Pharmacology of local

anesthesia and its toxicity

By:
Dr. Salah Abdel-Fattah
Assist. Prof.of Anesthesia
KFU
 LOCAL ANESTHETICS
Local anesthetics are
drugs, which
reversibly block
generation,
propagation and
oscillations of
electrical impulses
in the excitable
tissues.
 MECHENISM OF ACTION
• Block nerve fiber conduction by acting
directly on nerve membranes to inhibit
sodium ion from crossing the
membrane
– Nerves cannot depolarize
– Conduction of impulses is blocked
 Mechanism of Action

• Site of action - Inside the membrane

• Binding sites within the Na+ channel
Extracellular solution

pore
Ion selective
Gating

+++
Voltage sensor

Intracellular Solution
 Local Anesthetic Binding Site

LA LA
H+
Extracellular solution

H+

Intracellular Solution
Hyd
ro
Path phobic
way
LA+
LA
LA
+
LA+
+++
Voltage sensor
Hydrophilic
Pathway

-70 mV
-15 mV
 MODE OF ACTION

NERVE AXON MEMBRANE

LAH+ LA
SODIUM CHANNEL

INJECTION LAH+ LA
 SEQUENCE OF EVENTS WHICH RESULT
IN CONDUCTION BLOCKADE

• 1. Diffusion of the base form across the

nerve sheath and nerve membrane
• 2. Re-equilibration between the base and
cationic forms in the axoplasm
• 3. Penetration of the cation into and
attachment to a receptor site within the
sodium channel.
• 4. Blockade of the sodium channel
 Nerve Fiber and
Local Anesthetic Setup

Sequence of clinical anesthesia

 Sympathetic block (vasodilate & skin T0)
 Loss of pain and temperature sensation
 Loss of proprioception
 Loss of touch and pressure sensation
 Loss of motor function
 STRUCTURE OF LOCAL
ANESTHETICS
R
N
R

Aromatic Amine
Group Intermediate

Chain
STRUCTURE OF LOCAL
ANESTHETIC
LIPO- HYDR
PHILIC O-
GROUP PHILIC

GROUP

AMIDE OR
ESTER
LINK
 PHARMACOLOGY

• Vary in duration of action, site of

metabolism and potency
• Two Classes
– Esters
– Amides
 CLASSIFICATION OF LOCAL
ANESTHETICS

ESTERS AMIDES
• Procaine • Lignocaine
• Chlorprocaine • Bupivacaine
• Cocaine • Levo-Bupivacaine
• Tetracaine • Ropivacaine
• Benzocaine
• Etidocaine
• Prilocaine
• Mepivacaine
 Pharmacology - Continued
• Esters
– Short, moderate or long duration of effect
– Metabolized by cholinesterases in blood and
skin
– Chlorprocaine, cocaine and procaine (short
acting)
– Tetracaine - long duration of effect
 Pharmacology - Continued

• Amides
– Long duration of effect
– Metabolized by liver
– Lidocaine, mepivacaine and prilocaine
(moderate duration of effect )
 PROPERTIES OF LOCAL
ANESTHETICS
PROPERTIES ESTERS AMIDES
METABOLISM Rapid by plasma Slow, hepatic
cholinesterase
SYSTEMIC TOXICITY Less likely More likely

ALLERGIC REACIONS Possible - PABA Very rare

derivatives form
STABILITY IN Breaks down in Very stable
SOLUTION ampules (heat, sun) chemically
ONSET OF ACTION Slow as general rule Moderate to fast

pKa’s Higher (8.5-8.9) Close to body pH =

7.4 (7.6-8.1)
Common features of Local
Anesthetics
• Weak bases (pKa > 7.4)
[poorly water soluble]
• Packaged as an acidic hydrochloride
[pH 4-7]
• In solution- non-ionized lipid soluble (free base)
and ionized water soluble (cation)
• Lipid soluble form crosses axonal membrane
• Water soluble form blocks sodium channel
 Important Clinical Properties of
Local Anesthetics
• ONSET
• POTENCY
• DURATION OF ACTION
Important Clinical Properties of
Local Anesthetics

ONSET = pKa

• pKa = pH at which 50% of drug is

ionized
• LA’s < 50% exists in the lipid soluble
nonionized form
• Only the nonionized form crosses into
the nerve cell
Important Clinical Properties of
Local Anesthetics

