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Catecholamines 93
HO
H
3
Epinephrine
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Table6.8 Epinephrine: prominent pharmacological andclinical
factors.
Pharmacological factor Reference
● Name and synonym: epinephrine,
adrenaline, suprarenin
● First isolated by Takamine in 1901
and Aldrich in 1901
● Chemical name
1,1-
(3,4- dihydroxyphenyl)- 2-
Takamine (1901)
Aldrich (1901)
American Dental
Association (1984)
methylaminoethanol
● Formula: C
9H13NO3
Aldrich (1901)
USP38
CH
–CH2–
N
2
HO
● Molecular weight: Baseline:183.2
OH
CH
USP38
As bitartrate:333.3
● pKa value or dissociation constant: 8.6 Annex 6
● Adrenoreceptors stimulated: α
β
and β
1
2
● Vasoconstrictor potency: 100% Furchgott (1972)
● Clearance (l/min): 6.8 Annex 11
● Volume of distribution (l): 86.5 Annex 11
● Elimination half- life (min): <1 Annex 11
Clinical factor
● Usable during pregnancy: Yes
(FDAcategory=C)
, α2,
1
Goldstein (2001)
Haas etal. (2000)
Donaldson and
Goodchild (2012)
● Usable during lactation: Yes Haas etal. (2000)
Donaldson and
Goodchild (2012)
● Absolute maximum dose in
Report (1955)
dentistry.
0.2
mg=200 μg =2.85 μg/kg
● Maximum concentration in
Report (1955)
dentistry:
000=20 μg/ml=0.002%
1:50
● Other concentrations used in
dentistry:
000=12.5 μg/ml=0.00125%
1:80
1:100 000=10 μg/ml=0.001%
1:200 000=5 μg/ml=0.0005%
Table6.8 lists the most salient pharmacological and clinical factors. The safety of administering local anesthesia
containing epinephrine during pregnancy and lactation
(Haas et al.2000) and the establishment of the absolute
maximum dose at 200 μg (2.85 μg/kg) for adults weighing
70 kg or over (Report of the Special Committee of the
New York Heart Association1955) are among the most
prominent of the clinical indications. The maximum concentration authorized for dentistry is 1:50
while in general concentrations of 1:100
(10
μg/ml) and in some European countries as well as in
India and Japan of 1:80
standard. A concentration of 1:200
000 (12.5 μg/ml) are regarded as
000 (5 μg/ml) is regarded
000 (20 μg/ml),
000 (10 μg/ml)
as low in clinical dentistry.
The world over, epinephrine continues to be the most
commonly used vasoconstrictor by far in local anesthesia
today because it is more effective and safer than other sympathomimetic amines.
Norepinephrine
Chemically speaking, the difference between norepinephrine and epinephrine is the lack of a methyl group on the
side chain nitrogen in the former (Figure 6.2). The prefix
“nor” is taken from the German initials for “Nitrogenum
ohne Radikal” (nitrogen without the radical). It was first
isolated in 1946in Sweden by Ulf Svante von Euler and
named noradrenalin or arterenol (von Euler1946a,1946b).
Today US pharmacology (USP 38) calls it norepinephrine
while in Europe it is known as noradrenaline.
Norepinephrine is a natural hormone and neurotransmitter. It is released in all noradrenergic sympathetic nerve
endings, with around 30% reaching the circulatory system
(Kopin 1989; Eisenhofer et al. 2004). Norepinephrine is
also released by the adrenal medulla, where it accounts
for only 15–20% of the total released, while epinephrine
accounts for the remaining 80–85% (Kopin 1989;
Goldstein2001). The levo isomer (levo-
1
norepinephrine=Levophed
-
) is used in clinical settings
norepinephrine=
because, as for other catecholamines, it is much (10–40
times) more potent than the dextro form (Table6.5).
In the earliest experimental studies with animals norepinephrine was observed to induce a vasoconstrictive effect
less potent than but similar to that of epinephrine. Its softer
effect on the heart, lower toxicity, and lack of the vasodilating effects compared with epinephrine (Luduena
etal.1949; Berling and Björn1951; Tye etal.1967) encouraged its use in local dental anesthetics. After promising
results at concentrations of 1:30 000 (33 μg/ml) in early
clinical trials (Dobbs and de Vier1950; Epstein etal.1951;
Ekmanner and Persson1951), it began to be preferred over
epinephrine. Subsequent research and clinical practice
revealed a number of discouraging findings, however.
