Peripheral nerve transmission L2

Question 1

How is ACh release modulated?

Answer 1

ACh release is physiologically regulated by mediators, including ACh itself, acting on pre-synaptic receptors.

At postganglionic parasympathetic nerve endings, inhibitory muscarinic M₂ receptors participate in auto inhibition of ACh release;

other mediators, such as noradrenaline (NA), also inhibit the release of ACh.

At the NMJs, on the other hand, pre-synaptic nicotinic receptors (nAChRs) facilitate ACh release, a mechanism that may allow the synapse to function reliably during prolonged high-frequency activity.

Question 2

what does atropine inhibit?

Answer 2

muscarine

Question 3

what doesmtubocurarine inhibt?

Answer 3

nicotine

Question 4

are nAChRs ion channels?

Answer 4

yep

Question 5

A functional nAChR is a pentamer consisting of …

Answer 5

A functional nAChR is a pentamer consisting of a, b, g, d and e subunits with at least 2a subunits present.

Question 6

how many ACh are required to open the channel?

Answer 6

2

Question 7

Most nAChR isoforms are permeable to ….. whilst one of the CNS isoforms namely the (a7)5 channel, is highly …..permeable.

Answer 7

Most nAChR isoforms are permeable to Na+ and K+ whilst one of the CNS isoforms namely the (a7)5 channel, is highly Ca2+ permeable.

Question 8

how are mAChRs classified?

Answer 8

M2 /M4 receptors -> typically present pre-synaptically -> inhibit neurotransmitter (including ACh itself) release

Question 9

Within the synaptic or junctional cleft, most of the ACh is rapidly hydrolyzed into choline and acetate by acetylcholine esterase (AChE) which is located where?

Answer 9

Within the synaptic or junctional cleft, most of the ACh is rapidly hydrolyzed into choline and acetate by acetylcholine esterase (AChE) which is tethered to the post-synaptic membrane.

Question 10

A ‘soluble’ AChE is present in…..

Answer 10

A ‘soluble’ AChE is present in the cytoplasm of the pre-synaptic nerve but understandably it doesn’t affect the life span of the released AChE.

Question 11

As mentioned before, (α3)2(β2)3 represents the predominant N_n nAChR receptor variant. These channels are insensitive to _______ but are inhibited by _______ (a competitive antagonists) and ______ (you may use it during a practical).

Answer 11

As mentioned before, (α3)2(β2)3 represents the predominant Nn receptor variant. These channels are insensitive to α-bungarotoxin but are inhibited by trimetaphan (a competitive antagonists) and hexamethonium (you may use it during a practical).

Question 12

label the post ganglionic membrane potential changes

Answer 12

Question 13

ganglionic stimulants:

gieve some Nn receptor agonists

Answer 13

• Nicotine
• Varenicline

, tetramethylammonium (TMA, you may use it in a practical) and dimethylphenylpiperazinium (DMPP) are notable but these are not drugs but useful for experiments.

Question 14

give some nAChRs antagonists: ganglionic blockers

Answer 14

Type 1: agonsits - block tranmission due to sustained depolarisation

type 2: competitive antagonists & channel blockers (eg trimethaphan and hexamethonium)

Question 15

how does hexamethonium work

Answer 15

blocks the open nAChRs

Question 16

does hexamethonium show use dependance?

Answer 16

yep

Question 17

how does trimethephan work?

Answer 17

binds ACh binding site

competitive

very short acting

Question 18

. The adult Nm is irreversibly antagonised by

Answer 18

α-bungarotoxin (a- BuTx

Question 19

describe how Depolarizing neuromuscular blocking agents work?

give a main exmaple

Answer 19

bind nAChR

not hydrolyses

hold channel open

fasiculations

phase 1 flaccid paralysis

suxamethonium

Question 20

describe suxamethonium

Answer 20

effectively a dimer of ACh.

short term paralysis - used to aid tracheal intubation

brocken down by rapid hydrolysis in the plasma by butyrylcholinesterase (BuChE, also known as pseudocholinesterase).

Question 21

which patietns are at risk from suxamethonium?

Answer 21

rapid hydrolysis of suxamethonium in the plasma by butyrylcholinesterase (BuChE, also known as pseudocholinesterase). This enzyme is synthesized in the liver and patients with liver disease or genetic deficiency of this enzyme therefore run the risk of prolonged action of suxamethonium.

Question 22

problems associated with depolarising blocking agents?

Answer 22

depolarizing agents causes K⁺ loss from the muscles (can you predict how?) into blood, which may lead to hyperkalemia and can be life-threatening for some patients, especially if they already suffer from electrolyte imbalance.

Question 23

describe Non-depolarizing neuromuscular blocking agents

Answer 23

competitive antagonists of the Nm channels i.e. they compete with the endogenous ACh at its binding sites on the Nm channels without stimulating it (hence non-depolarizing). Thus, they prevent depolarization of the sarcolemma and inhibit muscular contraction, leading to a flaccid paralysis

Question 24

Non-depolarizing neuromuscular blocking agents: are there fasiculations?

Answer 24

nope

Question 25

Non-depolarizing neuromuscular blocking agents - how can we overcome their effecsts?

Answer 25

• Their competitive action can be overcome by administration of anti-cholinesterases (e.g. neostigmine, see later), which increase the concentration of ACh in the NMJ. This gives anaesthesiologists an option to shorten the duration of the neuromuscular blockade.

