Pharmacology of Local Anesthetics

(LAs)
Learning Objectives

By the end of the Block 2 Module 1, students should be able to

1. Identify the local anesthetic drugs for this topic:

Benzocaine

Bupivacaine

Cocaine

Lidocaine

Ropivacaine
2. List the factors that contribute to the differential sensitivity of nerves to local
anesthetics and explain the basis for their effects.
3. Explain the mechanism of action of local anesthetics.
4. Compare and contrast ester versus amide type LAs in terms of their: metabolism &
elimination; allergic potential; and systemic toxicity
5. Explain the relationships between pKa of local anesthetics and pH of medium (tissues).
Explain why local anesthetics are often less effective while draining abscesses.
6. Explain the lipid solubility of and vasodilation by local anesthetics. Discuss the
advantages and disadvantages of addition of vasoconstrictor (epinephrine) in local
anesthetic mixture.
7. Discuss important properties and clinical uses of cocaine, benzocaine, lidocaine,
bupivacaine and ropivacaine.
Local anesthesia
• Local anesthesia has the purpose of reducing nociceptive sensation in a limited region of the body. This is
accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation.
• Since most peripheral nerves are mixed sensory and motor, such blockade may bring with it other
physiologic changes such as muscle paralysis and suppression of somatic or visceral reflexes, and these
effects might be desirable or undesirable depending on the particular circumstances.
• Nonetheless, in most cases, it is the loss of sensation, or at least the achievement of localized analgesia,
that is the primary goal.
• Lidocaine was introduced by Löfgren and Lundqvist in 1948, and it is most widely used local anesthetic
agent. Additional agents have been developed based upon certain characteristics.
• Local anesthetics are classified as esters and amides based on their chemical structure
 Esters: Cocaine, Benzocaine
 Amides: Lidocaine, Bupivacaine, Ropivacaine

Lidocaine Cocaine
 Mechanism of Action of Local Anesthetics

Mechanism of action of local anesthetic agents:

 Local anesthetic agents (both amides & esters) block
voltage-gated Na+ channels from inside (cytosolic end) in
activated state  conduction blockade
 State-dependent (use dependent, block the channels
when they are in inactivated state channel recovery Activation gate

time is prolonged, Channel recovery rate 10 -1000

times slower) (see the diagram-at the right) Inactivation gate
 Nodes of Ranvier have abundant NaV channels (see the
picture below)
 Because a fixed number of axonal nodes must be Local anesthetics
blocked to prevent conduction, small nerve fibers with
closely spaced nodes of Ranvier are blocked more
rapidly than large nerve fibers.
Node of
Ranvier
Axon
+
+ +
3
 Inject local anesthetic BH+ with pKa = 7.4. BH+ undergoes acid dissociation & B
undergoes chemical equilibrium. Uncharged ‘B’ crosses lipid membrane and enters LO 3

cytosol, pH 6.9, where acid-base equilibrium occurs anew - ion trapping of BH+

Extracellular pH 7.4 Na+ Na+

BH+ B
View slide show
to see animation
Lipophilic
B

Cytosol ‘Ion
pH 6.9 trapping’
B BH+
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 Local anesthetic in the form of BH+ keeps ‘inactivation gate’ closed

Na+
BH+ B
Remember:
Local anesthetics act in a
state-, or use-dependent
manner. They bind to Na+
channels when they are in
inactivated state.
Nerves that are most
actively conducting
impulses by cycling
between the resting 
Activated  Inactivated
resting state are more B BH+ BH+ BH+
susceptible to blockade

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 Differential sensitivity to blockade by local anesthetics
Key concepts: It is important in establishing a rank order of sensory effect.
• Sensitivity to a local
anesthetic block depends Note:
on axonal degree of C and A fibers are blocked first. Reason: see the box in the left
myelination as well as Rank order of sensitivity to blockade:
decreasing fiber size, C > A > Aβ > A
consistent with high
sensitivity for pain
sensation mediated by
small fibers (low
Sensory
myelination) and low
sensitivity for motor A
Motor
function mediated by large
A Sensory

fibers. Muscle Touch Sensory
A
• The spacing of nodes of
Control Vibration
Ranvier (rich in Nav+ Pain, C
Position
channels) increases with Cold Pain,
the size of nerve fibers.
Because a fixed number of Heat
nodes must be blocked to
prevent conduction, small  Drug Concentration
fibers with closely spaced
nodes of Ranvier are Least sensitive Most sensitive
blocked more rapidly. 6
 Compare Metabolism of Ester vs Amide Local Anesthetics

