Postsynaptic Skeletal Neuromuscular Transmission

Question 1

three types of channels in the muscle membrane

Answer 1

ligand-gated ACh channels

voltage-gated sodium channels

voltage-gated potassium channels

Question 2

describe the process of the action potential

Answer 2

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

Question 3

What happens after sustained activation by exogenous nicotinic receptor agonists?

Answer 3

the ligand-gated sodium channels become desensitized and no longer let cations through, terminating the sustained activation

Question 4

tubocurarine

Answer 4

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

Question 5

non-depolarizing block

Answer 5

competitive inhibition, ex. tubocurarine

ACh excluded from receptor and surmountable

Question 6

Ohm’s Law

Answer 6

I = g(delta)V

g = conductance

I = current

deltaV = membrane potential

Question 7

depolarizing block

Answer 7

nicotinic receptor agonists, when applied exogenously in high concentrations, depolarize the muscle end-plate and block transmission from nerve to muscle

Question 8

E(ACh)

Answer 8

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

Question 9

the effect of high ACh on neuromuscular transmission

Answer 9

over time acts as a depolarizing block

Question 10

phase I depolarizing block

Answer 10

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

Question 11

phase II depolarizing block

Answer 11

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

Question 12

therapeutic uses of all of the neuromuscular blockers

Answer 12

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

Question 13

-curonium

Answer 13

the drug is a steroid

Question 14

pancuronium

Answer 14

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

Question 15

vecuronium

Answer 15

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

Question 16

atracurium

Answer 16

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

Question 17

cistacurium

Answer 17

properties similar to atracurium but is a single sterioisomer, which minimizes the side effects of atracurium

Question 18

rocuronium

Answer 18

ACh receptor antagonist

rapid onset but intermediate in duration

elimination is 100% biliary, similar to vecuronium

popular for intubation

Question 19

succinylcholine

Answer 19

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

Question 20

therapeutic use of succinylcholine

Answer 20

during early pahse of anesthesia to produce rapid but brief periods of block, generally Phase I

fast onset because huge doses may be used

Question 21

side effects of succinylcholine

Answer 21

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

Question 22

What is the receptor that lets calcium out of the sarcoplasmic reticulum in resposne to an actino potential?

Answer 22

ryanodine receptor

succinylcholine can open this receptor for long periods of time, which would allow massive calcium efflux

Question 23

dantroline

Answer 23

inhibits ryanodine receptors

Question 24

contraindications of succinylcholine

Answer 24

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

Question 25

general pharmacokinetics of neuromuscular blockers

Answer 25

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

Question 26

What transporter pushes neuromuscular blockers out of the body through the kidneys?

Answer 26

OCT1 transporters

Question 27

mechanism of cholinesterase inhibitors

Answer 27

interferes with the hydrolysis of ACh at at the skeletal neuromuscular junction

effectively increases the ACh concentrations, which can only be reduced by diffusion

Question 28

neostigmine

Answer 28

cholinesterase inhibitor used to treat myasthenia gravis and in surgery to reverse competitive blockade

Question 29

edrophonium

Answer 29

short acting anti-cholinesterase that can be used to test for myasthenia gravis

Question 30

practical uses of neuromuscular drugs

Answer 30

short term relaxation with rapid onset

duration of surgery

drug reversal of non-depolarizing block

NO reversal of depolarizing blocks

Question 31

synergy

Answer 31

when two drugs that have the same action biologically but work at different mechanistic sites

ex. pancuronium and streptomycin