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PNS > deck_15928464 > Flashcards

deck_15928464 Flashcards

1
Q

What is the somatic efferent motor system?

A

Component of PNS associated with VOLUNTARY control of skeletal muscles.
Also responsible for reflex arc - utilising interneurones.
Cell bodies of somatic motor efferent system are in the BRAIN STEM.

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2
Q

What is the motor unit?

A

1 motor neurone connects the CNS to the skeletal muscle fibre, cell bodies are in the brain stem.
BUT a single axon can innervate multiple fibres… just that each fibre is only innervated by a single motor neurone.

The motor unit = the skeletal muscle fibre and the single motor neurone that innervates it.

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3
Q

What is the NMJ?

A

Pre-synaptic terminal, with synaptic cleft and then the motor end plate.
high density of nicotinic ACh receptors.

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4
Q

How is ACh released at the NMJ?

A

AP causes Ca2+ influx, causing fusion of ACh storage vesicles with pre-synaptic terminal and release across synaptic cleft.

ACh metabolised by acetylcholinesterases…
Acts on nicotinic ACh receptors.

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5
Q

What ACh receptors are found on the motor end plate?

A

Ligand-gated ion channel allowing Na+ in, K+ out = to depolarise the end plate and generated end plate potential.
Contains 2 alpha subunits, 1 Beta, 1 Delta and 1 Gamma = pentameric = 5 subunits….

In autonomic ganglia = 2 alpha3, with 3beta..
in CNS, = a4, a7, B,D,Y…

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6
Q

How is NMJ signal spread?

A

ACh binds to nACh receptors in motor end plate, leads to Na+ influx, K+ efflux via its channel.
= Depolarisation is called the End Plate Potential.

This initiates the opening of proximal VG Na+ channels = amplifying the ion flux, to generate an AP in muscle cell.

but only once!
Signal is rapidly terminated by AChE…

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7
Q

How does NMJ lead to contraction?

A

Excitation-Contraction coupling.

AP propagates down T-tubules to penetrate into muscle fibre.

Depolarisation causes opening of L-Type Ca2+ channels
and stimulates Ca2+ induced, Ca2+ release from SR.
= by opening Ryanodine Ca2+ channels.

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8
Q

Why are NMJ blockers needed in surgery?

A

During anaesthesia induction, there are motor reflexes that can hinder intubation.
Need to immobilise areas under investigation…
Muscle spasm can occur with mechanical manipulation of limbs and nerves.

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9
Q

What are NMJ blocking drugs?

A

Non-depolarising agents = antagonists to nACh receptors.
Depolarising agents = weak nicotinic ACh receptor agonists!?

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10
Q

What is d-Tubocurarine?

A

Found in plant called Curare, but poor oral absorption…
Can cause paralysis by blocking NMJ transmission, but doesn’t hinder nerve conduction or muscle contractility.

Competitive antagonist to nACh receptor at NMJ…
But since an excess of ACh is released at NMJ, need to block most receptors to work…
= Tubocurarine reduces End Plate Potential so it cannot exceed threshold to initiate AP…

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11
Q

What are the synthetic derivatives of d-Tubocurarine?

A

Atracurium, Pancuronium and Gallamine.
With shorter durations of action, safer and paralysis fades rapidly after surgery…
= Non-depolarising NMJ blockers…

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12
Q

What is alpha-Bungarotoxin?

A

Irreversible binder to nACh receptors at NMJ.
Inhibits ACh from binding, stopping ACh-induced contraction…

But not used in clinic !!!

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13
Q

What are the side effects of non-depolarising blockers?

A

Hypotension = as also blockade of ganglion#

Cause histamine release in Mast Cells = which can cause bronchospasm..

Respiratory failure = so need to be assisted ventilation in surgery!!!

With Gallamine and Pancuronium = M2 blockade = tachycardia…

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14
Q

What are depolarising blocking agents?

A

Symmetrical bisquarternary ammonium compounds which are structurally similar to ACh…. but have +ve charged nitrogen atoms.
= Affinity to alpha subunits in post-synaptic nACh receptors…

Decamethonium, Suxamethonium..

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15
Q

What is the MoA of depolarising blocking agents?

A

Initially, they bind and activate nACh receptors…
to cause typical depolarisation of muscle…
But! Suxamethonium is slowly hydrolysed by plasma cholinesterases.
= so depolarisation is maintained at the end plate.
= LOSING electrical excitability..

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16
Q

What are the results of depolarising agents?

A

By being slowly hydrolysed by plasma cholinesterases, they maintain depolarisation at Endplate…
and muscle loses its electrical excitability…

Therefore, there is initial twitching of skeletal muscle… but then produces rapid block.

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17
Q

What is Phase 1 of depolarising agent block?

