymorphone, pethidine,
levorphanol,

MODERATE / WEAK AGONISTS

codeine, propoxyphene, oxycodone, hydrocodone,
buprenorphine

MIXED AGONIST-ANTAGONISTS
pentazocine , nalbuphine , butorphanol

Strong Opioid Agonists:

Prototype - Morphine
Structure
Phenanthrene derivative

Elimination
Excretion; urine (90% in 24h), CAUTON in renal failure

Administration
Multiple routes of administration
Adjunct to induction = 0.1 0.25 mg/kg IV

Clinical Uses

Onset
Duration

5 min
1-4 hrs

Notes
Administer IV in perioperative period, thus eliminating the
unpredictable influence of drug absorption
Crosses BBB slowly 5 min onset, but peak in 10-40 min
Metabolized in the liver by CYP3A4 glucoronidation to M-6G (inactive, 75-85%) and M-3-G (active, 5-10%)
Can decrease MAC to ~65%

Drug Interactions
Phenothiazines, TCAs & MAOIs potentiate CNS effects of
morphine
Resp. depression, sedation & hyperpyrexic coma

Analgesia for severe visceral pain

Adjunct to GA
High dose as primary agent (cardiac pt)
Should not be used as total anesthetics due to ceiling
effect
Post surgical pain
Acute pulmonary oedema
Venodilation preload; perception of SOB
Diarrhoea
Relief of cough

Contraindications / Cautions of Strong Opioid

Agonist

Head injury
CNS depression
Hepatic disease
Renal disease

Pregnancy
Hypersensitivity
(asthma)
COPD

Strong Opioid Agonists:

Prototype - Morphine
Opioid tolerance and dependence
Acquired tolerance develops after 2-3 weeks
Tolerance to analgesia, euphoria, sedation, ventilatory depression, but often NOT constipation
Addiction (physical and psychological dependence): usually takes ~ 25 days to develop
Some degree occurs within 48 hours

Withdrawal symptoms:
Occurs 8-12 hours after last dose
Peaks at 36-72 hours, lasts up to 7-10 days
Symptoms (Severe Flu-like illness; Super flu) include:
Loss of sedation:
insomnia, yawning, hyperactivity, tremors
Loss of stimulation:
diarrhea, abdominal cramps
Others:
Vomiting, chills, fever, lacrimation, sweating, rhinorrhea, sneezing

Opioid Agonists Used in Anaesthesia

Adapted from Gwinnutt, C. L., & Gwinnutt, M. (2012). Lecture notes: Clinical Anaesthesia.
Chichester, West Sussex, UK: Wiley-Blackwell.

Opioid Agonists Used in Anaesthesia

Adapted from Vacanti, C. A. (2011). Essential Clinical Anesthesia. Cambridge: Cambridge University Press.

Opioid Agonists Used in Anaesthesia

Adapted from Stoelting, R. K., & Hillier, S. C. (2015). Handbook of Pharmacology and Physiology in Anesthetic Practice.
3rd Edition. Philadelphia: Wolters Kluwer Health.

Moderate / Weak Agonists

Prototype: Codeine
Structure

Elimination

Phenathrene derivative

Renal excretion, feces

Administration

Clinical Uses

15-60 mg PO/SC/IM q4-6hr PRN

Often combined with non-opioid analgesic (e.g.

acetaminophen, paracetamol) to reduce dose of opioid
required to achieve adequate pain relief
Good antitussive & anti-diarrhoeal properties

Onset

30-60 min PO; 10 30 min IM

Duration

4 6 hrs

Notes
Side Effects
Oral analgesic that is less potent than morphine (mildConstipation
moderate pain)
Drowsiness
Up to 10% of a codeine dose is metabolized by the
hepatic CYP2D6 to morphine, which contributes
significantly to its analgesic effect
Around 8% western Europeans are CYP2D6 deficient
10% of Caucasians and 30% of Asian & Blacks are super
metabolizers opioid toxicity
Has little S/E on mental state, pupil size and respiration

MIXED AGONIST-ANTAGONISTS

Prototype - Pentazocine

Structure

Elimination

Benzomorphan derivative

Urine (mainly), feces

Administration

Clinical Uses

30mg IV/IM/SC moderate-severe pain relief

30 mg IV/IM/SC q3-4hr supplement to preoperative
surgical anaesthesia

Onset

IM 15-20 min; IV 2-3 min

Duration

IM 2 hr; IV 1 hr

Used for post-operative pain and chronic pain, esp.

