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vasoconstrictor concentration or both) (Annex 24)
than on the proximity to the inferior alveolar nerve,
the aponeuroses separating the anesthetic from the
nerve, accessory innervation, or anatomical variations (see Chapter19).
◼ Solutions with high concentrations of local anes-
thesia (4% articaine, 4% prilocaine) have not exhibited greater clinical efficacy in attaining pulpal
anesthesia under normal circumstances (Annex
24), while inducing four to nine times more longterm paresthesia in the inferior alveolar and lingual
nerves (Haas and Lennon1995; Garisto etal.2010)
(see Chapter22).
2) In children, for both mandibular blocks and maxillary
and mandibular buccal infiltrations to achieve pulpal
anesthesia because:
◼ The standard solution penetrates their smaller, more
porous bones very well.
◼ A larger volume in milliliters per child kilogram can be
administered because the maximum values are higher
than with most other anesthetic solutions used in dentistry (Annex 10). The result is greater safety.
3) Where infiltrations need not achieve deep pulpal
anesthesia, such as in gingivectomies, scaling and
root planing, or gross debridement in patients with
high dentinal sensitivity where only the gingival
needs to be anesthetized because while it is as effective as other solutions a larger volume of anesthetic
can be used at lower risk (before the maximum absolute dental dose is reached, therefore lowering the
risk of toxicity) (Annex 10).
L- 50, 2% Lidocaine with 1:50 000 (20 μg/ml) Epinephrine
As this solution has double the standard epinephrine concentration (20
μg/ml), it has a very beneficial hemostatic
effect, raising the potency to achieve pulpal anesthesia
more readily by keeping more local anesthetic in the infiltration area.
The maximum absolute dose of epinephrine in den-
tistry is 200
μg (2.8 μg/kg in adults >70 kg), the amount in
five and a half 1.8- ml cartridges (Annex 10). Its uses are as
follows:
1) Where hemostasis is required (Buckley et al. 1984)
because abundant bleeding is expected, such as in oral
surgery, scaling, and root planing (Chaikin 1977), the
area to be treated (the gum during proximal or class V
fillings or in the papillae when making impressions for
fixed prosthesis) is infiltrated.
2) When pulpal anesthesia is not achieved with 2% lido-
caine and 1:100 000 (10 μg/ml) epinephrine L- 50 can
reinforce buccal infiltration (Gruber 1950). As noted
Chapter5,two local anesthetics should not be used in
the same site (see). The approach suggested here therefore calls for the same anesthetic, although the epinephrine concentration is doubled to make pulpal anesthesia
more effective (Annex 21).
Interestingly, since the high epinephrine concentration
in this solution delivers greater anesthetic potency by keeping more solution in the target site, the effect is shorterlived (Klingenström and Westermar 1964) due to the
significant vasodilatory reaction observed 2–3
hours later
(Lindorf1979). The result is a shorter duration of soft
anesthesia than with other less potent solutions (Annex 21).
Articaine
Articaine was synthesized in 1969 (Frenkel1989; Rahn and
Ball2001) by German pharmacologist Roman Muschaweck
(1918–2007) for Farbwerke Hoechst AG at Frankfurt (Rahn
and Ball2001; Vogel2007). In the first paper, published in
1972, it was given the experimental name Hoe 40 045
(Winther and Nathalang 1972). In 1974 it was renamed
carticaine (Muschaweck and Rippel 1974; Winther and
Patirupanusara1974), acquiring its present name,
in 1983 (Kirch etal.1983; Mehta etal.1983). It was first marketed in Germany and Switzerland in 1976 and afterwards
very successfully in several countries (Table 7.3). Initially
packaged in 1.7- ml cartridges under the brand name
Ultracaín®, it is now available in 1.7-
Articaine is an amide-
type anesthetic but with two
special characteristics. The first is that although the
intermediate linkage is an amide, it also contains an
ester linkage in the side chain of its aromatic ring. The
other is that its aromatic ring is a thiophene rather than
a benzene. Articaine’s most prominent characteristics
are summarized in Table7.4.
Table7.3 Articaine commercial availability: dates
andcountries.
Year Country Reference
1976 Germany, Switzerland Isen (2000)
1978 Netherlands Isen (2000)
1980 Austria, Spain Isen (2000)
1983 Canada Isen (2000)
1998 United Kingdom Isen (2000)
2000 United States
Denmark
2005 Australia
a
In Australia in 2.2- ml cartridges.
a
or 1.8- ml cartridges.
