Test 3: Local Anesthetics Basic Overview (pt 2) Flashcards
Ions pass through pore channels in the ______. _____ channels are the most significant. (Blue Box!)
Ions pass through pore channels in the axolemma. Na+ Channels are the most significant.
What is Resting Membrane Potential?
The voltage difference across a membrane.
-An ionic imbalance between ECF and ICF (axoplasm) that causes an AP.
-Maintained by Na/K ATPase
-Axolemma is permeable to K efflux (pushing K out to maintain negative charge intracellularly)
-Axolemma is impermeable to Na
What is the normal resting membrane potential for a neuron in microvolts?
-70 to - 90 mV.
Describe the process of an action potential being created.
-Stimulation causes sudden influx of Na+, hit threshold, and depolarization occurs.
-K+ channels open rapidly
-Membrane potential rises to +20 mV
-Na channels close at the peak, but K+ channels stay open, and K exits the cell down its concentration gradient.
-Na/K ATPase actively removes intracellular Na (3 Na leave the cell for each 2 K that enter)
-K+ passively diffuses back into the cell to restore RMP.
Local anesthetics preferentially bind to both the ____ and ___________ states of the Voltage Gate Na Channel. (Blue Box!)
LA’s preferentially bind to both the OPEN & INACTIVATED states of the Nav.
When does the Resting (Closed) State occur?
When the membrane is at its resting membrane potential.
-Channel is closed.
What is the Open (active) state?
Action potential leads to the opening of the resting channel to allow passage of Na+ into the cell.
-Reversal of membrane potential until threshold is reached
-Conformational change in the proteins that compose the channel occurs, and it opens.
-LA can bind to the pore channel from the intracellular side in this state.
What is the Inactive State?
The inactivation gate closes the channel pore from the intracellular side, and the channel inactivates.
-Marked by the return of V-G Na Channels to an impermeable state, preventing the initiation of an AP.
-Lasts until the restoration of RMP
-LAs can still work in this state.
Where do Local Anesthetics bind?
LA’s bind reversibly to receptors within or adjacent to the internal opening of the NaV.
-Intracellular receptors have an inc affinity for ionized form of LA.
-Once the LA enters the lipid bilayer, intracellular pH is more acidic, so the LA is driven towards its ionized form. Which is good, because that is what can bind to the receptor.
What are the 2 pathways to the binding site?
-Hydrophilic: Through the pore interior. (If the pore happens to be open, it can go down and through the channel itself).
-Hydrophobic: Through the lipid membrane.
What are the actions of the LA after it binds to the receptor?
-Stabilizes the inactivated state of the channel, preventing further activation
-Can also bind inside the pore and prevent ion flux (“Open State Block”).
Why are Local Anesthetics called “Use Dependent”?
-LA’s work faster as the Nav is repetitively depolarized
-Greater # of Nav are in the inactivated & open state
-🡹 opportunity for LA binding = accumulation of LA bound Nav
Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials. Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers.
Local anesthetics also effect GPCRs, causing what effects?
-Affects intracellular Ca signaling pathways
-Inflammatory modulating actions result from interruptions in these pathways.
Local Anesthetics also suppress Polymorphonuclear Leukocyte priming, which does what?
-An additional inflammatory modulating action of LAs.
-Prevents overactive inflammatory responses without impairing host defenses or suppressing normal inflammation.
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What are the two stages of Polymorphonuclear leukocyte priming?
PMNL are activated via a two stage process (granulocyte type WBC):
-Priming – first encounter with a stimulus
-Full active – second encounter with a stimulus. Prevents overactive inflammatory responses.
How does Ca++ channel binding result in significantly less potent LA effects?
Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state).
How does K+ channel binding effect LAs?
From Katzung:
Increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.
List the components of a differential block in order of first onset of blockade to last.
-Autonomic Function
-Pain
-Touch
-Temperature
-Motor Function
-Proprioception
List the components of a differential block in order of first to recover -> last to recover.
-Proprioception
-Motor function
-Temperature
-Touch
-Pain
-Autonomic Function.
What factors can affect block onset?
-Dose of the drug (Depth of the blockade)
-Multi-layered membrane around the nerves
-pKa of the drug
-pH of the tissues
-Generally: myelinated fibers are blocked before non-myelinated
Why are myelinated fibers blocked before non-myelinated?
Myelin increases the diffusion barrier BUT only need to block the nodes of ranvier versus the entire length of the nerve.
