History of Local Anesthetics

Cocaine was the first local anesthetic; Peruvian Indians chewed the Coca leaves and made a bolus of the dried leaves, which they would mix with ashes (called chica). By chewing this, their physical endurance was increased. Cocaine was isolated in 1860 and used clinically as topical anesthetic in Vienna by Karl Choler (spelling?). Freud was a buddy of this Choler fellow, and experimented with cocaine with him. They eventually found that cocaine is highly addictive.

RJ Hall was the first dentist to use cocaine as an anesthetic when he extracted a tooth. It was found that a precise injection of cocaine will produce a nerve block, and that cocaine was a good local anesthetic. It blocks the amine pump in the adrenergic synapses, resulting in a sympathetic response.

Procaine was the first synthetic local anesthetic (1905), followed by Lidocaine (1948), which we obviously still use today.

Agents, Generic (and Brand) Names:

The suffix “-caine” is the official designation for local anesthetics (LA). The LA’s are divided into two classes, esters and amides. (There is only one ketone, which is dyclonine (Dyclone)).

Of the ester class, it is important to know the name and brand name for the following (as found in the handout): Procaine (Novocain, Procaine); tetracaine (Pontocaine, Tetracaine); cocaine; benzocaine, ethyl amino benzoate (Americaine, Anesthesin, Hurricaine, and many others); chloroprocaine (Nesacaine); propoxycaine (Ravocaine).

The amides are “more important for use” so know all of those listed.

The Local Anesthetics, unlike the general anesthetics, have a definite structure/ function relationship. The amines are molecules based on nitrogen. Each can be protonated to get a positive “+” charge (except the quaternary form, which has a permanent “+” charge), making them weak bases.

BH⁺  B + H⁺ -NH⁺  -N + H⁺

The carboxyl groups are weak acids.

AHA^- + H⁺ -COOH -COO^- + H⁺

Para-amino-benzoic acid (PABA) absorbs UV light because of its ring structure (it is an aromatic carboxylic acid).

An ester is made up of a carboxylic acid and an alcohol (R-COOH + R-OH). You must be able to recognize an ester from its structure: R-COO-R’. Also important, 2 ester bonds make up succinylcholine.

For LA’s (both esters and amides), the R group is an aromatic ring, and the R’ group is a short hydrocarbon chain plus a tertiary amine (see examples on handout). Thus, the LA molecule is an amphiphile (usually linear), with one hydrophobic side and one hydrophilic side.

*Procaine causes bleeding because of the alcohol group near the trauma site

Refer to the physiology text/ notes for basic cell potential information about sodium and potassium channels, etc. Remember that K-channels open slowly and stay open. LA acts on Na channels. Na-channels have three states: closed, open/activated, refractory.

** Know all the “pH effects”stuff! Know which form binds where, etc.

** You must know the pKa values of the following agents:

• Procaine 8.9
• Lidocaine 7.9
• Mepivacaine (Carbicaine) 7.6

The normal gingival pH is: 7.3-7.4. We know that weak bases accumulate in highly acidic (low pH) environments, so when there is an infection and the pH drops (pH=6, maybe even 4) and you inject your LA into this region, most of the drug will go to the B form and you will not get a block because the LA can’t reach the target site.

*see the Henderson-Hasselbalch equation to calculate which form goes where

Example: What % of lidocaine in the extraneural space is in the B form?

ie., [B] = [B]/[BH+]

[BH+] + [B] 1 + [B]/[BH+]

log B/BH+ = pH – pKa = 7.4 – 7.9 = -0.5

B/BH+ = 10 ^–0.5 = 0.32;

…we want % so, B .

(BH⁺ + B) …then divide everything by BH⁺

B/BH^{+ .} = 0.32 . = 0.24 = 24%

BH⁺/BH⁺ + B/BH⁺ 1 + 0.32

(Mepivacaine is better suited for infections)