By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 4

CHOLINERGIC PHARMACOLOGY IV

• A big advantage of competitive neuromuscular blockers is that you can reverse their effects by giving an
anticholinesterase (e.g. neostigmine). Neostigmine prevents Ach breakdown, allowing Ach to persist at high
concentrations to overcome the competitive blockade.
• Examples of neuromuscular blockers (non depolarising) are:
• Tubocurarine
• Pancuronium
• Gallium
• Atrucurium
• All these drugs competitively block the nicotinic receptors, preventing Ach from binding, but they differ in
some properties.
1. Histamine release
• Tubocurarine is good at stimulating histamine release. Hence it can cause vasodilation.
However, histamine is also a powerful bronchoconstrictor, and in asthmatic patients or
those with type I hypersensitivity, tubocurarine may be a problem. It is working as an
anaphylactoid (not anaphylatoxin which stimulates release of histamine via antibody
mediated mechanisms).
2. Ganglion block
• Although most of these drugs are effective at blocking the nicotinic receptor at the
neuromuscular junction, some can also block the nicotinic receptor in the ganglia.
Tubocurarine is one of these, being able to block ganglia even at therapeutic
concentrations. Hence, tubocurarine, as well as being a muscle relaxant, can also act to
lower blood pressure (by inhibiting sympathetic effects and also releasing histamine)
3. Muscarinic block
• Gallamine and pancuronium can also produce some muscarinic blocking activity. Hence,
they will produce a tachycardia due to loss of the Ach mediated resting tone.
4. NA upatke and release
• Uptake of noradrenaline is inhibited and its release is increased (mainly due to
pancuronium and gallamine. Hence, there is an initial Increase in heart rate and blood
pressure.
5. Anticholinesterase activity
• A feature of pancuronium when used in high and prolonged numbers.
6. Anesthesia
• All of the drugs interact with many inhalation anesthetics (neostigmine), producing
additive effects. Therefore, less concentrations of both the anesthetic and muscle relaxant
needs to be used, resulting in a quicker recover.

Depolarising blockers
• If Ach is injected into a muscle, we see a brief twitch and then Ach is rapidly broken down by
acetylcholinesterase. When poisoned by anticholinesterases, Ach can hang around for a long time, resulting
in continuous depolarisation of a muscle which leads to paralysis. Hence, Ach can act as a depolarising
blocker, although it is not practical to use it since it is rapidly broken down.
• The prototype depolarising blocker is suxamethonium (succinylcholine)
• It is not a substrate for acetylcholinesterase
• It is a substrate for butyrlchlolinesterase
• This means that when it is located at the neuromuscular junction (which is where we want it to act),
it is very stable, but when it gets into plasma, it is rapidly degraded.
• Other features:
• When given, there is an initial stimulation (twitch) before the blockade. Since mammalian
muscle fibres are innervated by a single end plate, a brief depolarisation of one end plate is
not enough to cause a full muscular contraction since it is too small an area. What happens
is that all the end plates of all the different muscle fibres cause a depolarisation, resulting in
fasciculations (but not a contraction).
• With muscles that are multiply innervated, depolarisation of multiple end plates of
a single muscle fibre is enough to cause contraction of the whole muscle fibre,
since the endplates are spread out along the whole length of the fibre.
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 4

• Persistent depolarisation means that the muscle cannot respond to a subsequent release of
Ach. Ach causes depolarisation of the muscle fibre, but how can it depolarise something
which is already depolarised!
• Tetanus is depressed but sustained
• There is no post tetanic potentiation
• You can have additive effects when given with another depolarizing blocker
(decamethonium).
• Anticholinesterases do not reverse the block, they tend to potentiate the block.
• If neostigmine is given, it means more Ach floating around (which itself can act as
a depolarising blocker)
• This is a major disadvantage of depolarising blockers - their actions cannot be
reversed pharmacologically. You need to wait for the effects of the drug to wear off
(which is not a problem for suxamethonium since it is not very long acting).

