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Injectable Anesthetic Solutions Used inDentistry
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This chapter describes the chemical and pharmaceutical
composition of injectable anesthetic solutions in dental
cartridges. It also analyzes procaine, which while rarely
used today constitutes a reference against which the efficacy of all the others are compared.
Solution Composition
Local anesthetic solutions available in cartridges have a number of components. In addition to the two most important,
the local anesthetic and the vasoconstrictor, they contain
other nonthat may have toxic or allergenic implications (Klein1983).
Local Anesthetic
This is the main drug and the one that induces the anesthetic effect. The five modern anesthetics used in dentistry
today are all amides: lidocaine, articaine, mepivacaine, prilocaine, and bupivacaine.
With the exception of lidocaine, which is achiral, i.e. has
no optical isomers (Tucker1986; Calvey1995; Mather and
Chang2001), the others are administered as a racemic mixture, i.e. equal parts of the two (levo or S- and dextro or R+)
stereoisomers or asymmetric carbons (Tucker 1986;
Strichartz etal.1990; Calvey1995; Mather and Chang2001).
In most, the two isomers have approximately the same
anesthetic activity (Calvey1995).
anesthetic constituents with specific functions
where the solution is injected, and lowers the toxicity of
the anesthetic by slowing its absorption into the bloodstream. There are two types of vasoconstrictors: one derived
from vasopressin, namely felypressin (Octapressin®), which
is less powerful and much less frequently used, and sympathomimetic vasoconstrictors such as epinephrine, norepinephrine, and levonordefrin, the three most powerful.
Epinephrine is the one most commonly used worldwide.
These sympathomimetic vasoconstrictors are character-
ized by features with implications for dentistry.
● As they are highly sensitive to primarily oxidation-
induced degradation, they determine the shelf life of
local anesthetic solutions.
● They are combined with an antioxidant (sulfite) to
increase shelf life (Milano etal.1982; Klein1983).
● They have an acidic pH, normally around 4 (Annex 14),
but ranging from 2.7 to 5.5 (USP38 2015), which also
improves their stability and enhances their solubility in
aqueous solutions.
● Their levo isomeric form is used, as it is 10–200 times
more powerful than the dextro form (Table 6.5,
Chapter6).
● The bitartrate form of epinephrine is used because it is
more stable than the base or hydrochloride forms
and like those forms is water soluble (Smith 1920;
Bonica1959).
Antioxidants (Sulfites)
Vasoconstrictor
This second most important component enhances the
effect of the local anesthetic by promoting vasoconstriction
of the blood vessels near the target tissue and inducing a
mass- volume- time effect that heightens potency, lengthens
the duration of the anesthetic effect, reduces hemorrhage
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
These compounds lengthen the half- life of sympathomimetic vasoconstrictors such as epinephrine because they
capture the oxygen penetrating the cartridge before it
engages with and inactivates the vasoconstrictor (Milano
etal. 1982; Klein1983; Huang and Fraser1984; Schwartz
and Sher1985; Seng and Gay1986).
The sulfites most widely used are 0.5 mg/ml sodium
bisulfite (Seng and Gay 1986), sodium or potassium
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108
metabisulfite (Klein 1983; Seng and Gay1986), and acetone sodium bisulfite 1
mg/ml (Seng and Gay1986). Other
characteristics associated with these compounds include
their bitter taste, to which local anesthetics owe that same
feature (Klein1983), their contribution to maintaining an
acid pH to preserve vasoconstrictors (Moorthy etal.1984),
and their efficacy in protecting vasoconstrictors for the
first 18
months (American Dental Association 1983;
Bennett1984; Jastak etal.1995). That capacity gradually
declines with the amount of active antioxidant, lowering
sympathomimetic vasoconstrictor activity and pH (Hondrum
and Ezell1996).