when there is a risk of physical dependence
Often combined with non-opioid analgesic (e.g.
acetaminophen) to reduce dose of opioid required to
achieve adequate pain relief
Good antitussive & anti-diarrhoeal properties

Notes

Side Effects

Agonist at receptors, and weak antagonist at &

receptors
Low potential for dependence
40mg pentazocine has analgesic potency of 10mg
morphine

Sedation
N/V less common than morphine
Dysphoria (high doses)
Ceiling effect of respiratory depression
(30-70mg IM, 30mg IV)

Atypical Analgesic
Prototype: Tramadol
Structure

Elimination

Non-opioid-derived synthetic opioid

Urine (90%)

Administration

Clinical Uses

Oral: 50 mg tablets; 100, 200, 300 mg extended-release

tablets

Effective analgesic (moderate pain; adjunct to

opioids in chronic pain syndromes)

Onset
Duration

~1 hr
9 hrs

Notes

Side Effects

Agonism mediated by metabolites stimulatory activity Constipation, nausea, vomiting

at & receptors
Sedation, headache, dizziness, tiredness
O-desmethyltramadol, has 200-fold higher affinity for over Sweating, rash
Enhances descending inhibitory system by inhibiting 5HT & NE reuptake
Less likely than pure opioids analgesics to depress
Contraindications
respiration and cause dependence
Effects not completely reversed by opioid antagonists
No histamine release (cf. morphine)

risk of seizures with MAOIs, SSRIs, TCAs

Use with caution in pts with hepatic impairment

Opioid Antagonists:
Naloxone & Naltrexone
Naloxone (Narcan )
Structure
Phenanthrene derivative

Elimination
Hepatic metabolism to naloxone-3-glucuronide; renal
excretion

Administration

Clinical Uses

1 4 g/kg IV. Repeat q2-3 min PRN

Not to exceed 10 mg (0.01 mg/kg)

Mx of acute opioid overdose reverses opioid-induced

resp. depression

Onset
Duration
Notes

Side Effects

1 2 mins
30 45 mins

Non-selective antagonist affecting all 3 opioid receptor

types (, , )
Continuous infusion of naloxone, 5 g/kg/hr, prevents
recurrence of respiratory depression (renarcotization)
without altering analgesia produced by neuraxial opioids

Tachycardia & Arrhythmias

Precipitate full blown withdrawal in dependent patients
N.B. titration of dose may acceptably antagonize while
maintaining partial analgesia (i.e. titrate to achieve
desired effect)

Naltrexone
In contrast to naloxone, is highly effective orally
Sustained antagonism of opioid agonist effects for up to 24 hrs

REFERENCES

Smith, G., Aitkenhead, A. R., Moppett, I. K., & Thompson, J. P. (2013). Smith and Aitkenhead's textbook of anaesthesia. New
York: Churchill Livingstone/Elsevier.

Butterworth, J. F., Mackey, D. C., Wasnick, J. D., Morgan, G. E., Mikhail, M. S., & Morgan, G. E. (2013). Morgan & Mikhail's
clinical anesthesiology. 5th Edition. New York: McGraw-Hill.

Rang, H. P., Dale, M. M., Flower, R. J., & Henderson, G. (2016). Rang and Dale's pharmacology. 8 th Edition. 6th Edition. United
Kingdom: Churchill Livingstone/Elsevier.

Katzung, B. G., Masters, S. B., & Trevor, A. J. (2012). Basic & clinical pharmacology. 12 th Edition. New York: McGraw-Hill
Medical

Campbell, J. (2014, February). Analgesics 1 & 2. Neuroscience 2. University of the West Indies (Mona), Kingston, Jamaica.

Stoelting, R. K., & Hillier, S. C. (2015). Handbook of Pharmacology and Physiology in Anesthetic Practice. 3 rd Edition.
Philadelphia: Wolters Kluwer Health.

Vacanti, C. A. (2011). Essential clinical anesthesia. Cambridge: Cambridge University Press.

Gwinnutt, C. L., & Gwinnutt, M. (2012). Lecture notes: Clinical Anaesthesia. Chichester, West Sussex, UK: Wiley-Blackwell.

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