Weaver (1999)
Hillerup and Jensen (2006)
Yapp etal. (2012)
tissue
articaine,
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Table7.4 Articaine.
Pharmacological factor Reference
● Name and synonyms: Articaine, carticaine,
Hoe 40 045
● First synthesized in 1969 by Roman Muschaweck Rahn and Ball (2001)
● Chemical name: methyl 4- methyl- 3- [2 (propylamino)
propionamida]-
● Formula: C
2- thiophenecarboxylate
13H20N2O3
3
S
CH
3
H
NH–CO–CH
N
C3H
Vogel (2007)
COO–CH
● Molecular weight: Base 284.4
● Clearance rate: 4.17 l/min Annex 11
● Volume of distribution: 120 l Annex 11
● Half- life: 25 minutes Annex 11
3
Hydrochloride 320.9
Muschaweck and Rippel (1974)
Winther and Patirupanusara
(1974)
Physical–chemical property
● pKa value or dissociation constant: 7.8
Annex 6
Denotes fast onset
● Lipid solubility or partition coefficient: n- heptane 0.7
Annex 7
n-octanol 15
Denotes medium anesthetic potency and no topical anesthesia
● Plasma protein binding: 60%
Annex 9
Denotes medium duration of the anesthetic effect
● Vasodilation: + (moderate)
Muschaweck and Rippel (1974)
Denotes need for a vasoconstrictor to be effective
Clinical factor Reference
● Relative anesthetic potency: 2
● Relative toxicity: 2 Annex 8
● Maximum absolute dose in dentistry: 500 mg (7 mg/kg) Council on Clinical Affairs (2015)
AAPD (2020)
● Usable during pregnancy: Yes (FDA category=C)
Table5.11 (Chapter5)
Denotes low risk
● Usable during lactation: Yes
Table5.11 (Chapter5)
Denotes low risk
● Usable with children: Yes, if over 4 years
Denotes low risk
Malamed etal. (2000)
Katyal (2010)
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Anesthetic parameter Variable A- 100 A- 200
Buccal infiltration
Superior lateral incisor
ml
1.8
(Annex 21)
Mandibular block
1.8
ml
(Annex 27)
Pharmacological, physical- chemical, and clinical properties and anesthetic parameter.
Summary: (A- 100) 2% articaine with 1:100 000 (10 μg/ml) epinephrine: 98%- 60′/190′- 260′.
(A- 200) 2% articaine with 1:200 000 (5 μg/ml) epinephrine:92%- 45′/190′- 260′.
Successful pulpal anesthesia (%)
Duration, pulpal anesthesia (minutes)
Duration, anesthesia upper lip (minutes)
Duration, anesthesia lower lip (minutes) 260 260
98
60
190
92
45
190
115
Metabolism
Much less articaine (5–15%) than other amide anesthetics
is metabolized in the liver by the P450microsomal enzyme
system (Isen2000; Rahn and Ball 2001). Therein lies the
advantage of this solution, as the ester side chain on its
thiophene ring is rapidly hydrolyzed by plasma pseudocholinesterases (Becker and Reed 2006), which catabolize
85–95% of the drug. As articainic acid, the compound
formed has no anesthetic activity or effect on the central
nervous system (Müller etal.1991; Oertel etal.1997), the
half- life of articaine is just 25 minutes. Nonetheless, in the
1in 3000individuals with deficient or altered plasma cholinesterases (Kalow and Gunn1959) the drug is metabolized in the liver. Catabolism is a two-
stage process (Vree
etal.1988; Van Oss etal.1989) accelerated by alkaline pH
(Oertel etal.1996).
Articaine is classified as an amidenot an ester, and exhibits no crosspara-
aminobenzoic acid anesthetics, nor is allergic sensiti-
type local anesthetic,
allergenic activity with
zation common (Becker and Reed2006). The reason for the
lack of allergic potential is that when articaine is metabolized to articanic acid, a metabolite with the structure similar to para-
aminobenzoic acid (PABA) is not formed. The
formation of a PABA metabolite is the reason for crossallergenicity amongst ester anesthetics, not amides including articaine.
Articaine is eliminated primarily (85%) in the urine, 75%
as articainic acid and only 3% as free and unaltered articaine (Annex 12). Two percent is also found in the feces
(Hornke etal.1984). This drug diffuses across the placenta
passively, lodging in the umbilical vein at 32% of the concentration found in the maternal blood vessels (Strasser
et al.1977). Its possible biotransformation pathways are
listed in Annex 12.
