Local Anesthetics

Local Anesthetics (LA)• L.A. reversibly block impulse conduction along nerve

axons and other excitable membrane.• A local anesthetic is a drug that causes reversible

local anesthesia and a loss of nociception. When it is used on specific nerve pathways (nerve block), effects such as analgesia (loss of pain sensation) and paralysis (loss of muscle power) can be achieved.

Structure

Mechanism of action of LA• They act by blockade of sodium channels so that: Impulse conduction slow The rate of rise of the action potential declines,

and The ability to generate an action potential is

abolished or canceled.

SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE

1. Diffusion of the base (nonionized) form across the nerve sheath and nerve membrane2. Re-equilibration between the base and cationic forms in the axoplasm3. 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 anesthesiaLoss of pain and temperature sensationLoss of proprioceptionLoss of touch and pressure sensationLoss of motor function

Effect of PH• Local anesthetics are weak bases and are usually

formulated as the hydrochloride salt to render them water-soluble. At the chemical's pKa the protonated (ionized) and unprotonated (unionized) forms of the molecule exist in an equilibrium but only the unprotonated molecule diffuses readily across cell membranes. Once inside the cell the local anesthetic will be in equilibrium, with the formation of the protonated (ionized form), which does not readily pass back out of the cell. This is referred to as "ion-trapping".

Effect of PH (cont.)• LA are weak bases and their activity increases by

increasing PH• This because if large amount of a drug is unpolar, it

will facilitate its penetration through the cell membrane

• Once the drug has penetrated the lipid barrier and reach its site of action it ionized and the ionized form is responsible for LA activity

• Acidosis such as caused by inflammation at a wound partly reduces the action of local anesthetics. This is partly because most of the anesthetic is ionized and therefore unable to cross the cell membrane to reach its cytoplasmic-facing site of action on the sodium channel.

• Local anesthetics block conduction in the following order: small myelinated axons (e.g. those carrying nociceptive impulses), non-myelinated axons, then large myelinated axons. Thus, a differential block can be achieved (i.e. pain sensation is blocked more readily than other sensory modalities).

Methods of Administration

• Surface anesthesia: direct application of the drug on the surface such as skin and wounds.

• Infiltration anesthesia: injection of LA in subcutaneous tissue in order to paralyze nerve endings at the site of action.

• 3- Nerve block: LA is injected in the vicinity of major nerve such as teeth

Methods of Administration• 4- Epidural anesthesia: injection of LA into the

epidural space.• 5- Sympathetic block: inject LA around sympathetic

nerves• 6- Spinal anesthesia: injection of LA into

subarachnoid space in the lumber region

Clinical use• 1- Systemic use as antiarrhythemic agents e.g.

Lidocaine• 2- Locally use to produce anesthesia

Clinical LA• Clinical local anesthetics belong to one of two classes:• 1- aminoamide and 2- aminoester • Synthetic local anesthetics are structurally related to

cocaine. They differ from cocaine mainly in that they do not produce hypertension or local vasoconstriction, with the exception of Ropivacaine and Mepivacaine that do produce weak vasoconstriction.

Classification of LA1-EstersA- esters of P- amine benzoic acid e.g. ProcaineB- Esters of benzoic acid e.g. Cocaine• Benzocaine• Chloroprocaine• Cyclomethycaine• Dimethocaine/Larocaine• Propoxycaine• Procaine/Novocaine• Proparacaine• Tetracaine/Amethocaine

Classification of LA2- Amide e.g. Lidocaine• Articaine• Bupivacaine• Cinchocaine/Dibucaine• Etidocaine• Levobupivacaine• Lidocaine/Lignocaine• Mepivacaine• Piperocaine• Prilocaine• Ropivacaine• Trimecaine

Classification of LA3- Combinations• Lidocaine/prilocaine4- Natural local anesthetics e.g. Saxitoxin and

Tetrodotoxin• Naturally occurring local anesthetics not derived

from cocaine are usually neurotoxins, and have the suffix -toxin in their names. Unlike cocaine produced local anesthetics which are intracellular in effect, saxitoxin & tetrodotoxin bind to the extracellular side of sodium channels.

Reference :• Essentials of medical pharmacology• 6th edition,K.D.tripathi

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