1 Levophed is the trade name for -norepinephrine, which was
brought to market in 1951 (Epstein 1951).
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● Norepinephrine proved to be less effective than epineph-
rine in clinical experience (Persson 1969; Boakes
etal.1972) and clinical trials conducted to a more rigorous methodology. In 2% lidocaine with 1:50
000 (20 μg/
ml) norepinephrine, pulp was found to be poorly anesthetized, with results comparable to those with 2% lidocaine and 1:200
● Toxicity was observed to be higher than in epinephrine.
000 (5 μg/ml) epinephrine (Annex 21).
Clinical studies detected higher hypertension with norepinephrine (Annex 15), as well as substantial cerebral
vasoconstriction rarely present with epinephrine (Hirota
etal. 1992). Frequent adverse and at time severe reactions were observed, with hypertension crises leading to
headaches (cephaleas) (Boakes et al. 1972; New
Zealand 1974; Barnard et al. 1987). Extreme cases of
death due to cerebral hemorrhaging (subarachnoid hemorrhage), arrhythmias, and heart failure were also
reported (Boakes et al. 1972; Tomlin 1974; Cawson
etal.1983; Barnard etal.1987; Okada etal.1989).
Table 6.9 lists the main pharmacological and clinical
properties of norepinephrine; note that its vasoconstrictive
effect in humans is 25% of the epinephrine value and it is
contraindicated during pregnancy, although during lactation we have no information. The contraindication during
pregnancy is due to its stimulation of α
receptors and
1
hence uterus contraction, raising the risk of miscarriage or
premature labor (Stepke etal.1994). As noted earlier, norepinephrine has little impact on β
receptors, which relax
2
the uterus.
Table6.9 also shows that the maximum absolute dose of
norepinephrine is 330
kg or more (Jastak and Yagiela 1983). The maximum
70
concentration is 1:30
μg (4.7 μg/kg) for adults weighing
000 (33 μg/ml) (ADA- AHA 1964),
while the standard concentration for local anesthesia in
dentistry is 1:50 000 (20 μg/ml).
There are currently no commercially available local
anesthetic formulations with norepinephrine in the United
States, although it is available in a few European countries.
Most authors presently advise against the use of norepinephrine as a vasoconstrictor because it is less effective and
carries higher risk and more complications than epinephrine (Haglund and Evers1985; Van der Bijl and Victor1992;
Jage1993; Malamed2004; Brown and Rhodus2005).
Levonordefrin
Nordefrin was introduced as a vasoconstrictor in dentistry
in 1933 at a concentration of 1:10 000 (100 μg/ml)
(Dobbs1965). At the time it also went by the trade names
of corbasil, cobefrin, corbadrine, and lirotil. In 1958 the
levo isomer (levonordefrin) was found to be 100–200 times
Table6.9 Norepinephrine: prominent pharmacological
andclinical factors.
Pharmacological factor Reference
● Name and synonym: noradrenaline,
norepinephrine, levartrenol,
levophed
● First isolated by Euler in 1946 Von Euler (1946a, b)
● Chemical name:
1,1-
(3,4- dihydroxyphenyl)- 2-
American Dental
Association (1984)
aminoethanol
● Formula: C
HO
● Molecular weight: Baseline 169.2
As bitartrate: 337.3
● Adrenoreceptors stimulated: α
and β
1
8H11NO3
CH–CH2–NH
OH
1
American Dental
Association (1984)
, α2
Goldstein (2001)
Langer and Hicks
(1984)
● Vasoconstrictive potency: 25% Furchgott (1972)
● Clearance (l/min): 5.6 Annex 11
● Elimination half- life (min): <1 Annex 11
Clinical factor
● Usable during pregnancy: No (not
Stepke etal. (1994)
classified by the FDA)
● Usable during lactation: ? (Table5.11)
● Absolute maximum dose in
dentistry:
0.33
mg=330 μg=4.7 μg/kg
● Maximum concentration in
Jastak and Yagiela
(1983)
AHA (1964)
ADA-
dentistry:
1
: 30 000=33 μg/ml=0.0033%
● Other concentrations used in
dentistry:
: 50 000 (20 μg/ml)=0.002%
1
1
: 80 000=12.5 μg/ml=0.00125%
more active than the dextro form (Luduena etal.1958) and
began to be used instead of racemic nordefrin, at concentrations of 1:20 000 (50 μg/ml), half the dose of the latter, in
the belief that the levo isomer generated the entire vasoconstrictive effect (Moose 1959).
