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Neuromuscular blocking

drugs
Dr Gitanjali Jayatilaka

At the end of this lecture you should


be able to
recapitulate the physiology of neuromuscular
transmission
understand the pharmacodynamics of depolarizing
and non depolarizing neuromuscular blocking drugs
describe and explain the pharmacokinetics, uses, side
effects of commonly used neuromuscular blockers
explain the pharmacological basis for the use of
anticholinesterases in reversal of neuromuscular
block, important side effects and their avoidance
be aware of the newer agent used in the reversal of
neuromuscular block
list the drugs that act presynaptically to cause
neuromuscular blockade

Physiology of neuromuscular
transmission

Indications for neuromuscular


blockade in clinical practice
To facilitate intubation and ventilation

To facilitate surgical procedures under


general anaesthesia

Non depolarizing neuromuscular


blocking drugs
Amino steroids
Pancuronium
Vecuronium
Rocuronium
Benzylisoquinolinium esters
Atracurium
Mivacurium

Pharmacodynamics
Competitive antagonism of acetylcholine at
nicotinic receptor at the post synaptic
membrane of the neuromuscular junction
Effects on organ systems:
cardiovascular
Pancuronium tachycardia
Respiratory
Atracurium, mivacurium bronchospasm related
to histamine release
Nervous System
Atracurium convulsions related to
accumulation of a metabolite
Critical illness myopathy with long term use in ICU

Pharmacokinetics
Absorption:
not lipid soluble, highly ionised (quaternary ammonium
groups) does not cross gastrointestinal epithelium therefore
cannot be given orally
Distribution:
Atracurium and vecuronium are highly protein bound (60-80%)
Pancuronium and rocuronium are less bound 30%
All are Ionised, water soluble at physiological pH, not lipid
soluble, VD equivalent to ECF volume
Do not cross blood brain barrier and crosses placenta in
significant amounts
Metabolism:
Atracurium Hoffman degradation and ester hydrolysis
Mivacurium plasma cholinesterase
Rocuronium not metabolised
Others undergo hepatic metabolism
Excretion:
Rocuronium unchanged via bile and urine

Duration of action
Pancuronium long acting
Atracurium, vecuronium - intermediate acting
Mivacurium short acting
Rocuronium depends on dose
Onset of action
Atracurium/ vecuronium/pancuronium 3-5
minutes
Rocuronium high dose within 60s

High incidence of anaphylactic reactions

Depolarizing neuromuscular
blockers
Suxamethonium
Equivalent to 2 acetylcholine molecules
joined together
Pharmacodynamics
Binds to acetylcholine binding site on
Nicotinic receptors, leading to prolonged
depolarization of skeletal muscle fibers to
a membrane potential above which no
further action potentials can be triggered.

Effects on organ systems


Cardiovascular
Bradycardia cardiac arrest
Respiratory
Apnoea
Bronchospasm histamine release
Nervous system
Initial Fasciculation prior to paralysis
Increased intracranial and intraocular pressure
GI
Intragastric pressure increases
Increased secretions
Other
Hyperkalaemia significant in renal failure and burns
Malignant hyperthermia

pharmacokinetics
Absorption intravenous administration
Distribution
? Protein bound
Metabolism
Hydroysed by plasma cholinesterase (not
present at NMJ) to succinic acid and choline
T1/2 less than 5 minutes
Excretion
Metabolites - kidney

Special points
Quick onset and offset therefore used
for tracheal intubation, treatment of
laryngospasm
Does not need reversal agent
Muscle pains post administration
Plasma cholinesterase affected by
genetic and acquired factors
prolonged apnoea
Reports of fatal anaphylactic
reactions

Reversal of neuromuscular blockade


Anticholinesterases
Short acting - Edrophonium
Medium acting - Neostigmine, pyridostigmine, physostigmine
Irreversible organophosphates/ ecothiopate
Pharmacodynamics
Binds to esteratic site of acetylcholinesterase and inhibits its action
on acetylcholine
Neostigmine carbamylates esteratic site
Organophosphates phosphorylates esteratic site
Leads to accumulation of acetylcholine at the nicotinic receptor and
competitive antagonism of non depolarising agent that may be
present
Large doses muscle twitching

anticholinesterases
Effects on organ systems
Cardiovascular
Bradycardia can cause cardiac arrest
Therefore always given with atropine/ glycopyrrolate
Respiratory
Bronchospams/ increased secretions
CNS
Physostigmine/ OP cross BBB excitation - convulsions
Eye
Miosis and failure of accommodation
GI
Increased salivation, increased lower oesophageal sphincter
tone, increased intestinal motility. Nausea and vomiting
GU
increased ureteric peristalsis involuntary micturition
Other
Sweating, lacrimation

anticholinesterases
Absorption
Poor oral absorption
Distribution
Highly ionized and does not cross the blood
brain barrier (except for physostigmine and OP)
Metabolism
Plasma esterases and liver metabolism
Excretion
50-67% excreted by renal system

Other uses
Diagnosis of Myasthenia gravis
Treatment of Myasthenia gravis

Other new agents used in


reversal
Suggammadex
Cylcodextrin compound
Encapsulates steroid portion of molecule,
decreases free drug in central compartment
resulting in concentration gradient of rocuronium/
vecuronium away from the neuromuscular
junction
Effective in reversal of vecuronium and
rocuronium only
Less side effects than anticholinesterases
expensive

Drugs that act presynaptically to


block the NMJ
Hemicholinium blocks transport of choline
into the nerve terminal and therefore
Blocks Ach synthesis
Magnesium and aminoglycoside
antibiotics inhibit calcium entry into nerve
terminal and therefore
Inhibits Ach release
Neurotoxins such as botulinum toxin and
beta bungarotoxin inhibit Ach release

Questions ?

The lecture has ended.


recapitulate the physiology of neuromuscular
transmission
understand the pharmacodynamics of depolarizing
and non depolarizing neuromuscular blocking drugs
describe and explain the pharmacokinetics, uses, side
effects of commonly used neuromuscular blockers
explain the pharmacological basis for the use of
anticholinesterases in reversal of neuromuscular
block, important side effects and their avoidance
be aware of the newer agent used in the reversal of
neuromuscular block
list the drugs that act presynaptically to cause
neuromuscular blockade

Thank you