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Anesthetic Concentration 73
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Concentration andSafety
In the early twentieth century the systemic toxicity of anesthetics was believed to rise exponentially with linear
increases in their concentration, so that 1
caine was deemed to be four times more toxic than 1
ml of 2% pro-
ml of
a 1% solution (Waters1933). That notion was accepted by
the Council on Dental Therapeutics, which prohibited the
use of 4% procaine (Council on Dental Therapeutics1944).
Everett was the first to prove that in laboratory animals
the median lethal dose, LD
, barely varied with concentra-
50
tion, but depended critically on the total dose administered
(Everett1949) (Table5.7). Those findings were confirmed
by clinical studies: the blood levels of local anesthetics are
directly related to the amount administered and not to the
concentration at which they are administered (Campbell
and Adriani1958; Braid and Scott1965; Jebson1971; Rood
and Cannell1978).
Concentration andAnesthetic Potency
Anesthetic potency has long been known to rise with concentration in animals (Gasser and Erlanger1929; Campbell
and Adriani1958). In clinical dental studies 5% lidocaine
was observed to yield better results than the 2% solution
(Eldridge and Rood 1977; Rood and Sowray 1980;
Lambrianidis et al. 1980). Clinical trials using the Björn
EPT also proved that more highly concentrated solutions
anesthetized dental pulp more effectively (Table5.8).
The reason is that a more highly concentrated local
anesthetic tends to maintain a higher concentration is
some of the injected local anesthetic may diffuse away
from the initial injection site. Starting off with a more concentrated local anesthetic will result in more of the local
anesthetic reaching the nerve fibers, thus translating into
greater efficacy (Tainter etal.1953; Schilli1977).
Concentration andTissue Irritation
At higher concentrations of local anesthetics, the postinjection damage to subcutaneous tissue is more likely to rise.
For reasons of tissue toxicity, bupivacaine cannot be administered at concentrations of over 1%, for instance, and is consequently used at 0.25–0.75% (Ekblom and Widman1966; Henn
and Brattsand1966). Similarly, an increase in concentration
can be correlated with an increased risk of tissue irritation for
other local ansesthetics (Bennett etal.1971).
Animal experiments have shown that the neurotoxicity
of anesthetic solutions rises with concentration (Lundy
etal.1933; Tui etal.1944; Skou1954; Fink and Kish1976;
Kalichman etal.1993).
These results are also confirmed in clinical studies. In
medical practice, spinal anesthesia with 5% lidocaine or 1%
tetracaine solutions (high concentrations) increases the
risk of producing cauda equina syndrome because of its
neurotoxic effect (Ringler etal.1991).
Long-
term paresthesia after mandibular block with high
concentrations of local anesthesia is a risk in dentistry.
Table5.7 Lethal dose (LD50, mg/kg) of local anesthetics in animals.
Anesthetic Ad. Animal Concentration (%) LD50 (mg/kg) Reference
Procaine SC Mouse 2 900 Everett (1949)
4 ±890
IV Rabbit 2 50
4 ±49
Mepivacaine IV Mouse 2 31 Luduena etal. (1960)
3 32
IV Rabbit 2 21
3 22
IV Guinea pig 2 24.5
3 20.0
SC Guinea pig 2 93
3 94
Articaine IV Rabbit 3 20.6 Baeder etal. (1974)
4 19.6
Ad, administered; SC, subcutaneous; IV intravenous.
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74
Table5.8 Percentage ofpulpal anesthesia andduration inminutes after buccal infiltration of1 ml ofanesthetic (without
vasoconstrictor) inmaxillary lateral incisor.
Duration pulpal
Anesthetic Concentration (%) Pulpal anesthesia (%)
Lidocaine 1 60 <1 Feldman and Nordenram (1959)
3 95 3 Feldman and Nordenram (1959)
Mepivacaine 1 85 2 Feldman and Nordenram (1959)
3 91 15 Annex 21
Articaine 2 63 7 Winther and Nathalang (1972)
4 76 11 Winther and Nathalang (1972)
Prilocaine 2 74 9 Berling and Björn (1960)
4 87 12 Annex 21
anesthesia (min) Reference
With 4% articaine and 4% prilocaine (Haas and
Lennon1995; Pogrel and Thambys2000) the risk is 22–35
times greater than with standard 2% lidocaine (Table22.8,
Chapter22). Fortunately, however, such complications are
very rare (see Chapter22).