Although deemed to be safe (Bush etal.1986; Seng and
Gay1986), low allergenic additives (Bush etal.1986), the
sulfites in local anesthetics used in dentistry have been
known to trigger allergic reactions (Huang and Fraser1984;
Schwartz and Sher 1985; Schwartz et al. 1989; DoomsGoossens et al. 1989; Campbell et al. 2001). For poorly
understood reasons this intolerance is associated with
severe, corticoid- treated asthma (Bush etal.1986; Schwartz
etal.1989).
Seng and Gay (1986) proposed replacing sulfites with
antioxidants suggested by Klein (1983), such as ascorbic
acid and thioglycerol (only with Marcaine®), but they are
less effective, more costly, and also pose health risks (Bush
etal.1986).
Preservatives (Methylparaben)
Preservatives are used to keep dental cartridges containing
local anesthesia sterile (i.e., bacterium-
free) (Latronica
etal.1969; Larson1977; Luebke and Walker1978). These
compounds are parabens (propyl- , butyl- , and methylparaben), the most widely used being methylparaben or methyl
4- hydroxy- benzoate (Larson1977; Klein 1983) at concentrations of 1
mg/ml=0.1% (Larson1977).
Parabens are used for their bacteriostatic and fungistatic
power (Schorr1968; Latronica etal.1969; Nagel etal.1977;
Larson1977; Luebke and Walker1978), low- dose efficacy
(Larson1977; Luebke and Walker1978), and scant toxicity
(Luebke and Walker1978). Their primary drawback is that,
like the alkyl- esters of aminobenzoic acid (Latronica
et al.1969; Nagel et al. 1977; Larson 1977; Luebke and
Walker1978; Giovannitti and Bennett1979), they share a
chemical structure with ester- type anesthetics. Allergic
reactions to anesthetic solutions induced by these compounds and the cross- sensitivity to ester- type local anesthetics (Aldrete and Jonhson1969; Latronica etal. 1969;
Larson1977; Luebke and Walker1978) are consequently
common (Aldrete and Jonhson 1969; Luebke and
Walker1978; Giovannitti and Bennett1979). The US Food
and Drug Administration (FDA) has therefore banned
these compounds in dental cartridges and single (although
not multipreparation and single-
dose) vials (Malamed 2004) because cartridge
dose packaging with modern industrial techniques guarantee sterility and prevent infectious
disease transmission. As a result, the use of parabens, the
primary cause of allergic reactions, is no longer necessary.
Since their prohibition this type of adverse reaction to local
dental anesthesia has declined drastically (Malamed2004).
Non-
parabenic preservatives exist, but are seldom used.
One, 0.25% (0.25
mg/ml) chlorobutanol (Klein1983), is less
effective (Luebke and Walker1978) and edetate disodium
calcium is only used in Marcaine, a brand name for bupivacaine (Klein1983).
pH Adjustment
Solutions with sympathomimetic vasoconstrictors such as
epinephrine are the most acidic, around pH = 4, ranging
from 3.5 to 4.5 (Annex 14), because a low (acid) pH is
needed to preserve the vasoconstrictor, which breaks down
in basic media (Tainter etal.1939; Fyhr and Brodin1987;
Bowles etal.1995). Epinephrine is most stable at pH=3.4
(Hondrum etal. 1993) and breaks down in a matter of
hours at pH
> 6 (De Jong and Cullen1963). Acidity poses
problems, however.
1) Clinical trials have shown that injections are more
painful, creating a burning or stinging sensation
(Oikarinen et al. 1975; Moorthy et al. 1984; Kramp
etal.1999; Wahl etal.2001).
2) The anesthetic effect may be delayed because at acidic
pHs, most of the anesthetic molecules are cationic and
unable to penetrate the cell membrane. Very few are
free bases, the lipid-
soluble form that crosses the membrane, establishing a new equilibrium with the cations
in the axoplasm. That in turn activates the receptor that
blocks the sodium channels, generating the anesthetic
effect. The tissue is alkaline in pH (= 7.4) and buffers in
the tissue mitigate the initial acidity of the solution
(Tainter et al.1939; Björn1947b), however, although
some studies (Björn1947b) have shown that to take
longer than initially believed. Today, it is known that
cations can penetrate the membrane in other ways,
crossing TRPV1 channels, for example (Butterworth
and Oxford2009) (see Chapter4).
