Chapter 12

-schwann cells – peripheral nervous system; afferent or efferent nerve fibers, myelinated or
nonmyelinated
 Voltage gated Na channels
 Nodes of ranvier – myelinated axons
-oligodendrocytes/glial cells – CNS

-resting membrane potential: -60- -70 mV. Na/K pump actively cotransports 3 Na ions out of
cell for every 2 K ions into cell. (passive diffusion is opposite). Maintains resting potential.
-initial depolarization  inc in Na permeability  accelerates depolarization with inward Na
current  triggering action potential
-propogation of impulse is unidirectional
-repolarization: dec in driving inward Na current, inactivation of voltage gated Na channels.
Membrane depolarization activates voltage gated K channels (outward)  returns to
hyperpolarization.

-local anesthetics – bind to specific region on alpha subunit. This prevents VG na activation 
inhibiting inward Na current that mediates membrane depolarization
-more local anesthetic = more inhibiting inward Na current for depolarization, inhibiting
threshold membrane potential  can’t get action potential; does not activate resting
membrane potential nor threshold potential

-local anesthetics must reach neural membrane (penetrate perineural tissue) to bind VGna
channels – 1-2% of local anesthetic reach.
-clinical progression of sensory/motor fxn blockage: first temperature > proprioception > motor
function > sharp pain > light touch
-susceptibility to block: small myelinated fibers > large myelinated fibers > small non myelinated
C fibers
-first proximal, then distal anesthesia diffusion of local anesthetic

-local anesthetics: weak bases, pos charge, hydrophobic group connected to hydrophilic group
by ester/amide
-aminoamide or aminoester, alkyl substitutions (aromatic or amine group, charge of amine
group, etc – determines potency, onset/duration of action, tendency to differential nerve block
-inc lipid solubtility – enhaces penetrating local anesthetic.
-anesthetics prepared in HCl salts (acidic) – inc solubility, stability, esp with epinephrine. This
slows penetration of cell membrane, delays onset of conduction block. May have to add Na
bicarb to inc onset/quality of conduction block (works on intermediate anesthetics, not long
acting/potent ones).
-adding epi to lidocaine – vasoconstricting (alpha 1), antagonizes vasodilating effect of
anesthetics. Dec vascular absorption facilitates/maintains intraneural local anesthetic uptake.
 Enhances quality of conduction block, prolongs duration of action
 Limits peak systemic toxic effects
  Adds 50% effect to lidocaine, no effect to bupivacaine (based on physiochemical
properties of local anesthetic and site of injection).
 Can add analgesic effects through interaction with alpha 2 adrenoreceptrs in CNS 
activating endogenous analgesic mechanics
-clonidine – direct a2 agonist, direct inhibitory effects on neural conduction (A and C peripheral
nerve fibers). Potential of brady/orthostatic hypotension.

-for any given site of administration – greater total dose of local anesthetic = greater systemic
absorption and peak plasma level; not based on speed of injection or anesthetic concentration
-more potent, lipid soluble local anesthetics = less systemic absorption
-adding epi = less systemic effects

-redistribution to highly perfused organs – brain, lung, heart, liver, kidneys. Beta phase (slower
redistribution) – muscle, gut.
-lower doses in arterial than venous injections cause systemic toxic effects

-elimination: aminoamides metabolized by liver (p450 via n-delakylation, hydroxylation), renal

excretion of metabolites
-aminoester local anesthetics metabolized by plasma cholinesterase; procaine and benzocaine
metabolized to PABA
-unbound drug can cause systemic effects – higher in low protein states (newborn, prego,
cirrhosis, acidosis – cardiac arrest, seizures, renal failure).
-some meds – beta blockers, h2 R, fluvoxamine inhibit hepatic enzymes – dec local anesthetic
metabolism

