PNS Pharmacology NMJ

Question 1

Describe the type of receptors the NMJ.

Answer 1

nicotinic ACh receptors are ligand gated Na+ channels that cause propagation of AP in muscle cells

BONUS: botulinum toxin cleaves SNARE proteins which stop ACh release

Question 2

Describe the binding pocket(s) for the NMJ nicotinic AChR.

Answer 2

two pockets for choline molecules cause the pore to open on binding (note only NMJ express the gamma and delta subunits which is why they can be targeted for therapy

Question 3

Describe the chemistry of the first NMJ blocker

Answer 3

d-Tubocurarine has two benzyllisoquilonline moieties arranged a circular pattern (non-depolarizing agent)

Question 4

What groups of steroid derivatives activate the nicotinic receptor?

Answer 4

basically a steroid with two acetylcholine groups, they bind the receptor; all contain a quaternary amine (don’t cross BBB)

Question 5

What is the mechanism of non-depolarizing NMB?

Answer 5

the are competitive antagonists of the NMJ nAChR

Question 6

What are the two structurally different classes of non-depolarizing NMBs?

Answer 6

Benzylisoquinolines
steroids

(both have rigid and bulky structures and permanently charged (+) quaternary amine)

Question 7

Differentiate different isoquinoline drugs based on important characteristics

Answer 7

tubocurarine: prototype, long time of action, longer time till onset, excreted by kidney, moderate histamine release
mivacurium: shortest duration of action, only drug metabolized by plasma ChE
atracurium: moderate duration, spontaneous degradation with some histamine release
cistracurium: moderate to long duration, spontaneous degradation

Question 8

Differentiate between steroid class non-depolarizing NMJ blockers based on their important characteristics.

Answer 8

Pancuronium (prototype): longer duration, metabolized in kidney
Rocuronium: shortest to onset, moderate duration, liver metabolism
Vecuronium: moderate onset and duration, liver metabolism

Question 9

What is the mechanism of action of depolarizing neuromuscular blockers?

Answer 9

agonist of NMJ nAChR which causes prolong depolarization of voltage gated Na+ channels and inactivation of muscle (usually fascinations with onset)

Question 10

What class of drug is succinylcholine and how is it metabolized?

Answer 10

depolarizing NMJ blocker, that is metabolized by PLASMA cholinesterase

Question 11

What pertinent characteristics of succinylcholine that make easy to use clinically?

Answer 11

fast onset (<10min- rapid metabolism) which is important for rapid sequence induction/intubation (min pulmonary aspiration of gastric contents) or useful for short procedures.

Question 12

What are the adverse effects of succinylcholine?

Answer 12

stimulates autonomic ganglia AChRs (HTN, tachy)
stimulates cardiac muscarinic receptors (bradycardia)
histamine release (caution with asthmatics)

specific to succinylcholine: mylagias, increased intracranial and intraocular pressure and hyperkalemia (in extra junctional nAChRs, denervation, burns or myopathies)

Question 13

What is phase II block with succinylcholine use?

Answer 13

occurs with prolonged admin or repeated bolus which leads to a clinically unpredictable duration of paralysis

may be through desensitization of nAChR, open channel block or competitive antagonism of nAChR

Question 14

What patients are at risk for prolonged block with succinylcholine?

Answer 14

decreased plasma ChE (liver disease or genetic mutation)

decreased activity of plasma ChE (ChE inhibitors like neostigmine or organophosphates or genetic condition)

Question 15

How do you treat prolonged block?

Answer 15

succinylcholine- have to wait for metabolism
blocks can be chemically reversed

note. muscle strength can appear adequate even when up to 75% of nAChR are still inhibited, this condition does not leave reserve for hypoxic or acidemic conditions