Remarks
Several features of articaine merit comment.
Maximum Dose andToxicity
This issue was discussed in Chapter 5. By way of summary, its acute experimental toxicity is very similar to
that of lidocaine (Annex 8; Albalawi et al. 2018),
although the enormous advantage of articaine is its high
clearance rate (4.17
l/minute) and short half- life (25 minutes) (Annex 11). The dose allowed in dentistry is therefore higher than for lidocaine (300 mg=4.3 mg/kg). The
maximum absolute dose proposed for dentistry is 500
(7
mg/kg) (Council on Clinical Affairs2015; AAPD2020),
equivalent at 4% to seven 1.8-
ml or seven and a half 1.7-
mg
ml cartridges. See Annex 10 of doses of dental local
anesthetic solutions.
The use of articiane is not recommended in children
under 4
years of age as there is little data to support its
safety and efficacy, although a few trials have shown it to
be safe (Wright etal.1989), thus more data and clinical
studies are needed to verify those findings (Malamed
et al. 2000; Malamed et al. 2001; Katyal 2010;
AAPD2020).
Anesthetic Potency
Articaine has been proven to carry higher anesthetic efficacy
than lidocaine. Two recent meta- analyses comparing 4%
articaine to 2% lidocaine solutions, both with 1:100 000 epinephrine, showed articaine to be more effective, particularly
in pulpal anesthesia in buccal infiltrations (Katyal 2010;
Brandt etal. 2011), while the adverse effects were observed
to be similar (Katyal2010). Clinical series have yielded the
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same results (Annexes 21 and 31). The reason for such
greater efficacy may be attributed to two factors:
1) The slightly higher anesthetic potency in articaine, par-
ticularly “in vitro” (Den Hertog 1974; Borchard and
Drouin1980; Potocnik et al. 2006) but also in clinical
trials using both solutions at the same concentration,
with and without epinephrine (Winther and
Nathalang 1972; Winther and Patirupanusara 1974).
Some authors (Robertson et al. 2007) have associated
higher potency with the thiophene ring in articaine,
although research has shown the benzene ring to be
more lipid soluble (Skjevik et al. 2011). The actual
explanation appears to be that articaine can form intra-
molecular hydrogen bonds that raise its lipid solubility to
levels above and beyond those observed in all local
anesthetics, enhancing diffusion and tissue penetration
(Skjevik etal.2011).
2) The concentration of articaine solutions is 4%, double
that of lidocaine (2%), due precisely to the pharmacokinetic features discussed above. Consequently, a higher
concentration yields greater anesthetic efficacy without
adversely affecting safety due to the speed with which
articaine is catabolized. In clinical studies 5% lidocaine
exhibited better results than the 2% solution, both with
epinephrine (Rood1976; Eldridge and Rood1977; Rood
and Sowray1980), although unfortunately they are not
equally safe.
Anesthetic Effect
Although articaine has a short half- life in the plasma, its
local effect is lengthy. The reason is that while in the blood
it rarely exceeds 5 μg/ml, after infiltration it gathers in the
dental alveolus, where it reaches a concentration of 120
μg/
ml. The effect consequently persists due to the saturation
of the local cholinesterases that catabolize the anesthetic
(Oertel etal.1993; Oertel etal.1996).
Methylparaben, an allergenic-
prone preservative, was
withdrawn by the FDA in 1984 and removed from articaine
in most European countries in the mid-
1990s.
Indications
Two local anesthetic solutions with epinephrine are presently available. Their characteristics and uses are discussed below.
A- 100, 4% Articaine with1:100 000 (10 μg/ml) Epinephrine
This effective anesthetic solution is designed to achieve
pulpal anesthesia with buccal infiltration. As articaine efficacy is comparable to that of lidocaine, to enhance the
effect double the concentration is used (4% vs. 2%) with the
same epinephrine concentration. It therefore diffuses more
readily across the periosteum and the cortical and spongy
bone to reach the dental pulp (Schilly1977). Clinical trials
with maxillary infiltrations have proven its higher efficacy
than the standard lidocaine solution (Kanna et al. 2006;
Robertson et al. 2007; Abdulwahab etal. 2009; da Silva
etal.2010).
