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Pharmacology

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Local Anesthetics

Local anesthetics differ from most other drugs in that they are applied very close to the site where they are intended to act. Consequently, they travel across very short distances and their effects are felt in a matter of minutes. Their action consists of reversibly blocking the transmission of peripheral nerve impulses, an essential feature in local anesthesia.

Local anesthetics are weak bases in the form of oily liquids or low melting point solids. They are scantly water soluble and highly soluble in lipids and organic solvents. They are very unstable, readily decomposing when exposed to heat, light, or oxidation. When anesthetics are combined with strong acids such as hydrochloric acid, they form hydrochloride salts: white, crystalline, water-

soluble powders that are very stable and compatible with epinephrine (Bonica1959). The local anesthetics most commonly used in dentistry are listed in Table5.1, together with the molecular weights of their bases and salts.

Chemical Structure

The chemical structure of the local anesthetics presently used in dentistry, which is always basically the same, consists of the following three components (Löfgren and Lundquist1946; Löfgren1948; de Jong1977) (Figure5.1):

1) Aromatic ring. This is the lipid- soluble portion of the mol-

ecule that governs local anesthetic penetration into cell membranes. It may also help block nerve impulse transmission (Ritchie and Ritchie1968). While the ring is normally a benzene, it may also be a thiophene, as in articaine.

2) Intermediate aliphatic chain. This is what determines

the type of biotransformation and metabolic breakdown of the anesthetic. There are two types (Figure5.2):

● Ester or amino- ester chains are rapidly broken

down via plasma cholinesterase (also known as plasma pseudocholinesterase, plasma esterase, or butyrylcholinesterase)- mediated hydrolysis.

● Amide or amino- amide bonds are broken down more

slowly in the liver, first via N-

dealkylation of their tertiary amino terminus and subsequently by other mechanisms.

3) Amino terminus. This is the hydrophilic component and

active principle in anesthetics. It exists in two forms (Figure5.1):

● The cationic, ionized (positive electric charge:

), quaternary amine (the amino terminus has

BH four bonds) or acid form is water-

soluble and binds to the transmembrane protein receptor. It blocks the sodium channels and subsequently prevents depolarization of the neuron and the eventual transmission of the nerve impulse (Ritchie et al.1965a, b; Wildsmith 1986; Butterworth and Strichartz1990), intensifying the effect of the aromatic ring (Ritchie and Ritchie1968).

● The free, nonionized or uncharged and consequently

electrically neutral (free neutral base: B) or tertiary amine (the amino terminus has three bonds) is lipid soluble and drives diffusion of the local anesthesia across the cell membranes and even to the protein receptor (Ritchie etal.1965a, b). This form also blocks the transmission of nerve impulses, although less effectively than the cationic form (Ritchie and Ritchie 1968; Wildsmith 1986; Butterworth and Strichartz1990).

Physical- chemical Characteristics

ofLocal Anesthetics

As local anesthetics act on a transmembrane receptor located in the sodium channel within the cell membrane, their effectiveness depends on the four main physical- chemical properties that govern their anesthetic activity.

Local Anesthesia in Dentistry: A Locoregional Approach, First Edition. Jesús Calatayud and Mana Saraghi. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/Calatayud/local

t.me/Dr_Mouayyad_AlbtousH

Local Anesthetics



Ester

Amide

N-dealkylation

Hydrolysis

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Table5.1 Molecular weight (in International Units) oflocal

anesthetics: bases andsalts (hydrochlorides).

Local anesthetic Base Salt

Esters Benzocaine 165.2 —

Procaine 236.3 272.8 Tetracaine 264.4 300.8 Cocaine 303.4 339.8

Amides Prilocaine 220.3 256.8

Lidocaine 234.3 270.8 Mepivacaine 246.2 282.8 Ropivacaine 274.4 310.8 Etidocaine 276.0 312.9 Articaine 284.4 320.9 Bupivacaine 288.0 324.9

Aromatic ring

(lipophilic)

Ester-type local anesthetic

Amide-type local anesthetic

Intermediate

chain

COO R

Ester

NH-CO

Amide

COO-R

NH-CO-RR N

Amino terminus

(hydrophilic)

Cation

Base

Figure5.1 Three components of the chemical structure of

local anesthetics and basic or cationic amino terminus.