3) If the acidic solution comes into contact with a metal,
such as in former hypodermic metal syringes, within a
few hours the release of nickel, zinc, and especially copper ions begins to irritate the tissues, an effect that may
last for several days (Lundqvist etal.1948). Dental solutions fortunately come in glass cartridges that elude
such problems.
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For anesthetic solutions with sympathomimetic
vasoconstrictors (epinephrine and levonordefrin) the
USP has established pH ranges of 3.3–5.5 for solutions
with lidocaine, mepivacaine, prilocaine, and bupivacaine, and of 2.7–5.2 for articaine with epinephrine
(USP382015). As these solutions age, their pH tends to
decline further, with both the active antioxidant and
vasoconstrictor content decreasing (Hondrum and
Ezell1996).
Solutions with non- sympathomimetic vasoconstrictors
such as felypressin (Octapressin®), which is available in
many European countries although not in the United
States, have a pH of around 5 (Annex 14), more or less midway between solutions without vasoconstrictors and those
with the sympathomimetic type.
The chemical compounds added to solutions to attempt
to regulate their pH include hydrochloric acid (ClH) to
lower it, and sodium hydroxide (NaOH) and sodium lactate (C
bupivacaine) to raise it (Klein1983).
NaO3) (only in Marcaine®, a brand name for
3H5
Other Compounds
Sterile water is used as a vehicle and salts, normally 3–6 mg/
ml sodium chloride (NaCl), to render the solutions isotonic
(Klein1983). Clinical studies have shown that non- isotonic
solutions do not raise anesthetic efficacy (Nordenram1966)
and irritate subcutaneous tissue, with concomitant pain
(Lewis 1919; Nordenram1966).
Metabolism
When injected alone, procaine is retained in the injection site
hours and in the presence of epinephrine for up to 3 h
for 1.5
(Sung and Truant1954). It has a short halfutes (Seifen etal.1979), because once in the bloodstream it is
hydrolyzed by pseudocholinesterase (or plasma cholinesterase or butyrylcholinesterase). It scarcely penetrates the placenta. Its metabolites are eliminated in the urine, with only
2% eliminated in the free non- metabolized form (Brodie
etal.1948). Nonetheless, the pseudocholinesterase deficits or
alterations found in one per 3000 people (Kalow and
Gunn 1959) lengthen the halfbiotransformation pathways are listed in Annex 12.
life of procaine. Its possible
life, under 8min-
Procaine withEpinephrine
Procaine is no longer marketed in dental cartridges, although
2% procaine ampoules and 1:1000 (1000
ampoules are available. Therefore 50
be mixed with 1
2% procaine with 1:50
The maximum absolute dose of this local anesthetic
solution for adults weighing 70 kg or more is five and a half
ml cartridges. The limiting factor is the high epineph-
1.8rine concentration, at 1:50
dose established for procaine alone in dentistry is 400
(5.7
mg/kg) (American Dental Association1984).
ml of 1:1000 epinephrine to obtain 51 ml of
000 (20 μ/ml) epinephrine.
000. The maximum absolute
μg/ml) epinephrine
ml of 2% procaine can
mg
Remarks
Procaine (Novocaine)
Procaine, or Novocaine, is a derivative of para- amino
benzoic acid, synthesized by German chemist Alfred
Einhorn in 1904 (Farbwerke vorm 1904; Einhorn and
Uhlfelder 1909). The first clinical trial of this anesthetic
together with epinephrine was reported by Heinrich Braun
(Braun1905) under the name Novocaine. In 1910 German
dentist Guido Fischer published the first book on local
dental anesthesia featuring Novocaine as the primary anesthetic (Fischer1910). It met with such success that it was
translated into several languages and its second edition
was translated into English (Fischer 1912). (The first
German edition sold out in just a few months.) Around
1916, Novocaine began to be known among clinicians as
procaine in the United States (Benedict et al.1932; Link
and Alfred Einhorn1959).
