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)
At physiologic pH (~7.4), the higher the pKa of the LA, the (less/more) ionized it will be and the (faster/slower) the onset.
more
slower
In cases where the tissue is more acidic (such as in an infected region)
lower local pH → LA is more ionized
slows the onset & may decrease effectiveness
dont memorize
understand concept/trends
higher pka = less unionized = less crossing membrane = slower onset
Voltage-gated Sodium Channels
structure
alpha subunit: 4 additional subunits
additional beta subunits (external)
alpha subunits open the channel
Voltage-gated Sodium Channels
structure at 0 mv
inactivated
inactivation gate into mouth of channel
The inactivation gate plugs the channel closed until…
all protein subunits change conformation to close mouth of channel themselves
(the gate essentially stops ion influx while the proteins work on closing the channel)
contains the sodium pore
The alpha subunit
Local anesthetics bind to & stabilize which form?
open, inactivated
When is the LA binding site exposed?
when the channel is open
How do LAs affect the inactivation gate?
makes it harder for the gate to separate/unplug the channel
the LA will eventually diffuse away when the channel opens if concentration gradients favor that
The beta subunits fxn
stabilize the channel
not part of the opening of the channel
T/F
The 4 alpha subunits are actually one continuous protein structure.
True
Selectivity filter
selects which particular ions that can pass thru
Why are C fibers so much slower?
unmyelinated
small diameter
Benefit of C fibers
unmyelinated = LAs can block easily bc no obstructing myelin
T/F
LAs cannot cross the myelin sheath.
False
they can, but takes a lot longer
First fibers that tend to be blocked
C fibers
How does diameter affect:
susceptibility to LAs
speed of conduction
↑ diameter = less susceptible & faster conduction
Autonomic preganglionic fibers
B fibers
Motor fibers
Aa fibers
fastest condxn
myelinated
largest diameter
If we give enough LA to block motor fxn….
potential respiratory issues
Low LA doses are more likely to block (pain/motor)
pain
T/F
C fibers recover before Aa fibers do.
False
C fibers = first to be blocked
Aa fibers = last to be blocked
recovery is in the opposite order
Use as antiarrhythmic agents is due to
-blockade myocardial Na+ channels
-decreases firing rate
-decreases signal passage thru conductive fibers
topical use
decrease pain of wounds, burns, mucous membranes
infiltration
injected around area - i.e. - for surgery
regional nerve block
injected close to nerve that innervates the area to be anesthetized
spinal
injected into lumbar subarachnoid space to get to nerves in that area going to various body sites
epidural
given inside spine above the dura mater
intravenous use
usually for surgery on a specific limb
T/F
Selection of agents is mainly based on its pharmacodynamics.
False
pharmacokinetics
Which are fast? Which are slower?
Procaine
prilocaine
tetracaine
lidocaine
usually fastest: lidocaine & prilocaine
slower: Procaine and tetracaine
shortest duration
Procaine and chloroprocaine
15 - 30 minutes
intermediate durations
lidocaine and prilocaine
30-90 mins
long duration
tetracaine
2-3 hours
Effect of epi on doA
EPI may be used to increase duration, but is not always effective.
fastest onset when applied to mucous membranes
Benzocaine
followed by lidocaine & cocaine
Topical duration of most
30 - 60 minutes
Other targets besides Na channels
K+ Channels
Ca++ channels
NMDA receptors
G-protein receptor complexes
Nicotinic Ach receptors
most common cause for LA cessation of action
swept away in bloodstream
moved thru body & metabolized/destroyed
This receptor is a/w the anti-inflammatory effect of LAs
G-protein receptor complexes
K+ Channels
-Mainly amides
-more intense blockade
Ca++ channels
antiarrhythmic action of lidocaine?
NMDA receptors
Lidocaine antagonism (via a metabolite?)
analgesic-effect
Action at this receptor enhances NMB (insignificantly)
Nicotinic Ach receptors
T/F
Adding epi will increase systemic effects of the LA.