One may conclude that a more highly concentrated local
anesthetic will deliver better clinical results for the comfort
of the dental patient. An important caveat is that smaller
volumes of solution must be administered to avoid exceeding the maximum recommended dose, and preventing systemic toxicity or local neurotoxicity. In short, a balance
must be consistently pursued between maximum efficacy
and minimum risk.
Maximum Doses
A standard maximum dose cannot be determined because
conditions vary widely between individuals and even in
one and the same person under different circumstances.
Nonetheless, maximum doses based on animal experiments and clinical experience afford very useful guidelines
for preventing toxicity in dental procedures (Campbell and
Adriani1958; Adriani and Zepernick1966).
The absolute maximum doses for adults weighing 70 kg
or over differ in dental and medical practice. In the early
1980s, the American Dental Association’s Council on
Dental Therapeutics recommended lower maximum doses
for dental applications of lidocaine, mepivacaine, and prilocaine than established by the United States Food and
Drug Administration (US FDA) and the pharmaceutical
industry for applications in other types of medical practice
(Table5.9) (American Dental Association1984). At around
the same time, the FDA authorized 1.8- ml cartridges of
bupivacaine for dental use, likewise a lower maximum
dose than used in medicine (Dean1983; ADA Guide2003).
This criterion was justified by the greater frequency of local
anesthetic administration in dentistry, most of which are
performed in the office setting, making the recognition and
management of adverse reactions less predictable
(Moore1984). This lower dose criterion has always been
regarded as one of the factors contributing to the extreme
safety of dental anesthesia (Seldin1958). Such prudence in
using lower maximum doses than established for medical
practice is recommended here as well as by other authors
(Jeske and Blanton2002).
Articaine, a local anesthetic, was approved by the FDA in
2000 for dental use at a concentration of 4%, double the
concentration approved for 2% lidocaine (Weaber 1999;
Malamed etal.2001). Articaine and lidocaine have similar
characteristics. In vitro studies have shown articaine to be
slightly more effective (Den Hertog 1974; Borchard and
Drouin1980; Potocnik etal.2006) and in clinical trials to
yield similar or slightly better results with or without
epinephrine at a given concentration (Winther and
Nathalang 1972; Winther and Patirupanusara 1974).
Performance was also better in animal experiments studying acute toxicity (Annex 8).
Further to the Council on Dental Therapeutics’ prudent
criterion, the absolute maximum dose of articaine in dentistry would be 300 mg (4.3 mg/kg) (Table5.9). However,
the pharmacokinetic properties of articaine differ from
those of lidocaine and mepivacaine. At 4.17 l/min, its clearance level is much higher than the 0.83 l/min for lidocaine
and 0.74 l/ml mepivacaine. Articaine’s half- life is much
shorter: 25 minutes compared to 110 minutes for lidocaine
and 120 minutes for mepivacaine (Annex 11). The reason
for the above behavior is that 85–95% of the ester side chain
on the thiophene ring in articaine is rapidly hydrolyzed by
plasma cholinesterases (Figure5.4). The result is the rapid
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75
CH
7
7
Hydrolysis
Articainic acid
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Table5.9 Absolute maximum doses inmilligrams (mg/kg inparentheses) recommended by different sources formedical
anddental practice foradults weighing 70
Without
Anesthetic
vasoconstrictor
Lidocaine 300 (4.3) 500 (7.1)
Articaine 300 (4.3)
—
Mepivacaine 400 (5.7)
300 (4.3)
Prilocaine 600 (8.5)
400 (5.7)
Bupivacaine 175 (2.5)
—
150 (2.1)
a
AMA Drug Evaluation (1983).
b
Die Arzneimittelkommission (1985).
c
ADA Guide (2003).
d
American Dental Association (1984).
e
AAPD (2020).
f
Council on Clinical Affairs (2015).
kg or over.
Medical practice Dental practice
With
vasoconstrictor Reference
a,b,c
500 (7.1)
500 (7.1)
400 (5.7)
500 (7.1)
600 (8.5)
600 (8.5)
225 (3.2)
225 (3.2)
150 (2.1)
b
c
a,c
b
a,c
b
a,d
c
b
With and without
vasoconstrictor Reference
300 (4.3)
500 (7)
300 (4.3)
400 (5.7)
90 (1.3)
d
c,e,f
d
d
c,e
S
S
3
NH–CO–CH
COO–CH
CH
3
NH–CO–CHN
COOH
3
Articaine
CH
CH
3
H
N
C3H
3
H
C3H
Figure5.4 Hydrolysis of the ester side chain on the thiophene
ring in articaine and its conversion to articainic acid.
inactivation of articaine and conversion to articainic acid,
which lacks anesthetic or CNS effects. Moreover, as in lidocaine, only 5–15% of the drug is broken down in the liver
(Isen2000; Rahn and Ball2001). Consequently, clinical trials have shown articaine doses of 7 mg/kg to be well tolerated in both adults (Hersh et al. 2006) and children
(Dudkiewiez etal.1987; Malamed etal.2000).