In the first half of the twentieth century procaine was the
prototypical local anesthetic and it is the standard used in
this chapter for comparison of all others. Its most prominent characteristics are summarized in Table7.1.
While procaine is less efficacious than other anesthetics
(see anesthetic parameters and physicalties in Table7.1), in the first half of the twentieth century it
proved to be sufficiently effective and much safer than its
predecessor cocaine, the first of the local anesthetics. Its
primary drawback is the potential for hypersensitivity reactions (allergy reactions) and in particular its cross- sensitivity
with all ester- type anesthetics (Aldrete and Johnson1970).
Today procaine can be used in the event of multiple and
severe allergies to several amide group anesthetics,
although it has fallen into disuse and been replaced by
modern amidegenic and exhibit an anesthetic parameter that attests to
higher potency and efficacy.
type anesthetic solutions that are less aller-
chemical proper-
Lidocaine (Lignocaine)
Lidocaine was synthesized in 1943 by Swedish researchers
Nils Löfgren (1913–1967) and Bengt Lundqvist (1922–1953)
(Björn and Huldt IV 1947a; Löfgren 1948; Gordh
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5
H
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Table7.1 Procaine.
Pharmacological factor Reference
● Name and synonym: Procaine, Novocaine
● First synthesized in 1904 by Alfred Einhorn Farbwerke vorm (1904)
● Chemical name: 2- (diethylamino) ethyl 4- aminobenzoate American Dental Association (1984)
● Formula: C
13H20N2O2
N
2
COO–CH2–CH2N
C2H
● Molecular weight: Base 236.3
Hydrochloride 272.8
● Clearance rate: 6.23 l/minute Seifen etal. (1979)
● Volume of distribution: 58.7 l Seifen etal. (1979)
● Half- life: <8 minutes Seifen etal. (1979)
Physical–chemical property
● pKa value or dissociation constant: 9.0
Annex 6
Denotes retarded onset
● Lipid solubility or partition coefficient: n- heptane 0.02
Annex 7
n-octanol 2
Denotes low anesthetic potency and no topical anesthesia
● Plasma protein binding: 5%
Annex 9
Denotes short duration of the anesthetic effect
● Vasodilation: +++ (high)
Denotes need for a vasoconstrictor to be effective
Du Mesnil de Rochemont and Hensel
(1960)
Lindorf etal. (1974)
Clinical factor Reference
● Relative anesthetic potency: 1
● Relative toxicity: 1 Annex 8
● Maximum absolute dose in dentistry: 400mg (5.7mg/kg) American Dental Association (1984)
● Usable during pregnancy: Yes (FDA category=C)
Haas etal. (2000)
Denotes low risk
● Usable during lactation: Yes
Denotes low risk
● Usable with children: Yes
Denotes low risk
Anesthetic parameter Variable 2% procaine + 1:50 000 epinephrine
Buccal infiltration
Superior lateral incisor
(Annex 21)
Mandibular block
(Annex 27)
Pharmacological, physical–chemical and clinical properties, and anesthetic parameter.
Summary: 2% procaine with 1:50 000 (20 μg/ml) epinephrine: 80%- 25′/95′- 110′.
1 ml
1.8 ml
Successful pulpal anesthesia (%)
Duration, pulpal anesthesia (minutes)
Duration, anesthesia upper lip (minutes)
Duration, anesthesia lower lip (minutes) 110
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80
25
95
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et al. 2010), who first published their findings in 1946
(Löfgren and Lundqvist 1946). It was initially known as
compound LL 30, the letters designating the two researchers’ initials and the number the consecutive order of the
compound of the many they studied (Gordh etal.2010).