Esters: Cocaine, Benzocaine

20 Cardiovascular &
Metabolism by Respiratory arrest
Pseudocholinesterase/ Plasma - Rapid (1-5 min)
Butyrylcholinesterase/
Plasma cholinesterase
More common – due to para-
Hypersensitivity aminobenzoic acid (PABA) Coma
metabolite Convulsions
10
Loss of consciousness
Systemic Toxicity Less likely due to rapid Disorientation
metabolism

Amides: Lidocaine, Bupivacaine, Ropivacaine

Metabolism by Hepatic - Slow (1 - 4 hrs.) Muscle Twitching
CYP 450 Light-headed
Hypersensitivity Less common 2 Tinnitus
µg/ml Numb Tongue
More likely – especially if metabolism is
Systemic Toxicity slow
or cardiac output is impaired
Local Anesthetics Systemic Toxicity
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 Relationship between pH and pKa
pKa of drug and pH of medium

pKa of local anesthetics:

 pKa is the acid dissociation constant.
 pKa dictates how much of a drug exists as a charged, protonated, acidic
species [BH+], and how much exists as a neutral, free base species [B].
Remember:
 Only free, uncharged drug ‘B’ can diffuse into, and across, the lipid bilayer
of cell membranes.
* At pH 7.4

Note:
• Diffusion of local anesthetic into nerve occurs rapidly,
proportional to the amount of B and inversely
proportional to pKa .
• The local pH, and the pKa of drug dictate the ratio B/
BH+
• Higher is the gap between pH and pKa more is the
ionization of local anesthetic decreases efficacy

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 A 70-kg patient experiences pain on incision of a thigh abscess. The area
around the abscess had been infiltrated with 30 ml of 1% lidocaine in
1:200,000 epinephrine. The local anesthetic was most likely less effective
because of

(A) acidosis at the site of the injection

(B) epinephrine-induced limitation of drug diffusion
(C) insufficient dose
(D) low ionization of lidocaine
(E) protein binding of lidocaine
Correct answer:
(A) acidosis at the site of the injection
Explanation:
The pH of an abscess ranges from pH 6.0 - 7.3.
This acidic pH may slow the onset of action of a local anesthetics. At lower pH, more lidocaine is
ionized and ionized drug can’t enter the neurons blockade of sodium channels is decreased ↓
efficacy of lidocaine. So using adequate amount of lidocaine, allowing sufficient time for onset of
action and/or supplementing with oral and parenteral analgesics may be needed to increase patient’s
comfort. https://www.nejm.org/doi/full/10.1056/nejmvcm071319
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 Lipid Solubility of Local anesthetic Drugs
Both Affect Potency, Toxicity & Duration of Effect

 Local anesthetics with a greater lipophilicity  greater penetration of the lipid

nerve membrane (& blood vessels).
 Some systemic absorption of local anesthetics is inevitable because nerves &
blood vessels are in proximity
Highly
Blood vessel B perfused
tissues

BH+ B B
B

Nerve

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 Vasodilation by Local Anesthetics
Decreases Efficacy & Confers Risk for Systemic Toxicity,
epinephrine is combined to circumvent vasodilation
 Some local anesthetics cause vasodilation hastens distribution & promotes
systemic absorption ↓ anesthetic efficacy & potency at the site of injection
and increases risk for systemic toxicity.
 So, many local anesthetics are combined with epinephrine vasoconstriction
↑duration of action, limit systemic exposure/toxicity, ↓bleeding during surgery
(these are advantages of adding epinephrine)

Lidocaine without epinephrine  duration of action 30 min

Lidocaine with epinephrine  duration of action of 90 min
Disadvantages of adding epinephrine:
 In patients with peripheral vascular disease, myocardial infarction, diabetes
mellitus and hypertension (may increase blood pressure), decrease wound
healing.
 In tissue perfused by an end artery with no collateral circulation (such as a
finger) with risk of ischemia and possible necrosis due to vasoconstriction.

