Exam 4 - Lecture 37, Muscarinic antagonists and neuromuscular junction blockers

Question 1

major classes of cholinoreceptor antagonist

Answer 1

Muscarinic antagonist

Neuromuscular, nAChR blockers (Depolarizing and non-depolarizing)

ganglion blockers (little clinical use)

Question 2

M1 receptor

Answer 2

CNS, ANS pre- and postganglic neurons

Coupled to Gaq

Question 3

M2 receptor

Answer 3

Myocardium, smooth muscle (SM), some neurons

Coupled to Gai

Question 4

M3 receptor

Answer 4

common on effector cells (glandular and SM)

Coupled to Gaq

Question 5

M4 & M5

Answer 5

Least prominent subtypes, CNS > PNS

M4 = Gai and M5 = Gaq

Question 6

Atropine

Answer 6

MoA:
Competitive antagonist of M1-5 receptors

Medical Applications:
can treat bradycardia, reduce saliva during surgery, Used for OOP poisoning, mydriatic in othalmology, IV atropine effective within minutes and lasts 30-60min, effect on central M receptors reduces Parkinsonian tremors

Side effects:
Tachycardiac, dry mouth, mydriasis, urinary retention and constipaton, crosses BBB

OD:
Antidote if physostigmine or pilocarpine

Question 7

Paradoxical effect of low dose atropine

Answer 7

At low doses, atropine decreases heart rate because it inhibits presynaptic M2 receptors. It preferentially activates presynaptic receptors

Question 8

Atropine as inverse agonist

Answer 8

Atropine is a ACh-antagonist, but its effects go beyond simple opposition of ACh, therefore its an inverse agonist

M2 receptor has a baseline activity, and atropine bring its below that

Question 9

Scopolamine, Hyoscine

“Devils death” street name

Answer 9

Medical use:
motion sickness and postoperative nausea
GI-spasm, biliary spasm and IBS
can do IM,SC or transdermal

side effects:
Similar to atropine, less severe

Overdose: treat with physostigmine

Question 10

Glycopyrronoum or (glycopyrrolate)

Answer 10

Muscarinic antagonist

FDA approved for excessive sweating and peptic ulcers

Most commonly used with neostigmine during reversal of a NM blockade to mitigate side effects of neostigmine, such as bradycardia and reflect hypertension

side effects:
similar to atropine but does not cross BBB

Question 11

Activation of nAChRs

Answer 11

depolarizes skeletal muscles

Question 12

Activation of Nav1.4 channels

Answer 12

initiates and propagates action potentials

Question 13

3 types of neuromuscular blockers

Answer 13

Nondepolarizing

Depolarizing

Inhibitors of ACh release

Question 14

Nondepolarizing

Answer 14

Antagonists that prevent the action of ACh (agonist) on nAChRs by occupying the receptor binding site

Ex. Rocuronium

Question 15

Depolarizing

Answer 15

Agonists that have a longer half-life at the nAChR than ACh, leading to sustained depolarization of the muscle and inactivation of Nav channels causing phase 1 block

Ex. Succinylcholine

Question 16

Inhibitors of ACh release

Answer 16

ex. Botox

Peptide toxins that prevent the Neurotransmitter vesicle machinery from releasing ACh into the synaptic cleft

Question 17

Tubocurarine

Answer 17

naturally occurring

causes slow skeletal muscle paralysis and histamine release

Minimal medical utility because it also acts at ganglia, modern compounds safer

Can be used to reduce painful neurotransmitter release following a-latrotoxin envenomation (black widow)

Question 18

Tubocurarine

Answer 18

naturally occurring

causes slow skeletal muscle paralysis and histamine release

Minimal medical utility because it also acts at ganglia, modern compounds safer

Can be used to reduce painful neurotransmitter release following a-latrotoxin envenomation (black widow)