After 1946 it was renamed Xylocaine® (Löfgren and
Lundqvist1946), a combination of the product from which
it is derived, “xylidine,” and the local anesthetic suffix
“caine” (Gordh et al. 2010). In 1948 it was patented in
Sweden and the United States (American Dental
Association 1984; Gordh et al. 2010), where it quickly
replaced procaine (American Dental Association1984). In
1951 Xylocaine was adopted as the brand name and lidocaine as the generic name (McMahon and Woods1951). It
is presently known as lidocaine in the United States and
most of the rest of the world and lignocaine in the United
Kingdom. Lidocaine was the first amide-
type local anesthetic to be successfully used and the only anesthetic discussed in this book, with the exception of tetracaine, that is
achiral, i.e. with no levo/dextro stereoisomers (Calvey1995).
Lidocaine has also been used since the 1960s as an antiarrhythmic drug in medical emergencies (Harrison
et al. 1963; Katz and Epstein 1968). Its most prominent
characteristics are summarized in Table7.2.
Metabolism
At a 2% concentration with 1:100 000 (10 μg/ml) epinephrine, lidocaine is removed from the injection site in around
4 hours and without epinephrine in less than 2 hours (Sung
and Truant1954). Once in the bloodstream it accumulates,
in descending order, in the kidneys, lungs, brain, and heart
(Sung and Truant1954; Akerman etal.1966). The hepatic
microsomal system (Sung and Truant 1954; Akerman
etal.1966; Boyes etal.1971; Stenson etal.1971; Thomson
et al. 1973), primarily isoform 3A of cytochrome P450
(Bargetzi et al. 1989), catabolizes 70% of the anesthetic
(Boyes etal.1971; Stenson etal.1971). Around 80% is eliminated in the urine, although only 4% of it is excreted
unchanged (Annex 12). Elimination is enhanced in acidic
urine (Eriksson etal.1966; Mihaly etal.1978).
Lidocaine has a half- life of around 110 minutes (Annex
11). Severe liver and kidney disorders affect its catabolism,
albeit in different manners (Thomson etal. 1973). Severe
liver disease may raise its half- life by up to three times,
whereas severe kidney conditions affect not half- life but
the metabolites in the blood (Thomson etal.1973), particularly monoethylglycinexylidide (MEGX) and glycinexylidide (GX), active agents involved in lidocaine toxicity
(Blumer etal.1973; Strong etal.1973).
This drug diffuses passively across the placenta, reaching
a concentration in the umbilical vein of 60% of that found
in the maternal blood vessels (Covino1971). Its possible
biotransformation pathways are listed in Annex 12.
Remarks
L- 100 or 2% lidocaine with 1:100 000 (10 μg/ml) epinephrine and L-
80, the same solution with 1:80 000 (12.5 μg/ml)
epinephrine, are deemed to be the standard solutions in
dentistry for several reasons (Cowan1964):
1) Their efficacy in attaining pulpal anesthesia via buccal
infiltration is only exceeded by potent solutions such as
4% articaine (double the anesthetic content) with
000 (10 μg/ml) epinephrine (A- 100), or 2%
1:100
lidocaine with 1:50 000 (20 μg/ml) epinephrine (L- 50)
(double the vasoconstrictor content) (Annex 21).
2) It is very safe, with a maximum absolute dose in den-
tistry of eight and a half cartridges in adults weighing
70 kg or over, more than most other solutions (Annex 10).
3) As an FDA pregnancy risk category B drug, it is very
safe for pregnant or nursing women.
Lidocaine concentrations of 5% have shown to be highly
toxic in animal experiments and are consequently not recommended (Lambert et al. 1994; Strichartz et al. 1994;
Strichartz and Lambert 1995). Conversely, 2% lidocaine
solutions with 1:200 000 (5 μg/ml) epinephrine (half the
vasoconstrictor as in the standard solution) have proven to
be scantly effective in clinical trials (Annex 21).
