2.

3-02
August 14, 2013
Frederick C. Loyola, M.D. CNS Pharmacology II:
I've become so numb, I can't feel you there.
Local Anesthesia

SECTION PAGE
I. Local Anesthesia 1
A. Chemistry 1
B. Pharmacokinetics 1
1. Absorption 1
2. Distribution 2
3. Metabolism and Excretion 2
C. Pharmacodynamics
1. Mechanism of Action 2
a. Toxins Acting on Na+ Channels 2
2. Structure-Activity Characteristics 2
3. Neuronal Factors Affecting Block 2 Constituents of local anesthetics – lipophilic group (left),
4. Other Actions 3 intermediate chain (center), ionizable group (right)
D. Clinical Uses 3
E. Toxicity  Weak bases (pKa = 8)
1. Tachyphylaxis 3  Clinically available as salts   solubility and stability
2. Organ Level Effects 3  Forms:
F. Amide-Type Local Anesthetics 3-4 o Ionized (protonated)
 Most active form at receptor site
G. Ester-Type Local Anesthetics 4
 Cannot readily exit from closed channels
II. Review Questions 5
o Non-ionized (non-protonated)
 Important for rapid penetration of biologic
TRANSMASTER'S NOTE membranes to produce clinical effects
References: Katzung 10th and 12th, lecture
 Italic – transmaster's notes PHARMACOKINETICS
 Aminoester anesthetic
LOCAL ANESTHESIA o Elimination half-life of <1 minute
 Loss of sensation in a limited region of the body  ROA
 Accomplished by disruption of afferent neural traffic via o Parenteral
inhibition of impulse generation or propagation o Topical application
 May be associated with physiologic changes:  Transmucosal
o Muscle paralysis  Transdermal
o Suppression of somatic or visceral reflexes
 Primary goal – achievement of localized analgesia ABSORPTION
 Depends on several factors:
A* L* G* o Dosage
LOSS OF SENSORY MODALITIES - + + o Site of injection
DIRECT ACTION - + -  Vascular area (e.g. mucosa)  rapid absorption
*A – analgesic; L – local anesthetic; G – general anesthetic  Tendon, dermis, fat  slow absorption
o Drug-tissue binding
 Achieved with a narrow spectrum of compounds o Local blood flow
 Recovery o Vasoconstrictors (epinephrine)
o Spontaneous  Effects of  blood flow in area:
o Predictable ‒  systemic absorption from site
o No residual effects ‒  localized neuronal uptake
 Cocaine – first local anesthetic ‒  systemic toxic efffects
 Action on CNS α2 adrenoceptors  inhibits
CHEMISTRY substance P release   sensory neuron firing 
 Constituents: enhances and prolongs spinal anesthesia
o Lipophilic group (aromatic ring)  Significant in short-acting or intermediate-acting
o Intermediate chain local anesthetics
 Ester ‒ Procaine
 Amide ‒ Lidocaine
o Ionizable group (tertiary amine) ‒ Mepivacaine
 Less effect on lipid-soluble long-acting agents
‒ Bupivacaine
TRANSMASTER'S NOTE
‒ Ropivacaine
To determine whether a local anesthetic is an aminoester
o Physicochemical properties of the drug
or an aminoamide, check the number of i's in the drug name.
An aminoester only has one i in its name (e.g. procaine)
while an aminoamide has two (e.g. lidocaine). DISTRIBUTION
1. LOCALIZED
 Injection into subarachnoid space  diluted in CSF