In spite of articaine’s rapid metabolic inactivation and
safety profile, the provider must be cognizant of the potential for this metabolism to be affected in individuals with a
hereditary defect in plasma cholinesterase, either quantitatively or qualitatively. One in every 3000 individuals is
known to have a hereditary deficit of or alteration in
plasma cholinesterase (Kalow and Gunn1959). In those
cases, like lidocaine, the metabolism of articaine would
rely on the liver. The maximum dose of articaine in dentistry is deemed here to be higher than 300 mg (4.3 mg/kg),
and as signs of toxicity may appear at 500–800
mg (Rahn
and Ball 2001), the absolute maximum dose proposed is
500
mg (7 mg/kg), which at 4% is equivalent to seven 1.8- ml
or seven and a half 1.7- ml cartridges (Council on Clinical
Affairs2015; AAPD2020) (Table5.9).
Maximum Doses forChildren
The maximum doses for adults must be corrected for
children for several reasons:
1) Children have less body mass and hence a lower capac-
ity to metabolize drugs.
2) Children’s organ systems are immature and in children
under 3 years enzymatic capacity is relatively lower.
3) The distribution of total body water differs between
children and adults. Children around 7 years old have
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Local Anesthetics
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76
(proportionately) 5% more body water than adults and
medication is distributed primary in the extracellular space.
4) Many drugs tend to be stored in adipose tissue, of which
children have approximately 10% less than adults.
Ritschel (1992) reviewed 24 methods for calculating
pediatric doses, examining a total of 52equations as well as
adjustment tables on body surface area, age, and weight in
an attempt to draw some relationship between body mass
and maturity. The three methods used in dentistry are:
1) Body surface area, such as the Butler–Ritchie (Butler
and Ritchie1960) method, which specifies the highest dose for each pediatric age group (Calatayud
etal.1996).
2) Age, such as the Bastedo (1918) or Young (Ritschel1992)
methods, which specify the lowest doses for each pediatric age group (Calatayud etal.1996). That approach is
in line with growth trends over the last 100
according to which children are now taller and heavier
(Tanner1966) due to improved nutrition, medical progress (fewer infections thanks interventions such as to
antibiotics and vaccinations), and higher standards of
living (housing, clothing, etc.). Many authors consequently prefer weight- based over age- based methods
(Goodson and Moore1983).
3) Weight, such as the Clark weight method (American
Dental Association 1984; Ritschel 1992; Anderson
et al. 1994). This method, the one most commonly
applied, consists of dividing the absolute maximum
dose by 70 (weight in kilograms of a standard adult)
and multiplying the quotient by the child’s weight in
kilograms. The resulting dose is an intermediate value
for each pediatric age group specified in the two preceding methods. Weight, moreover, has proven to be
the factor with the greatest effect on oxygen consumption, biochemical activity, physiological activity, and
the size and activity of the body’s organs and viscera
(Adolph1949).
Annex 10 is based on weight (Council on Clinical
Affairs2015; AAPD2020), although adapted to the number
of cartridges. It includes a very useful table for determining
the number of (1.8- ml) cartridges of a given local anesthetic solution that can be administered to a child or small
adult depending on their weight.
years,
Pregnancy andLactation
Pregnant and breastfeeding women require special consideration because some drugs may have an adverse effect on
the fetus or breastfed infant.
Pregnancy
Most drugs cross the placental barrier during pregnancy
and can consequently affect the fetus. The first quarter
(15th–90th day of gestation), characterized by organogenesis, is regarded as the period when the fetus is most vulnerable to possible drug- induced congenital alterations
(Ouanounou and Haas2016).
In 2014 the FDA published its new “pregnancy and lactation labeling rule” (PLLR) (also know as the “final rule”),
which entered into force on June 30, 2015. The timelines
for implementing the final rule are variable. Prescription
drugs submitted for FDA approval after June 30, 2015will
use the new format, while drugs approved prior to June 30,
2001 will be phased in gradually (Department of Health
and Human Services, Food and Drug Administration2014).