Hydroxylation

and conjugation

COO-R

Hydrolysis

NH-CO-R

Figure5.2 Standard metabolism of ester- and amide- type local

anesthetics, catabolic action. Source: Redrawn from Jastak

etal. (1995).

Table5.2 pKa, proportions of cationic (BH+), and free base (B)

forms at physiological pH (7.4) and 25 °C, and relative onset for

10local anesthetics.

pKa BH+/B ratio %BH+%B Anesthetic Onset

7.6 1.6/1 61 39 — Early

7.7 2/1 65 35 Mepivacaine Etidocaine

7.8 2.5/1 71 29 Articaine

7.9 3.2/1 76 24 Lidocaine Prilocaine

8.0 4/1 80 20 —

Intermediate

8.1 4.8/1 83 17 Bupivacaine Ropivacaine

8.5 6.3/1 92 8 Tetracaine Late

8.8 25/1 96 4 Cocaine

9.0 40/1 97 3 Procaine

pKa values as in Annex 6.

Dissociation Constant or pKa

The dissociation constant or pKa, also known as the ionization constant, is related to the amino terminus. As noted above the N-

terminus has two forms, cationic (BH free base (B), that are in equilibrium, although the proportion of one and the other depends on the following two factors (Covino1972).

1) The dissociation constant or pKa specific to each anes-

thetic is defined as the pH at which 50% of the molecules in the local anesthetic adopt the BH other 50% the B form (Table5.2).

2) The pH of the tissues because this modifies the pro-

) and

form and the

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portion of the dissociated forms in keeping with the Henderson–Hasselbalch equation (Henderson 1908; Hasselbalch1917):



pKapH tissues

log

whereby



pH tissues

log

pKa

    69

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Although the physiological pH is 7.4, the pH in tissues may drop to 6 or lower in the presence of inflammation or pus (Schade etal.1921; De Jong and Cullen1963). The proportion of the B form, which diffuses across cell membranes, consequently declines, rendering the anesthetic less effective since a smaller amount reaches the axon interior.

The pKa value effects two properties of local anesthetics: the onset of action and anesthetic potency.

1) Onset of local anesthetic action. The lower the pKa, the

greater the proportion of free base (B) in the anesthetic in tissues at physiological pH (7.4) and the speedier its diffusion inside the axon after crossing the cell membrane. In the axon interior (axoplasm) it reaches a new B↔BH

equilibrium, enabling the cationic form (BH

) to act on the protein receptor (Ritchie etal.1965a, b), blocking the sodium channels and with them the nerve impulse. This is the property that pKa affects most significantly.

2) Anesthetic potency. The lower the pKa, the higher the

potency of the local anesthetic, as more anesthetic penetrates the membrane more quickly, leaving less outside to be captured by the bloodstream (Courtney 1980; Wildsmith etal.1987). The effect of pKa is minor here, acting merely as a coadjutant. As discussed below, other factors such as lipid solubility have a heavier impact on the potency of local anesthetics.

Partition Coefficient or Lipid Solubility

The partition coefficient or lipid solubility, also known as the diffusion coefficient, a measure of the relative penetration of drugs in biological membranes, is closely related to

drug–cell membrane component binding. While the partition coefficient is actually a measure of lipid solubility, in practice the two terms are used indistinctly (Tucker etal.1970). The two best-

known methods for determining lipid solubility yield very different values, although as the data in Table5.3 shows, they exhibit a consistent pattern.

Lipid solubility affects a number of properties of local

anesthetics, as discussed below.

1) Relative anesthetic potency. The higher the lipid solubil-

ity, the higher the anesthetic potency. Although it is the single most important factor in anesthetic potency (Courtney 1980; Wildsmith et al.1987), others act as

coadjutants: (i) as noted earlier, pKa impacts potency, which is greater at lower pKa values; (ii) binding to blood plasma proteins also plays a role, for the more strongly the anesthetic binds, the higher is it potency (Truant and Takman 1959; Tucker et al. 1970); and (iii) the larger the size of the drug molecule, the higher the potency (Courtney 1980; Butterworth and Strichartz1990). The reference for anesthetic potency, procaine, is assigned a value of 1 and all other anesthetics are measured against that standard.