The maximum absolute dose in adults weighing 70
over is 500
1.7-
mg (7 mg/kg) or seven 1.8- ml or seven and a half
ml cartridges (Annex 10). The objective with this solu-
kg or
tion is to achieve pulpal anesthesia with buccal infil-
tration in:
● All adult teeth in the maxillary arch.
● Incisors, canines, and premolars in the mandibular arch.
● Post- mandibular block buccal reinforcement in
molars and premolars to enhance mandibular block
efficacy in achieving pulpal anesthesia (Haase
etal.2008).
It is neither advisable nor contraindicated in:
1) Buccal infiltrations, the sole technique (without man-
dibular block) to achieve pulpal anesthesia in mandibular molars. It only successfully anesthetizes the pulp
in 65% of such cases (Annex 31) because the solution is
deposited at a fair distance from the apices due to the
presence of very thick barriers (cortical and spongy
bone) (Arens et al. 1984; Denio et al. 1992; Poorni
etal.2011).
2) In mandibular block for two reasons:
◼ Mandibular block efficacy in achieving pulpal anes-
thesia depends less on the potency of the anesthetic
solution (higher anesthetic or vasoconstrictor concentration) (Annex 24) than on its proximity to the
inferior alveolar nerve, the aponeuroses or fascias
that separate the solution from the nerve, accessory
innervation, and anatomical variations. Consequently,
under normal conditions the standard L- 100 solution
delivers similar results.
◼ In mandibular block, solutions with high local
anesthetic concentrations, such as 4% articaine,
may induce long- term paresthesia or persistent
inoperable neuropathies due to anesthetic neurotoxicity. The incidence of that complication is fortunately very low, estimated to be 1in 100 000 blocks,
but the risk with 4% articaine is 22 times higher
than with 2% lidocaine with epinephrine (L- 100)
(see Chapter22).
Nonetheless, 4% articaine is indicated for acute pulpitis in the posterior mandibular teeth, in light of the difficulty involved in anesthetizing the area in such cases
(Annex 35; Chapter19).
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3) It is not generally recommended in children because:
◼ The standard 2% lidocaine solution with epinephrine
is very successful in children, whose bones are smaller
and more porous than adults’, and can be administered
at higher doses, depending on the child’s weight, as
the limits are higher (eight and a half cartridges in
adults weighing >70
kg vs. seven for 4% articaine with
epinephrine).
◼ The anesthetic effects generated by articaine solu-
tions last longer in the soft tissue, raising the risk of
biting-
induced self- injury to the tongue, lips, or buc-
cal mucosa in children, especially those under 7
years
of age (Adewuni etal.2008).
This articaine solution would be indicated, however,
to anesthetize the second primary mandibular molar
with infiltration (e.g., in hemophilic children for
whom mandibular blocks are contraindicated)
because infiltration with the standard L- 100 solution
is less successful in that tooth (Wright etal. 1991;
Sharaf1997).
A- 200, 4% Articaine with1:200 000 (5 μg/ml)
Epinephrine
This solution has double the local anesthetic as the standard lidocaine solution (4% vs. 2%) but half the epinephrine
(5 μg/ml vs. 10 μg/ml). As a result its efficacy in achieving
pulpal anesthesia is similar to or slightly lower than in
L- 100 (Annex 21).
The maximum absolute dose in adults weighing 70
over is 500
1.7-
mg (7 mg/kg) or seven 1.8- ml or seven and a half
ml cartridges (Annex 10).
kg or
This solution would be indicated especially in patients
for whom the epinephrine dose needs to be reduced (Mehta
et al. 1983; American Dental Association 2003; Elad
etal.2008) but not eliminated altogether (see Chapter10),
such as:
○ ASA III cardiovascular patients (with severe but not
incapacitating illness, no symptoms during ordinary
exercise such as fatigue, shortness of breath, dizziness,
or chest pain) could be administered a maximum dose of
4.5 A- 200 cartridges (40 μg of epinephrine). This includes
patients with:
◼ Uncontrolled high blood pressure: 95–115/
160–200 mmHg.
◼ Cardiac insufficiency and difficulty breathing on
exertion or under stress but not when in repose.
◼ Who have had a heart transplant.
◼ Who more than 3 months prior had:
– an acute heart attack
– a stroke
– a coronary bypass
– stents in coronary artery disease.