Local dental anesthetics and vasoconstrictors are consequently still subject to the 1979 FDA “pregnancy risk
classification” rule with five categories: A, B, C, D, and X
(Department of Health, Education, and Welfare, Food and
Drug Administration 1979; FDA 1979; Millstein 1980)
(Table5.10). The 0.7% of medications are classified in category A and the 19% in B are deemed safe (Haas etal.2000).
Two-
thirds (66%, Haas etal.2000) are classified in category
C, further divided into two subcategories: (i) those that
have proven to induce fetal alternations in animals and (ii)
those for which no data is in place for animals or humans,
a finding difficult to interpret. Moreover, the alterations in
animals vary widely, from clearly teratogenic (birth defects)
to merely toxic (Hubbard1997). Even when listed under
category C, however, the local anesthetics and vasoconstrictors used in dentistry can be regarded as safe (Haas
etal. 2000; Donaldson and Goodchild2012; Ouanounou
and Haas2016) (Table5.11). A trial study with 351women
at 13–21 weeks´ gestation (Michalowicz etal.2008), and a
cohort study with over 1000 pregnant women (Hagai
etal.2015) showed that neither dental local anesthesia nor
dental treatment during pregnancy raise the newborn malformation rate (teratogenic risk) or serious adverse events
(spontaneous abortions).
Epinephrine can alter the blood flow to the uterus,
although at the doses used in dentistry the effect is negligible (Stepke et al.1994; Haas et al.2000). Felypressin
however, as a derivative of vasopressin and oxytocin, not
only reduces the blood flow to the uterus as a result of
vasoconstriction, but also increases contraction in the
organ, which may raise the risk of premature delivery or
miscarriage (Oliver1974; Stepke etal.1994). It is consequently contraindicated during pregnancy, as is norepinephrine, which has effects on the uterus not generated
by epinephrine (Stepke etal.1994).
Lastly, a reminder: the fetal–maternal equilibrium is
only affected by the free form of drugs circulating in the
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Table5.10 US FDA pregnancy risk classification.
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Mixing Local Anesthetics 77
Risk
category Definition
A The results of controlled studies in women fail to demonstrate a risk to the fetus in the first trimester
(and there is no evidence of risk in later trimesters), and the possibility of fetal harm appears remote
B Either the results of animal reproduction studies have not demonstrated a fetal risk but there are no
controlled studies in pregnant women
Or
The results of animal reproduction studies have shown an adverse effect (other than a decrease in
fertility) that was not confirmed in controlled studies in women in the first trimester and there is no
evidence of risk in later trimesters
C Either the results of studies in animal have reveled adverse effects (teratogenic, embryocidal, or
other) on the fetus and there are no controlled studies in women
Or
Results of studies in women and animals are not available; drug should be given only if the potential
benefit justifies the potential risk to the fetus
D There is positive evidence of human fetal risk, but the benefits of use in pregnant women may be
acceptable despite the risk (e.g., if the drug is needed in a life- threatening situation or for a serious
disease for which safer drugs cannot be used or are ineffective)
X Results of studies in animals or humans have demonstrated fetal abnormalities or evidence of fetal risk based
on human experience, or both, and the risk of the use of the drug in pregnancy women clearly outweighs any
possible benefit; use of the drug is contraindicated in women who are or may become pregnant
Source: Department of Health, Education, and Welfare, Food and Drug Administration (1979), FDA (1979), Millstein (1980), Donaldson and
Goodchild (2012), Ouanounou and Haas (2016).
Clinical guidelines,
dentistry
Very safe
Safe
Uncertain
Contraindicated
Contraindicated
bloodstream unbound to plasma proteins and therefore
able to cross the placenta (Poppers1975).
Lactation
For most drugs, the infant is exposed to a much higher concentration during pregnancy than during lactation.
Therefore, if a drug is considered acceptable for use during
pregnancy, it usually is reasonable to continue its use during
breast- feeding (Donaldson and Goodchild 2012). As a general rule, the infant ingests approximately 1% of the maternal dose, although that percentage may vary depending on
blood flow in the mammary gland, blood, or milk pH, drug
molecular weight, lipid solubility, etc. (Haas etal.2000).
Clinical studies (Lebedevs etal.1993; Ortega etal.1999;
Giuliani etal.2001) have shown that local anesthetics can
be administered to nursing mothers because at the doses
normally applied in dentistry they are safe for the baby
(Haas et al. 2000; Donaldson and Goodchild 2012)
(Table5.11).