Other features of depolarising neuromuscular blockers

• Reversed by competitive blockers
• Theoretically, by giving a competitive blocker such as tubocurarine, it binds to receptors and
effectively reduces the numbers of receptors available for suxamethonium. This means that
suxamethonium cannot cause as effective a depolarisation of the muscle due to reduced numbers of
receptors. However, the effects are too unpredictable for competitive blockers to be used in
conjunction with deoplarising blockers.
• Dual block
• At high doses and prolonged exposure, the block becomes a competitive block (it has the properties
of a competitive blocker)
• Receptor desensitisation
• Receptors become desensitised to all nicotinic agonists
• Different effects in multiply innervated muscles
• Some muscles in the body are multiply innervated:
• Extraocular eye muscles
• Muscles of the upper oesophagus
• There are heaps of endplates and so heaps of depolarisation along the entire length of a muscle fibre,
which results in a contracture rather than a twitch. The muscle goes into a contractive spasm. This
results in a spastic paralysis rather than a flaccid paralysis (which occurs with competitive blockers).
Depolarising blockers must therefore not be used for eye operations.

Inactivation of suxamethonium
• When suxamethonium diffuses out into the plasma, it is rapidly inactivated by butyrlcholinesterase. Some
people have a genetic deficiency of butyrlcholinesterase.
• There may be a problem with drug interaction (especially drugs which are also substrates for
butyrlcolinesterase, e.g. procaine). Procaine will compete with suxamethonium for the enzyme, resulting in
the prolongation of action of both these drugs.

Side effects
• A rare condition known as malignant hypertermia.
• Intense muscle spasm leads to heaps of heat release due to muscle metabolism. This leads to a
marked increase in body temperature. The condition is genetically based (people mainly have red
hair)
• Depolarisation is due to an influx of Na+ and an outflow of K+. Hence, continual depolarisation would lead to
lots of K+ in the circulation (hyeprkalemia), which can cause cardiac arryhtmias, cardiac arrest and
hypertension.
• Initially, there can be bradycardia and hypotension, followed by tachycardia and hypertension
• This is due to muscarinic stimulation of the heart followed by nicotinic stimulation of the ganglia.
• Myotonia
• Intense muscle spasm which is not relieved by other muscle relaxants
• On recovery, there is muscle soreness in those muscles which have undergone contracture. During induction
of the blockade, there were lots of fasciculations, resulting in muscles rubbing against each other and causing
tearing.
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 4

Other drugs acting at the neuromuscular junction

• Dentroline
• Does not act on the nicotinic receptors. It acts directly on the muscle fibre
• It reduces the release of Ca2+ from the sarcoplasmic reticulum
• It has very little effect on cardiac and smooth muscle which are dependent on Ca2+ fluxes across the
membrane rather than stored intraceullular Ca2+.
• Useful in spasticity, stroke, multiple sclerosis, malignant hyperthermia

Myasthenia gravis
• A condition where there is rapidly developing weakness of a muscle
• There is no impairment of:
• Conduction in a nerve
• Contractility of a muscle
• Release of Ach is normal
• What happens is that these people have autoantibodies against the nicotinic receptor in the neuromuscular
junction. This results in a reduction in the numbers of receptors available for Ach to act on.
• These people are insensitive to depolarising blockers since there are too few receptors for the drugs to act on,
to cause a sustained depolarisation.
• These people are very sensitive to competitive blockers
• If a tiny amount of tubocurarine is injected (below therapeutic levels), the people get extreme muscle
weakness.
• This is because there are already a small amount of nicotinic receptors. If a competitive blocker is
added, it will just reduce the numbers of available receptors even further.
• Treatment involved:
• Enhanced release of neurotransmitter
• Anticholinesterases (pyridostigmine is the drug of choice) which prolong the action of Ach
• Immunosuppressants to reduce the levels of nicotinic receptor antibodies
• Glucocorticoids
• Azathioprine which inhibits clonal proliferation of T and B cells