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Vasoconstrictors

Introduction

Blood vessel constrictors, the second most important drugs in local anesthesia, enhance the efficacy and safety of the primary drug, the local anesthetic itself.

Two families of blood vessel constrictors or vasoconstric-

tors are presently used in dentistry:

1) Sympathomimetics or catecholamines, so- called

because they share a catechol core, including the natural hormones and neurotransmitters epinephrine and norepinephrine, and the synthetic drug levonordefrin.

2) Felypressin, a polypeptide derived from the posterior

pituitary hormone vasopressin.

The most effective and by far most commonly used vasoconstrictor is epinephrine, oddly enough the first vasoconstrictor ever to be used.

Advantages

As noted, vasoconstrictors heighten local anesthetic effects and safety.

1) In dentistry that enhanced efficacy and potency trans-

late into a higher percentage of successful anesthetization of dental pulp, the most difficult tissue to numb (Table6.1). The massthe vasoconstrictor’s ability to hold the local anesthetic in place raises the potency of lower doses (1–2% for action comparable to 6–7%).

2) Vasoconstrictors lengthen anesthesia duration in both

pulp and soft tissues (Table6.1), likewise as a result of the mass- volume- time effect.

3) Both epinephrine (Curtis et al. 1966; Meyer and

Allen1968; Hecht and App1974; Sveen1979; Buckley et al. 1984; Moore et al. 2007) and felypressin (Shanks 1963; Light et al. 1965; Fisher et al. 1965) reduce hemorrhaging in surgeries by constricting blood

volume- time effect attributable to

vessels. An additional advantage is that they shorten the duration of oral surgeries by affording the surgeon a wider field of view (Hecht and App 1974; Buckley etal.1984; Moore etal.2007).

4) Vasoconstrictors reduce the toxicity of local anesthetics.

● Experimental studies in animals have shown that the

subcutaneous injection of a local anesthetic in conjunction with a vasoconstrictor such as epinephrine (Campbell and Adriani1958; Henn1960; Henn and Brattsand1966) or felypressin (Akerman1969) lowers the toxicity of the former (Table6.2). The subcutaneous injection of 2% lidocaine in rats has been shown to disappear in 2 hours, whereas if administered with epinephrine it lasts more than 4

hours

(Sung and Truant1954).

● Clinical studies have found that adding a vasocon-

strictor lowers the anesthetic peak (Bromage and Robson 1961; Braid and Scott 1965; Lund and Cwik 1965; Cannell and Beckett 1975a; Perovic et al. 1980) (Table6.3) and delays its appearance in plasma (Bromage and Robson 1961; Braid and Scott1965; Lund and Cwik1965) (Figure6.1). This is because the slower absorption of the anesthetic (Campbell and Adriani1958; Lund and Cwik 1965; Cannell and Beckett 1975a) reduces its capacity to reach toxic levels in the blood by giving the body more time to break the drug down.

● The greater potency afforded local anesthetics by

vasoconstrictors (see (1) above) also enhances safety indirectly because it enables clinicians to inject smaller quantities to achieve the same effect.

Disadvantages

Vasoconstrictors are characterized by two major drawbacks.

1) They heighten the toxicity of intravascularly injected

local anesthetics (hence the importance of aspirating

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

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Vasoconstrictors

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Table6.1 Anesthetic efficacy ofupper lip andmaxillary lateral incisor pulp (measured withelectric

pulpometer), withand without vasoconstrictors.

Variable 2% lidocaine 3% prilocaine 2% mepivacaine

No vasoconstrictor

Pulpal anesthesia 58% 85% 83% Duration pulpal anesthesia 6 Duration lip anesthesia 67

Reference Annex 21 Berling and Björn (1960)

Epinephrine 1:100

Pulpal anesthesia 95% 100% 93% Duration pulpal anesthesia 45 Duration lip anesthesia 190

Felypressin 0.01 IU/ml 0.03 IU/ml

Pulpal anesthesia 82% 88% — Duration pulpal anesthesia 15 min 25 min — Duration lip anesthesia 141 min 180 min —

000

Reference Annex 21 Berling and Björn (1960) Annex 21

Reference Berling (1966) Annex 21

min 11 min 13 min

min 86 min 82 min

Berling (1958)

Berling (1966)

min 26 min 35 min

min 135 min 160 min

IU/ml, international units per milliliter.