Mixing Local Anesthetics
Local anesthetics may be mixed to combine a long duration, late onset solution (tetracaine, bupivacaine) with an
anesthetic with a medium or short duration and rapid
onset time (procaine, lidocaine, mepivacaine, prilocaine).
Theoretically, the result is a quick- acting, long- lasting
anesthetic solution, usable subject only to possible rises in
toxicity.
Clinical studies have delivered uneven findings. Some
authors have observed advantages (Moore et al. 1972;
Cunningham and Kaplan1974) while others the contrary:
Oka etal. (1997) found a bupivacaine- lidocaine mix to be
long-
lasting but with a delayed onset. Animal experiments involving a mix of bupivacaine and chloroprocaine
showed early onset but a short duration (Galindo and
Witcher1979). In such cases mixes afford no advantage:
the effects would appear to depend on only one of the
anesthetics. The explanation suggested is that the use of
two local anesthetics at the same site might induce competition for the transmembrane receptor, with one of the
two effects prevailing to the detriment of the other (Grima
etal.1985; Oka etal.1997).
Toxicity experiments in animals also yield contradictory
results. According to some studies toxicity is merely the
sum of the effects of the solutions involved (Munson
et al. 1977), whereas others report a higher value (Daos
etal.1962; Akamatsu and Siebold1967).
In light of that data and in the absence of further information, mixing local anesthetics at the same injection site
is not recommended here. The following alternatives are
suggested.
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Table5.11 FDA pregnancy risk category andpossible use ofdentistry anesthetics andvasoconstrictors during pregnancy
andlactation.
Drug FDA category Can be used in pregnancy Can be used in lactation
Injectable local anesthetic
Lidocaine B
a–f
Articaine C
Mepivacaine Ca–
Prilocaine B
a–f
Bupivacaine C
b,d–f
f
a–f
a,c–f
Yes
f
Yes
With caution
a,f
Yes
With caution
a,c–f
Yes
a,f
Yes
With caution
a,c–e,g
Yes
a
d,e
c–e
c–e
Yes
With caution
a,c–e
Yes
a,c–e
Yes
a,c–e
Yes
Vasoconstrictor
Epinephrine 1:100
1:200
000
000
a,e
C
Levonordefrin 1:20 000 Unclassified Yes
Felypressin 0.03 UI/ml Unclassified No
Norepinephrine 1:30
1:50
000
000
Unclassified No
a
Yes
With caution
a
h,i
i
a,e
e
Yes
Yes
a
?
?
Topical local anesthetic
Benzocaine C
Lidocaine B
Tetracaine C
Cocaine C
a
Haas etal. (2000).
b
ADA Guide (2003).
c
Suresh and Radfar (2004).
d
Fayans etal. (2010).
e
Donaldson and Goodchild (2012).
f
Ouanounou and Haas (2016).
g
American Academy of Pediatrics (2001).
h
Oliver (1974).
i
Stepke etal. (1994).
a,b,f
a,b,e,f
a,b,e,f
b
a
Yes
With caution
a,e,f
Yes
a
Yes
With caution
e,f
e,f
? ?
a
Yes
With caution
a,e
Yes
a
Yes
With caution
d,e
e
e
1) If periapical infiltration with 2% lidocaine and 1:100 000
epinephrine (10 μg/ml) fails in a maxillary tooth, it can
be reinforced with a second injection of 2% lidocaine
and 1:50 000 epinephrine (20 μg/ml). Note that the rein-
forcement consists of injecting a larger volume of the
same local anesthetic while enhancing its potency by
administering a higher concentration of the vasoconstrictor (epinephrine).
2) Mandibular block with 2% lidocaine and 1:100 000 epi-
nephrine can be used to anesthetize mandibular molars,
reinforced with periapical infiltration on the buccal side
of these teeth with 4% articaine and 1:100 000 epinephrine. Note that although different anesthetics are used,
they are not mixed, but administered at different sites.
By way of summary, as the data available are inconclusive, until further research findings are forthcoming, mix-
ing local anesthetics at the same site is not recommended here.
Isomers
The chemical structure of most local anesthetics is characterized by isomers or enantiomers, i.e. compounds with the
same chemical structure but a different configuration, in
which atoms or groups of atoms occupy different spatial
positions. Because such substances rotate polarized light in
opposite directions, they are also called optical isomers
(Calvey1995).
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References 79
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Table5.12 Local anesthetics andoptical isomers.