Toxicity:
-CNS: anesthetics cross BBB  drowsiness, tingling, tremors, twitching, conulsions.
-CVS: can lead to hemodynamic instability  myocardial depression, arteriolar vasodilation,
dysrhythmias, impaired ANS regulation, hypotension
 Require larger doses to cause toxicity
 more potent lipid soluble local anesthetic has greater toxicity
 bupivacaine vs lidocaine - much more able to cause cardiovascular collapse b/c of how
long it binds to VG na channels (minimal accumulation in lidocaine, dissociates
quickly)
Treatment of toxicity:
-use minimum effective dose to avoid systemic toxicity
-basic tx for CNS is supportive. If needed, oxygenate, maintain airway. Convulsions lead to
metabolic acidosis, hypoventilation, hypoxemia, hypercarbia  exacerbate CNS toxicity. Can
give propofol/midazolam. If not available, can terminate convulsions w/NMBA
(Succinylcholine).
-CVS toxicity: maintain O2, coronary perfusion pressure. If ventricular dysrhythmias develop 
amiodarone > lidocaine. In severe CVS collapse/toxicity by bupivacaine – can tx with IV
intralipid emulsion.
Neural Toxicity/Myotoxicity: can lead to lumbosacral subarachnoid space  cauda equine
syndrome, transient neuro sx.
-also destruction of myocytes, esp in extraocular muscle damage in eye surgery

-allergies rare but can occur with aminoester anesthetics (metabolism by allergen, PABA)

Local Anesthetics:
Aminoamide:
1. Lidocaine
-for infiltration, peripheral nerve block, IV regional anesthesia (biers block), central neuroaxial
(subarachnoid, epidural).
-rapid to intermiediate onset of action, intermediate duration action for peripheral nerve
block/epidural anesthesia
-IV at low plasma levels – systemic analgesia, blunt SNS response to laryngoscopy/intubation;
also dec burning of propofol
-infusions: chronic neuropathic pain, acute post op pain
-patch: neuropathic postherpetic neuralgia (superficial nocioreceptors)

2. Mepivacaine
-ring of cocaine and ring of lidocaine – slightly longer duration of action than lidocaine b/c less
vasodilation
-topically – ineffective
-spinal anesthesia – lower TNS than lidocaine
-metabolism of fetus/neonate prolonged – no use in OB

3. Bupivacaine
-lipid soluble, methyl group on piperidine ring.
-slower onset than lidocaine (most potent), prolonged duration of action.
-Prolonged sensory anesthesia, analgesia in infusions – used for labor epidural analgesia and
acute postop pain
-single injections for PNS block – surgical anesthesia for 12 hours, sensory for 24 hours.
-subarachnoid anesthesia use (unlike lidocaine) – 2-3 hours, rare TNS

4. Prilocaine
-used for infiltration, peripheral nerve blocks, spinal, epidural anesthesia
-high clearance – least systemic toxicity of amides.
-high doses – methemoglobinemia (treat with IV methylene blue). Limit widespread use.

5. Ropivacaine –
-structurally similar to bupivacaine, mepivacaine but with propyl group, S-enantiomer.
-potency for neural blockage but less cardiotoxicity than bupivacaine. Inherent vasoconstricting
effect – less CVS toxicity, augment duration.
-epinephrine has no effect, similar with bupivacaine
Aminoester Local Anesthetics:
1. Procaine
-infiltration, spinal anesthesia (subarachnoid)
-slow onset of action (high pka), short duration action – limited use.
-maybe use for subarachnoid anesthesia? Low TNS. + Nausea.

2. 2-Chloroprocaine
-low potency, rapid metabolism by cholinesterases – used in high concentrations with lowest
systemic toxicity
-high concentration = rapid onset of surgical anesthesia. No transmission to fetus  good for
epidural (csection, etc).
-inc popularity for ambulatory spinal (subarachnoid) anesthesia – rapid onset, duration action.
-LOW TNS

3. Tetracaine
-potent, slow onset and long duration of action
-duration prolonged with + epinephrine (unlike bupivacaine).
-rare for epidural/peripheral nerve block – slow onset, lack dissociation with significant motor
block
-used for extended duration spinal subarachnoid block

4. Cocaine
naturally occurring, used for topical to ear, nose, throat procedures – intense vasoconstriction
to reduce bleeding
-inhibits neuronal reuptake of Norepi  neurogenic vasoconstrictive effects.
-CVS side effects: hypertension, tachy, dysrhythmias.

Eutectic Mix of Local Anesthetics (EMLA):

-mix of lidocaine/prilocaine, 2.5% concentration each – viscous liquid (EMLA)
-low melting point than either individually – exist at room temp as OIL  penetration,
absorption through dermis
-EMLA cream: dermal analgesia, dec pain with venipuncture of IV catheter place. Only to intact
skin surface
-application to breached skin: rapid systemic absorption