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 Spread within subarachnoid space – dependent on
specific gravity of anesthetic relative to CSF
o Hyperbaric – anesthetic descends
o Isobaric – static
o Hypobaric – anesthetic ascends
2. SYSTEMIC
 Two-compartment model
o Alpha (rapid distribution) phase
 Uptake into highly perfused organs:
‒ Brain
‒ Heart
‒ Kidneys
‒ Liver
 Steep exponential decline in concentration
o Beta (slow distribution) phase
 Uptake into less well-perfused tissue:
‒ Gastrointestinal tract
‒ Muscles
 Slower, nearly linear rate of decline
METABOLISM AND EXCRETION
 Conversion into water-soluble metabolites
 Non-ionized form
o Readily diffuses into lipid membranes
o Little to no urinary excretion
o Acidification  ionization   urinary excretion
 Amide-type local anesthetics
o Converted by amidase in liver
o Complex biotransformation
 Hydroxylation
 N-dealkylation
o Varied rate of hepatic metabolism (fastest to slowest)
 Prilocaine > lidocaine > mepivacaine > ropivacaine
= bupivacaine and levobupivacaine
o  liver blood flow   hepatic elimination of anesthetics
o  risk of hepatotoxicity
 Ester-type local anesthetics
o Rapidly hydrolyzed by plasma butyrylcholinesterase
to inactive metabolites  very short serum half-life
PHARMACODYNAMICS
MECHANISM OF ACTION
 Blockade of voltage-gated Na+ channels (in activated
and inactivated states but not in rested state)
  extracellular Ca2+  Ca2+-induced  surface potential on
membrane (favors rested state)
  extracellular K+  membrane depolarization (favors
inactivated state)   local anesthetic effect
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CNS Pharmacology II: Local Anesthesia
 Bind with low affinity and poor specificity
o Can also act on:
 Other ion channels
‒ K+
‒ Ca2+
 Enzymes
‒ Adenylate cyclase
‒ Carnitine-acylcarnitine translocase
 Receptors
‒ NMDA
‒ G protein-coupled
‒ 5-HT3
‒ NK1
TOXINS ACTING ON Na+ CHANNELS
MARINE TOXINS
 Tetrodotoxin (puffer fish) and saxitoxin (dinoflagellates)
 Bind externally to "ready" state of Na+ channels in
both cardiac and neuronal membrane   conduction
 Similar effects to those of local anesthetics
OTHER BIOLOGIC TOXINS
 Batrachotoxin (frogs), ciguatoxin (Moray eel), aconitine,
veratridine, and scorpion venom
 Bind internally to receptors in Na+ channel  prevents
inactivation   Na+ influx and persistent depolarization
STRUCTURE-ACTIVITY CHARACTERISTICS
 Smaller and more lipophilic local anesthetics
o Faster rate of interaction with Na+ channel receptors
o More potent
o Longer-acting
o High protein binding
o  latency (takes longer to achieve effects)
FACTORS AFFECTING BLOCK
 Fiber diameter and firing frequency
o Preferential blockade of:
 Smaller fibers
 Fibers with high firing frequency
o Myelinated fibers  blockaded first
 Blockade of 2-3 successive nodes of Ranvier 
halts impulse propagation
o Larger fibers   resistance to blockade
o Sequence of blockade
 Type B (myelinated, small-diameter)
 Type C (unmyelinated, small-diameter, fast-firing)
 Type A delta (small-diameter)
 Type A beta and gamma
 Type A alpha (large-diameter)
 Motor fibers (large-diameter, slow-firing)
 Anatomic arrangement
o Large mixed nerve trunks
 Motor fibers
‒ Located circumferentially
‒ Exposed first to local anesthetic
‒ Blockaded before sensory fibers
o Nerve trunks in extremities
 Proximal sensory fibers
‒ Located in outer portion of trunk
‒ Infiltration block  sensory analgesia develops
proximally and spreads distally
OTHER ACTIONS
 Limit ability of patient to:
o Cooperate during osbtetric delivery
o Ambulate after outpatient surgery
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 CNS Pharmacology II: Local Anesthesia

 Spinal anesthesia o Electromechanical dissocation

o Motor paralysis  impaired respiratory activity o Reversed with intravenous lipid emulsion
o Autonomic blockade  hypotension upon ambulation
 Weak neuromuscular blocking effects 4. HEMATOLOGIC EFFECTS
 Anti-arrhythmic (lidocaine)  o-toluidine
 Lethal arrhythmias at high levels (bupivacaine, ropivacaine) o Prilocaine metabolite
o Oxidizing agent
CLINICAL USES o o-toluidine accumulation  methemoglobinemia
 Infiltration  cyanosis and "chocolate-colored" blood
 Peripheral nerve blockade  Reversed with reducing agents (methylene
 Central neuraxis blockade blue or ascorbic acid)
 Intravenous regional anesthesia
o Bier block 5. ALLERGIC REACTIONS
o Used for short surgical procedures involving upper  Caused by para-aminobenzoic acid derivatives
and lower extremities o Metabolites of ester-type local anesthetics
 Infiltration block of autonomic sympathetic fibers
o Used in sympathetic tone evaluation in peripheral AMIDE-TYPE (AMINOAMIDE) LOCAL ANESTHETICS
vasospastic disorders (Buerger's or Raynaud's d/o)
 Used in conjunction with vasoconstrictors ARTICAINE
 Dental anesthetic
TOXICITY  Thiophene ring
o Unique characteristic
 Major forms:
o  lipophilicity
o Systemic effects after absorption from injection site
o Better tissue penetration
o Direct neurotoxicity from local effects of drugs
 Ester inclusion  shortens plasma half-life in <20 minutes
administered close to spinal cord or major nerve trunks
 better therapeutic index