Question 19

Cisatracurium besilate

Answer 19

** Not reversed by sugammadex **, use neostigmine

Non-depolarizing neuromuscular blocker

Derived from atracurium

Facilitates placement of endotracheal tubes and relaxes skeletal muscle in surgery

Hoffmann elimination, temp and plasma pH dependent, therefore increased temp speeds elimination

Adverse effects:
Hypotension and reflex tachycardia

Question 20

Rocuronium

Answer 20

** Reversed using sugammadex **

designed to be less potent than pancuronium

aminosteroid non-depolarizing neuromuscular blocker

facilitate tracheal intubation and relax skeletal muscle

used for euthanasia/lethal injection w/ midazolam

Question 21

Pancuronium

Answer 21

** Reversed using sugammadex **

Curare mimic based on 2 ACh molecules, partially reversal w/ neostigmine

aminosteroid non-depolarizing neuromuscular blocker

facilitate tracheal intubation and relax skeletal muscle

used for euthanasia/lethal injection w/ midazolam

Question 22

Cisatrucurium vs Atracurium

Answer 22

Longer duration

Question 23

Pancuronium vs Rocuronium

Answer 23

Longer lasting, more potent

Question 24

Sugammadex (Bridion)

Answer 24

FDA approved in 2015, EU 2008

Reverses NMJ block by chelating amino steroid drugs

Alternative to neostigmine and glycopyrrolate

Can theoretically chelate other polar steroids, including oral contraceptives

Question 25

Succinylcholine

Answer 25

Activator of nAChRs, depolarizing NM blocker

Similarly fast onset but faster recovery than rocuronium

Paralytic for general anesthesia or ECT

Degraded by serum butrylChE not AChE

Side effects:
constipation (treat w/ neostigmine)
Hyperkalemia (lead to K+ wasting and cardiac arrest in susceptible patients)
Ocular hypertension
Malignant hyperthermia (v low probability; treat with dantrolene)

Question 26

Depolarizing agents can have two phases of block

Answer 26

Phase 1: (Goal)
Nicotine depolarizes the membrane and spontaneous action potentials are lost in response to Orthodromic electrode or Antidromic electrode. The neuron is refractory to electrical activity due to inactivation of NaV channels

Phase 2:
In continued presence of agonist, the cell depolarizes and is electrically excitable BUT is unresponsive to Orthodromic electrode because the nAChRs are desensitized

Question 27

Phase 1 block: Inactivation of Nav Channels

Succinylcholine

Answer 27

1. Succinylcholine binds to the ACh binding site, opening nAChR channels
2. This depolarizes the skeletal muscle, activates Nav, Cav and K+ channels
3. Fasciculation (muscle twitches/spontaneous contractions) often observed prior to paralysis
4. nAChRs desensitize and the muscle is refractory to further stimulation (The membrane remains depolarized so Nav channels are inactivated)
5. T1/2 of Succinylcholine in synapse&raquo_space; ACh so effect is maintained

Question 28

Low conc of Succinylcholine….

Answer 28

limits downward channel openings

Question 29

High Conc of Succinylcholine…

Answer 29

causes flickering of the channel as the pore opens and is repeatedly blocked

Question 30

Phase I vs Phase II

Answer 30

Phase I:

Much faster recovery

Question 31

Botulinum toxin (Botox) mechanism

Answer 31

1. Release of ACh mediated by SNARE protein complex
2. During depolarization Ca2+ influx facilitates conformational changes that allow vesicle fusion
3. Fusion and release of ACh; disassembly of machinery
4. First internalization step of Botox is unknown. Toxin has light and heavy chains
5. BoTox internalized into vesicles, Lc released
6. Lc cleaves SNARE proteins, preventing assembly of the fusion complex and blocking release of ACh

Question 32

Botox

Answer 32

Prevents release of ACh onto NMJs

Its one of most potent toxins, 1.5ng/kg IV

Medical use:
Muscle spasm, excessive sweating, migraine, neuropathic pain and cosmetic smoothing of skin wrinkles