Pharmacology of Local Anesthesia

PharmacologyPharmacology ofof locallocal anesthesiaanesthesia andand itsits toxicitytoxicity

By:By:

DrDr. Salah Abdel-Fattah. Salah Abdel-Fattah

Assist. Prof.of AnesthesiaAssist. Prof.of Anesthesia

KFUKFU

LOCAL ANESTHETICSLOCAL ANESTHETICS

Local anesthetics are drugs, which reversibly block generation, propagation and oscillations of electrical impulses in the excitable tissues.

MECHENISM OF ACTIONMECHENISM 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 ActionMechanism of Action

• Site of action - Inside the membrane

• Binding sites within the Na+ channel

GatingGatingE

xtra

cell

ular

sol

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Intr

acel

lula

r S

olut

ion

Ion selectivepore

+ + +Voltage sensor

Ext

race

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ar s

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Intr

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LocalLocal AnestheticAnesthetic BindingBinding SiteSite

+ + +Voltage sensor

LA

LA+

H+

LA

HydrophobicPathway

LALA

LA+

H+

-70 mV-15 mV

LA+

HydrophilicPathway

SODIUM CHANNEL

MODEMODE OFOF ACTIONACTION

NERVE AXON MEMBRANE

LA

LA

INJECTION LAH+

LAH+

SEQUENCE OF EVENTS WHICH RESULT SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADEIN 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

1. Sympathetic block (vasodilate & skin T0)

2. Loss of pain and temperature sensation

3. Loss of proprioception

4. Loss of touch and pressure sensation

5. Loss of motor function

STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICSANESTHETICS

Aromatic Group Intermediate

Chain

R

N R

Amine

STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICANESTHETIC

AMIDE ORESTER LINK

LIPO-PHILIC GROUP

HYDRO-

PHILIC

GROUP

PHARMACOLOGYPHARMACOLOGY

• Vary in duration of action, site of metabolism and potency

• Two Classes– Esters– Amides

CLASSIFICATION OF LOCAL CLASSIFICATION OF LOCAL ANESTHETICSANESTHETICS

ESTERS• Procaine• Chlorprocaine• Cocaine• Tetracaine

AMIDES• Lignocaine• Bupivacaine• Levo-Bupivacaine• Ropivacaine• Benzocaine• Etidocaine• Prilocaine• Mepivacaine

Pharmacology - ContinuedPharmacology - 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 - ContinuedPharmacology - Continued

• Amides– Long duration of effect– Metabolized by liver– Lidocaine, mepivacaine and prilocaine

(moderate duration of effect )

PROPERTIES OF LOCAL PROPERTIES OF LOCAL ANESTHETICSANESTHETICS

PROPERTIES ESTERS AMIDESMETABOLISM Rapid by plasma

cholinesteraseSlow, hepatic

SYSTEMIC TOXICITY Less likely More likely

ALLERGIC REACIONS Possible - PABA derivatives form

Very rare

STABILITY IN SOLUTION

Breaks down in ampules (heat, sun)

Very stable 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 Common features of Local AnestheticsAnesthetics

• 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

ImportantImportant ClinicalClinical PropertiesProperties ofof LocalLocal AnestheticsAnesthetics

• ONSET• POTENCY• DURATION OF ACTION

Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal 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


Speed of Onset

• low pKa = fast onset

• Bupivacaine 8.1Lidocaine 7.7

• ? LA action in septic tissue– acid tissue -> ionized % of LA

-> slow entry into membrane -> low concentration of LA for block

Effects of pHEffects of pHon Local Anesthesiaon Local Anesthesia

pH Ionized form

Weak Bases ( pka of 8-9)

pH Ionized form

Important Clinical Properties of Local Important Clinical Properties of Local AnestheticsAnesthetics

INCREASED DOASGE

• Intensity & Duration <=> INCRESED

• Increase dose via increased volume or concentration of LA


DURATION OF ACTION

Duration <=> protein binding• Bupivacaine 95%• Lidocaine 65%• Procaine 6%


Anesthetic Potency

Potency <=> lipid solubility

Higher solubility <=> can use a lower concentration and reduce potential for toxicity [LA]

Important Clinical Properties of Local Important Clinical Properties of Local AnestheticsAnesthetics

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)

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

Distribution

FACTORS AFFECTING DURATION FACTORS AFFECTING DURATION OF NERVE BLOCKOF NERVE BLOCK

Type of Local anestheticConcentrationVolumeUse of additives Type of nerve block

ADDITION OF EPINEPHRINEADDITION OF EPINEPHRINE

Concentration 5microgram/ml

Identifying intravascular injection

Duration of action

Peak plasma concentration of by 20% - 50%.

Quality of motor block.

� 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

ADDITION of ADDITION of Sodium BicarbonateSodium Bicarbonate


Metabolism

• ESTERSMetabolism via pseudocholinesterase

So pt with abnormal pseudocholinesterase at high risk for toxic side effects

• AMIDES Metabolism via hepatic enzymes (hepatic, CHF)

CommonCommonRoutes of AdministrationRoutes of Administration

• Topical– Usually ester– Usually ointments or drops

• Injection– Intradermal– Spinal– Epidural– Caudal

Clinical use of LAClinical use of LA

• Regional anesthesia and analgesia

• Intravenous regional anesthesia

• Blunt tracheal intubation stress response

• Antiarrhythmic e.g. Lidocaine

• Topical

COMMONLY USED LOCAL COMMONLY USED LOCAL ANESTHETICSANESTHETICS

• Lignocaine

• Bupivacaine

• Prilocaine

• Mepivacaine

NEW LOCAL ANESTHETICSNEW LOCAL ANESTHETICS

• Levo-Bupivacaine

• Ropivacaine

Adverse Effects and toxicityAdverse 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 toxicityAdverse effects and toxicity(Continued)(Continued)

• Respiratory system:

- Depress hypoxic drive

- Apnea: central or peripheral

Adverse effects and toxicity Adverse effects and toxicity (Continued)(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 - ContinuedAdverse Effects - Continued

• Topical– Blanching

• Difficult to find vein

– Erythema (redness)– Rash and itching in response to histamine

release

Treatment of systemic toxicityTreatment 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 DOSEMAXIMUM 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

Pharmacology of Local Anesthesia

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