Local Anesthetics Flashcards
lipophilicity of the ______ controls the compounds ability to ….
aromatic group
penetrate the nerve sheath and enter the nerve membrane
Most LAs are ____ & can exist as …. (2)
ionizable weak bases
freebase
or
positively charged form
(this will affect their action at the site)
MoA as antiarrhythmic
decrease sodium entry
alters conductivity
can increase/decrease HR
Which part of neuron do they act on?
axon (lipid soluble)
can cross at other places but the axon has high [ ] of Na channels
why their lipophilicity is so important?
determines ability to penetrate nerve membranes
Most preparation solutions are ____.
weakly acidic
T/F
Most LAs have an amide structure.
False
they’re amines
(ionizable weak bases)
can bond to another H and become charged
What happens to an LA in acidic conditions?
LA = weak base
will pick up + (H) in an acidic environment
become charged/ionized
now harder to cross lipid bilayer (nerve)
The non-pronated form of an LA is also called
the freebase form
How to get quicker onset
alkalinization prior to use (add bicarb)
↑ free base form = ↑ lipid solubility & ↓ onset
Placing LAs in an acidic environment makes it more (water/lipid) soluble.
water
which compounds show the greatest benefit of alkalinization prior to use?
LAs with longer onset
Once the LA crosses the axon, what must happen?
must convert to ionized form so it can bind to the inside of the Na channel and exert its effects
T/F
alkalization prior to use increases lipid-soluble molecules that can penetrate the axon & also increases the amount that can be converted to ionized form and bind to the inside of the channel.
True
more will enter the cell and thus more is available to convert to ionized and bind to inside of channel
T/F
LAs irreversibly block the generation and propagation of nerve impulses.
False
reversibly
primary location of effect
the axon
d/t its high density of sodium channels
T/F
LAs can alter both sensory & motor fxn.
true
bi-directional blockade
block function in all excitable cells
can alter sensory and motor function
The decrease in pain, temperature, and touch perception, skeletal muscle tone is mostly d/t….
decreased stimulation of the muscle’s motor neuron
local effect plays a part but not primary
Level of effect depends on
agent used
route of administration
drug concentration at site (prob #1)
lipophilicity
T/F
A drug can still be a good LA even if its not lipophilic
False
has to cross the membrane
routes
topically: skin. mucous membranes
parenteral: peripheral, central, spinal
rectally
ophthalmically
Cocaine isolated from
South American plant
Erythroxylon coca
1800’s
first synthetic local developed
Procaine
What gives cocaine its medical use?
potent vasoconstrictor
ie: nasal packing (LA effect & reduces bleeding)
Cocaine’s basic structure led to …
development of synthetic compounds that did not have its toxic or addictive action
Noted for its high [ ] of Na channels
the axon
Normal resting potential
~ -80 mv (most cells)
Ion [ ]
ICF & ECF
Primary contributor to resting charge
K+ channels
only channel open at rest
K+ channels (some of them, not all)
Dendritic Conduction
is a (passive/active) electrical process
passive
Axonal Conduction
is a (passive/active) electrical process
active
“Axon = Active”
Response from the cell body depends on… (2)
how many Na ions enter
where they enter (closer to body = more likely response)
Cell body vs Axon
signal regeneration
no regeneration in cell body
axon = signal constantly regenerated
Axonal Conduction
-Active electrical process
-voltage-gated Na+ & K+ channels
-Some Ca++ also (mostly terminal)
-Na/K/ATPase: restore chemical (ionic) equilibrium
-Signal initiated at axon hillock by internally ligand-gated Na+ channels
T/F
At the axon, the charge slowly diffuses out.
False
This applies to dendrites
axon = constant regeneration; no concern for charge diluting out or slow process of diffusion
T/F
The charge first initiated at the axon will equal the charge that reaches the nerve terminal.
True
charge from dendrite → axon may not be equal
but
charge from axon → terminal will be equal
T/F
As the signal is passed down the axon, Na+ comes in & K+ exits. This restores ion concentrations.