False
increases duration of effect at that local site
Topical blood flow is (higher/lower) than most other tissues, so the LA is removed (faster/slower) here.
higher
faster
All agents are ___ or ___.
esters
amides
All LAs contain
an aromatic ring
Having an amine makes a compound more (acidic/basic).
basic
Lipophilic and hydrophilic regions
Lipophilic group = aromatic ring
Hydrophilic group usually an amine (ionizable)
Lipophilic and hydrophilic groups are joined by…
an ester or amide
The ester/amide linkage between the lipophilic and hydrophilic regions determine (2)
metabolism
allergic potential
Increasing lipid solubility results in what 2 effects?
faster onset
increased duration
Altering groups besides the ester/amide linkage results in…
alters metabolism rate and other effects.
Most important factor in limiting toxicity
metabolic rate
(wont be around long enough to cause toxicity)
Esters
Metab
-plasma esterases (ie: plasma cholinesterase)
-Also by liver esterases & other tissue esterases
Spinal agent
metab
spinal fluid lacks esterases
intrathecal injxns remain active until absorbed back into systemic circulation
T/F
esters are not metabolized in spinal fluid.
True
Amide
metab
mainly liver CYP enzymes
e.g. CYP1A2, CYP3A4
Which is more protein bound?
ester
amide
amide
Amide
protein binding
55-95%
Mostly alpha-1 acid glycoproteins
affects toxicity!
low protein levels = higher tox risk
Lung uptake of amide LA’s also important in limiting toxicity
T/F
Lung uptake of ester LA’s is also important in limiting toxicity.
False
amide
Amide LAs
Factors that increase/decrease toxicity
Increases: smoking, trauma, cancer, etc
Decreased: oral contraceptives, neonate
T/F
Amides are uptaken by the lungs and metabolized partially there.
False
yes uptaken
but not metabolized there
The Esters
Procaine (DC’ed)
Proparacaine (Alcaine) – used as an ophthalmic
Chloroprocaine
Tetracaine
Cocaine
Benzocaine
Cetacaine
Procaine (Novocain) (DC’ed)
First synthetic local anesthetic.
Slower onset
short duration
weak potency
Fairly low systemic toxicity
Best for infiltration and nerve block.
Use superceded by better agents (amides).
Chloroprocaine (Nesacaine)
fastest & shortest acting
Low systemic toxicity
pKa 9.0
but
Rapid onset b/c high [ ]s used!
Direct acting vasodilator (shortens doA)
For infiltration, nerve block, IV and epidural use.
Used in high concentration solutions (since toxicity is low)
Chloroprocaine (Nesacaine)
Tetracaine (Synera – w/ Lidocaine for topical)
⚠️Ten times more potent than procaine, but also ten times more toxic.
Long duration with slow onset.
spinal anesthesia (decrease diffusion & toxicity)
absorption across mucous membranes limits use as topical
❌sulfonamide Abx: m’lite (aminobenzoic acid) inhibits sulfonamide action
Avoid in patients taking sulfonamide antibiotics
Tetracaine (Synera – w/ Lidocaine for topical use)
applying this agent topically risks crossing mucous membranes
Tetracaine (Synera – w/ Lidocaine for topical use)
Cocaine
C-II
from coca leaves
only topical b/c too toxic
potent vasoconstrictive activity & addiction liability along with LA effect
topically:
-mucous membranes (nasal/oropharyngeal cavities preop)
-packed post-op: decrease bleeding & pain
Benzocaine (Oragel) (many other tradenames)
Poorly water soluble, so only topical
pKa ~ 3.5
⚠️Excessive absorption risk methemoglobinemia
Cetacaine (Cetylite)
Topical agent for local skin disorders
for various mucous membranes (except eyes)
mixture of Benzocaine, Tetracaine, and Butyl Aminobenzoate used topically, rectally or as a spray to inhibit the gag reflex
(ie: bronchoscope exam).
Amides
Lidocaine
Prilocaine
Bupivacaine
Ropivacaine
Mepivacaine
Articaine
Lidocaine (Xylocaine)
Most common LA
Rapid onset
intermediate duration
-vasodilates so often mixed w/ EPI
Transient Neurologic Symptoms
reported worse with which agents?
lidocaine and mepivacaine
(versus prilocaine, bupivacaine or procaine)
Transient Neurologic Symptoms
Transient hyperalgesia after spinal anesthesia
Treat pain w/ NSAIDs
Mechanism unclear (direct neurotoxic effect?)
