neuromuscular junction pharmacology Flashcards
‘the organ bath’
the phrenic nerve hemi-diaphragm is dissected and prepared and mounted in an organ bath
the phrenic nerve is electrically stimulated 1/10 sec, and the resultant muscle twitch is recorded on a chart recorder or computer.
what is tubocurarine?
a muscle relaxant
blocks the nicotinic acetylcholine receptor
is a reversible competitive antagonist that is overcome by increasing acetylcholine concentration
neostigmine can reverse affects of tubocurarine
what is neostigmine?
an antagonist of acetylcholinesterase
what are non-depolarising neuromuscular blockers?
e.g. tubocurarine
compete with acetylcholine for binding to skeletal muscle nicotinic acetylcholine receptors
reduce the amplitude of the endplate potential to below the threshold for muscle fibre action potential generation
what happens in the absence of a neuromuscular blocker?
depolarisation
muscle fibre action potential
what happens in the presence of a neuromuscular blocker?
no depolarisation
no action potential = no contraction
how is tubocurarine action investigated at a single synapse?
the nerve muscle preparation is incubated in a high magnesium / low calcium solution to block muscle twitch in response to nerve stimulation
intracellular recording is used to obtain control EPPs and MEPPs
tubocurarine is added
tubocurarine effects on quantal content
the amplitude of the MEPP and the EPP both decrease
little or no effect on quantal content
what are the clinical uses of tubocurarine?
used during surgery to produce skeletal muscle paralysis
allows the surgeon to conduct intricate surgery without the complexity of unwanted skeletal muscle contraction
patient requires artificial respiration as the diaphragm muscle is also paralysed
patient is left to recover naturally, or recovery is aided by administration of an anticholinesterase e.g. neostigmine
clinically replaced by synthetic drugs e.g. vecuronium
give a summary of tubocurarine
competitive non-depolarising neuromuscular blocking agent
used clinically as a skeletal muscle relaxant
muscle block reversed by anticholinesterases e.g. neostigmine
what is ⍺-bungarotoxin
not reversed by washout, or, by anticholinesterases
binds irreversibly to the agonist recognition site on the nicotinic receptor of the skeletal neuromuscular junction
⍺-bungarotoxin effects on quantal content
decreases the amplitude of both the EPP and the MEPP
no effect on quantal content
give a summary of ⍺-bungarotoxin
skeletal muscle paralysis is produced by ⍺-bungarotoxin and is irreversibe
cannot be reversed by neostigmine
what is succinylcholine (suxamethonium)
a nicotinic acetylcholine receptor agonist that causes skeletal muscle paralysis
rapid onset (30sec)
short duration of action
metabolised by plasma cholinesterase
what are the clinical uses of suxamethonium
used for rapid tracheal intubation and to prevent violent muscle contraction associated with electro-convulsant therapy
what is the mechanism of action of depolarising blockers?
e.g. suxamethonium
1. phase one block
a) persistent activation of endplate nicotinic receptors
b) prolonged depolarisation of endplate
c) inactivation of voltage-gated sodium channels
2. phase two block
d) desensitisation of endplate nicotinic receptors
e) repolarisation of endplate
f) receptor desensitisation maintains blockade
pharmacology of the neuromuscular junction nicotinic acetylcholine receptors
acetylcholine - agonist
nicotene - agonist
suxamethonium - agonist
tubocurarine - competitive antagonist
⍺-bungarotoxin - irreversible antagonist
how does inactivation of cholinergic transmission occur?
acetylcholine is terminated by an enzyme, acetylcholinesterase, which breaks down acetylcholine into acetate and choline
drugs which inhibit acetylcholinesterase, anticholinesterases (e.g. nerve gases, neostigmine) increase the effects of acetylcholine
cholinesterase enzymes
are inhibited by most clinically-relevant anticholinesterases
‘true’ acetylcholinesterase
present at cholinergic synapses
bound to the postsynaptic membrane in the synaptic cleft
pseudo-cholinesterase
e.g. butyrylcholinesterase, or plasma cholinesterase
widely distributed and found in plasma
important in inactivating the depolarising neuromuscualr blocker, suxamethonium
what is the effect of anticholinesterases on quantal content
increase the amplitude of both the EPP and the MEPP
no effect on quantal content
neostigmine prolongs the duration of the MEPP and the EPP due to the increased ‘lifetime’ of Ach in the synaptic cleft, which permits receptor rebinding
what are the clinical uses of anticholinesterases
used to reverse non-depolarising skeletal muscle relaxants
diagnosis and treatment of myasthenia gravis
alzheimers disease - tacrine
what is myasthenia gravis
auto-immune disease
loss of neuromuscular junction nicotinic acetylcholine receptors
causes muscular weakness, paralysis
reversed by inhibitors of acetylcholinesterases
> treated with neostigmine, diagnosed with edrophonium
organophosphates
bind very stably to the enzyme
recovery requires synthesis of new enzymes
include sarin, soman and novichok
what are dyflos?
volatile
non-polar
lipid soluble
rapidly absorbed through mucous membranes and unbroken skin
can cross the blood brain barrier
how are organophosphates reversed?
atropine - conteract effects of excessive muscarinic receptor stimulation by acetylcholine
oximes - e.g. pralidoxime, antidote to nerve gas, reactivates the acetylcholinesterase
what are insectisides?
rapidly absorbed through the insect cuticle
