Local Anesthetic Pharmacology Lec

8/3/2019 Local Anesthetic Pharmacology Lec

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Local Anesthetic Pharmacology

Azza Baraka

Professor of Pharmacology, Faculty of Medicine

Alexandria University


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History

Cocaine was the first topical anesthetic, dating backto 3000 B.C.

By 1900 the addictive properties of cocaine were wellrecognized.

1905: procaine was developed.


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Definition

A local anesthetic (LA) is an agent thatinterrupts pain impulses in a specific region

of the body without loss of patient

consciousness.


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Chemical Structure LAs consist of a hydrophobic group (often an

aromatic ring) connected by an intermediate chain

(containing an ester or amide bond) to an ionizable

group (usually a tertiary amine group).


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Administration Routes

Surface anesthesia: topical gel or spray-applied to skin and

mucous membranes.

Infiltration anesthesia: inject subcutaneous around area for

minor surgery. Nerve endings exposed to the anesthetic

solution are quickly rendered unresponsive. Nerve block anesthesia: Injection of drug around nerve

trunk proximal to the intended area of anesthesia.

Spinal anesthesia: inject into epidural space, diffuses across

dura into subarachnoid space. LA solution injected into thesubarachnoid space blocks conduction of impulses along all

nerves with which it comes in contact, although some

nerves are more easily blocked than others.


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Mechanism of Action

Blocks the sodium channel, from theintracellular side

Must enter the neuron to work Increased lipophilicity is associated

with increased potency

Increased un-ionized fraction increasespotency


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Site of Action

Local Anesthetic


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Pharmacokinetics

Following injection into the area of nerve fibers to be

blocked, LAs are absorbed into the blood.

Ester-linked LAs are quickly hydrolyzed by cholinesterase

in the blood.

Amide-linked LAs are hydrolyzed by liver microsomal

enzymes. Thus, their half life is significantly longer.

Absorption of LAs is affected by the following factors:

dosage, site of injection, drug-tissue binding, and presence

of vasoconstricting drugs. Presence of vasoconstrictingdrugs significantly reduces absorption of LAs, thus

enhancing the local drug concentration, prolonging the LA

effect, and reducing blood levels.


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Factors affecting onset, intensity, and

duration of neural blockade

Lipid solubility: a lipophilic LA is more potent and have a faster

onset of action because it is easier to cross nerve membranes. Protein binding:LAs with a higher degree of protein binding have a

prolonged duration of action.

The pKa: The pKa is the pH at which 50% of the LA is in the ionized

form and 50% is in the unionized form. All LAs are weak bases withpKa = 8-9:

Thus LAs at physiologic pH will be associated with a greater fraction of

the molecules existing in the unionized form more penetration

across nerve membranes faster onset. Local infection (acidosis) decreases tissue pH , and thus increases the

ionized drug fraction which means less drug will be available to

penetrate across membranes slower onset.

Dose: Increasing dose of the LA will increase the duration of theblock.


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Differential sensitivity of nerve fibers to LAs

Fiber diameter: LAs preferentially block small nerve fibers.Small C fibers (pain signal) are blocked before larger fibers

(touch, and motor signals)

Myelination: For the same diameter, myelinated nerves will be

blocked before unmyelinated nerves. Why preganglionic nerves are blocked before the smaller

unmyelinated C fibers (pain nerves) in spinal anesthesia.

Use-dependent block: Nerves with higher firing frequency are

more sensitive to LA block. This is because LA molecules aremore likely to access to the binding sites in the open Na+

channel. Pain fibers, have a high firing rate than motor fibers,

and thus are more sensitive to lower concentrations of LAs.


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Nerve Sensitivity

1. Autonomic

2. Pain

3. Temperature

4. Touch

5. Motor


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Side effects [1] Local:

Irritation and inflammation at the site of administration. LAs produce vasodilatation but local ischaemia may arise

from a co-administered vasoconstrictor, therefore this

should be avoided in the extremities such as the digits.

Cocaine differs from the other LAs: it blocks norepinephrine

reuptake, resulting in vasoconstriction .Cocaine is restricted

to topical use in otolaryngeal procedures, to produce

vasoconstriction and reduce mucosal bleeding.


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[2] Systemic:

Toxicity of LAs is mostly related to their inhibitory effects

on excitable cells such as neurons & cardiac muscle.

CNS: Following absorption, LAs cause stimulation of theCNS, producing restlessness and tremors that may proceed

to convulsion. Stimulation is caused by inhibition of

inhibitory neuronal activity. At high blood concentrations,

LAs cause depression and even respiratory failure.

CVS: Decrease conduction rate, and force of contraction in

the myocardium. Bupivacaine is more cardiotoxic than

other LAs and may cause cardiovascular collapse andventricular tachycardia.

Allergic reactions: Ester-linked LAs may cause allergic

reaction in a small population of patients related to their

metabolism to PABA.


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Toxicity of LAs could be prevented by

observing three precautions1. Administer the smallest dose that will provide

effective anesthesia.

2. Use proper injection technique.

3. Use of a vasoconstrictor containing solution.


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Classification and main differences

between local anestheticsAmidesEsters

Have an amide (-NHCO-) link between

the aromatic group and the amino

terminal.

Have an ester (-COO- ) link

between the aromatic group and the

amino terminal.

Chemistry

Lidocaine: has fast onset

Bupivacaine: dissociate slowly

from cardiac Na+ Channels

risk ofcardiotoxicity.

Procaine: short acting

Tetracaine: long acting

Examples

Few hoursFew minutest1/2

By the liver.By plasma pseudocholinestrase.P-aminobenzoic acid is a metabolite

Metabolism

RareMoreIncidence ofallergic

reactions

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Local Anesthetic Pharmacology Lec