Levonordefrin, a derivative of norepinephrine, is the
primary alternative to epinephrine as a vasoconstrictor in
the United States and Canada. This drug is not used
inEurope. Moreover, unlike epinephrine and norepinephrine, which are natural hormones and neurotransmitters,
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levonordefrin is an artificial catecholamine designed to
constrict blood vessels.
The earliest animal experiments appeared to suggest that
the vasoconstrictive effect of levonordefrin was approximately half the value observed for epinephrine (Luduena
etal.1958; Tye etal.1967) and the first clinical studies proved
to be promising (Dobbs and de Vier1950; Epstein etal.1951;
Moose1959). As the vasoconstrictive effect was later found to
be around 20% of the -
epinephrine value, a 1:20 000 (50 μg/
ml) concentration was used, as the theoretical equivalent of
000 (10 μg/ml) of - epinephrine (Robertson etal.1984).
1:100
Subsequent clinical experience and clinical research (Annex
21) has nonetheless shown that levonordefrin is approximately 15% as potent as -
epinephrine (Robertson etal.1984).
The major pharmacological and clinical properties of
levonordefrin are summarized in Table 6.10. It can be
safely used during pregnancy and lactation (Haas
etal.2000) because it acts only weakly on the α
receptors
1
in the uterus (Langer and Hicks1984). The absolute maximum dose for an adult weighing 70 kg or over is 1000 μg
(14.3
μg/kg) (Jastak and Yagiela 1983). Levonordefrin is
used in the United States and Canada with 2% mepivacaine
at a fixed concentration of 1:20 000 (50 μg/ml). It is less
effective and more toxic than epinephrine, although not as
toxic as norepinephrine (Barnard etal.1987).
Table6.10 Levonordefrin: prominent pharmacological
andclinical factors.
Pharmacological factor Reference
● Name and synonym:
levonordefrin,
α- methylnorepinephrine
Me- Ne),
(αα-
methylnorepinephrine,
neocobephrine, Corbadrine
● First synthesized: ?
● Chemical name:
1,1-
(3,4- dihydroxyphenyl)- 2-
aminopropanol
● Formula: C
HO
● Molecular weight: Baseline 183.2 USP38
● pKa value or dissociation
constant: 8.6
● Adrenoreceptors stimulated: α
and β
● Vasoconstrictive potency: 15% Robertson etal. (1984)
Clinical factor
1
9H13NO3
CH–CH–NH
OH CH
3
American Dental
Association (1984)
USP38
Annex 6
Robertson etal. (1984)
2
Langer and Hicks (1984)
Phentolamine (OraVerse®)
As a nonselective α- adrenergic antagonist, phentolamine
neutralizes the vasoconstrictive effect of epinephrine and
the other vasoconstrictive sympathomimetics (norepinephrine and levonordefrin). Phentolamine was synthesized in
1950 at the CIBA laboratory in Basel, Switzerland, by Urech
etal. (1950) and marketed in the United States in 1952 (Hersh
et al.2008; Rutherford et al. 2009) under the trade name
Regitine® (Weaver2008). In medicine it is used to treat hypertension caused by pheochromocytoma, a rare chromaffin tissue tumor in the adrenal medulla that produces excess
epinephrine and norepinephrine, or to extravasate injectable
catecholamines administered intravenously to prevent them
from inducing dermic necrosis (Hersh et al.2008; Laviola
etal.2008; Saunders etal.2011; Elmore etal.2013).
