Local Anaesthetics Flashcards
what do nerve and muscle cell produce for electrical excitability
- they generate propagated action potentials
what is the purpose of the action potentials?
in nerve cells: communication in nervous system
in muscle cells: initiation of mechanical activity in cardiac and striated muscle
When does the voltage-gated sodium channels open?
they open transiently when membrane is depolarised
why Na+ can only enter the cells intracellularly through a sodium channel?
- they are ions vs phospholipid mem
- always from extracellular (more Na outside) to intracellular
- resting potential inside cell is negative
3 types of voltage-gated sodium channel receptor states that prevents Na+ from entering the cell
- inactivated state: ion flow blocked by gating mechanism (BUT not the closing of the channel itself)
- deactivation state: ion flow blocked by closing of the channel + gate closed
- resting (closed) state: channel is closed
what are the four receptor states of a voltage-gated sodium channel?
- closed (gating mechanism not closed, channel closed)
- activated
- inactivated (gating mechanism closed)
- deactivated (both gating mechanism and channel closed)
what is the MOA of LA?
stop axonal conduction by blocking sodium channels in the axonal membrane when applied locally in appropriate concentration –> prevent sodium ion entry –> slow down or bring conduction to a halt
- bind mostly to inactivated and activated states
note: the passage of train of action potentials causes the open [activated] and inactivated states of VG sodium channels –> causing the depolarisation which causes the pain signal to be activated
how does the LA enter the cell and causes its therapeutic action?
LAs are weak bases; which converts into more into B form in physiological pH and enters the cell through the phospholipid membrane
inside the cell, the B protonates to B-H+ to be able to exert its therapeutic action
why is LA’s MOA based on use-dependency?
its depth of LA nerve block is more potent/better with increased frequency of action potentials (more cycles of open [activated] and inactivated states) as:
- it can gain access to the channel more readily when channel is open
- have higher affinity for the inactivated than for the resting (closed) channels
e. g. when person is in more pain compared to the rest
LA binds to which VG sodium channels?
- they are non-selective modifiers of neuronal function –> block action potentials in ALL neurons that they have access to
how to achieve selectivity for LAs?
deliver the LA to a limited area
what are the factors affecting LA’s action
- more lipid soluble drugs are more potent and act longer
- more hydrophobic: tetracaine, etidocaine, bupivacaine
- less hydrophobic: lidocaine, procaine, mepivacaine
Acts on all nerves BUT:
- size: smaller > bigger
- myelination: myelinated > non-myelinated
- freq of firing: high (sensory) > low (motor)
- position: circumferential (skin surface) > deep (large nerve trunk)
- pH dependency
- LA are weak bases (pKa 8-9), mainly (but not completely) ionised at physiological pH
- in alkaline pH –> increased LA activity (low proportion of ionized molecules)
- acidic pH –> decreased LA activity (high proportion of ionized molecules)
(pH is IMPT in LA penetrate nerve sheath and axon membrane to reach the inner end of the sodium channel (LA binding site))
which axons will LA have greater potency?
small myelinated axons > small non-myelinated axons > large myelinated axons
therefore,
nociceptive & sympathetic transmission is blocked first (their axons are small +/- myelinated)
which fibre types have greater sensitivity to block by LAs? (most sensitive [++++] to +++)
- type C dorsal root (pain): diameter 0.4-1.2um; no myelination [++++]
- type C sympathetic (postganglionic): diameter 0.3-1.3; no myelination [++++]
- type B (preganglionic autonomic): diameter <3um; light myelination [++++]
- type A delta (pain & temp): Diameter 2-5um; heavy myelination [+++]
what are the names of the ester LA?
Cocaine, Procaine (Novocain), Tetracaine (Pontocaine), Benzocaine