2) Relative toxicity. Lipid solubility is closely related to tox-

icity (Covino 1987; Garfield and Grugino 1987), such that the higher the former the higher the latter (Covino1972; Gangorosa1981). Procaine, which is also the reference for toxicity, is assigned a value of 1 and all other anesthetics are measured against that standard.

3) Topical anesthetic effectiveness (Gangorosa 1981).

Although topical anesthesia depends on both the lipid solubility and anesthetic concentration, a certain level

Table5.3 Relationship between lipid solubility (calculated withtwo methods) andproperties oflocal

anesthetics.

Anesthetic N- heptane N- octanol Topical anesthesia Relative potency Relative toxicity

Procaine 0.02 2 No 1 1 Articaine 0.7 15 No 2 2 Mepivacaine 0.8 20 No 2 2 Prilocaine 0.9 25 No 1.5 1.5 Lidocaine 2.9 45 Yes 2 2 Benzocaine 3.1 80 Yes — — Ropivacaine 3.4 115 Ye s — — Tetracaine 4.1 220 Ye s 8 8 Bupivacaine 27.5 350 Yes 8 8 Etidocaine 141.0 800 Yes 6 6

Lipid solubility as in Annex 7; relative toxicity as in Annex 8.

Lipid solubility Anesthetic property

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Local Anesthetics

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of lipid solubility can be defined that ensures good topical anesthetic action with no need to increase the concentration to intolerably high proportions (Table5.3).

Protein Binding

The ability of local anesthetics to bind to plasma proteins has been studied primarily for α

- acid glycoprotein

(Routledge et al. 1980; Meunier etal.2001) and to a lesser extent, albumin (Mather etal.1971; Meunier etal.2001). An equilibrium between the fraction of anesthetic bound to proteins and the free portion is reached in a matter of microseconds (Widman1975), the latter being the pharmacologically active fraction (Tucker etal.1970; Tucker and Mather1975).

Anesthetic binding to proteins conditions the duration of their effect: the more strongly they bind, the longer the duration (Covino 1981; Milam and Giovannitti Jr.1984). That is because the transmembrane receptors for local anesthetics are also proteins (Covino1981). These considerations are summarized in Table5.4.

Vasodilation

Nearly all local anesthetics generate vasodilation in two ways: (i) they cause the smooth muscle cells lining the vessels to relax (Aps and Reynolds 1976; Covino and Giddon1981) and (ii) they block sympathetic type B nerve fibers that control vasoconstriction. However, exceptions exist.

● Cocaine has an indirect vasoconstrictive effect because it

blocks mono-

amine- oxidase (MAO), an enzyme, preventing the recapture of nerve ending norepinephrine, which is a vasoconstrictor (Muscholl1961; Covino and Giddon1981).

Table5.4 Percentage oflocal anesthetics bound toproteins

andduration ofanesthetic effect.

● Mepivacaine is slightly vasoconstrictive (Du Mesnil de

Rochemont and Hensel 1960; Lindorf et al. 1974; Lindorf1979; Vongsavan etal. 2000), as is ropivacaine (Iida etal.2001; Timponi etal. 2006), although the effect is less widely acknowledged in the latter (De Oliveira etal.2014).

Vasodilation increases blood flow and with it, anesthetic transport, which in turn lowers anesthetic potency and duration (Widman 1975; Aps and Reynolds 1976). One curious effect is that the higher the concentration of the drug, the greater is its vasodilatory effect, partially offsetting the increase in potency afforded by higher concentrations (Aps and Reynolds1976; Reynolds et al. 1976). The clinical conclusion is that the greater the vasodilatory effect of an anesthetic, the greater the benefit to be administered with a vasoconstrictor, which enhances anesthetic potency and duration, hindering vascular absorption of the local anesthetic and thereby lowering the risk of systemic toxicity. Further to the data listed in Table5.5, in amide-

type anesthetics, the vasodilatory effect rises with anesthetic potency (Covino and Giddon1981).

Assessment ofAnesthesia andthe Anesthetic Parameter

A number of methods have been deployed to assess the efficacy of local anesthetic solutions. The earliest involved invitro trials with the sciatic nerves from frogs (Truant and Takman 1959; Bianchi and Strobel 1968) or the pneumogastric nerves from rabbits (Wildsmith etal.1987). In humans, efficacy has been assessed via needle prick after dermal infiltration or (more sophisticated) ulnar nerve infiltration (Löfström1975), in addition to evaluation using the various local anesthetic techniques.