(Vasoconstrictor & concentration: epinephrine 1:50000 to 1:200000)

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 Properties of clinically important drugs
Cocaine:
 Used for surface or topical anesthesia (corneal or nasopharyngeal)
 It is a vasoconstrictor, and a CNS stimulant
 Current clinical use of cocaine is largely restricted to topical anesthesia
for ear, nose, and throat procedures, where its intense vasoconstriction
can serve to reduce bleeding (such as a nosebleed)
 Even here, use has diminished in favor of other anesthetics combined
with vasoconstrictors because of concerns about systemic toxicity, as well
as the inconvenience of dispensing and handling this controlled
substance
Cocaine- drug of abuse; with nasal or palatal perforation of unknown etiology suspect
cocaine abuse
Intranasal cocaine abuse can lead to destruction of the
palate and perforation of the nasal septum. (due to local
ischemia secondary to vasoconstriction)

Palatal perforation from intranasal cocaine abuse

https://pubmed.ncbi.nlm.nih.gov/11913063/
https://www.nejm.org/doi/full/10.1056/nejmicm066935
Benzocaine:
 Benzocaine’s pronounced lipophilicity has relegated its application to topical
anesthesia. However, despite over a century of use for this purpose, its
popularity has recently diminished owing to increasing concerns regarding
its potential to induce methemoglobinemia.
Lidocaine:
 Most widely used local anesthetic agent
 Good for surface application as well as injection., blocks conduction within 2-3 min.
 Used for surface/topical application, infiltration, nerve block, epidural, spinal and IV regional
block anesthesia
 Also used as antiarrhythmic (blocks cardiac Na+ channels)
Adverse Effects of Lidocaine !!
 Central effects – drowsiness, mental clouding
 Overdose – muscle twitching, seizure/convulsions, cardiac arrhythmias, fall in BP, coma and
respiratory arrest.
Bupivacaine:
 Potent and long-acting amide local anesthetic
 Used for infiltration, nerve block, epidural and spinal (Levobupivacaine and ropivacaine  S (-)
enantiomer of bupivacaine  less cardiotoxic than bupivacaine for spinal block)
 Anesthesia of long duration, minimal motor blockade while using for labor pain
 A 0.25 – 0.5% solution injected epidurally produces adequate analgesia without significant
motor blockade.
 More prone to induce ventricular tachycardia and cardiac depression (death reports- at
0.75% bupivacaine)
Ropivacaine:
 Ropivacaine, another S(–) enantiomer, has reduced affinity for cardiac sodium channels
(greater margin of safety), while being slightly less potent than bupivacaine or
levobupivacaine.
 However, despite the reduced channel affinity, a recent advisory panel of the American
Society of Regional Anesthesia concluded that in most clinical settings ropivacaine and
bupivacaine probably have similar toxicity when administered on an equipotent basis.
 Techniques of Local Anesthesia

Infiltration
 Inject into tissues to reach nerve branches and terminals; Used in minor surgery; Immediate
onset with variable duration
Surface (Topical)
 Nose, mouth, bronchial tree, cornea and urinary tracts; drugs: Lidocaine, Benzocaine,
Cocaine
Nerve block or Field block
 Inject into the region of nerve plexus or trunk.
 Used for surgery, dentistry, analgesia. Drug: Lidocaine
Spinal
 Inject into subarachnoid space, surgery to abdomen, pelvis or leg; drugs: Ropivacaine,
Bupivacaine, Lidocaine
Epidural & Caudal
 Inject into epidural space, Uses: similar to spinal and for painless childbirth.
 Drugs: Ropivacaine, Bupivacaine

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 Adverse Reactions of Local Anesthesia
Allergic reactions
LA adverse reactions can include local contact dermatitis and systemic anaphylaxis. Most are
reported with dental procedures with a high proportion related to epinephrine absorption from
the mucosal tissues.

Systemic toxicity

LA toxicity is related to systemic exposure to LAs. An LA’s potential for toxicity is related to its
lipophilicity and systemic absorption. Local Anesthetic Systemic Toxicity (LAST) produces a
spectrum of disease ranging from mild perioral numbness and tinnitus to hallucination, altered
mental status, and eventually to cardiovascular collapse due to asystole.

The more potent, longer-acting agents like Bupivacaine have the highest potential for toxicity,
where shorter, lower-potency agents like Lidocaine have very little.

Treatment for LAST is supportive with early lipid emulsion administration to sequester any
systemic LA by scavenging effect (“lipid sink”) Recall that these agents are lipophilic.

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