Achirala (non- isomers) Racemica (isomers) Levoisomers
Lidocaine
Tetracaine Articaína
a
Calvey (1995).
b
Tucker (1986).
c
Van Oss etal. (1989).
d
Vree etal. (1988).
e
Mather and Chang (2001).
f
de Jong (1977).
a,b
Procaine Levobupivacaine
c,d
Mepivacaine
Prilocaine
Bupivacaine
Etidocaine
e,f
Cocaine
Ropivacaine
a
There are two optical isomers (Cahn et al. 1956;
Calvey1995). Dextro (d) or (+) or R, from the Latin rectus,
isomers rotate plane- polarized light clockwise or to the
right, while the levo (l) or (−) or S, from the Latin sinister,
counterparts rotate it to the left or counter- clockwise. Most
local anesthetics adopt a racemic form, which means that
50% of their molecules are dextro and the other 50% levo.
However, a few are achiral or not optically active because
their chemical structure can only exist in one configuration, with no isomers (Table5.12). Both lidocaine and tetracaine are achiral.
In some cases, one isomeric form may behave like an
independent chemical structure, featuring higher activity
or lower toxicity than the other isomer or the racemic mix.
In such cases the more active isomer is dubbed the
“eutomer” and the less active the “distomer” (Calvey1995).
Some long-
lasting local anesthetics have been developed
with the levo isomer only because it is more active, less
toxic (Luduena 1969; Luduena et al. 1972; Aberg 1972;
Foster and Markham2000), or (especially) less cardiotoxic
(Mather and Chang2001). These include:
1) Levobupivacaine or S- bupivacaine is the pure levo iso-
mer of bupivacaine. Its clinical use was introduced in
1999 and while its efficacy is similar to that of bupivacaine, it appears to be less cardiotoxic (Bardsley
etal.1998; Branco etal.2006).
2) Ropivacaine is the pure levoisomer of propivacaine, a
long-
lasting local anesthetic very similar to bupivacaine.
It differs in that instead of a four-
carbon atom terminus
(butyl, hence bupivacaine) in the piperdine ring, it has a
three- C terminus (propyl, hence propivacaine). This
shorter chain lowers its potency (Aberg etal.1977) but
also its toxicity for the nervous system and the heart
(Akerman et al. 1988; Scott et al. 1989; Knudsen
et al. 1997; Simpson etal. 2005). This anesthetic was
first used in clinical practice in 1997 (Malamed2004).
Although neither of these medications is presently marketed in cartridge form for use in dentistry, they may be a
substitute for bupivacaine in the future.
References
AAPD (American Academy of Pediatric Dentistry) (2020).
Use of Local Anesthesia for Pediatric Dental Patients. The
Reference Manual of Pediatric Dentistry. Chicago IL:
American Academy of Pediatric Dentistry. 318–323.
Aberg, G. (1972). Toxicological and local anaesthetic effects
of optically active isomers of two local anesthetic
compounds. Acta Pharmacol. Toxicol. 31 (4): 273–286.
Aberg, G., Dhuner, K.- G., and Sydnes, G. (1977). Studies on
the duration of local anesthesia: structure/activity
relationships in a series of homologous local anesthetics.
Acta Pharmacol. Toxicol. 41 (5): 432–443.
ADA Guide (2003). ADA Guide to Dental Therapeutics, 3e.
Chicago: American Dental Association. 1–16 and 611.
Adolph, E.F. (1949). Quantitative relations in the physiological
constitutions of mammals. Science 109 (2841): 579–585.
Adriani, J. and Zepernick, R. (1966). Influence of the status
of the patient on systemic effects of local anesthetic agents.
Anesth. Analg. 45 (1): 87–92.
Akamatsu, T.J. and Siebold, K.H. (1967). The synergist
toxicity of local anesthetics. Anesthesiology 28 (1): 238.
Akerman, B., Aström, A., Ross, S., and Telc, A. (1966). Studies
on the absorption, distribution and metabolism of labeled
prilocaine and lidocaine in some animal species. Acta
Pharmacol. Toxicol. 24 (4): 389–403.
Akerman, B., Hellberg, I.B., and Trossvik, C. (1988). Primary
evaluation of the local anesthetic properties of the amino
amide agent ropivacaine (LEA 103). Acta Anaesth. Scand.
32 (7): 517–518.
AMA Drug Evaluation (1983). American Medical Association,
5e. Philadelphia: WB Saunders Co. 373–394.
American Academy of Pediatrics Committee on Drugs
(2001). The transfer of drugs and other chemicals into
human milk. Pediatrics 108 (3): 776–789.
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