Assessment ofLocal Anesthesia inDentistry

Anesthetic

Procaine 5 Short Prilocaine 55 Medium Articaine 60 Lidocaine 65 Mepivacaine 75 Tetracaine 85 Long Ropivacaine 95 Etidocaine 95 Bupivacaine 95

Data on protein bonds as in Annex 9.

Binding to proteins (%)

Duration of anesthetic

Such methods are insufficient in dentistry, as the dental pulp is an organ not present in any other part of the body and which is very difficult to anesthetize. Unlike readily anesthetized soft tissues where the effect is long- lasting, the duration of pulpal anesthesia is much shorter (Björn1946; Björn and Huldt1947) (Figure5.3).

An effective assessment method was developed in 1946 by Hilding Björn (1907–1995), who used an electric pulp tester (EPT) to study the efficacy of anesthetic solutions. The device may be applied repeatedly to assess the duration of pulpal anesthesia, the criteria for which is if the tooth fails to respond to the maximum stimulus of the EPT. The reasoning behind this is that if the patient feels discomfort atless than the maximum stimulus, then there is a risk that

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Table5.5 Vasodilatory effect oflocal anesthetics.

Onset time

Histic concentration

Time

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Anesthetic Type Vasodilatory effect Intensity of effect Reference

     71

Procaine Ester +++ Very high Du Mesnil de Rochemont and Hensel (1960), Lindorf etal.

Tetracaine Ester ++ High Martindale (1982) Bupivacaine Amide ++ Aps and Reynolds (1976), Reynolds etal. (1976) Etidocaine Amide ++ Eicholizer and Feldman (1976) Lidocaine Amide + Moderate Du Mesnil de Rochemont and Hensel (1960), Lindorf etal.

Articaine Amide + Muschaweck and Rippel (1974) Prilocaine Amide ± Dilation, weak Aström and Persson (1961), Akerman etal. (1966), Lindorf etal.

Mepivacaine Amide − Weak Du Mesnil de Rochemont and Hensel (1960), Lindorf etal.

Ropivacaine Amide − Iida etal. (2001), Timponi etal. (2006) Cocaine Ester − High Muscholl (1961)

+ vasodilation; − vasoconstriction.

Figure5.3 Concentration required to

anesthetize soft tissue and pulp, showing much lower concentration and much longer duration in soft tissue. Source: Redrawn from Haglund and

Evers (1985).

(1974), Lindorf (1979)

(1974), Lindorf (1979), Muschaweck and Rippel (1974), Aps and Reynolds (1976), Reynolds etal. (1976)

(1974), Lindorf (1979), Reynolds etal. (1976), Chng etal. (1996)

(1974), Lindorf (1979), Vongsavan etal. (2000)

PULPAL ANALGESIA

the patient may respond to stimuli during the dental procedure (Björn 1946; Björn and Huldt 1947; Certosimo and Archer1996). Moreover, successive electrical testing over a given time has been shown to induce no harm in the dental pulp (McDaniel etal.1973). Recent research has found that the myelinated Aδ fibers in the pulp are stimulated by the EPT, whereas the unmyelinated polymodal C fibers are not (Lin and Chandler2008; Sampaio etal.2012).

Björn standardized the procedure by selecting the maxillary lateral incisor (LI) as the target, as this tooth exhibits scant anatomical variations and can be anesthetized with buccal infiltration, a simple technique which also limits individual variation. By injecting 1 ml of solution, Björn ensured that the experimental conditions were standardized and reproducible in all the series studied (Björn1947; Björn and Huldt1947).

SOFT TISSUE

ANALGESIA

Such standardization is lacking in other methods (i.e. restorations, scaling, root canals, extractions) and uniform pain stimulus is difficult to attain and assess, and such methods furnish no information on the anesthetic effect in the pulp.

Mandibular block studies are useful for obtaining clinical information on that anesthetic technique and its limitations, but are of scant utility in assessing the effectiveness of local anesthetic solutions for a number of reasons.

1) Technique sensitivity: As the technique is more difficult,

failures due to technical errors are common. High interindividual variability, in turn, renders it more difficult to standardize.

