Neuropharmacology – 2009

John Schriefer, Ph.D.

LOCAL ANESTHETICS
Objectives:

The student shall be able to:

1. indicate which one of the following is most likely to be cardiotoxic; which is

most widely used clinically; which is most likely to cause CNS sedation; which is
limited to surface or topical anesthesia only; which is most likely to produce
vasoconstrictor effects.
• cocaine benzocaine procaine tetracaine
• lidocaine mepivacaine bupivacaine

2. describe the nature of ‘differential nerve sensitivities’ to local anesthetics.

3. describe the site and proposed mechanism(s) of action of local anesthetics.

4. indicate the clinical significance of distinguishing between the two general

chemical classes of local anesthetics in respect to elimination processes, duration
of action, and allergic phenomenon.

5. indicate which drug characteristics best correlates with rate of onset of local
anesthesia. Indicate the relationship between local duration of anesthesia and
vasodilation. Explain how local inflammation my adversely influence the
effectiveness of local anesthetics.

6. explain the rationale for inclusion of vasoconstrictors in local anesthetic

preparations and the potential risks associated with this drug combination.

7. indicate which system is most sensitive to systemic effect of local anesthetics and
which system is second most sensitive.

8. indicate in what ways cocaine differs from most local anesthetics with regards to
CNS and vascular effects.

9. compare procaine, lidocaine, bupivacaine, and tetracaine regarding onset and

duration of action, lipid solubility, and chemical classification.

10. list two agents that are not classified as local anesthetics but have local anesthetic
properties.

11. indicate which local anesthetic is almost 100% uncharged at physiological pH

and used in many OTC preparations as a surface anesthetic.

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I. Local Anesthetics

A. Definition

1. Drugs which produce a reversible loss of sensation in a localized

part of the body when applied directly onto nerve tissues or mucous
membranes

2. Local anesthetics are local only because of how they are

administered (selectivity).

B. Desirable Characteristics

1. rapid onset of action

2. brief, reversible block of nerve conduction

3. low degree of systemic toxicity

4. soluble in water and stable in solution

5. effective on all parts of the nervous system, all types of nerve

fibers, and muscle fibers

None totally meets these completely yet.

C. Mechanism of action

1. Block activation of voltage-gated sodium channels in neuronal

membranes.

a. bind to specific receptors at the intracellular end of the

voltage gated sodium channel

b. prevent axonal conduction by a functional blockade

2. LA have greatest affinity for sodium channel in inactivated state

and interfere with its reversion to the resting state.

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 Na+
LA receptor

++ ++ -- -- -- --

-- -- ++ ++
++ ++

Resting Open
(Closed**) inactivated
(brief) LA have highest
affinity for the
Very slow inactivated form
repolarization in
presence of LA Refractory period

**Closed state may exist in various forms as it moves from resting to open. LA have a
high affinity for the different closed forms and may prevent them from opening.

3. action is voltage dependent

a. this may be due to

i. voltage changes induce changes in form on Na+

channels

ii. LA have a higher affinity for Na+ channel in

- some closed forms of the channel preventing

them from opening

- the inactivated state; their binding slows the

return to resting form

iii. increased entry into neuron through opened Na

channel (myocardium)

4. action is also frequency dependent

a. because high affinity forms of Na+ channel (e.g.,

inactivated) are more frequently presented in neurons that
are firing more frequently

b. this provides a degree of LA selectivity

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 i. frequent firing pain neurons more affected than
slow firing motoneurons

5. LA are weak bases and access to receptor site is dependent on

a. pKa

b. lipid solubility

c. molecular size and level of neuronal activity

6. LA act in cationic form (charged)

7. An effective LA must enter, pass through and leave the cell

membrane and bind to receptor; compounds most likely to do this
are moderately lipophilic/moderately hydrophobic.

Differential sensitivity of neurons to LAs

Fiber type Function Diameter Myelinatio Conductio Sensitivity
(μM) n n velocity to LA block
(m/s)
Type A 12 – 20 Heavy 70 – 120 +
Alpha proprioception,
motor
Beta touch, pressure 5 – 12 Heavy 30 – 70 ++

Gamma muscle tone 3–6 Heavy 15 – 30 ++

Delta 1st pain, 2–5 Heavy 12 – 30 +++

temperature

Type B preganglioniic <3 Light 3 – 15 ++++

autonomic,(e.g.
vasomotor)
Type C
Dorsal 2nd pain, 0.4 – 1.2 None 0.5 – 2.3 ++++
root temperature
postganglionic, 0.3 – 1.3 None 0.7 – 2.3 ++++
sympathetic (e.g. vasomotor)

D. Factors influencing LA action – lipid solubility (LS)

1. potency and systemic toxicity directly correlate with LS

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2. local duration positively correlated with LS and inversely related
to vasodilation