In early dentistry phentolamine was used under a different formulation, phentolamine mesylate, experimentally
known as NV- 101 (Weaver2008; Laviola et al. 2008). In
2008 the US Food and Drug Administration (FDA) authorized the inclusion of this drug in dentistry cartridges under
the trade name OraVerse® (OraVerse2015) for administration in standard syringes to reduce the duration of anesthe-
sia in soft tissue (Tavares etal.2008; Malamed2008; Hersh
etal.2017).
● Usable during pregnancy: Yes
(not classified by the FDA)
● Usable during lactation: Yes Haas etal. (2000)
● Absolute maximum dose in
dentistry:
1
mg=1000 μg=14.3 μg/kg
mg=500 μg=7.15 μg/kg
0.5
● Sole concentration used in
dentistry:
1:20
000=50 μg/ml=0.005%
Haas etal. (2000)
Jastak and Yagiela (1983)
Bennett (1984)
Jastak and Yagiela (1983)
Phentolamine is injected into the same site as the vasoconstrictive sympathomimetic- bearing local anesthetic to
block the effect on the α adrenoreceptors. The outcome is
vasodilation that raises the local blood flow, carrying the
local anesthetic from the oral submucosa into the bloodstream to restore normal sensation in the oral and perioral
tissues much more quickly (Malamed 2008; Hersh
etal.2008; Tavares et al. 2008). Research has shown that
after injecting phentolamine the level of the local anesthetic in the blood rises, an indication of speedier
elimination from the injection site (Moore et al. 2008).
Thepharmacological and clinical characteristics are given
in Table6.11.
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Table6.11 Phentolamine: prominent pharmacological
andclinical factors.
Pharmacological factor References
● Name and synonym:
phentolamine
● First synthesized by Urech etal.
Urech etal. (1950)
in 1950
● Chemical name: 3- [[(4,5- dihydro-
1H- imidazol- 2- yl)- methyl]
methylphenyl)- amino]- phenol
(4-
● Formula: C
N
C
3
● Molecular weight: Baseline:281.35
17H19N3
NH
N
O
Mesylate:377.46
● Clearance (l/min): 2.88 Moore etal. (2008)
● Volume of distribution (l/min): 407 Moore etal. (2008)
● Elimination half- life (min): 155 Moore etal. (2008)
Clinical factor
● Usable during pregnancy: ? (FDA
Malamed (2008)
category=C)
● Usable during lactation: ?
● Absolute maximum dose in
dentistry: ? but 0.8 mg accepted,
equivalent to two 1.7- ml
cartridges containing
Tavares etal. (2008)
Hersh etal. (2008)
Fowler etal. (2011)
0.0235%=0.4 mg per
cartridge=0.235
● Usable with children: Yes (but
mg/ml
Hersh etal. (2019)
not authorized by the FDA in
children under 3)
OraVerse®
This product comes in 1.7- ml cartridges with 0.4 mg
(400 μg) of phentolamine mesylate, equivalent to a concen-
tration of 0.235 mg (235 μg) per milliliter or 0.0235%. The
glass cylinder cartridges bear a transparent green label and
a blue aluminum ring at the mouth to ensure they are not
mistaken for cartridges containing the local anesthetic.
This drug is made by two laboratories, Novolar
Pharmaceuticals Inc. at San Diego, California and
Septodont at Lancaster, Pennsylvania and New Castle,
Delaware. The ingredients are (Moore etal.2008):
– sterile water
– ethylene diamino tetraacetic acid (EDTA)
– - manitol
– sodium acetate
– acetic acid
– sodium hydroxide to adjust the pH.
Advantages andIndications
While most routine dental procedures take less than an
hour, soft tissue (primarily lips and tongue) anesthesia may
last for 3–4
drinking, speaking, and smiling and favoring self-
hours (Annexes 21 and 27), hampering eating,
inflicted
injury as a result of biting lips, tongue, or cheeks, particularly in children. Moreover, as most procedures generate
minimal post-
operation pain, there is no advantage to prolonging the effect of anesthesia in the soft tissue
(Malamed2008; Hersh etal.2008). In light of the foregoing, the indications for this drug are as follows:
1) Routine dentistry procedures such as obturation, scal-
ing, root planning, etc.
2) Root canals in asymptomatic teeth (Fowler etal.2011),
which are not usually characterized by a painful prognosis (Mattscheck etal.2001).