Table6.2 Lethal doses (LD50, mg/kg) after subcutaneous or intravenous injection of anesthetic with or without epinephrine.

Subcutaneous injection Intravenous injection

Anesthetic Animal No epinephrine With epinephrine No epinephrine With epinephrine Reference

Procaine Mouse — — 56 22 Keil and Vieten (1952)

Mouse 620 670 59 17 Henn (1960)

Lidocaine Mouse — — 30 14 Keil and Vieten (1952)

Mouse 314 317 30 9 Henn (1960) Rat — — 28 16 Hardin etal. (1981) Rat — — 28 18 Yagiela (1985)

Mepivacaine Mouse 285 320 40 20 Henn (1960)

Mouse — — 40 23 Henn and Brattsand (1966

Tetracaine Mouse — — 9.5 4.2 Keil and Vieten (1952)

Mouse 62 101 8 2.4 Henn and Brattsand (1966)

Conclusion Higher toxicity with NO

epinephrine, subcutaneous

administration

Using felypressin as the vasoconstrictor delivers very similar results (Akerman1969).

Higher toxicity WITH epinephrine,

intravenous administration

after every injection). Experimental studies with animals show that if administered intravenously, anesthetic solutions are more toxic if they bear vasoconstrictors than if they do not (Table6.2), i.e. exactly

the opposite behavior as observed in subcutaneous injections.

2) Counterindications and interactions are discussed in

Chapter10.

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Catecholamines 87

µg/ml

Minutes

120

Lidocaine with no vasoconstrictor

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Table6.3 Peak blood level oflocal anesthetic (ng/ml) andtime toappearance (minutes) after perioral injection of1.8- ml cartridge

solutions ofanesthetic withand without epinephrine andlevonordefrin.

Quantity No vasoconstrictor With vasoconstrictor

Anesthetic

Lidocaine 36 1 310 15 220 30 Goebel etal. (1979,1980a,b) Mepivacaine 36 1 400 10 370 30 Goebel etal. (1979,1980a,b) Lidocaine 80 2.2 1000 10 800 30 Cannell and Beckett (1975a) Lidocaine 160 4.5 1450 10 1150 60 Cannell and Beckett (1975b)

2% lidocaine with 1:80 000 (12.5 μg/ml) epinephrine; 2% mepivacaine with 1:20 000 (50 μg/ml) levonordefrin.

mg Number of cartridges ng/ml Minutes ng/ml Minutes Reference

Table6.4 lists examples of the vasoconstrictor concentra-

0,3

Lidocaine with epinephrine

tions most commonly used in dentistry, along with the maximum doses allowed.

0,2

0,1

Catecholamines

These vasoconstrictors derive their name from the fact that

6030105

they consist of a catechol group (a benzene ring with two adjacent hydroxy groups) and an amine side chain

Figure6.1 Lidocaine vein blood levels with no

vasoconstrictor and with epinephrine. Source: Data from Goebel etal. (1980b).

(Figure 6.2). They are also known as sympathomimetic vasoconstrictors because they act on the autonomic sympa-

thetic nervous system or adrenergic amines because some of them (epinephrine and norepinephrine) are released by the adrenal medulla or are artificial derivatives of such substances (levonordefrin).

Dilutions andConcentrations

Vasoconstrictor dilutions are measured as a ratio of parts

Vasoconstrictor sympathomimetics administered in dentistry anesthetic solutions are characterized by three properties.

per thousand, written as, for instance, 1:1000. Doses may also be expressed in milligrams (mg) or micrograms (μg). Concentrations are expressed in milligrams or micrograms per milliliter (mg/ml, μg/ml) or percentage (%). Some examples are listed below.