○ Patients who are on:
◼ Non- selective beta- blockers (propanolol, carvedilol,
nadolol, etc.) (Table 10.4, Chapter 10) could be
administered a maximum dose of three Atridges (27
◼ COMT (anti- Parkinson) inhibitors (tolcapone, enta-
μg of epinephrine).
200 car-
capone) could be administered a maximum dose of
three A-
◼ Digoxin could be administered a maximum dose of
four and a half A-
◼ Amphetamines and psychostimulant derivatives (dex-
200 cartridges (27 μg of epinephrine).
200 cartridges (40 μg of epine phrine).
troamphetamine, methylphenidate, atomoxetine, etc.)
could be administered a maximum dose of five and a
half A-
200 cartridges (50 μg of epinephrine).
◼ Tri- and tetracyclic antidepressants (amitriptyline,
nortriptyline, imipramine, mirtazapine, etc.)
(Table 10.5, Chapter 10) could be administered a
maximum dose of five and a half A-
μg of epinephrine).
(50
200 cartridges
In all these cases patients can be administered double the
volume of the A- 200 solution than with epinephrine
1:100
000 (10 μg/ml).
Mepivacaine
Mepivacaine was synthesized in 1956 by Bo af Ekenstam
et al. from piperidine carboxylic acid (Ekenstam
etal. 1957). This anesthetic was the eighth of 35 compounds they produced. It was initially named Carbocaine®
(Ekenstam etal.1957) and renamed mepivacaine in 1960
(Luduena etal.1960), retaining Carbocaine as the brand
name. It was introduced in the United States in 1960
(Malamed2004).
This anesthetic has two aromatic rings, the benzene typical of the amide group anesthetics, and piperidine in the
amino terminus. Its most prominent characteristics are
summarized in Table7.5.
Metabolism
Like all amide anesthetics, mepivacaine is metabolized in
the liver and at least 50% is eliminated in the urine, with
only 7% excreted unchanged (Annex 12). A higher proportion of unaltered mepivacaine is eliminated in acidic urine
(Reynolds 1971; Meffin et al. 1973b). It crosses the placenta, with 70% of the maternal plasma found in the
umbilical vein (Covino 1971). Its possible biotransformation pathways are listed in Annex 12.
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Table7.5 Mepivacaine.
Pharmacological factor Reference
● Name and synonym: mepivacaine, Carbocaine®
● First synthesized in 1956 by Ekenstam etal. Ekenstam etal. (1957)
● Chemical name: 1- methyl- 2,6- pipecoloxylidide American Dental
● Formula: C
15H22N2
3
O
Association (1984)
NH–CO
CH
3
● Molecular weight: Base 246.16
N
CH
Hydrochloride 282.8
● Clearance rate: 0.74 l/min Annex 11
● Volume of distribution: 85 l Annex 11
● Half- life: 120 minutes Annex 11
Physical- chemical property
● pKa value or dissociation constant: 7.7
Annex 6
Denotes fast onset
● Lipid solubility or partition coefficient: n- heptane 0.8
Annex 7
n-octanol 20
Denotes medium anesthetic potency and no topical
anesthesia
● Plasma protein binding: 75%
Annex 9
Denotes medium duration of the anesthetic effect
● Vasodilation: − (weak vasoconstriction)
Denotes efficacy with no need for a vasoconstrictor
Du Mesnil de Rochemont
and Hensel (1960)
Lindorf etal. (1974)
Lindorf (1979)
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
● Usable during pregnancy: Yes (FDA category=C)
● Usable during lactation: Yes
● Usable with children: Yes
Association (1984)
Table5.11 (Chapter5)
Denotes low risk
Table5.11 (Chapter5)
Denotes low risk
Denotes low risk
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Table7.5 (Continued)
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Anesthetic parameter Variable M- 3 M- 20 M- 100
Buccal infiltration
Superior lateral incisor
ml
1
(Annex 21)
Mandibular block
1.8
ml
(Annex 27)
Pharmacological, physical- chemical, and clinical properties and anesthetic parameter.
Summary: (M- 3) 3% with no vasoconstrictor: 91%- 15′/100′- 190′.
(M- 20) 2% mepivacaine with 1:20 000 (50 μg/ml) levonordefrin: 91%- 45′/190′- 240′.
(M- 100) 2% mepivacaine with 1:100 000 (10 μg/ml) epinephrine: 93%- 35′/160′- 190′.