Speed of Onset
• low pKa = fast onset
• Bupivacaine 8.1
Lidocaine 7.7
• ? LA action in septic tissue
– acid tissue -> ionized % of LA
-> slow entry into membrane
-> low concentration of LA for block
 Effects of pH
on Local Anesthesia
Weak Bases ( pka of 8-9)

pH Ionized form

pH Ionized form
Important Clinical Properties of Local
Anesthetics

INCREASED DOASGE

• Intensity & Duration <=> INCRESED

• Increase dose via increased volume or
concentration of LA
Important Clinical Properties of
Local Anesthetics

DURATION OF ACTION

Duration <=> protein binding

• Bupivacaine 95%
• Lidocaine 65%
• Procaine 6%
Important Clinical Properties of
Local Anesthetics

Anesthetic Potency

Potency <=> lipid solubility

Higher solubility <=> can use a lower
concentration and reduce potential for
toxicity [LA]
Important Clinical Properties of Local
Anesthetics

Absorption of local anesthetics

• Site of injection: IV > tracheal > intercostal > caudal

> epid > brachial plexus > sciatic > SC
• Presence of vasoconstrictors
• LA agent highly tissue bound are more slowly
absorbed (e.g. etidocaine)
 Distribution
1-Tissue perfusion:
The highly perfused organs (brain, lung,
heart, kidney) are responsible for rapid
uptake
2-Tissue/Blood partition coefficient:
Strong plasma protein binding tends to
retain anesthetic in the blood
FACTORS AFFECTING DURATION
OF NERVE BLOCK

 Type of Local anesthetic

 Concentration
 Volume
 Use of additives
 Type of nerve block
ADDITION OF EPINEPHRINE

Concentration 5microgram/ml
Identifying intravascular injection
Duration of action
Peak plasma concentration of by 20% -
50%.
Quality of motor block.
 ADDITION of
Sodium Bicarbonate
 NaHCO3 - increase pH & nonionized base
 Speeds onset of block
 1 mEq NaHCO3 per 10 ml Lido/Mepivacaine
 0.1 mEq NaHCO3 per 10 ml Bupivacaine
 Important Clinical Properties of
Local Anesthetics

Metabolism
• ESTERS
Metabolism via pseudocholinesterase
So pt with abnormal pseudocholinesterase
at high risk for toxic side effects
• AMIDES
Metabolism via hepatic enzymes (hepatic, CHF)
 Common
Routes of Administration
• Topical
– Usually ester
– Usually ointments or drops
• Injection
– Intradermal
– Spinal
– Epidural
– Caudal
 Clinical use of LA
• Regional anesthesia and analgesia
• Intravenous regional anesthesia
• Blunt tracheal intubation stress response
• Antiarrhythmic e.g. Lidocaine
• Topical
COMMONLY USED LOCAL
ANESTHETICS

• Lignocaine
• Bupivacaine
• Prilocaine
• Mepivacaine
NEW LOCAL ANESTHETICS

• Levo-Bupivacaine
• Ropivacaine
 Adverse Effects and toxicity
• Cardiac Effects
– Depress cardiac conduction system
– Negative chronotropic effect
– Negative ionotropic effect

• Central Nervous System

– Capable of crossing blood-brain barrier
• Nervousness
• Excitation
• Tremors
• Convulsion
• Coma and death
 Adverse effects and toxicity
(Continued)
• Respiratory system:
- Depress hypoxic drive
- Apnea: central or peripheral
 Adverse effects and toxicity
(Continued)
• Vascular Effects
– Cocaine produces intense vasoconstriction
• Can lead to destruction of tissue by reducing
blood supply
– All other local anesthetics
• Vasodilation hypotension
– High doses may lead to hypotension causing
cardiovascular collapse
 Adverse Effects - Continued
• Topical
– Blanching
• Difficult to find vein
– Erythema (redness)
– Rash and itching in response to histamine
release
 Treatment of systemic toxicity
• Stop injection of LA
• Oxygen
• Tracheal intubation and control ventilation if
necessary
• Suppress seizure activity (thiopental or
midazolam
• Treat ventricular dysrhythmia and CVS support.
MAXIMUM RECOMMENDED DOSE
 Lignocaine (Infiltration, Epidural)
4mg/Kg body wt.
 Lignocaine With Adrenaline
7mg/Kg body wt.
 Bupivacaine Infiltration & Epidural
3mg/kg body wt.
 Adrenaline as vasoconstrictor
5mcg /ml - 20mcg/ml. Total dose should
not exceed over 20ml of 1:200,000 in 10
minutes