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BMSC - Anaesthetics and Analgesia > Local Anaesthetics > Flashcards

Local Anaesthetics Flashcards

1
Q

Describe pain transmission along axons

A

Pain causes stretch in neurons which leads to AP firing in nociceptors
Na+ moves in
K+ starts to move
Depolarises sequentially

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2
Q

Why cant the AP move back in the direct it comes from?

A

It leaves a hyperpolarisation behind it

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3
Q

What are the nodes of ranvier?

A

Spaces between myelin sheaths where Na+ receptors are located at high density

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4
Q

What is saltatory conduction?

A

APs jumping between nodes of ranvier instead of smooth flow

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5
Q

How are APs recorded using current clamp methods?

A

Electrode goes in the cell and ground

Different between these is the AP

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6
Q

Which channels are open at rest to establish the resting membrane potential?

A

K+

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7
Q

Why does the Na+ influx occur first?

A

Because the K+ channels respond more slowly to voltage

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8
Q

Outline the structure of the VGNC

A

24 membrane spanning domains forming a main alpha subunit
With 4 voltage sensors in the 4th TMD
Re-entrant pore loop

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9
Q

How do ions pass through the VGNC?

A

Arrive with a hydration shell which they lose when they travel through the channel
They then get re-hydrated on the other side

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10
Q

Explain how a VGNC opens

A

Positive amino acids means the transmembrane regions attract to the inside of the membrane
The depol of the cell reduces the attraction making space for Na+

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11
Q

What is the H gate?

A

The inactivation particle

This is positively charged nd binds to the channel in the same manner as Na to inactivate it

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12
Q

What are the three main configurations of an ion channel?

A

Open and active
Open and inactive
Closed and not active

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13
Q

What are the diff types of VGNC?

A

Na(v) 1.1 - 1.9

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14
Q

Are LAs lipophilic or hydrophilic?

A

Amphipathic

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15
Q

What is the basic explanation of LA action?

A

Binds to Na channels when inactive
So sodium cant
So the channel can’t be activated

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16
Q

Which mutations are found in inherited erythromelalgia?

A

N395K (Sheets et al 2007)

L858H

17
Q

Which conditions are caused by NaV1.7 mutations?

A

Inherited erythromelalgia
Paroxysmal extreme pain disorder
Congenital insensitivity to pain

18
Q

Where are NaV1.7’s mostly expressed?

A

DRG

19
Q

What is seen in NaV1.7 KO mice?

A

Increased mech and thermal thresholds

Reduced inflam responses

20
Q

Are NaV1.7 mutations in increased pain loss of function or gain of function?

A

Gain
L858H and N395K show more AP firing in the DRG

Waxman 2007

21
Q

Why is the grasshopper mouse cool af?

A

Mutation in the NaV 1.8 channel which means it cannot be recruited by NaV1.7 to propagate pain signals further

22
Q

How should bark scorpion venom normally work?

A

It should bind to the NaV1.7 channel

This is then activated and recruits NaV1.8 to propagate the signal

23
Q

Which key structure is present in all local anaesthetics?

A

Aromatic ring adding to lipid solubility

Intermediate chain which joins this to the amina

24
Q

Which part of the LA attracts protons?

A

The intermediate chain between the aromatic ring and the amine

25
Q

What is the ester portion of the LA metabolised by?

A

Psuedocholinesterase in plasma and liver

26
Q

What is the amide portion of the LA metabolised by?

A

P450s

27
Q

What happens to the amide once is accepts the proton?

A

Becomes more positively charged
Becomes water soluble
Cant cross the cell membrane

28
Q

Infected tissue is more alkaline than healthy tissue

T/F

A

F

Infected tissue has a lower pH and is more acidic than healthy tissue

29
Q

Why do LAs not work as well in infected tissue?

A

Lower pH means more charged LAs which cant cross the membrane as well

30
Q

Which fibres are most easily blocked by LAs?

A

Small, myelinated

31
Q

What may charge lidocaine derivatives target?

A

TRPV1

Binshtok et al 2007

32
Q

Why would charged lidocaine derivatives be preferable to lidocaine?

A

More selective so as to not cause motor control and numbness

33
Q

What compound may assist QX-314 entry into cells? Why do we think this?

A

Capsaicin

Because Capsaicin appears to enhance the entry of FM1-43 dye which is a similar size and charge to QX-314

34
Q

Why must QX-314 act via TRPV1 channels

A

Enhanced by capsaicin
Doesn’t work on motor neurons (no TRVP1)
Cap + QX-314 greatly increased mechanical pain threshold vs either of them alone

Binshtok et al 2007

35
Q

What is SVmab1?

A

Antibody selective to NaV1.7

36
Q

Is SVmab1 an effective anaesthetic?

A

Reduces inflammatory pain in the presence of formalin without affecting motor/balance

37
Q

How is SVmab1 different from other antibodies?

A

Can be given IV without it being degraded

BMSC - Anaesthetics and Analgesia (8 decks)

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