Pharmacology of local anaesthetics / Flashcards
How is resting membrane potential of axons maintained?
Na+/K+ ATPase pump - 3Na+ out, 2K+ in
K+ channel allows K+ diffusion either in or out of the axon
Voltage gated Na+ channel (VAGNaC) activation (m) gate closed, inactivation (h) gate open
Creates electrochemical gradient - resting membrane potential around -70 mV
What occurs in the membrane during and after an action potential?
m gate of VGNac channel open rapidly in response to voltage > m gate and h gate open = VGNaC open
Na+ influx > further depolarisation
AP is propagated
Repolarisation
h gate closes slowly in response to same voltage > m gate open, h gate closed > VGNaC inactivated > no Na+ current > increased K+ efflux > repolarisation
What happens to the VGNaC during refractory periods?
m gate closes rapidly in response to voltage
m gate and h gate closed = VGNaC closed but reactivating
h gate slowly opens in response to same voltage
m gate closed and ha gate open = VGNaC closed but resting
Resting membrane potential restored
VGNaC channels closed and activatable
Intra and extracellular concentrations of Na and K+ do not change greatly during the AP
Sodium pump preserves Na+/K+ gradient
What is the general mechanism of local anaesthetics?
Prevent generation and transmission of impulses along nerve fibres
More effective at smaller fibres - Ad and C
Targets VGNaCs
Channel blocker
What is the hodgkin-huxley model of VGNaCs?
Depolarising open channel > inactivated form
Repolarising inactivated channel > resting
Depolarising resting channel can either form open or inactivated form
Two voltage sensitive gates - m (activation) and h (inactivation) determine function of channel
Interaction of LAs on VGNaC
Different states of VGNaC have different structures and affinities
LAs binds to and stabilises the inactivated form of VGNaC
Increases proportion of refractory VGNaCs
What are LAs dependent on?
pH dependence
Use-dependence
Voltage-dependence
Use-dependence of LAs
Repeated stimulation of channel leads to increased binding of LAs > increased inhibition
LAs are therefore more effective when either open or inactivated
When rub and area, LAs will be able to have faster onset in that area
pH dependence of LAs
LAs are weak bases
The more acidic the pH the slower the onset of the block
At low pH, more protonated form
At high pH, more unprotonated form
Uncharged form crosses membranes more easily
Access to channel via hydrophilic pathway on cytoplasmic side
Inflamed tissue more acidic - LAs more preferential to inflamed areas
How do neutral LAs e.g. benzocaine get into the cell?
Via the hydrophic pathway - through fenestrations in the channel wall
Not pH dependent
Voltage dependence of LAs
More effective at more depolarised potentials
With charged drugs, when AP is passing through, positive charge on inside and negative charge outside (opposite to resting) allows drug to be driven from cytoplasm into open channel via the hydrophilic pathway
Strong depolarisation increases the rate of onset of block
What can local anaesthetics be used for?
Local anaesthetics: therapeutic, facilitation, diganosis
Anti-epileptic drugs
Anti-dysrhythmic drugs
What are the use of LAs as local anaesthetics?
Analgesics: reduce pain and sensation
Surgical procedures (facilitative): avoids use of general anaesthesia
Other procedures: epidural, catherisation, endoscopy
How do LAs work as anti-epileptic drugs?
Selectivity arises due to use-dependent properties of LAs
During seizures, overload of neuronal activity, more the neurone fires, the more sensitive it is to LAs
It is systemic - everywhere in body, but at a concentration where it only makes a difference to neurones that are firing excessively
LAs as anti-rhythmic drugs
e.g. lidocaine
treatment of abnormal cardiac rhythms
- Dysrhythmias normally due to damage to heart due to tissue ischemia
- Damage dependent on location, duration and extent of ischaemia
- Damaged tissue slows AP transmission, so lasts longer than other neighbouring APs, and the refractory zone behind the electrical wave front that prevent transmission in any direction > ectopic beats, fibrillation
- Increased inactivated VGNaC in damage area
LAs preferentially target and block inactivated channels, suppresses all conduction in affected area, prevent ectopic beats, fibrillation etc.