2) Accessory innervations: Despite a successful block indi-

cated by an anesthetized lower lip, the patient may still

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Local Anesthetics

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have sensation in the pulp due to the high frequency of accessory innervation in the lower arch such as the buccal nerve and mylohyoid nerve (see Chapter19).

3) Anatomic variation: Anatomic variation in the mandible

such as double mandibular foramen, accessory canals, high lingula, and variable gonial angle may result in anesthetic failure despite the use of correctly implemented standardized techniques to fail (seeChapter19).

All the above- mentioned variables are difficult to control and standardize, and thus reduce the utility of using mandibular block injections to assess local anesthetic solution efficacy.

Anesthetic Parameter

Certain variables, listed below, may be used as surrogate indicators of the clinical efficacy of anesthetic solutions, and these indicators may vary depending on the specific local anesthetic and vasoconstrictor, and their respective concentrations.

● Of the four variables selected here (Annexes 21 and 27),

three are related to buccal infiltration of the maxillary lateral incisor (LI) with 1 ml of the local anesthetic solution (Annex 21):

1) The percentage of LI pulpal anesthesia, i.e. the % of

times the tooth is successfully anesthetized: 95%, for example.

2) The mean duration in minutes of pulpal anesthesia

in the LI: 45

minutes (written as 45′), for example.

3) The mean duration in minutes of soft tissue anesthe-

sia (upper lip anesthesia): 190

minutes (190′), for

example.

● The fourth is related to mandibular block with 1.8 ml

(equivalent to one cartridge) of the solution using the direct or conventional technique (Annex 27):

4) The mean duration in minutes of lower lip anesthe-

sia (soft tissue anesthesia): 200 minutes (200′), for example.

in minutes of pulpal anesthesia) assess the potency and efficacy of the local anesthetic solution and the other two (duration of upper and lower lip anesthesia) provide information that can be conveyed to patients about the approximate post-

procedure duration of the perceivable effects

(Figure5.3).

The main advantage to this approach is that different solutions can be compared in a standard format, helping to choose the anesthetic solution best suited to the circumstances and to predict the expected results.

Anesthetic Concentration

Concentration is a factor particularly relevant to the efficacy and toxicity of local anesthetics, which are typically available in a number of dilutions.

Concentration andVolume

Medical practice often calls for anesthetizing large areas of (readily anesthetized) soft tissue, which in turn requires large volumes of anesthetic solution (20–30 ml for caudal or epidural block and up to 60 plexus block). More diluted solutions are used under such conditions, with a lower concentration of anesthetic (Moore etal.1972,1977) and a standard epinephrine concentration of 1:200 000 (5 μg/ml) (Bonica 1959; Moore etal.1972).

In dentistry, by contrast, the area involved is small and the target tissue is the dental pulp, which is very difficult to anesthetize. As a result, small volumes of more highly concentrated anesthetic solutions and vasoconstrictors are used (note: doses of over 5–7 ml per session, equivalent to three to four 1.8

ml cartridges, are rare) (Table5.6). In dentistry, the standard epinephrine concentration is 1:100 000 (10 μg/ml), double the standard value applied in other areas of medical practice.

ml for intercostal or brachial

These four variables were used to build the anesthetic parameter, as follows: 95%- 45′/190′- 200′. This is the param- eter for the standard solution, 2% lidocaine with 1:100 000 epinephrine (10 μg/ml) (L- 100) or 1:80 000 epinephrine (12.5 μg/ml) (L- 80). It means that injection of 1 ml of this solution in the maxillary lateral incisor ensures pulpal anesthesia in 95% of individuals that lasts on average for 45 minutes. In addition, soft tissue anesthesia lasts 190 minutes in the upper lip and 200 minutes in the lower, in the latter case after mandibular block with 1.8 ml of anesthetic solution. The first two values (% of anesthesia and duration

Table5.6 Most commonly used concentrations oflocal

anesthetics andepinephrine inmedical anddental practice.

Drug Medicine Dentistry

Lidocaine 1–2% 2% Mepivacaine 1–2% 2–3% Prilocaine 2% 3–4% Epinephrine

Standard concentration

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1:200 000 (5 μg/ml)

1:100 000 (10 μg/ml)

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