Local Anaesthetics Flashcards
Describe pain transmission along axons
Pain causes stretch in neurons which leads to AP firing in nociceptors
Na+ moves in
K+ starts to move
Depolarises sequentially
Why cant the AP move back in the direct it comes from?
It leaves a hyperpolarisation behind it
What are the nodes of ranvier?
Spaces between myelin sheaths where Na+ receptors are located at high density
What is saltatory conduction?
APs jumping between nodes of ranvier instead of smooth flow
How are APs recorded using current clamp methods?
Electrode goes in the cell and ground
Different between these is the AP
Which channels are open at rest to establish the resting membrane potential?
K+
Why does the Na+ influx occur first?
Because the K+ channels respond more slowly to voltage
Outline the structure of the VGNC
24 membrane spanning domains forming a main alpha subunit
With 4 voltage sensors in the 4th TMD
Re-entrant pore loop
How do ions pass through the VGNC?
Arrive with a hydration shell which they lose when they travel through the channel
They then get re-hydrated on the other side
Explain how a VGNC opens
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+
What is the H gate?
The inactivation particle
This is positively charged nd binds to the channel in the same manner as Na to inactivate it
What are the three main configurations of an ion channel?
Open and active
Open and inactive
Closed and not active
What are the diff types of VGNC?
Na(v) 1.1 - 1.9
Are LAs lipophilic or hydrophilic?
Amphipathic
What is the basic explanation of LA action?
Binds to Na channels when inactive
So sodium cant
So the channel can’t be activated
Which mutations are found in inherited erythromelalgia?
N395K (Sheets et al 2007)
L858H
Which conditions are caused by NaV1.7 mutations?
Inherited erythromelalgia
Paroxysmal extreme pain disorder
Congenital insensitivity to pain
Where are NaV1.7’s mostly expressed?
DRG
What is seen in NaV1.7 KO mice?
Increased mech and thermal thresholds
Reduced inflam responses
Are NaV1.7 mutations in increased pain loss of function or gain of function?
Gain
L858H and N395K show more AP firing in the DRG
Waxman 2007
Why is the grasshopper mouse cool af?
Mutation in the NaV 1.8 channel which means it cannot be recruited by NaV1.7 to propagate pain signals further
How should bark scorpion venom normally work?
It should bind to the NaV1.7 channel
This is then activated and recruits NaV1.8 to propagate the signal
Which key structure is present in all local anaesthetics?
Aromatic ring adding to lipid solubility
Intermediate chain which joins this to the amina
Which part of the LA attracts protons?
The intermediate chain between the aromatic ring and the amine
What is the ester portion of the LA metabolised by?
Psuedocholinesterase in plasma and liver
What is the amide portion of the LA metabolised by?
P450s
What happens to the amide once is accepts the proton?
Becomes more positively charged
Becomes water soluble
Cant cross the cell membrane
Infected tissue is more alkaline than healthy tissue
T/F
F
Infected tissue has a lower pH and is more acidic than healthy tissue
Why do LAs not work as well in infected tissue?
Lower pH means more charged LAs which cant cross the membrane as well
Which fibres are most easily blocked by LAs?
Small, myelinated
What may charge lidocaine derivatives target?
TRPV1
Binshtok et al 2007
Why would charged lidocaine derivatives be preferable to lidocaine?
More selective so as to not cause motor control and numbness
What compound may assist QX-314 entry into cells? Why do we think this?
Capsaicin
Because Capsaicin appears to enhance the entry of FM1-43 dye which is a similar size and charge to QX-314
Why must QX-314 act via TRPV1 channels
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
What is SVmab1?
Antibody selective to NaV1.7
Is SVmab1 an effective anaesthetic?
Reduces inflammatory pain in the presence of formalin without affecting motor/balance
How is SVmab1 different from other antibodies?
Can be given IV without it being degraded
