Drugs affecting neuromuscular
transmission
• Professor Ian Hughes, 9.83; i.e.hughes@leeds.ac.uk
• motor nerve - skeletal (striated) muscle ONLY
• single long cell from CNS; action potential (Na
channels) invades terminal opening Ca
channels; intracellular Ca rises; vesicles
release ACh by exocytosis; diffusion to
receptors (ligand operated ion channel
[2xalpha,beta,gamma,delta]); Na flows out;
depolarisation of endplate; if sufficient
depolarisation then voltage operated Na
channels open and a propogated action
potential followed by contraction results in
muscle.
choline
recapture
action
potential
Choline
acetylcholine
esterase
choline acetylase
R
ACh (10,000)
ACh
in vesicle
- +
Ca++
calcium entry
presynaptic
receptors
diffusion
Pre-synaptic actions
• block nerve action potential; lignocaine
• prevent choline uptake; hemicholinium
triethylcholine
• block choline acetylase
• affect release mechanism; Ca++ entry
excess Mg++ ; botulinus toxin;
• affect pre-synaptic receptors;
• discharge vesicles; beta bungarotoxin ; black widow
spider venom
• affect potassium channels; 4-aminopyridine; TEA
Post-synaptic actions
• competitive blockers; tubocurarine,
pancuronium, gallamine, fazadinium,
atracurium, vecuronium
• depolarising blockers; suxamethonium
(succinylcholine)
• odds and sods; decamethonium, dantroline
Competitors (Tc) and depolarisers
(Sux) - mechanism of action
mV
map
. . .. . .
stim
[Tc]
epp
Sux
Compare:-------------------------------competitors -- depolarisers
•
•
•
•
•
•
•
•
•
fasciculations
paralysis (man)
paralysis (bird)
tetanic stimulation
anticholinesterase
K channel blocker
+depolariser
+competitor
multiply innervated
muscle
no
flaccid
flaccid
fades
reverse
reverse
reverse
deepen
---------
yes
flaccid
spastic
maintain
deepen
deepen
deepen
reverse
contracts
Uses of neuromuscular blockers
• entubation - fast and short action
• relaxation during surgery - long action,
reversible, controlled
• soften electro-convulsive therapy - short and
fast action (use with anaesthetic)
• special conditions - renal or hepatic failure;
manipulations; exceptionally convulsions.
Drugs
• tubocurarine - quaternary; release
histamine;some ganglion block hence BP falls;
hepatic 70%, renal 30%; 30-40 min
• pancuronium - longer lasting; renal 75%
• vecuronium - short (20 min); hepatic 85%,
renal 15%
• gallamine - renal 90%; 30-40 min
• fazadinium - short; hepatic 90% (diazo
reduction)
• atracurium - short; pH dependent chemical
destruction
• rocuronium, mivacurium
Drugs
• suxamethonium - (Scoline); depolariser;
short (3-10min); scoline pains and muscle
damage; K+ levels increased; dysrhythmias;
hydrolysed by esterases (defect).
• decamethonium - initial depolarising, later
competitive characteristics; longer lasting.
• dantroline - acts to inhibit Ca++ release in
muscle; used in malignant hyperthermia and
severe muscle spasm.