the pharmacology of local anesthetics

lecture given 4/13/2026 or 4/14/2026, who knows anymore

local anesthetics

agents that prevent or relieve the sensation of pain by interrupting never conduction in peripheral nervous tissue

bind reversibly to a specific receptor site within the pore of Na+ channels in nerves and block ion movement through this pore

what do local anesthetics do when applied locally to nerve tissue?

reversibly block nerve conduction on any part of the nervous system and on every type of nerve fiber in the area innervating causing both sensory and motor paralysis

cocaine!

first local anesthetic discovered

unique in class due to selective effect to block reuptake transporter for amines

sympathomimetic effects- vasoconstrictor

addicitive potential

what are the required characteristics of local anesthetics?

block nerve conduction reversibly

no tissue damage

hydrophilic property for aqueous formation and solubility in interstitial fluid- conferred by tertiary amino group pKa 8-9

lipophilic property for penetration of nerve sheath and membrane- conferred by aromatic ring

how is local ansesthetic distributed into the nerve fiber membrane?

administered outside a nerve trunk or into a nearby extracellular region for diffusion into nerves

must diffuse through many membranes to get to the cytosol of the neuronal axon

the aromatic ring on local anesthetics is…

lipophilic

the linker on local anesthetics is…

an ester or amide

the amine on local anesthetics is…

hydrophilic

when local anesthetics do not have a terminal amino group they have ______ and are formulated in______ for ______ administration

low aqueous solubility

ointements, gels

topical administration

ester local anesthetic characteristics

deesterificaition

pseudocholinesterase in plasma and tissues

inactivation hydrolysis

NOT in CNS

amide local anesthetic characteristics

n-dealkylation

CYP450 oxidation in liver

ClT affected by hepatic blood flow, hepatic disease

some metabolites may contribute to toxicity (de-ethylated metabolites of lidocane cause sedation)

which statement describes the major difference between an ester and amide type local anesthetic?

a) the amides have an aromatic group to enhance their diffusion into the neuron

b) esters are eliminated and unchanged by renal clearance mechanisms

c) the esters have a tertiary amino group that can be protonated for formulation of an injectable solution

d) amides are eliminated from the body by metabolism in the liver

d) amides are eliminated from the body by metabolism in the liver

a is true but esters also have an aromatic group

nerve conduction

mediated by a change in voltage across the membrane that allows for a change in Na+ permeability

increased Na+ permeability depolarizes the axonal membrane leading to conduction of an impulse along the axon

the change in the axonal membrane permeability is mediated by a voltage-induced alteration in the structure of the neuronal Na+ channel protein

what is the mechanism of action of local anesthetics?

prevent increased membrane permeability to Na+ thereby inhibiting membrane depolarization

interact with amino acids within the pore of alpha subunit

impair channel opening to Na+ influx and enhance channel inactivation

nonselective block of the Na+ channel (as well as other voltage- gated and ligand gated ion channels) contributes to their toxicity

where is sodium conduction through voltage- gated sodium channels inhibited when local anesthetic is used?

along axonal membrane of unmyelinated fibers (Na+ channels are uniformly distributed along the axonal membrane)

at nodes of ranvier in myelinated fibers (Na+ channels are clustered at the nodes)

what is the structure of Na+ channels?

a single alpha subunit that forms a pore and 2 beta subunits

how do large biological toxins like tetrodotoxin (TTX) and saxitoxin (ScTX) inhibit Na+ conductance?

binding to extracellular sites on Na+ channels

tell me about the alpha subunit of the neuronal sodium channel?

4 repeat transmembrane domains (I-IV)

each domain contains 6 membrane spanning segments (S1-S6)

S4 is a voltage sensor that moves towawrd the extracellular side of the membrane in response to a change in transmembrane voltage

S4 movement increases membrane permeability to ions

what is the specific binding site of local anesthetics?

amino acids in S6 of domains I, III, IV on the intracellular side of channel pore

how do local anesthetics distribute into nerve fiber?

they are weak bases (pKa from 7.5-9.0) formulated as salts for increased aqueous solubility and stability

predominantly in the charged, cationic form at physiologic pH

uncharged form readily diffuses across the neuronal membrane

in the cytoplasm, the charged form binds the active site in Na+ channel and produces anesthesia

more lipophilic drugs are (more/less) potent and have a (shorter/longer) duration of action

more, longer

rank lidocaine, procaine, mepivacaine, and bupivacaine in order of longest duration

bupivavaine > lidocaine > mepivacaine > procaine

distribution into nerve fiber is (increased/decreased) by lower pKa

increased

lower pKa associated with faster onset time

distribution into nerve fiber is (increased/decreased) with inflammation-induced drop in tissue pH

decreased

more drug is protonated

tldr on inflammation and local anesthetic

reduces efficacy

lowers pH, which may slow drug diffusion through nerve membranes to target site

may provide other mechanisms which may contribute to decreased efficacy (increased blood flow, decreased catecholamine effectiveness, ect)

which statement(s) describes the chemical characteristics that enhance(s) the distribution of a local anesthetic into a nerve fiber?

a) the greater the LA lipophilicity, the greater its potency

b) the higher the LA pKa, the faster its onset time

c) the greater the LA lipophilicity, the longer its duration of action

d) the lower the pH of the injection site, the faster its onset time

a) the greater the LA lipophilicity, the greater its potency

c) the greater the LA lipophilicity, the longer its duration of action

t/f different types of neurons have different sensitivities to LA agents

true

which diameter fibers are the least sensitive

largest- the larger the fiber, the greater the distance between the nodes of ranvier

*in myelinated fibers, ___ nodes must be blocked to inhibit impulse propagation

3

what is the order in which nerve fiber types are blocked?

