Diffusion and Effect

During diffusion from the injection site (i.e., the interstitial space of connective tissue) to the axon of a sensory nerve, the local anesthetic must traverse the perineurium. The multilayered perineurium is formed by connective tissue cells linked by zonulae occludentes (p. 22) and therefore constitutes a closed lipophilic barrier.

Local anesthetics in clinical use are usually tertiary amines; at the pH of interstitial fluid, these exist partly as the neutral lipophilic base (symbolized by particles marked with two red dots) and partly as the protonated form, i.e., am-phiphilic cation (symbolized by particles marked with one blue and one red dot). The uncharged form can penetrate the perineurium and enters the endoneural space, where a fraction of the drug molecules regains a positive charge in keeping with the local pH. The same process is repeated when the drug penetrates the axonal membrane (axo-lemma) into the axoplasm, from which it exerts its action on the sodium channel, and again when it diffuses out of the endoneural space through the unfenes-trated endothelium of capillaries into the blood.

The concentration of local anesthetic at the site of action is, therefore, determined by the speed of penetration into the endoneurium and the speed of diffusion into the capillary blood. In order to ensure a sufficiently fast build-up of drug concentration at the site of action, there must be a correspondingly large concentration gradient between Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

drug depot in the connective tissue and the endoneural space. Injection of solutions of low concentration will fail to produce an effect; however, too high concentrations must also be avoided because of the danger of intoxication resulting from too rapid systemic absorption into the blood.

To ensure a reasonably long-lasting local effect with minimal systemic action, a vasoconstrictor (epinephrine, less frequently norepinephrine (p. 84) or a vasopressin derivative; p. 164) is often co-administered in an attempt to confine the drug to its site of action. As blood flow is diminished, diffusion from the endoneural space into the capillary blood decreases because the critical concentration gradient between endo-neural space and blood quickly becomes small when inflow of drug-free blood is reduced. Addition of a vasoconstrictor, moreover, helps to create a relative ischemia in the surgical field. Potential disadvantages of catecholamine-type vasoconstrictors include reactive hy-peremia following washout of the constrictor agent (p. 90) and cardiostimulation when epinephrine enters the systemic circulation. In lieu of epinephrine, the vasopressin analogue felypressin (p. 164, 165) can be used as an adjunc-tive vasoconstrictor (less pronounced reactive hyperemia, no arrhythmogenic action, but danger of coronary constriction). Vasoconstrictors must not be applied in local anesthesia involving the appendages (e.g., fingers, toes).

Endoneural Bloodflow

Perineurium

Endoneural space

Axon

Cross section through peripheral nerve (light microscope)

Perineurium

Inter- Axolemma stitium

Axoplasm

Endoneural space

Capillary wall

Vasoconstriction e.g., with epinephrine

Vasoconstriction e.g., with epinephrine

O lipophilic Axoplasm CDamphiphilic

A. Disposition of local anesthetics in peripheral nerve tissue

Axon

Characteristics of chemical structure. Local anesthetics possess a uniform structure. Generally they are secondary or tertiary amines. The nitrogen is linked through an intermediary chain to a lipophilic moiety—most often an aromatic ring system.

The amine function means that local anesthetics exist either as the neutral amine or positively charged ammonium cation, depending upon their dissociation constant (pKa value) and the actual pH value. The pKa of typical local anesthetics lies between 7.5 and 9.0. The pka indicates the pH value at which 50% of molecules carry a proton. In its protonated form, the molecule possesses both a polar hydrophilic moiety (pro-tonated nitrogen) and an apolar lipo-philic moiety (ring system)—it is amphi-philic.

Graphic images of the procaine molecule reveal that the positive charge does not have a punctate localization at the N atom; rather it is distributed, as shown by the potential on the van der Waals' surface. The non-protonated form (right) possesses a negative partial charge in the region of the ester bond and at the amino group at the aromatic ring and is neutral to slightly positively charged (blue) elsewhere. In the proto-nated form (left), the positive charge is prominent and concentrated at the ami-no group of the side chain (dark blue).

Depending on the pKa, 50 to 5% of the drug may be present at physiological pH in the uncharged lipophilic form. This fraction is important because it represents the lipid membrane-permeable form of the local anesthetic (p. 26), which must take on its cationic amphi-philic form in order to exert its action (p. 204).

Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy; even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

terases. This is advantageous because of the diminished danger of systemic intoxication. On the other hand, the high rate of bioinactivation and, therefore, shortened duration of action is a disadvantage.

Procaine cannot be used as a surface anesthetic because it is inactivated faster than it can penetrate the dermis or mucosa.

The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the C-atom adjacent to the nitrogen group. Ar-ticaine possesses a carboxymethyl group on its thiophen ring. At this position, ester cleavage can occur, resulting in the formation of a polar -COO- group, loss of the amphiphilic character, and conversion to an inactive metabolite.

Benzocaine (ethoform) is a member of the group of local anesthetics lacking a nitrogen that can be protonated at physiological pH. It is used exclusively as a surface anesthetic.

Other agents employed for surface anesthesia include the uncharged poli-docanol and the catamphiphilic cocaine, tetracaine, and lidocaine.

Procaine

Lidocaine

Prilocaine

Articaine

Mepivacaine

Benzocaine

Diuretic Adverse Reactions
A. Local anesthetics and pH value
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