3) After installing implants in the posterior jaw for the
early detection of lesions in the inferior alveolar nerve
and, in the event, withdrawal of the implant as soon as
possible to limit the lesion (Froum etal.2010).
4) In children to reduce the post- procedure duration of the
anesthesia in soft tissue and with it possible self-
inflicted
injury due to biting lips, tongue, or cheeks (Tavares
etal.2008; Zurfluh etal.2015; Hersh etal.2017,2019).
Technique andDose
After completing the dental procedure, phentolamine is
injected into the same site as the anesthetic solution containing the sympathomimetic vasoconstrictor (buccal infiltration, mandibular blockage, etc.) at a proportion of 1:1
(1 ml of anesthetic per 1 ml of phentolamine) to block the
vasoconstrictor effect (Tavares etal.2008; Hersh etal.2008;
Fowler et al. 2011; Saunders et al. 2011). Phentolamine
injection causes no pain because the soft tissues are still
anesthetized (Malamed2008; Fowler etal.2011).
No maximum dose is presently in place for dental use,
although there are recommended ceilings (Tavares
et al. 2008; Hersh et al. 2008, 2019; Fowler et al. 2011;
Saunders etal.2011):
○ Children 3–6 years old (15–30 kg): half a cartridge
○ Children 6–12 years old (25–40 kg): one cartridge
○ Children over 12 and adults: two cartridges
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The ratio of the amount to be injected is, as noted earlier,
1:1, although if a patient receives two cartridges of anesthesia for mandibular blockage and a third for buccal infiltration, just two cartridges of phentolamine would be
injected, one in the mandibular blockage site and the other
in the buccal infiltration site (Fowler etal.2011).
Clinical Efficacy
A number of clinical trials have shown that the duration of
the anesthesia in soft tissue is shortened by approximately
50% (around 55% in the upper lip and 45% in the lower) to
about 80
minutes after phentolamine injection (Table6.12).
The duration depends on individual variations as well as
on the time of the dental procedure. The shorter the procedure, the longer the post-
procedure duration of the anesthetic in the soft tissue and therefore the more effective
phentolamine is in reducing that time (Fowler etal.2011).
According to an in-
practice assessment, around 80% of
patients are satisfied with phentolamine and about 50% of
dentists contemplate using it in their treatments (Saunders
etal.2011).
Tolerance, Toxicity, andAdverse Side Effects
In medical practice, phentolamine is administered intramuscularly or intravenously at doses of 1
and up to 15
mg in adults (Saunders et al. 2011; Hersh
mg in children
etal.2019). In dentistry, the dose is half to two cartridges or
0.2–0.8
mg, i.e. about five to 19 times less, and this dose is
not administered intravenously or systemically but rather
is injected submucosally in the same site as the original
infiltration or block injection. Therefore, the dental dose
and method of administration result in hemodynamic stability, mitigating a potential decrease in blood pressure (in
response to general vasodilation) as well as any potential
reflexive increase in heart rate (Hersh etal. 2008; Tavares
et al. 2008; Laviola et al. 2008; Fowler et al. 2011).
Experiments in animals have shown phentolamine to have
low local and systemic toxicity under the conditions used
in dentistry (Rutherford etal.2009).
Adverse side effects are infrequent and short-
lived (a few
hours or days) and barely differ from the discomfort
reported by a placebo group (Tavares et al.2008; Laviola
etal.2008; Fowler etal.2011). They include the following.
Table6.12 Clinical efficacy ofphentolamine: clinical trials studying duration ofanesthesia insoft tissues andpercentage reduction
after phentolamine injection.