A

Depolarising phase.
As they are agonists to nACh receptors…
Slowly hydrolysed by plasma cholinesterases…
Muscle gets held in a depolarised state and proximal VG Na+ channels become refractory = so don’t respond to ACh binding at nicotinic receptor.
= Muscle becomes flaccid as Ca2+ is taken into stores…

Channel will remain inactive until the membrane repolarises….

This depolarised state keeps VG Na+ channels refractory

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18
Q

What is Phase 2 of depolarising agent block?

A

The desensitiation phase.
With persistent stimulation, leads to nACh receptor desensitisation.
The receptor will remain inactive until the ligand is removed…

Transmission is blocked despite partial repolarisation occuring due to Na+/K+ ATPase.

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19
Q

What is the train of Four?

A

An assessment to measure the depth of anaesthesia?

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20
Q

What are the advantages to suxamethonium/depolarising block?

A

Less likely to elicit Histamine release like non-depolarising blockers…

Can be used for surgery during pregnancy/ C sections.
As suxamethonium is poorly crossed to placenta as ionised = safer for babies.

Rapid onset with a short duration of action… used to intubate.

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21
Q

What are the side effects of suxamethonium?

A

Bradycardia as acts on muscarinic receptors.

K+ release at End Plates causes hyperkalaemia and this can cause ventricular dysrhythmias..

Post-operative pain due to twitching.

Increased intraocular pressure, prolonged paralysis when people are deificient of plasma cholinesterases….

22
Q

What are other uses of NMJ blockers?

A

Lethal injections use non-depolarising agents..

ECT - need general anaesthesia.

23
Q

What are the key differences between depolarising and non-depolarising agents?

A

Non-depolarising block is reversible by increasing levels of ACh (such as with anti-AChE drugs)..
Depolarising agents are unaffected, or even potentiated by increased ACh…

Depolarising causes initial twitching, non-depolarising does not…

Suxamethonium is hydrolysed by plasma cholinesterases… therefore, can be prolonged if mutant…

Non-depolarising closes + blocks the channel, whereas depolarising keeps channel open, but it is blocked…

24
Q

How is NMJ block reversed?

A

Neostigmine = AChE inhibitor…. to raise ACh in synapse.
this will work for reversing non-depolarising block.
BUT WILL POTENTIATE non-depolarising block!

25
Q

What is neostigmine?

A

A competitive inhibitor of AChE as similar structure to ACh…
With rapid onset, that is slowly metabolised…

26
Q

What are the side effects of Neostigmine?

A

Can cause bradycardia as it results in parasympathetic stimulation…

GI disturbances and cause increase postoperative nausea.

Usually co-administered with anti-muscarinics like hyoscine.

27
Q

What is Sugammadex?

A

Used to reverse non-depolarising block!
= chelates aminosteroid non-depolarising agents…

Effective for rocuronium, vercuronium but NOT Atracurium!!!
Which is the main non-depolarising agent…

= spares the use of Neostigmine or depolarising agents..

28
Q

What is the process of ACh biosynthesis?
How degraded?
Rate limiting step to biosynthesis?

A

Ac-CoA synthetase converts Acetate and CoA into Acetyl-CoA

Acetyl-CoA + Choline forms ACh with Choline acetyltransferase.

AChE degrades ACh into acetate, which is removed by the blood, and choline, which is reuptaken by choline transporters..

The reuptake of choline is the rate limiting step of the synthesis of ACh.

29
Q

What is the MoA of Hemicholinium?

A

Competitive inhibitor of Choline transporter.
= Blocking the reuptake of choline by the high affinity choline transporters….
The rate limiting step of ACh synthesis = so would have big effect on ACh synthesis and release.
= Used in research, with somatic and autonomic effects as doesn’t discriminate.

30
Q

What is the Vesamicol + MoA?

A

Vesamicol blocks ACh transport into synaptic vesicles, by inhibiting VAChT’s.
= reducing ACh release and used experimentally.

Somatic and autonomic effects don’t discriminate.

31
Q

What is Triethylcholine + MoA?

A

Triethylcholine is uptaken into neurone using choline transporter.
Choline acetyltransferase converts triethylcholine into Acetyltriethylcholine (ATC)…

ATC then acts as a false transmitter, packaged into vesicles and released, but has no effect on ACh receptors!

= Causes long-lasting neuromuscular weakness and ganglionic blocking effects like hypotension.

Doesn’t discriminate between somatic and autonomic NS, as affects both ganglia and NMJ

32
Q

What is tetrodotoxin?

A

From puffer fish.
Blocks fast VG Na+ channels, so blocks AP and decreases ACh release at the NMJ.

Causing muscular paralysis, respiratory failure, very low LD50, heat stable too!

33
Q

How can neuronal Ca2+ influx be blocked to prevent ACh release?

A

High concentration of Mg2+ competes with N-Type Ca2+ channels at pre-synaptic terminal.

Streptomycin and Neomycin also block N-Type Ca2+ channels.

