Postsynaptic Skeletal Neuromuscular Transmission Flashcards
three types of channels in the muscle membrane
ligand-gated ACh channels
voltage-gated sodium channels
voltage-gated potassium channels
describe the process of the action potential
after the ligand-gated channels open, the influx of cations depolarizes the membrane and opens the voltage-gated sodium channels, causing the upstroke
the downstroke results from an influx of potassium ions and the inactivation of sodium channels
What happens after sustained activation by exogenous nicotinic receptor agonists?
the ligand-gated sodium channels become desensitized and no longer let cations through, terminating the sustained activation
tubocurarine
blocks transmission by reducing the sensitivity of the end-plate to ACh
binds to the ligand-gated channels but does not activate them
surmountable competitive inhibition
non-depolarizing block
prototype drug, used during surgery to safely facilitate the procedure
used to be used during surgery
also used in experiments
side-effects include ganglionic block and histamine release
non-depolarizing block
competitive inhibition, ex. tubocurarine
ACh excluded from receptor and surmountable
Ohm’s Law
I = g(delta)V
g = conductance
I = current
deltaV = membrane potential
depolarizing block
nicotinic receptor agonists, when applied exogenously in high concentrations, depolarize the muscle end-plate and block transmission from nerve to muscle
E(ACh)
the potential of the ligand-gated sodium channel, also lets other cations in so the E(ACh) is inbetween the membrane potential and the equilibrium potential of sodium
the effect of high ACh on neuromuscular transmission
over time acts as a depolarizing block
phase I depolarizing block
after rapid initial firings of action potentials, the muscle membrane potential stabilizes at E(ACh) due to the permanent inactivation of voltage-gated sodium channels
current can no longer flow
phase II depolarizing block
when the presence of the depolarizing drug returns to resting level due to the inactivation of the ACh receptors after long periods of time
at this point the muscle can be electrically stimulated, but there is still no neuronal communciation because of the desnsitized liganed-gated channels and the drug is still present
therapeutic uses of all of the neuromuscular blockers
used for the duration of surgery to relax muscles for abdominal surgery and allow for orthopedic manipulations
used for intubation by relaxing the masseter and lateral cricoarytenoid muscles
also used for scopys as diagnostic procedures
-curonium
the drug is a steroid
pancuronium
ACh receptor antagonist, keeps channel closed
steroid, long duration of action
5-10 times more potent than tubocurarine, does not release histamine, ganglionic blockade is minimal
side effect is that it blocks vagal tone causing tachycardia
vecuronium
ACh receptor antagonist
structurally teh same as pancuronium
intermediate duration of action (30-40 min)
produces no tachycardia
does not release hsitamine
very popular, currently in use
eliminated via the bile instead of the kidney
atracurium
possesses the benzylisoquinolium structure
another popular neuromuscular blocker due to ACh antagonism
intermediate duration of action (20-30 min)
eliminated in plasma by rapid non-enzymatic reactions (Hoffman elimination) by plasma esterases and ubiquitous carboxylases
eliminated by liver to a significant degree, good for kidney failure patients
some histamine release, may produce a product that causes seizures
cistacurium
properties similar to atracurium but is a single sterioisomer, which minimizes the side effects of atracurium
rocuronium
ACh receptor antagonist
rapid onset but intermediate in duration
elimination is 100% biliary, similar to vecuronium
popular for intubation
succinylcholine
depolarization blocker
equivalent to 2 ACh molecules end to end, hydrolyzed by ChE in two steps
easy to control duration and intensity of the ffects of this agent
rapid onset and short duration
therapeutic use of succinylcholine
during early pahse of anesthesia to produce rapid but brief periods of block, generally Phase I
fast onset because huge doses may be used
side effects of succinylcholine
activates muscarinic cholinergic receptors in the heart and nicotinic receptors in the vagal ganglia, which produces bradycardia
on aoccasion there it may stimulate nicotinic receptors int he sympathetic ganglia and produce tachycardia
malignant hyperthermia because of massive skeletal muscle contractions
What is the receptor that lets calcium out of the sarcoplasmic reticulum in resposne to an actino potential?
ryanodine receptor
succinylcholine can open this receptor for long periods of time, which would allow massive calcium efflux
dantroline
inhibits ryanodine receptors
contraindications of succinylcholine
in burn patients, receptors are formed along the entire muscle surface, so it owud allow high serum K+ and cardiovascular collapse
bad for patients with cardiac arrhythmias
results can be unpredictable when tehre is liver disease or genetic ChE deficiency
not to be used for the duration of surgical procedures because of muscle damage
general pharmacokinetics of neuromuscular blockers
absorption - oral and gastrointestinal is poor
distribution - unremarkable
metablosim - non or variable, generally in liver - succinylcholine through plasma cholinesterases and atracurium undergoes Hoffman elimination and some enzymatic degradation
mivacurium als through plasma esterases
excretion - mostly in kidneys except vecuronium and rocuronium in the bile
What transporter pushes neuromuscular blockers out of the body through the kidneys?
OCT1 transporters
mechanism of cholinesterase inhibitors
interferes with the hydrolysis of ACh at at the skeletal neuromuscular junction
effectively increases the ACh concentrations, which can only be reduced by diffusion
neostigmine
cholinesterase inhibitor used to treat myasthenia gravis and in surgery to reverse competitive blockade
edrophonium
short acting anti-cholinesterase that can be used to test for myasthenia gravis
practical uses of neuromuscular drugs
short term relaxation with rapid onset
duration of surgery
drug reversal of non-depolarizing block
NO reversal of depolarizing blocks
synergy
when two drugs that have the same action biologically but work at different mechanistic sites
ex. pancuronium and streptomycin