Successful pulpal anesthesia (%) 91 91 93
Duration, pulpal anesthesia (minutes) 15 45 35
Duration, anesthesia upper lip (minutes) 100 190 160
Duration, anesthesia lower lip (minutes) 190 240 190
Mepivacaine 119
Remarks
Two features of mepivacaine merit comment: the recommended maximum doses and the solutions that can be
used in dentistry.
Maximum Doses
In the 1980s some European institutions proposed maximum mepivacaine doses of 500
and 300
mg without (Die Arzneimittelkommission der
mg with vasoconstrictor
Deutschen Ärzteschaft Informiert 1985). The FDA criterion is 400 mg with or without vasoconstrictor as the maximum absolute dose in dentistry (American Dental
Association2003). The maximum absolute dental dose rec-
ommended here is 300
mg with or without vasoconstrictor,
further to the prudent recommendation published by the
Council on Dental Therapeutics in 1984 (American Dental
Association1984).
Mepivacaine Solutions
The three solutions of this local anesthetic presently available are discussed below.
● M- 3, 3% mepivacaine with no vasoconstrictor
This solution is deemed here to pose a significant advan-
tage because it performs better than any other
vasoconstrictor- free local anesthetic for dentistry:
91%- 15′/100′- 190′ (Table5.8, Chapter5). While its results
are modest compared to those of any other vasoconstrictorenhanced solution, it is indisputably the best possible of
those without such drugs, perhaps due to its own “inherent” vasoconstrictive effect, but very poor (Du Mesnil de
Rochemont and Hensel 1960; Lindorf et al. 1974;
Lindorf 1979). It is the most useful of the mepivacaine
solutions because it constitutes a solution with the mini-
mum requirements to attend to patients in whom vaso-
constrictors are
● M- 20, 2% mepivacaine with 1:20 000 (50 μg/ml)
contraindicated for one reason or another.
levonordefrin
This solution is marketed primarily in the United States
and since 2004has been difficult to find (Malamed2004).
Its two drawbacks are the small number of clinical stud-
ies and its lower anesthetic parameter (91%-
45′/190′- 240′)
than observed for the standard lidocaine solution with
epinephrine (95%- 45′/190′- 200′).
● M- 100, 2% mepivacaine with 1:100 000 (10 μg/ml)
epinephrine
This solution is marketed in some European countries,
but has the same drawback as Mparameter (93%-
35′/160′- 200′) lower than in L- 100, the
20: its anesthetic
standard lidocaine solution with the same epinephrine
concentration.
Indications
The only mepivacaine solution of interest is the one with
3% concentration and no vasoconstrictor, for the reasons
discussed above. This solution is indicated when vasoconstrictors are absolutely contraindicated (see Chapter10), as
listed below.
● Sympathomimetic vasoconstrictors (epinephrine, nor-
epinephrine, and levonordefrin), in:
1) Insulin- dependent, poorly controlled diabetes.
2) Patients with sulfite sensitivity or intolerance.
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3) Patients with severe, corticoid- controlled asthma
because many are sulfite-
intolerant.
4) Patients with pheochromocytoma, a tumor of the
adrenal gland cromaffin tissue, which releases excess
epinephrine and norepinephrine.
5) Patients who have consumed cocaine in the last
24
hours.
6) Cardiovascular patients simultaneously taking
amphetamines or psychostimulants.
7) Exceptionally, patients allergic to artificial vasocon-
strictors such as levonordefrin and the bitartrate or
hydrochloride forms of natural vasoconstrictors such
as epinephrine and norepinephrine (allergies to the
base forms would be incompatible with life because
they are natural hormones and neurotransmitters).
● Vasoconstrictors such as felypressin (Octapressin) are
contraindicated during pregnancy due to the risk of provoking a premature birth or miscarriage. Felypressin (0.03
UL/ml=0.54
μg/ml) is found in 3% prilocaine solutions.
Note: The contraindications for vasoconstrictors are discussed at length in Chapter10.
The maximum absolute dose in adults weighing 70 kg
or over is 300
cartridges of M-
mg (4.3 mg/kg) or five and a half 1.8- ml
3 (Annex 10).
Prilocaine (Propitocaine)
Prilocaine was synthesized in 1953 by Nils Löfgren
(1915–1967) and Claës Tegnér (Wielding 1960). A paper
describing its synthesis was published in 1960 (Löfgren
and Tegner 1960). Initially named L67 (Löfgren and
Tegner1960; Wielding1960), in 1964 it was renamed propitocaine (Sadove et al. 1964) and prilocaine (Daly
etal.1964), and marketed under the name Citanest®. It was
approved by the FDA for use in the United States in 1966
(Widman 1975). It is presently known as prilocaine the
world over except in the United Kingdom, where the name
propitocaine has prevailed (de Jong1977). Prilocaine is an
amide anesthetic derived from toluidine. Its most prominent characteristics are summarized in Table7.6.