FACTORS INFLUENCING LA ACTION

~ Hydrogen ion concentration ~
 LA are tertiary amines and WEAK BASES
with pKa ~ 8-9
C2 H5 C2H5

R-CH2-NH+ R-CH2-N + H+

C2H5 C2H5

Quaternary amine Tertiary amine

(LIPID SOLUBLE)
(ACTIVE FORM)

1. at pH 7.4 80-90% is ionized and can’t enter cells

a. non-ionized (lipid soluble) form needed for penetration

b. cationic form required for binding to receptor

c. rate of onset is related to pKa

2. inflammation tends to produce lower pH in tissues therefore

a. LA are more ionized

b. don’t penetrate very well

c. decreased ability of LA to produce effects

3. rate limiting factor for LA onset is the time to penetrate nerve

sheath and permeate cell membrane

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E. Chemical Classification

LAs are Weak Bases

Intermediate chain
Aromatic portion Amine portion
O
R

C O R N
R
ESTER

O R

NH C R N
R
AMIDE

LIPOPHILIC HYDROPHILIC

Two types of linkages

give rise to 2 chemical classes of
LAs. ESTER LINKAGE AMIDE LINKAGE (2 EYES!!)

LIDOCAINE
PROCAINE
lidocaine (Xylocaine)
procaine (Novocaine)
mepivacaine (Carbocaine)
tetracaine (Pontocaine)
bupivacaine (Marcaine)
benzocaine
etidocaine (Duranest)
cocaine
ropivacaine (Naropin)

F. Clinical significance of chemical classification

1. Cross sensitivity (allergy)

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 a. occurs with drugs in the same chemical class

b. esters are metabolized to common metabolite PABA

c. allergy rarely occurs with amide linkage class

2. Biotransformation/duration of action

a. esters are rapidly metabolized in the plasma by a

cholinesterase

b. amides are more slowly destroyed by liver microsomal

P450 enzymes

G. Pharmacokinetics

1. Absorption

a. LA generally have good absorption from mucous

membranes and intradermal injection sites (into tissues)

b. Systemic absorption terminates local action (out of tissues)

(Not local metabolism!)

c. Factors influencing peak plasma concentration

i. site of injection (vascularity)

ii. total dose

iii. specific drug characteristics

- tendency to produce vasodilation

iv. presence of vasoconstrictor (e.g., epinephrine,

phenylephrine)

d. effects of vasoconstrictors

i. decrease rate of systemic absorption and decrease

systemic toxicity

ii. increase local drug concentration and increase

neuronal uptake of LA

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 iii. increase local duration of action (e.g., lidocaine’s
duration may increase twofold with EPI)

e. potential adverse effects of vasoconstrictors

i. don’t use in areas of toes, fingers, ear lobes, penis

ii. may produce tissue necrosis

iii. may produce systemic toxicity (CV)

2. Distribution

a. LA can be widely distributed to all parts of the body

including CNS

b. distribution is a means of terminating local drug action…

not metabolism

3. Metabolism

a. ester type LA

i. hydrolysis by cholinesterase in plasma to PABA

derivatives

- pseudo cholinesterase or butyrylcholinesterase

ii. generally, short acting and low systemic toxicity

iii. prolonged effects seen with genetically determined

deficiency or altered esterase (cholinesterase
inhibitors)

b. amide type LA

i. hydrolyzed by liver microsomal enzymes (P450)

ii. longer acting and more systemic toxicity than esters

iii. caution with severely compromised hepatic function

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Comparison of LA characteristics
Relative Relative Onset pKa Local Vasodilation Plasma
lipid potency duration protein
solubility binding
procaine 1 1 slow 8.9 short +++ 5%

lidocaine 4 4 rapid 7.9 moderate +++ 55%

tetracaline 80 16 slow 8.5 long + 75%

bupivacaine 130 16 slow 8.1 long + 90%

Plasma protein binding may be used as an indirect measure of tissue binding tendencies

H. Systemic Effects (toxicities)

1. extensions of pharmacological action

2. intensity is dependent on blood levels

3. toxic levels of LA in blood will not occur if absorption (into

systemic blood) is slow or metabolism is rapid

4. CNS (more sensitive than CVS)

a. dose-related spectrum of effects and all effects are due to

depression of neurons

i. first an apparent CNS stimulation (convulsions most

serious)

ii. followed by CNS depression (death due to respire

depression)

b. cocaine – euphoria (unique in its ability to stimulate CNS)

c. lidocaine – sedation even at non-toxic doses

5. cardiovascular system

a. hypotension: arteriolar dilation is a result of:

i. direct effect (procaine and lidocaine have most

effect)

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 ii. block of postganglionic sympathetic fiber function

iii. CNS depression

iv. avoid by adding vasoconstrictor to prep

NOTE:cocaine is exception: produces vasoconstriction,

blocks NE reuptake.

