Pharmacology 7 – Neuromuscular Blocking Drugs
Anil Chopra
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What is the neurotransmitter at the skeletal neuromuscular junction and on which
receptor type does it act?
Define the nature of the antagonism of tubocurarine on the effects of
acetylcholine (ACh) at the motor end-plate.
Draw a log dose-response curve showing the response of skeletal muscle to
increasing concentrations of ACh. How would the shape of this curve be altered
in the presence of tubocurarine?
Why is tubocurarine not effective if given orally and why does it not act
centrally?
By what route is tubocurarine administered, what is its duration of action, and
how is it eliminated from the body?
Why are tubocurarine-like drugs used in surgery and how may their actions be
reversed?
The major unwanted effects of tubocurarine include a reduction in blood
pressure, bronchospasm, tachycardia and apnoea. Explain how these effects arise.
The autonomic and Somatic Nervous Systems
Parasympathe
tic arises in
cranial and
sacral regions
ANS
Sympathet
ic - arises
in thoracic
and
lumbar
regions
ACh
ACh
ACh
ACh
NA
Adrenal
medulla
A (and NA)
released into
bloodstream
Somatic
nervous
system
Motor neurone
ACh = acetylcholine
A = adrenaline (epinephrine)
NA = noradrenaline (norepinephrine)
-
Effector
organ
Effector
organ
ACh
ACh
Effector
organ
Effector
organ
e.g. sweat
gland
ACh
Skeletal muscle
In the somatic nervous system, ACh is released at the neuromuscular junction.
There are no ganglia
Neuromuscular blocking drugs act here.
(5) nAChR - different to ganglionic
nAChR (nicotinic Acetylcholine
receptor). Have a different structure
and morphology. These are opened by
both nicotine and acetylcholine and are
inotropic (ion channels).
The Nicotinic ACh Receptor:
 5 sub-units – 2xα, β, γ, and δ
 Binding of ACh causes a
conformational change that allows
Na+ influx
 ACh binds to α-subunits –
therefore 2xACh molecules are
required for channel to open, one
for each α-subunit
 Strictly cation channels – some
Ca2+ also flows in, and some K+
flows out when open as well as
bulk inward Na+ flow
Stages of Neuromuscular Transmission:
1. Synthesis of ACh in the nerve end
2. Arrival of action potential
3. Influx of Ca2+ through voltage gated channels
4. ACh released into synaptic cleft via endocytosis
5. ACh binds to receptors on post synaptic membrane (Type 1 nicotinic receptors
(Type-1 ion channel linked)). This causes Na+ influx into skeletal end-plate
leading to a graded end-plate potential
6. ACh comes into contact with AChEsterase which breaks ACH down into choline
and acetic acid in 1-2 msecs. The acetic acid is absorbed by the blood stream and
removed
7. Choline uptake into the pre-synaptic nerve terminal so it can be used again to
generate ACh
At the postsynaptic neurone, there are 2 types of drug that can act:
NON-DEPOLARISING (COMPETITIVE ANTAGONISTS):
Names
These block the nAChR:
- Tubocurarine
- Pancuronium
Usage - Neuromuscular blocking
Mode of Action
Tubocurarine is a competitive neuromuscular blocker that binds to and antagonises
nicotinic acetylcholine receptors on the postsynaptic nerve terminal stopping
depolarisation. They can bind to receptors but are not flexible enough to allow
channel opening. It is used in surgery to stop reflex actions.
• Naturally occuring 4° ammonium compound (alkaloid) found in s. american plant
(arrow poison)
• Range of synthetic drugs now available.
• 70-80% of the receptors need to be blocked in order for the drug to have effect.
• There is a graded block i.e. different proportions of fibres are blocked.
• It causes flaccid paralysis of:
• extrinsic eye muscles (double vision)
• small muscles of face, limbs, pharynx
• respiratory muscles –
hence patients should
be on ventilators.
epp
Side Effects and Pharmacokinetics
N.B.
• They DO NOT affect consciousness
• They do NOT affect pain sensation
• ALWAYS ASSIST RESPIRATION (until drug inactive or antagonised).
The actions of non-depolarising blockers can be reversed by anticholinesterases. E.g.
neostigmine (+ atropine)
-
Should be administered i.v.
Does not cross blood brain barrier, or placenta.
Onset is 2-3 minutes and effects last from 40-60 minutes.
It is not metabolised.
It is excreted via the bile (30%) and urine (70%).
Side effects include:
o Histamine release due to ganglion block.
o Hypotension
o Can result in tachycardias.
o Histamine release can lead to bronchospasm.
o Excessive brochial and salivary excretions.
DEPOLARISING (AGONISTS):
Name - suxamethonium (a.k.a. succinylcholine)
Usage
Used for muscle relaxation in operations and to facilitate artificial respiration
Mode of action
» Binds to and excites the postsynaptic nAChR for a long period of time (mins vs
msec for ACh)
» Eventually action potentials cannot be generated because the voltage sensitive Na
channels have been inactivated causing flaccid paralysis
Side effects and Pharmacokinetics
» Initial spasms due to binding to receptors causing post-operative pain
» Muscarinic receptor activation causing bradycardia (prevented by administering
atropine).
» Potassium release from muscle causes elevated potassium levels
» Some people with Myasthenia Gravis – and auto-immune disease that causes loss
of function of ACh receptors the drug has no effect
» People with poor AchEsterase function the block may last for hours
» Duration of action is around 4 mins before it is hydrolysed by AChEsterase
» Only drug used clinically