Metabolism
Prilocaine concentrates, in descending order, in the lungs,
kidneys, brain, and heart, more intensely than lidocaine
(Akerman etal.1966). It exits the bloodstream more rapidly than lidocaine, metabolized by amidase in the liver
and to a lesser extent in the kidneys and lungs (Geddes1965;
Akerman et al. 1966). It is eliminated primarily in the
urine, with less than 1% excreted unchanged (Akerman
etal.1966; Mather1972), although that value is higher in
acidic urine (Eriksson etal.1966). Very little is eliminated
in the feces (Akerman etal.1966). Its possible biotransformation pathways are listed in Annex 12.
Prilocaine diffuses passively across the placenta, and
although the concentration in the umbilical vein is the
same as in the mother’s plasma (Covino 1971;
Poppers1975), it is less toxic for the fetus than lidocaine or
mepivacaine (Shnider and Gildea1973).
Its main metabolite is ortho-
methylalanine, the primary cause of toxic methemo-
2-
toluidine (o- toluidine) or
globinemia, which may be induced by this anesthetic (Onji
and Tyuma1965; Lund and Cwick1965a; Spoerel etal.1967).
A second prilocaine metabolite, 4-
hydroxy- o- toluidine, is
also associated with methemoglobinemia, although to a
lesser extent (Frayling etal.1990).
Remarks
The three most prominent factors meriting comment are
toxicity and safety, clinical efficacy, and commercial
solutions.
Toxicity andSafety
Prilocaine has a demonstrably lower toxicity than lidocaine
in both laboratory animals (Annex 8) and human beings
(Lund and Cwick1965a; Lund etal.1975). That may
be because it is eliminated more quickly (Lund and
Cwick 1965a), with blood levels declining more rapidly
than in other anesthetics (Eriksson and Granberg1965), in
as much as it is metabolized not only in the liver but also in
the lungs and kidneys, as noted.
Although its concentration in the fetal bloodstream is
the same as in the mother’s (Covino1971; Poppers1975),
as it is less toxic than lidocaine and mepivacaine (Shnider
and Gildea 1973), which are found in lower concentrations, it merits an FDA pregnancy risk category B
(American Dental Association2003).
The risk posed by prilocaine is that it causes toxic methe-
moglobinemia, an adverse effect directly related to the
amount administered (Onji and Tyuma1965; Hjelm and
Holmdahl 1965; Lund and Cwick 1965b; Spoerel
etal.1967). Methemoglobinemia may be induced at doses
of 400 mg (Daly etal. 1964; Lund and Cwick 1965b) and
certainly at ≥900 mg (Scott et al. 1964; Lund and
Cwick1965b), although these values may vary depending
on the individual (Spoerel etal.1967). In 1984 the American
Dental Association’s Council on Dental Therapeutics consequently recommended 400 mg as the maximum absolute
dose of prilocaine, with or without vasoconstrictor
(American Dental Association1984).
As discussed below, prilocaine comes in high concentrations (3–4%), raising the risk of long- term paresthesia or
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Table7.6 Prilocaine
CH
7
Prilocaine
https://t.me/med1917
Pharmacological factor Reference
● Name and synonyms: prilocaine, propitocaine, L 67
● First synthesized in 1953 by Löfgren and Tegnér Wielding (1960)
● Chemical name:
2-
propylamino- o- propionotoluidide
● Formula: C
13H20N2
3
O
NH–CO–CH
C
H
3
N
American Dental Association
(1984)
H
CH
3
● Molecular weight: Base 220.3
Hydrochloride 256.8
● Clearance rate: 2.6 l/min Annex 11
● Volume of distribution: 190 l Annex 11
● Half- life: 95 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 0.9
Annex 7
n-octanol 25
Denotes medium anesthetic potency and no topical
anesthesia
● Plasma protein binding: 55%
Annex 9
Denotes medium duration of the anesthetic effect
● Vasodilation: ± (very weak vasodilation)
Denotes efficacy with no need for a vasoconstrictor
Lindorf etal. (1974) Lindorf (1979)
Aström and Persson (1961)
121
Clinical factor Reference
● Relative anesthetic potency: 1.5
● Relative toxicity: 1.5 Annex 8
● Maximum absolute dose in dentistry: 400 mg (5.7 mg/kg) American Dental Association
● Usable during pregnancy: Yes (FDA category=B)
● Usable during lactation: Yes
● Usable with children: Yes
(1984)
Table5.11 (Chapter5)
Denotes low risk
Table5.11 (Chapter5)
Denotes low risk
Denotes low risk
(Continued )
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https://t.me/med1917
122
Table7.6 (Continued)
Anesthetic parameter Variable P- 03 P- 200 P- 4
Buccal infiltration
Superior lateral incisor
ml
1
(Annex 21)
Mandibular block
1.8
ml
(Annex 27)
Pharmacological, physical- chemical and clinical properties and anesthetic parameter.