Time (min)
Location Reference Number Treatment duration Control group Phentolamine group Reduction
Upper lip Hersh etal. (2008) 120 20–60
Tavares etal. (2008) 77 20–60
Laviola etal. (2008) 61 20–70 155 50 68%
Fowler etal. (2011)
Lower lip Hersh etal. (2008) 122 20–60 155 70 55%
Tavares etal. (2008) 75 20–60 —
Laviola etal. (2008) 61 20–70 150 101 33%
Fowler etal. (2011) 85 85 217 170 22%
Global Hersh etal. (2008) 240 20–60 140 60 57%
Tavares etal. (2008) 152 20–60 135 60 56%
Laviola etal. (2008) 122 20–70 155 70 55%
Fowler etal. (2011) 85 67–85 220 153 30%
Saunders etal. (2011) — — — 60 —
a
The time in minutes is the median except in the Fowler etal. (2011) paper, where it is the mean.
b
Time estimated by Fowler etal. (2011).
b
85 67–71 224 136 38%
a
a
133 50 65%
— — 47%
79 54%
— 67%
114 44%
80 50%
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1) Sensitivity may linger in the injection zone, with slight
swelling and discomfort (Hersh et al. 2008; Laviola
etal.2008) in 4–6% of cases.
2) Some 2–4% of patients complain of headaches
(cephalea) (Hersh etal.2008; Elmore etal.2013).
3) Around 3% of mandibular blockage patients report
soreness on opening their mouths (Elmore
etal.2013).
Felypressin (Octapressin®)
Felypressin (Octapressin or Octopressin®) was synthesized
by Du Vigneaud etal. in 1953 (Du Vigneaud etal.1953) as
a derivative of the posterior pituitary hormones (oxytocin
and vasopressin, the latter is also known as antidiuretic
hormone or ADH) and more exactly as a derivative of vasopressin, replacing two amino acids: tyrosine with phenylamine in position 2 and arginine with lysine in position
8. The chemical name is consequently 2-
vasopressin (PLV- 2) (Berde and Cerletti1964; Altura
sineet al. 1965; Anonymous 1965) (Figure 6.4). This new
compound is a vasoconstrictor, and the antidiuretic or
oxytocin-
like effects are not seen as it is injected in the oral
phenylamine- 8- ly
mucosa (Berde and Cerletti1964). The major pharmacological and clinical properties of felypressin are summarized
in Table6.13.
This vasoconstrictor is not marketed in the United
States, although it is sold in several European Union countries under the trade name Octapressin, synthesized by
Sandoz at Basel, Switzerland. Felypressin is measured in
international units (IU) and used in dentistry at a fixed
concentration of 0.03
IU/ml (0.54 μg/ml) in solution with
3% prilocaine.
Cardiovascular Effects
Experimental studies in animals (Cecanho et al. 2006),
children (Meechan et al. 2001), healthy adults (Aelling
et al. 1970; Meechan and Rawlins 1988), hypertensive
patients (Sunada etal. 1996), and patients with arrhythmias and coronary insufficiency (Caceres etal.2008) show
that felypressin induces very mild cardiovascular side
effects, raising mean blood pressure very slightly and lowering heart rate barely perceptibly. These slight effects are
observed when over three and a half cartridges of anesthesia are administered with the standard 0.03
IU/ml concen-
tration of felypressin (Sunada etal.1996).
1
Cys--Phe--Phe--Glu—Asp—Cys—Pro—Lys--Gly (NH
S
H2N
34567
2
CH
2
CO
CH
2
NH
CO
1
CH
CH
2
S
S
CH
2
8
S
CH
NH
6
CH
CO
2
CH
CO
3
NH
CH
CH
4
CO
NH
5
CH
CH
CH
CH
CH
CH
NH
2
2
2
2
2
2
CO
NH
7
CO NH CH
N
CH
2
CO
CO NH CH2CO NH
9
)
2
NH
CO
2
NH
2
2
(b) full formula. Source: Modified from Berde and Cerletti
(1964) and Anonymous (1965).
Figure6.4 Felypressin formula: (a) abbreviated formula;
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Table6.13 Felypressin: prominent pharmacological andclinical factors.