False
this restores net voltage
Na/K/ATPase restores ion [ ]s
Na/K/ATPase
MoA
cleaves ATP to obtain energy for:
3 Na out
2 K in
restores ion [ ]s
Signals are initiated at ____ by …
axon hillock
internally ligand-gated Na+ channels
The axon hillock contains ___ gated Na channels while the axon contains ___ gated Na channels
hiLLock = Ligand
axon = voltage
Are C fibers myelinated?
No
T/F
Myelination decreases the amount of energy needed.
True
Schwann cells vs Oligodendrocytes
Schwann cells: wrap their membrane around nerve (PNS)
Oligodendrocytes: 1 cell can myelinate multiple nerves (brain); helpful bc limited space in brain
what allows for saltatory conduction?
deficit in charge
proper spacing of myelin sheaths
(too far = charge can’t jump
too close = don’t get max benefit)
T/F
a signal generated at the hillock can travel backwards towards the cell body.
False
but
if we take a probe and stimulate near terminal the signal can travel backwards toward the cell body/axon hillock
Factors leading to increased conduction rates:
-Myelination (most important)
(↓ Capacitance; Saltatory Conduction)
-less neg. resting potential (closer to threshold)
-↑ Na+ channel density
-↑ Axonal diameter (less resistance to flow)
MoA
mainly believed to be…
(Classical hydrophilic pathway):
-enters axon by diffusion in uncharged form
-re-ionizes in cytoplasm
-binds to the inside opening of open, inactivated sodium channels
blocks channel & repulses Na entry d/t positive charge
MoA
Hydrophobic pathway
uncharged LA molecule enters
binds to locations on sodium channel that are located within the membrane
(e.g. Benzocaine)
MoA
Alternative hydrophilic pathway
permanently charged LA can interact with other channels triggering their opening and allowing a pathway for the charged local anesthetic to enter
(ie: QX-314)
Quaternary amine
Nitrogen w/ 4 bonded Carbon structures
not ionizable bc it is permanently charged
won’t solubilize across membranes
can use pores/channels
can then bind to inside of channel bc its charged
Ie: QX-314
The (uncharged/charged) form of an LA is the active form.
charged
QX-314 acts on which receptor?
TRPV1 (vanilloid, capsaicin)
benefit of using permanently charged (quat amines)
once inside cells, can bind to inside of Na channel (if they’re the correct shape)
not directly limited by lipophilicity
All agents act to…
decrease the permeability of the membrane to sodium ions
Some K+ inhibition also
LAs bind to ____ gated Na channels, and inhibit Na inflow during ___.
voltage
depolarization
“holds” the plug & makes it harder for channels to open up completely again
T/F
LA bonding is covalent.
False
competitive
so its dependent on [ ]
T/F
LAs can diffuse out of the cell if ECF [ ] is much lower than ICF, restoring normal conduction.
True
T/F
LAs can damage the axon terminal.
False
Effect of LAs @
High vs. Low [ ]
(ICF)
Low = ↓ rate of rise & height of AP (fewer Na channels working normally)
Higher = can abolish it totally
↑ Firing threshold & total propagation time
In myelinated fibers, LA effects only occur at …
the Nodes of Ranvier
LA binding site
intracellular mouth of the transmembrane voltage-gated sodium channels
LA’s are too big to cross through pores into cell so they must diffuse across lipid membrane UNLESS …
its small enough to utilize certain pores such as the TRPV1
All LA’s are ____.
weak bases
may be ionized at physiologic pH
onset time can be predicted by (2)
which 2 LAs are the exception?
pKa & local tissue pH
benzocaine & chloroprocaine
Which LA can we not use internally & why
benzocaine
methemoglobenemia
base w/ very low pka 3.5
permanently UNcharged at any phys. pH
Why is chloroprocaine different in predicting onset?
relatively weak & nontoxic
so
we use large doses which makes comparison of its onset difficult
Henderson Hasselbach equation for bases (LAs)
pH = pKa + log [B]/[HB+]
🔷
All LA’s have pKa’s in range of
7.6 – 9.0
Benzocaine is the exception (3.5; almost entirely unionized at physiologic pH)