Summary: (P- 03) 3% prilocaine with 0.03 IU/ml (0.54 μg/ml) felypressin: 88%- 25′/180′- 220′.
(P- 200) 4% prilocaine with 1:200 000 (5 μg/ml) epinephrine: 85%- 25′/130′- 200′.
(P- 4) 4% prilocaine with no vasoconstrictor: 87%- 10′/75′- 180′.
Successful pulpal anesthesia (%)
Duration, pulpal anesthesia (minutes)
Duration, anesthesia upper lip (minutes)
Duration, anesthesia lower lip (minutes) 220 200 180
88
25
180
85
25
130
87
10
75
persistent inoperable neuropathies in the wake of mandibular block due to its neurotoxicity. The incidence of that complication is fortunately very low, estimated to be 1in 100 000
blocks, but the risk with 4% prilocaine is 35 times higher
than with 2% lidocaine with epinephrine (L- 100) (see
Chapter22).
Clinical Efficacy
As this anesthetic has been shown to be less potent in both
laboratory animals (Aström and Persson1961) and human
beings (Annex 21), a higher concentration is needed for
results comparable to those of lidocaine (3–4% vs. 2%).
In contrast, as it induces weaker vasodilation than lidocaine, likewise in laboratory animals (Aström and
Persson1961; Akerman etal.1966) and humans (Lindorf
etal.1974; Lindorf1979), it can be used without a vasoconstrictor, although such drugs enhance its efficacy
(Annex 21).
Prilocaine Solutions
All prilocaine solutions exhibit lower performance than
other solutions.
● P- 4, 4% prilocaine with no vasoconstrictor
This solution would be indicated where vasoconstrictors
are contraindicated, although as its anesthetic parameter
(87%- 10′/75′- 180′) is lower than in 3% mepivacaine with
no vasoconstrictor (91%- 15′/100′- 190′), the latter is
preferred in such situations.
● P- 200, 4% prilocaine with 1:200 000 (5 μg/ml)
epinephrine
This solution would be indicated especially in patients in
whom the epinephrine dose needs to be reduced but not
eliminated altogether (see Chapter10). As its anesthetic
parameter (85%- 25′/130′- 190′) is lower than in 4% articaine with 1
A-
200 is preferred under these conditions.
● P- 03, 3% prilocaine with 0.03 IU/ml (0.54 μg/ml)
: 200 000 epinephrine (92%- 45′/190′- 260′),
felypressin
This solution would likewise be indicated where
sympathomimetic vasoconstrictors are contraindicated.
Although its anesthetic parameter is poor
(88%- 25′/180′- 220′), as it induces longer- lasting pulpal
and soft tissue anesthesia than vasoconstrictormepivacaine (91%-
15′/100′- 190′), it may be an alterna-
free 3%
tive in such cases.
Indications andContraindications
The only prilocaine solution of interest is the one with a 3%
concentration and 0.03 UI/ml (0.54 μg/ml) felypressin, for
the reasons discussed above.
The maximum absolute dose of prilocaine in dentistry for
adults weighing 70 kg or more is 400 mg (5.7 mg/kg), which at
3% is equivalent to seven and a half 1.8- ml cartridges. The
maximum dose of felypressin, however, is 7.02 μg (Oliver1974;
Roberts and Sowray 1987), lowering the number of 1.8- ml
cartridges to 7.2 at a concentration of 0.54 μg/ml (Annex 10).
Indications
This solution is indicated when sympathomimetic
vasoconstrictors (epinephrine, norepinephrine, and
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