Prilocaine
Similar to lidocaine, but less vasodilation
Rapid onset
intermediate duration
Least toxic of the amides, but can still cause methemoglobinemia
Least toxic of the amides, but can still cause methemoglobinemia
Prilocaine
Which has higher risk of methemoglobinemia?
Esters
Amides
amides
Bupivacaine (Marcaine)
Long duration
slower onset
High potency
(More toxic than Lidocaine (cardiotoxic)
Most likely to cause adverse effects
infiltration, epidural, spinal
Bupivacaine (Exparel) – liposomal formulation
interscalene brachial plexus block
single-dose postop infiltration
postop regional
(not for IT, epidural use)
Not recommended <18 yrs, pregnancy, hepatic disease
Which amide is most likely to cause adverse effects?
Bupivacaine (Marcaine)
Ropivacaine (Naropin)
Long duration
(similar to Bupivacaine, but less cardiotoxic)
S-isomer (vs. bupivacaine(racemic) has a more cardiotoxic R-isomer)
Less lipid soluble
more rapidly metabolized (vs Bupivacaine)
Uses similar to Bupivacaine (infiltration, nerve block, epidural, spinal)
Ropivacaine vs Bupivacaine
Ropiv = less toxic (S isomer)
Bupiv = racemic; has R isomer (more toxic)
ropiv = less lipid sol.; faster metab
BOTH:
infiltration, nerve block, epidural, spinal
similar structures
Mepivacaine (Carbocaine)
Uses Similar to lidocaine
(infiltration, nerve block, epidural)
Not effective topically
Racemic mixture
(structurally similar to Bupivacaine & Ropivacaine)
❌ OB: biotransformation in fetus is prolonged.
“no Mepiv for Mommy”
Racemic mixtures
Mepivacaine
Bupivacaine
Articaine (Septocaine)
Only in U.S. with EPI.
Similar to Lidocaine
short duration
rapid onset
Low systemic toxicity
(rapid breakdown: ester group along w/ amide)
Used for dental and periodontal procedures.
Which amide also has an ester group?
Articaine (Septocaine)
Pramoxine (Proctofoam)
Not a true amide or ester
for pts w/ amide/ester sensitivity
Topical:
hemorrhoids, rectal pain, itching (pruritus)
Weak potency (will not totally abolish gag reflex)
Mixed in combination with many products (ex. Hydrocortisone, calamine).
Which LA will not cause enough numbing of the gag reflex?
Pramoxine (Proctofoam)
mostly for topical hemorrhoids & itching
Local hypersensitivity reactions more common with
ester type
Some preps include ….., which also increase sensitivity risk
tartrazine and sulfites
Systemic absorption
cardiotoxic risk
potential CNS symptoms
(sedation, dizziness, disorientation, tremors, seizures, respiratory arrest)
Neurotoxicity more common in
epidural/subarachnoid
Cauda Equina syndrome & Transient Neurologic Symptoms
T/F
Topical agents are safer as they do not carry risk of methemoglobinemia.
False
Methemoglobinemia possible with topical anesthetics
Methemoglobinemia
mechanism
Oxidize hemoglobin to ferric (+3) instead of normal ferrous (+2) state
(prilocaine, benzocaine, lidocaine, Cetacaine)
Agents w/ risk of methemoglobinemia
prilocaine
benzocaine
lidocaine
Cetacaine
Except for allergic or hypersensitivity reactions, actual risk for most patients is fairly low due to …
their use in small amounts in a localized area for most procedures
Lipid Rescue
-systemic toxicity
-known overdose
-accidental IV injxn
Intralipid: soybean emulsion
10%, 20%, 30%
lacks strong evidence
mechanism not fully understood
T/F
Lipid rescue mechanism of action is not completely understood.
True
What do we actually know? fr
T/F
The antidote for poor regional technique is lipid rescue.
False
gotta have skillz
Future Local Anesthetics
-Exploitation of other mechanisms (QX-314)
-Selective Na channel blockers
(specific to axon & avoid 🩷)
-Targeted dose forms with magnetic carriers
(target specific site)