b. arrhythmias: direct effect (more resistant than CNS)

i. decrease cardioexcitability and contractility

ii. decreased conduction rate

iii. increased refractory rate (bupivicaine)

iv. NOTE: cocaine is exception…it stimulates heart

v. all can cause arrhythmias if conc. is high enough

c. allergic reactions…fairly rare

i. mostly with ester types, rarely amides (procaine)

- esters metabolized to PABA which has

allergenic properties

ii. cross-sensitivity within same chemical class of LA

iii. anaphylactic reactions are rare…diphenhydramine

can be used to control minor reactions

iv. the preservative paraban in multidose vials may be

responsible for some allergic phenomenon

d. neurotoxicity

i. LA can cause concentration-dependent nerve

damage to central and peripheral NS

ii. mechanism(s) not clear

iii. permanent neurological injury is rare

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 iv. may account for transient neurological symptoms
after spinal anesthesia

- cauda equine syndrome

II. Selective pharmacological properties of some ester – type LA

A. cocaine (schedule II substance)

1. Medical use limited to surface or topical anesthesia (corneal or

nasopharyngeal)

2. avoid epinephrine because cocaine already has vasoconstrictor

properties. (exception)

3. a toxic action on heart may induce rapid and lethal cardiac failure

4. a marked pyrexia is associated with cocaine overdose.

B. benzocaine (Americaine)

1. pKa ~ 3, essentially all non-ionized (results in weak action)

2. available in many OTC preps for relief of pain and irritation

3. for surface anesthesia (topical) only…ointments, sprays, etc.

4. used to produce anesthesia of mucous membranes and to suppress

gag reflex during endoscopy

C. procaine (Novocaine)

1. topically ineffective

2. used for infiltration because of low potency and short duration but
most commonly used for spinal anesthesia

3. short local duration…produces significant vasodilation.

Epinephrine used to prolong effect.

4. systemic toxicity negligible because rapidly destroyed in plasma

D. tetracaine (Pentocaine)

1. topical, infiltration, and spinal anesthesia

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 a. frequently used for topical ophthalmogical anesthesia

2. slow onset and more prolonged effect than procaine (longest

duration of the esters)

3. ~10X more toxic and more potent than procaine

III. Selective Pharmacological properties of some Amide – type LA

A. lidocaine (Xylocaine) most widely used LA

1. effective by all routes

2. faster onset, more intense, longer lasting than procaine

3. good alternative for those allergic to ester type

4. more potent than procaine but about equal toxicity

5. more sedative than others

6. prilocaine similar except has a vasoconstrictor action

B. mepivicaine (Carbocaine)

1. effective by all routes except topical

2. similar onset and duration as lidocaine

3. more toxic to neonates so not used in obstetrical anesthesia (fetus

poorly metabolized mepivicaine)

C. bupivacaine (Marcaine)

1. no topical effect

2. slower onset and one of longer duration agents

3. unique property of sensory and motor dissociation and provide

sensory analgesia with minimal motor block

a. has been popular drug for analgesia during labor

4. more cardiotoxic than other LA

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 D. ropivacine (Naropin)

1. enantiomer of bupivacaine

2. no topical effectiveness

3. clinically ~ equivalent to bupivacaine

4. similar sensory versus motor selectivity as bupivacaine with

significantly less CV toxicity

IV. Clinical Applications

A. Surface anesthesia (topical)

1. nose, mouth, bronchial tree, cornea, urinary tract, skin

a. lidocaine, tetracaine
b. EMLA – mixture of lidocaine and prilocaine

B. infiltration anesthesia

1. direct injection into tissues to reach nerve branches and terminals

2. used in minor surgery

3. immediate onset with variable duration

a. most LA’s used

C. nerve block or field block

1. interruption of nerve conduction upon injection into the region of

nerve plexus or trunk

2. used for surgery, dentistry, analgesia

3. less anesthetic needed than for infiltration if a large area must be

anesthetized

a. most LA’s used

D. spinal anesthesia

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 1. injection into subarachnoid space below level of L2 vertebra to
produce effect in spinal roots and spinal cord

2. use hyperbaric or hypobaric solutions depending on area of

blockade

3. used for surgery to abdomen, pelvis, or leg when can’t use general
anesthesia.

a. lidocaine, tetracaine

4. problems

a. spinal headache due to increased CSF

b. hypotension and bradycardia, respiratory depression

5. advantages over epidural

a. greater predictability

b. faster onset

c. shorter duration

E. epidural and caudal anesthesia

1. injection and epidural space usually at lumbar or sacral levels

2. used like spinal and also painless childbirth

3. unwanted effects similar to that of spinal except less likely because

longitudinal spread is reduced.

a. lidocaine, bupivacaine, ropivacaine

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