Indications
Two local anesthetic solutions with epinephrine are
presently available. Their characteristics and uses are discussed below.
Standard 2% Lidocaine: L- 100with 1:100 000 (10 μg/ml)
Epinephrine or L- 80with 1:80 000 (12.5 μg/ml) Epinephrine
The epinephrine concentration used in the United States and
many other countries is 1:100 000, although in some European
countries, Japan, and India the standard is 1:80 000 (12.5 μg/
ml). As in practice the two deliver similar results, they are
indistinctly deemed to be the standard (Cowan1964; Yamazaki
et al. 2006). Nonetheless, while some authors eschew the
12.5 μg/ml dose where epinephrine is relative contraindicated,
they find the 10 μg/ml concentration acceptable (Annex 17).
The maximum absolute dental dose in adults weighing
70
kg or more is 300 mg (4.3 mg/kg) of lidocaine, or eight and
a half 1.8- ml cartridges (Annex 10). Its uses are as follows:
1) In mandibular blocks because:
◼ Pulpal anesthetic efficacy in mandibular nerve
blocks depends less on the potency of the local
anesthetic solution (higher anesthetic or
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Table7.2 Lidocaine.
CH
Lidocaine
5
5
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Pharmacological factor Reference
● Name and synonyms: Lidocaine, lignocaine, LL 30, Xylocaine®
● First synthesized in 1943 by Löfgren and Lundqvist Löfgren (1948)
● Chemical name: alpha- diethylamino- 2,6- acetoxylidide American Dental
Association (1984)
● Formula: C
NH–CO–CH
14H22N2
3
O
H
C
2
N
2
Löfgren (1948)
C2H
CH
3
● Molecular weight: Base 234.3
Hydrochloride 270.8
Löfgren (1948)
De Jong (1977)
Strichartz (1990)
● Clearance rate: 0.83 l/min Annex 11
● Volume of distribution: 85 l Annex 11
● Half- life: 110 minutes Annex 11
Physical–chemical property
● pKa value or dissociation constant: 7.9
Annex 6
Denotes fast onset
● Lipid solubility or partition coefficient: n- heptane 2.9
Annex 7
n-octanol 45
Denotes medium anesthetic potency and topical anesthesia
● Plasma protein binding: 65%
Annex 9
Denotes medium duration of the anesthetic effect
● Vasodilation: + (moderate)
Denotes need for a vasoconstrictor to be effective
Du Mesnil de Rochemont
and Hensel (1960)
Lindorf etal. (1974)
Clinical factor Reference
● Relative anesthetic potency: 2
● Relative toxicity: 2 Annex 8
● Maximum absolute dose in dentistry: 300 mg (4.3 mg/kg) American Dental
Association (1984)
● Usable during pregnancy: Yes (FDA category=B)
Table5.11 (Chapter5)
Denotes low risk
● Usable during lactation: Yes
Table5.11 (Chapter5)
Denotes low risk
● Usable with children: Yes
Denotes low risk
Anesthetic parameter Variable L- 100 or L- 80 L- 50
Buccal infiltration
Superior lateral incisor
1 ml
(Annex 21)
Mandibular block
1.8 ml
(Annex 27)
Pharmacological, physical–chemical, and clinical properties and anesthetic parameter.
Summary: (L- 100) 2% lidocaine with 1:100 000 (10 μg/ml) epinephrine and (L- 80) 2% lidocaine with 1:80 000 (12.5 μg/ml) epinephrine: 95%- 45′/190′- 200′.
(L- 50) 2% lidocaine with 1:50 000 (20 μg/ml) epinephrine: 100%- 60′/165′- 200′.
Successful pulpal anesthesia (%)
Duration, pulpal anesthesia (minutes)
Duration, anesthesia upper lip (minutes)
95
45
190
100
60
165
Duration, anesthesia lower lip (minutes) 200 200
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