Question 26

give some examples of antagonists of nAChR at the NMJ

Answer 26

• Curare (major component d-tubocurare)
• aminosteriod group (suffix uronium)
  
  • pancuronium, rocuronium
• benzylisoquinoline group (suffix urium
  • atracurium, mivacurium
  *

Question 27

. Drugs with a _____ or _____ duration of action, such as atracurium and rocuronium, are more widely used than those with a _____ duration of action, such as pancuronium.

Answer 27

. Drugs with a shorter or intermediate duration of action, such as atracurium and rocuronium, are more widely used than those with a longer duration of action, such as pancuronium.

Question 28

all non-depolarising blocking agents are quaternary ammonium (=charged) compounds and as such…. how are tey administered?

Answer 28

all non-depolarising blocking agents are quaternary ammonium (=charged) compounds and as such poorly absorbed (cannot be given orally) and rapidly excreted.

Question 29

describe tetanic fade

Answer 29

nAChR antagonists: also block facilitatory presynaptic autoreceptors ® inhibit ACh release during repetitive stimulation of the motor nerve ® the ‘tetanic fade‘® often used by anaesthetists to monitor postoperative recovery of neuromuscular transmission

Question 30

Some clinical responses to neuromuscular blocking agentsappear to be caused by …

Answer 30

appear to be caused by the release of histamine

Question 31

1, 2, 3 - cause histamine release,

but to a lesser extent than 4 unless administered rapidly.

The amino steroids such as 5 and6 have lesser tendency to release histamine

Answer 31

Suxamethonium, mivacurium, and atracurium cause histamine release, but to a lesser extent than d-tubocurarine unless administered rapidly.

The amino steroids such as pancuronium and rocuronium have lesser tendency to release histamine

Question 32

describe how agents which interfere with Ca signlas afect the NMJ

and give some exmaples of drugs which do

Answer 32

agents that interfere with the generation of Ca²⁺ signals in the motor neurone can also impair ACh release into the NMJs.

For example, members of the aminoglycoside antibiotics (e.g. streptomycin, neomycin etc.; see lectures on anti-microbial agents), in large doses inhibit Ca_v channels and thus can produce neuromuscular blockade, especially in patients with myasthenia gravis.

These antibiotics in normal or low doses can unpredictably prolong muscle paralysis when used clinically in patients treated with neuromuscular blocking agents as an adjunct to general anaesthesia.

Tetracyclines can also produce similar effects due to their ability to chelate Ca²⁺.

Question 33

pharmacology at NMJ: summary

Answer 33

Question 34

Of the 5 different mAChR subtypes, ……… are the most important in the periphery.

Answer 34

Of the 5 different mAChR subtypes, M1, M2 and M3 are the most important in the periphery.

Question 35

describe M1 receptors

Answer 35

1. CNS, autonomic ganglia and on gastric parietal cells.
2. coupled to Gq/11 and agonist binding at these receptors leads to the activation of PLCβ,
3. then hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers - inositol 1, 4, 5-trisphosphate (IP3) and diacylglycerol (DAG).
4. IP3 then leads to intracellualr calcium release
   5.

Question 36

muscarinic M1, M3 & M5 ® ____-coupled ® ……

Answer 36

muscarinic M1, M3 & M5 ® Gq/11-coupled ® increase cell [Ca2+]

Question 37

does location (& thus specific signalling) of mACRs matters:

Answer 37

yesss

Question 38

• in smooth muscle -> M3 -> …..

Answer 38

• in smooth muscle ® M3 ® Ca2+-CaM ® MLCK® contractions

Question 39

• in vasuclar endothelium® M3 ®……..leads ti>

Answer 39

• in vasuclar endothelium® M3 ® Ca2+-CaM ® NO ® relaxation

Question 40

in ganglia/CNS neurons ® M1 ® ,…..

Answer 40

n ganglia/CNS neurons ® M1 ® PIP2 depletion ® Kv7 inhibition

Question 41

In the heart, ____ receptors are the predominant mAChR subtype and are largely confined to the sinoatrial and atrioventricular nodes (SA and AV nodes, respectively), to some extent in the atria but much less in the ventricles.

Answer 41

In the heart, M₂ receptors are the predominant mAChR subtype and are largely confined to the sinoatrial and atrioventricular nodes (SA and AV nodes, respectively), to some extent in the atria but much less in the ventricles.

Question 42

stim of M2 receptors in the heart leads to >

Answer 42

stimulation of these receptors reduces the rate of myocardial contractions (= the negative chronotropic effect) that involve several mechanisms

• reduced Ca²⁺ current via the L and T-type Ca_vs due to reduced PKA-mediated phosphorylation of these channels
• the βγ subunit dissociated from G_i/o protein following stimulation of M₂ receptors binds to and open the G protein-coupled inwardly rectifying K⁺ channels (GIRK1 or Kir3.1) present in the nodal pacemaker cells. The resultant K⁺ efflux (the current is often designated as I_K-ACh) then makes these cells hyperpolarised and thus difficult to excite.
• due to reduced availability of cAMP, the threshold for the opening of the HCN channels which mediate the slowly-depolarizing inward Na⁺ current (the I_f current), is shifted towards a more negative value.
• stimulation of atrial M₂ receptors reduces atrial contractility via triggering the I_K-ACh.

Question 43

do you knwo how stimulating differnet Mtype mAChRs can affect differnet tissues?

Answer 43

you should look that up i nthe notes / slides 3.1

Question 44

summary slide for you

Answer 44

Question 45

fat

Answer 45

mamba