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local anesthetic



drug that reversibly blocks impulse conduction along nerve axons and other excitable membranes that utilize voltage-gated Na channels as primary means of AP generation


binding to other receptors (Ca, K, adenylate cyclase, NMDA) is potentially important but currently poorly understood


characteristics of the "perfect local anesthetic"

  • non-irritating
  • transient effect
  • low systemic toxicity
  • quick onset
  • action able to span duration of surgery


structure-activity relationship

1. aromatic ring : lipophilic group

2. intermediate chain : ester vs amide

  • account for diffs in metabolism and allergenicity

3. ionizable group (usually tertiary amine)


local anesthetics are...weak acids/weak bases?


which one


weak BASES (pKa usually 7.6-9)

  • the more acidic the pH, the more base in BH+ form
  • the more basic the pH, the more base in B (neutral) form

only neutral can diffuse to site of action BUT the charged form is the active form


mechanism of action of local

  • block Na channels in excitable membranes without changing resting potential
    • reduce aggregate inward sodium current


modulated receptor hypothesis

LAs have higher affinity for receptors in activated and inactivated states (versus resting state)

  • binding is a function of the conformation state of the channel

implication: fibers that fire at raster rate → more susceptible to effects of LAs

  • repeated depol leads to more effective anesthetic binding
  • aka "Frequency Dependent Block"


key properties of LAs

1. lipophilicity : more lipophilic → more potent, longer duration of action (and slower onset of action)

2. pKa : higher pKa → slower onset of action

3. protein binding : more protein binding → longer duration of action

  • high potency, hydrophobic drugs tend to be highly bound to serum and tissue proteins → longer duration of action


clinical uses of LAs

1. topical use (benzocaine, cocaine)

2. infiltration 

3. regional anesthesia/analgesia

  • peripheral blocks
    • plexus anesthesia (single injection or continuous infusion)
    • individ nerve blocks
    • IV regional (Bier block)
  • neuraxial blocks
    • spinal (low vol, usually single injection)
    • epidural/caudal (high vol - single injection or continuous infusion)


differential blockade

different nerve fiber types (A, B, C) vary in their sensitivity to LAs

  • likely results of combination of geographic arrangement of nerve fibers  and intrinsic sensitivity of nerve fiber types


in vivo studies are more clinically relevant and consistent than in vitro studies

in clinical practice, incremental increases in local anesthetic conc result in progressive interuption of

  • autonomic pain fibers [most sensitive]
  • sensory fibers
  • motor fibers [least sensitive]


neuraxial blockade


peripheral blockade


neuraxial blockade order:

  • autonomic/pain
  • sensory
  • motor

peripheral blockade

  • motor block
  • proximal sensory loss
  • distal sensory loss

why? peripheral motor fibers are more peripheral, while sensory are more central; proximal sensory fibers are further outside, distal sensory fibers are further inside


PK of local anesthetics



role of vasoconstrictors

absorption, distribution, elimination varies from classical paradigm


  • site-dependent
  • ICE-BS : intercostal, caudal, epidural, brachial plexus, sciatic nerve blocks

role of vasoconstrictors: epi, phenylephrine

  • decreases absorption (irrespective of site of inj) → can prolong effect of shorter acting drugs
  • also used as a test dose to make sure you're not accidentally injecting intravascularly! (if you are, HR will rise within 2 min)



PK of local anesthetics



esters: plasma pseudocholinesterase → derivatives: PABA

  • pl pseudocholinesterase enzyme def may lead to protentiation of action
  • usually have a short duration of action

amides: liver, cytochrome P450, water soluble metabolites, urinary excretion

  • low flow states to liver (via portal HTN, CHF, etc) decreases delivery of LAs to liver → decreased amide LA metabolism, increased lifetime and serum conc


adverse effects of LAs

1. system toxicity

2. local (neural tissue) toxicity

3. allergic rxns

4. methemoglobin formation


system toxicity

results from effects of LA on excitable membranes and tissues (other than target nerves)

  • range of effects proportional to serum LA concentration

manifests first as CNS tox → cardio tox

  • CNS tox : tinnitus, preioral numbness, blurred vision, metallic taste, change in mental status, convulsions
  • cardiotox : mostly with bupivicaine (ropivacaine less tox, more safe)
    • depression of excitability + doncution (ventricular + prolonged QRS) as well as arteriolar dilation (Ca channel effect)
    • systemic acidosis or hypercarbia, incre sensitivity to LA tox
    • pregnancy : incr sensitivity to LA tox
  • rescue via IV lipid emulsion


local toxicity

neural tissue injury

  • high concentrations of LA for extended periods can lead to nerve tissue destruction via membrane damage, cytoskel disruption, etc
    • NOT due to blockade of Na channel
  • leads to motor and sensory loss
  • can lead to paralysis, paresis


transient neurological symptoms

  • transient pain syndrome associated with spinally administered Lidocaine and certain surgical positions (ex. lithotomy)
  • NOT associated with motor/sensory loss
  • self-ltd neuropathic pain syndrome



Prilocaine metabolines (O-toluidine) act as an oxidizing agent to convert Hb+2 to Hb+3

Benzocaine has also been implicated


see chocolate colored blood

pulse oximiter @ 85% saturation


tx: methylene blue


allergic rxns


PABA → hapten formation → true IgE mediated allergy


do not form the same metabolites, no hapten formation

allergic rxns are rare


methylparaben (preservative) can cause allergic rxns irrespective of LA type




cocaine: stimulant, vasoconstrictor

benzocaine: primarily topical, MetHb potential

tetracaine: long duration, potent; mostly used for spinal anesthesia, toxic at relatively low doses (except to short-acting ester rule)

procaine (Novocain)quick onset, short duration; hypersensitivity rxns and TNS implication (so rarely used)

chloroprocaine: used to have a lousy rep but now a commonly used quick onset, short duration LA



lidocaine: quick onset, moderate duration; tox/TNX implication

mepivacaine: longer duration than lidocaine, lowest pKa of injectable LAs, acts as vasoconst

prilocaine: assoc with methemoglobinemia, component of EMLA

bupivacaine: excellent long dur LA with devastating potential for cardiac tox (sensory > motor block)

bupivacaine SR: liposomally encapsulated for delivery up to 72hr/dose

ropivacaine: single enantiomer, long dur LA with props similar to bupivacaine but with less cardiotox; acts as vasoconst

EMLA: eutetic mix of LA (Prilocaine/Lidocaine) for topical anesthesia

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