small myelinated > small unmyelinated > large myelinated > large unmyelinated

what is the order of loss of function?

pain → temperature → touch → proprioception → skeletal muscle tone

conduction blockage is greater in nerves that (have been/have not been) recently depolarized, compared to (resting/active fibers)

have been, resting

access and/or binding of local anesthetic to active site is greater when the channel is open or inactivated

frequently firing pain fiber (ad or C) have higher sensitivity compared to motor efferent fiber (Aa)

higher firing rate results in…

more inhibition- greatest inhibition of Na+ current occurs with the application of the electrical pulses with the greatest frequency

why do analgesia and sympatolytic effects of local anesthetic precede motor paralysis?

noxious stimuli and sympathetic nervous system transmissions are typically encoded in bursts of impulses

motor function usually uses low-frequency discharges

what position fibers (circumferential or core) get blocked first?

circumferential fibers

in large mixed nerve bundles in extremities, proximal sensory fibers are _____, distal are more _____

this means during infiltration block, sensory and analgesia begin _____ and spreads _____

circumferential, core

proximally, distally

which of the following statements correctly describes the relative selectivity of local anesthetic agents?

a) LAs block circumferential fibers before fibers in the core of the nerve bundle

b) LAs have lower affinity for activated and inactivated channels than Na + channels at rest

c) large diameter fibers are more sensitive to LA blockade than small diameter fibers

d) use dependence of LAs preferentially targets motor efferent fibers that mediate skeletal muscle tone

a) LAs block circumferential fibers before fibers in the core of the nerve bundle

local anesthetic system toxicity

CNS effects- tremor, restlessness, convulsions

cardiac effects- decreased automaticity, myocardial depression

vascular effects- arteriolar relaxation

only ______ blocks presynaptic transporters for NE and DA and casues sympathomimetic effects and euphoria

cocaine

what is the antidote for local anesthetic systemic toxicity?

20% lipid emulsion IV

what are the risk of hypersensitivity reactions with ester type agents?

cross reactivity among ester type agents

attributed to para aminobenzoic acid metabolite (PABA)

solution preservative methylparaben also metabolized to PABA

what are the risk of hypersensitivity reactions with amide type agents?

no risk

preservatives (methylparaben, sulfites) may elicit allergic response

what are effects for block of non-sensory nerves?

decreased blood pressure due to sympathetic block following spinal injection in lumbar region

skeletal muscle paralysis

the most important effect of inadvertent in intervenous administration of a large dose of an amide local anesthetic is:

a) bronchoconstriction

b) hepatic toxicity

c) renal failure

d) seizures

e) tachycardia

d) seizures

the rate of local anesthetic absorption into the blood stream depends on…

dose, vascularity of the injection site, and presence of a vasoconstrictor

what is the mechanism of action of vasoconstrictor use in local anesthetics?

a1 receptor activation decreases blood flow at the injection site

reduces absorption rate of local anesthetic into systemic circulation (bloodstream)

adds risk of vasoconstrictor side effects (hypoxia and local tissue damage)

what are the effects of vasoconstrictors?

increases duration of local anesthetic effect- increases neuronal uptake and decreases the rate of absorption into the bloodstream

decreases risk of local anesthetic side effects in brain and cardiovasculature

the addition of a vasoconstrictor such as epinephrine, to a solution of local anesthetic will:

a) decrease the risk of a seizure

b) increase the duration of the anesthetic effect

c) both a and b

d) neither a nor b

c) both a and b

what are the routes of administration of local anesthetics?

topical, injection, central block spinal or epidural

topical local anesthetic

administration to skin and mucous membranes

formulated as a patch, solutions, ointments, creams, gels

eg lidocaine, benzocaine

infiltration injection local anesthetic

intraderma, subcutaneous, and/or intramuscular administration to block sensory nerve endings in operative field (lidocaine, procaine, bupivacaine)

peripheral nerve block injection local anesthetic

injection near single nerve or nerve plexus to anesthetize its area of innervation (procaine, lidocaine, mepivicaine, bupivacaine)

iv injection local anesthetic

short term regional anesthesia in limb isolated by tourniquet (lidocaine)

central block spinal local anesthetic

injection into subarachnoid space (CSF)

provides anesthesia to a relatively large fraction of the body with a dose that produces negligible plasma levels (lidocaine, tetracaine, bupivacaine)

specific gravity of injection solution and position of patient controls the upward diffusion of the drug

may be combined with intrathecal opioids for improved pain management

decreased blood pressure due to LA block of the preganglionic sympathetic fibers causing vasodilation

risk of transient neurological syndrome (backache)

central block epidural local anesthetic

injection into the space between the dura of the spinal cord and the periosteal lining of the spinal canal

onset of anesthesia is slower than subarachnoid injection

where is a spinal block injected?

into CSF in the subarachnoid space of the spinal canal

where is an epidural block injected?

outside the dura

caudal block

epidural block where the needed is inserted into the caudal canal

*what is the duration (in min) of pulpal anesthesia using 2% lidocaine?

30

*what is the duration (in min) of pulpal anesthesia using 2% lidocaine with epi?

60

*what is the duration (in min) of pulpal anesthesia using 3% mepivacaine?

30-60

*what is the duration (in min) of pulpal anesthesia using 2% mepivacaine with levon?

60

what is the duration (in min) of pulpal anesthesia using 4% prilocaine?

30

what is the duration (in min) of pulpal anesthesia using 4% prilocaine w epi?

>90

what is the duration (in min) of pulpal anesthesia using 1.5% etidocaine w epi?

>90

*what is the duration (in min) of pulpal anesthesia using 0.5% bupivacaine w epi?

>90