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Pharmacological factor Reference
● Name and synonym: felypressin, octapressin, PLV- 2
● First synthesized by Du Vigneaud etal. in 1952 Du Vigneaud etal. (1953)
● Chemical name: 2- phenylalanine- 8- lysine- vasopressin Berde and Cerletti (1964)
Altura etal. (1965)
● Formula: C
NH
CO
CH
N
2
CH
2
S
42H65N13O11S2
CH
2
CO
CH
2
1
S
CH
2
NH
6
CH
CO
N
CH
2
CH
CO
3
4
5
CH
CO
NH
7
CO NH CH
NH
CH
CH
2
CH
CO
NH
CO
CH
2
CO NH CH2CO NH
CH
2
CH
2
CH
2
CH
2
NH
NH
NH
CO
2
2
2
Anonymous (1965)
Felypressin (Octapressin®) 99
● Molecular weight: 1040.2
● Receptors stimulated: v
● Vasoconstrictive potency: less than in catecholamines
1
Cecanho etal. (2006)
Clinical factor
● Usable during pregnancy: No (not classified by the FDA) Oliver (1974)
Stepke etal. (1994)
● Usable during lactation: ? (Table5.11)
● Absolute maximum dose in dentistry: 7.02 μg=0.39 IU
a
Dunlop Committee
a
0.1 μg/kg=0.0056 IU/kg
● Sole concentration used in dentistry:
1:1 850 000=0.54 μg/ml (0.03 IU/ml)=0.000000 54%
Berling (1966)
Barnard etal. (1987)
a
See Tables6.4 and6.14. IU, international units.
As the side effects are much less intense in felypressin
than in epinephrine (Aelling et al. 1970; Meechan
etal.2001; Cecanho etal.2006), it is generally regarded as
safe for patients with cardiovascular disease.
impacting antidiuretic v
receptors. Its vasopressive properties
2
differ from those of catecholamines in a number of ways.
1) It acts essentially on the microcirculation venules,
rarely affecting arterioles, metarterioles, or precapillary
Vasoconstrictive Effect
Felypressin induces vasoconstriction by binding to vasopressive
and oxytocic v
receptors (Cecanho etal. 2006), while barely
1
sphincters (Cerletti et al. 1963; Altura et al. 1965;
Burcher etal.1977).
2) It spreads to the tissues and penetrates the nerve
trunk vasa nervorum less readily than epinephrine
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Vasoconstrictors
due to its higher molecular weight (1040.2 vs. 183.2)
(Burcher etal.1977; Olgart and Gazelius1977; Chng
etal.1996).
3) The vasoconstrictive effect is consequently slow, taking
several minutes as opposed to the immediate action
observed in epinephrine (Burcher et al. 1977;
Lindorf1979).
4) Hypoxia does not occur in the infiltrated tissue
(Klingenström and Westermar1964), making it less of
an irritant for tissue than catecholamines, thereby eluding late-
stage rebound vasodilation.
As a result of the above, felypressin is a less potent vasoconstrictor than catecholamines, epinephrine in particular
(Fisher etal.1965; Altura etal.1965; Burcher etal.1977).
As the use of high felypressin concentrations does not
deliver good results, concentrations of only 0.05–0.03
IU/
ml are recommended (Berling1966; Akerman1969).
Adverse Effects
Two adverse effects have been detected in connection with
the use of felypressin in dentistry and medicine:
1) Pale skin on the face, neck, and arms due to cutaneous
vasoconstriction (Shanks1963; Light etal. 1965; Katz
and Katz1966; Berling1966; Anonymous1970).
2) Abdominal discomfort due to intestinal contraction and
the sudden need to defecate (Light et al. 1965;
Akerman1969).
Adverse reactions are fewer, less frequent, and much
less severe in felypressin than in the catecholamines, particularly norepinephrine and levonordefrin (Barnard
etal.1987).
Contraindications
The two major contraindications for the use of felypressin
in dentistry are discussed below.
1) It is contraindicated in patients who have had a heart
attack (angina or myocardial infarction) but only relatively so, given that it is administered at very low doses.
○ Felypressin- induced vasoconstriction of the coronary
vessels reduces the blood flow and the supply of oxygen to the heart (Light etal.1965; Miyachi etal.2003).
Interestingly, however, doses equivalent to 14 cartridges of 0.03 IU/ml barely affect ischemia in hypertensive patients (Sunada etal.1996).
○ The United Kingdom’s Dunlop Committee on Safety
of Drugs recommends a maximum dose of five 1.8- ml
cartridges of 0.03 IU/ml felypressin for such patients
(Oliver 1974; Roberts and Sowray 1987), while
experimental data with dogs suggests similar values
(Miyachi etal.2003).