= inhibit Ca2+ influx to stimulate exocytosis of ACh vesicles.

34
Q

Generally, How do Botulinum toxin and B-bungarotoxin work?

A

Block NMJ ACh release by blocking ACh vesicular fusion.

35
Q

What is Botulinum toxin?

A

Botulinium toxin is produced by Clostridium botulinum - can grow as spores in canned food leading to botulism.

Leads to progressive parasympathetic and motor paralysis, dry mouth, respiratory paralysis and blurred vision….

Irreversible!!!

36
Q

What is the MoA of Botulinum A and B?

A

Botulinum A (Botox) cleaves the synaptosome-associated protein, SNAP.

Botulinum B (Myoblock) cleaves VAMP, also tetanus toxin target.

= in nerve terminals, they act as proteases to cleave SNARE proteins required for vesicular fusion and ACh release.
Last a long time!

37
Q

What are the uses of Botulinum toxin?

A

In cosmetics as botox.

Have been used for cerebral palsy, Belpharospasm - persistent eyelid spasming.

Cervical dystonia = neck spasms…

Migraine

38
Q

What is the MoA of B-bungarotoxin?

A

Blocks ACh release at nerve terminals by preventing vesicular fusion.
Also Phospholipase PLA2 activity = may destroy nerve terminals too.

= leads to paralysis, respiratory failure…. found in Krait snakes..

39
Q

What is Atracotoxin?

A

Found in tunnel-web spider venom.
Prolongs the opening of Na+ channels, prolonging AP’s and stimulates repetitive firing of the neurone, with more ACh released at the terminals in both somatic and autonomic nerves….

= Seizures, dilated eyes, foaming at the mouth…

40
Q

What do AChE inhibitors do?

A

AChE hydrolyses ACh to choline + acetate.
There is a large density of AChE in synaptic cleft in cholinergic synapses.
= Increase ACh in synaptic cleft.
+ Cause profound autonomic activation… = SLUDGE= cholinergic crisis…
and activate chromaffin cells in adrenal glands… which produce NA and A.

41
Q

How does AChE work?

A

AChE contains a catalytic and an anionic site.

The anionic site binds choline moiety of ACh.
Catalytic site breaks down ACh…
Acetylserine is rapidly hyolysed to return AChE to active conformation…

42
Q

What is the MoA of short-acting anti-cholinesterases?

A

Edophonium or Ed.
Forms a reversible ionic bond with the anionic site of AChE…. That is in competition with ACh…

Very short-acting… so not used anymore.

43
Q

What is the MoA of medium-duration anticholinesterases?

A

Neostigmine, Physostigmine.

Competitive inhibitors to anionic and catalytic site..
Form a carbamylate-enzyme complex that is much more slowly hydrolysed.
So makes AChE from returning to active conformation much slower…

= Used in recovery of anaesthesia in non-depolarising block.

44
Q

What are the irreversible anticholinesterases?

A

Dyflos, Sarin and Novichock.
Very toxic organophosphates.
Absorbed through the lungs and the skin.
Irreversible.
WAR!

45
Q

What is the MoA of irreversible anticholinesterases?

A

Bind to catalytic site of AChE… covalently bind Serine-OH group.
= Not hydrolysed, so AChE recovery depends on enzyme re-synthesis.

Which can take weeks!!

46
Q

How can you be rescued from cholinergic crisis?

A

Pralidoxime.
Strips the bound organophosphate (Sarin, Dyflos, Novichock) from the enzymes catalytic site…
But needs to be done immediately!!!

47
Q

What are the therapeutic uses of Anticholinesterases?

A

Used to overcome non-depolarising block at the end of anaesthesia…
Used to be treatment for Myasthenia Gravis (Edrophonium).

Overcome muscarinic receptor block in Datura or Belladonna poisoning.

Increase cholinergic signalling in Alzheimer’s.

48
Q

What is Myasthenia Gravis?

A

Production of auto-antibodies that destroy nicotinic ACh receptrs in NMJ.

That causes skeletal muscle weakness, eyelid drooping, weak limbs + diaphragm.
Contraction of muscle isn’t sustained and becomes weaker.

Antibodies generated from modified muscle cells with nACh receptors expressed, on the surface of thymus gland…

49
Q

How can Myasthenia Gravis be treated?

A

Neostigmine, Pyridostigmine.
= Medium-Duration Anticholinesterases (competitive inhibitors to active and catalytic site, slowly hydrolysed).

Glucocorticoids, immunesuppressives, thymectomy…

50
Q

What are the side effects of Neostigmine/Pyridostigmine?

A

Improves muscle contraction in Myasthenia Gravis… Overcome anaesthesia from non-depolarising block BUT!

Cause muscle twitching, autonomic side effects like salivation, bradycardia, GI disturbance…

You need to administer with antimuscarinics like Hysocine.

PNS (14 decks)

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