TACHYPHYLAXIS
BUPIVACAINE
 Repeated injections   buffering capacity of local tissues 
 Excellent choice for spinal anesthesia
extracellular acidosis   extracellular cationic form of
 Used to achieve prolonged peripheral anesthesia and
anesthetic  loss of effectiveness (tachyphylaxis)
analgesia for post-operative pain control
o Common in areas with limited buffering (e.g. CNS)
 Used in epidural infusions for post-operative pain control
and labor analgesia
ORGAN LEVEL EFFECTS   risk for cardiotoxicity
1. CENTRAL NERVOUS SYSTEM EFFECTS
 Low concentrations: ETIDOCAINE
o Sleepiness
 Limited application due to its poor block characteristics
o Dizziness or lightheadedness
o Tends to produce inverse differential block
o Sensory (visual and auditory) disturbances
o Restlessness
 Circumoral and tongue numbness LEVOBUPIVACAINE
 Metallic taste  S-enantiomer of bupivacaine
 Higher concentrations:  Less cardiotoxic than bupivacaine
o Nystagmus  Better sequestration in "lipid sink"  better toxicity reversal
o Muscular twitching
o Overt tonic-clonic seizures LIDOCAINE
 Depression of cortical inhibitory pathways   Intermediate-acting anesthetic
unopposed excitatory activity  Reference standard agent of local anesthetics
o Generalized CNS depression   risk for transient neurologic syndrome

2. NEUROTOXICITY
 Direct neural toxicity
o Pooling of high concentrations of local anesthetic in
cauda equina  transient radicular irritation
 Transient neurologic symptoms (TNS)
o Sudden transient pain or dysthesia linked to
lidocaine use for spinal anesthesia
3. CARDIOVASCULAR EFFECTS
  strength of cardiac contractions
 Arteriolar dilation  systemic hypotension
 Cocaine
o NET (NE reuptake) blockade   norepinephrine 
vasoconstriction, hypertension, arrhythmia
o Local ischemia
o Ulceration of mucous membranes
 Bupivacaine-induced cardiotoxicity
o Slow idioventricular rhythm
o Broad QRS complexes
MEPIVACAINE
 Structurally similar to bupivacaine and ropivacaine
 Vasoconstricting tendencies > vasodilating tendencies
 Slightly long-acting – useful in major peripheral blocks
PRILOCAINE
 Spinal anesthetic
 Highest clearance among aminoamide local anesthetics 
 systemic toxicity
 ortho-toluidine metabolite  methemoglobinemia
ROPIVACAINE
 Propyl group off the piperidyl ring
 Useful in high-volume peripheral blocks
 Used in epidural infusions for control of labor and post-
operative pain
 Less cardiotoxic than bupivacaine

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 CNS Pharmacology II: Local Anesthesia

ESTER-TYPE (AMINOESTER) LOCAL ANESTHETICS COCAINE

 First local anesthetic
BENZOCAINE  Restricted to topical anesthesia in ear, nose, and throat
 Topical anesthetic with high lipophilicity procedures
 Can potentially induce methemoglobinemia o Vasoconstrictory properties   bleeding

CHLOROPROCAINE
 Used in very short procedures

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 CNS Pharmacology II: Local Anesthesia

REVIEW QUESTIONS
1. Not a general chemical constituent of a local anesthetic:
a. Aromatic ring
b. Intermediate chain
c. Ionizable group
d. None of the above

2. Site of aminoester metabolism:

a. Liver
b. Lungs
c. Kidney
d. Plasma

3. Major mechanism of action of local anesthetics:

a. Cl- channel facilitation
b. K+ channel facilitation
c. Voltage-gated Ca2+ channel blockade
d. Voltage-gated Na+ channel blockade

4. All of the following are pharmacodynamic properties of

local anesthetics except:
a. Can act at other sites
b. Low affinity binding
c. Low specificity
d. None of the above

5. Neuron blockade by local anesthetic occurs preferentially

in all of the following fibers except:
a. Fast-firing sensory fibers
b. Myelinated fibers
c. Slow-firing motor fibers
d. Small-diameter fibers

6. All of the following are toxins that induce depolarization

by binding to intra-Na+ channel receptors except:
a. Batrachotoxin
b. Ciguatoxin
c. Scorpion venom
d. Tetrodotoxin

7. All of the following conditions occur in the mechanism of

tachyphylaxis in local anesthesia except:
a. Acidosis
b. Decrease in buffering capacity of local tissues
c. Increase in extracellular ionized forms of anesthetic
d. Saturation of Na+ channels

8. Implicated in transient neurologic symptoms:

a. Cocaine
b. Lidocaine
c. Procaine
d. Tetracaine

9. Local anesthetic of choice in spinal anesthesia:

a. Bupivacaine
b. Levobupivacaine
c. Mepivacaine
d. Ropivacaine

10. Methylene blue was administered to a 40-year-old female

patient who experienced dizziness and dyspnea after
being given regional spinal anesthesia for her operation.
What is the most likely local anesthetic involved here?
a. Bupivacaine
b. Lidocaine
c. Prilocaine
d. Procaine

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