2) It is absolutely contraindicated in pregnancy (Anony-
mous1970; Oliver1974) because the residual oxytocic
effect of felypressin resulting from stimulation of v
receptors may cause the pregnant uterus to contract,
reducing the blood flow to the placenta and raising the
risk of contraction, premature labor or miscarriage
(Anonymous 1970; Oliver 1974; Stepke et al. 1994).
Moreover, felypressin is used with prilocaine, a local
anesthetic that can induce fetal methemoglobinemia,
which would worsen the situation (Anonymous1970;
Oliver1974).
Advantages andDisadvantages
● Felypressin has three advantages over epinephrine.
1) Its small cardiovascular effects make if safe for such
patients, except those who have had a heart attack (as
mentioned earlier), although even in such cases it
can be used in small doses.
2) It does not interact with:
○ tricyclic antidepressants (Goldman 1971; Persson
and Siwers 1971; Boakes etal.1973), eliminating
the risk of prompting hypertension or arrhythmias
○ halothane (general anesthetic) (Shanks1963; Light
etal.1965; Katz1965; Katz and Katz1966), eliminating the risk of arrhythmias
○ sodium thiopental, an ultra- speedy barbiturate
used in general anesthesia induction (Light etal.
1965), eliminating the risk of arrhythmias.
3) It is less irritating than epinephrine because it does
not induce tissue hypotoxia (Klingenström and
Westermar1964).
● The disadvantages relative to epinephrine include the
following.
1) As its vasoconstrictive effect is less potent, it delivers
poorer results:
○ lower percentage of pulpal anesthesia (Table6.1)
○ shorter duration of pulpal anesthesia (Table6.1)
○ less effective hemostasis (Fisher etal.1965).
2) It is wholly contraindicated during pregnancy, as
noted above.
Maximum Doses
Experimental studies on acute toxicity in animals have
shown that felypressin is much safer than epinephrine and
the tolerance levels are much higher (Annex 18). The absolute maximum doses cited in the literature vary across
a wide spectrum (Table 6.14), a discrepancy possibly
1
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Table6.14 Maximum recommended doses forfelypressin.
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101References
0.03 IU/ml
IU μg ml 1.8-
Author
0.27 4.86 9.0 5 Healthy Jastak and Yagiela (1983)
16.70 300 555 308 Healthy Jage (1993)
Dunlop Committee
0.262 4.75 8.8 5 Ischemia Oliver (1974)
0.39 7.02 13.0 7.2 Healthy Oliver (1974)
spawned by a fear of coronary vasoconstriction. The
recommendations for healthy patients and those with
ischemia (angina and myocardium infarction) cited here
are taken from the United Kingdom’s Dunlop Committee
(full name: the Committee on Safety of Drugs).
2
Further to the Committee’s findings, the maximum recommended dose of 3% prilocaine with 0.03
ml) is five 1.8-
ml cartridges in patients with ischemia and
IU/ml (0.54 μg/
7.2 cartridges in healthy patients (Oliver1974; Roberts and
Sowray1987).
Combinations ofVasoconstrictors
The few papers published on the combination of two vasoconstrictors in the same anesthetic solution can be divided
into two groups.
● The combination 1:100 000 (10 μg/ml) epinephrine and
000 (10 μg/ml) norepinephrine was introduced in
1:100
ml cartridges Type of patient Reference
Roberts and Sowray (1987)
Roberts and Sowray (1982)
Germany in the 1950s to reduce the palpitations (tachycardia) induced by epinephrine and the cephalea
prompted by norepinephrine, initially with promising
results (Holler1954; Adler and Kelentey1965). Today,
however, most authors concur that these combinations
of vasoconstrictors are contraindicated, in as much as
they may have exactly the opposite effect: norepinephrine may cause rises in blood pressure (and concomitant
cephalea) and epinephrine tachycardia (Reynolds1972;
Evers and Haegerstam1981; Jage1993; Malamed2004).
● Epinephrine and felypressin combinations also fail to
lower anesthetic solution toxicity as initially believed
and are consequently not recommended either (Volpato
etal.1999).
In conclusion, based on the small amount of data available, combinations of vasoconstrictors not only afford no
advantages but may have adverse effects and are therefore
not recommended at this time.
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