1) In their basic form catecholamines are not water solu-

ble. As hydrochloric salts they, like local anesthetics, dissolve in water, but are unfortunately not stable in that medium. They are consequently used as bitartrates, i.e. the bitartrate salts such as epinephrine bitartrate

● A 1:1000 dilution is 1 g (1000 mg) of drug in 1000 ml of

solution. Hence: 1:1000=1 mg/ml=1000 μg/ml=0.1% One liter (1000 ml) contains 1000 mg (1 g) of drug

● A 1:100 000 dilution is 0.01 g (10 mg) of drug in 1000 ml

of solution, whereby: 1:100 000=0.01 mg/ml=10 μg/ml=0.001% One liter (1000 ml) contains 10 mg (0.01 g) of drug

● A 1:200 000 dilution is 0.005 g (5 mg) of drug in 1000 ml

of solution, whereby: 1:200 000=0.005 mg/ml=5 μg/ml=0.000 5% One liter (1000 ml) contains 5 mg (0.005 g) of drug

resulting from the reaction with two molecules of tartaric acid, which are both stable and water soluble (Smith1920; Bonica1959).

2) They are combined with sulfites, the antioxidizing

action of which lengthens catecholamine life because these vasoconstrictors are highly vulnerable to oxidation (Milano etal.1982; Klein1983).

3) Vasoconstrictor solutions must have a low pH of 2.7–5.5

(USP 38 2015) because otherwise they are oxidized and degraded (Fyhr and Brodin1987): at a pH >6 epinephrine breaks down in a matter of hours (De Jong and Cullen1963).

t.me/Dr_Mouayyad_AlbtousH

Vasoconstrictors

Catechol group Amino side chain

2 2

FORMULAMW

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Table6.4 Maximum doses established forvasoconstrictors androutine concentrations anddilutions.

Vasoconstrictor Maximum dose μg (mg)

Levonordefrin 1000 (1)

Norepinephrine 330 (0.33) Epinephrine 200 (0.2)

Sympathomimetic

Felypressin 7.02 (0.00702)

*IU, international units.

References: 1, Jastak and Yagiela (1983); 2, ADA- AHA (1964); 3, Report of the Special Committee of the NewYork Heart Association (1955); 4, Dunlop Committee (Oliver1974; Roberts and Sowray1987); 5, Berling (1966), Goldman and Evers (1969); 6, Barnard etal. (1987); 7,Bennett (1984).

Epinephrine H

Norepinephrine

Levonordefrin

Figure6.2 Chemical structure common to all catecholamines,

showing catechol group and amino side chain: vasoconstrictor drugs differ in side- chain terminations. Source: American Dental Association (1984).

Isomers andCatecholamines

The three vasoconstrictive sympathomimetic amines used with local anesthetics in dentistry are isomeric or enantiomeric, i.e. they may present as either of two molecular configurations that differ in the positions of their atoms or atomic groups. As a result, a plane of polarized light can rotate in one of two opposite directions, hence the name optical isomers.

Unlike local anesthetics, most of which adopt racemic forms ( or ± or RS), i.e. 50% of their molecules are dextrorotated ( or + or R, rectus) and 50% levorotated ( or– or S, sinister), only levorotated catecholamines are used as vasoconstrictors, resulting in a more potent effect (as well as higher toxicity). Levo epinephrine is 15–20 times more potent and more toxic than the dextro form (Table6.5), while racemic forms are half as potent and toxic.

Parts per thousand

500 (0.5)

1:20 000

1:30 000 1:50 000 1:80 1:100 1:200

(0.39

IU)* (0.03 IU) (0.054 IU)

1:185 000060.00000054% 0.54

Percentage (%) μg/ml mg/ml

0.005% 50 0.05 90

0.00333% 33 0.033 59.4

2,3

0.002% 20 0.02 36

000 0.00125% 12.5 0.0125 22.5

000 0.001% 10 0.01 18 000 0.0005% 5 0.005 9

0.00054 0.972

Hereafter, all references to epinephrine and norepi-

nephrine are understood to be to - epinephrine and

-norepinephrine, while nordefrin is referred to throughout as levonordefrin.

C9H13NO3183,

C8H11NO3169,

C9H13NO3183,

Adrenergic Receptors

Dale (1906) was the first researcher to realize that epinephrine action is mediated by two receptors, although it was Raymond Ahlquist who actually typified the two types of adrenoreceptors: alpha (α) or stimulant and beta (β) or inhibitory receptors (Alquist1948).

Each type was later subdivided, β receptors into β tors, located primarily in the heart as well as in adipose tissue and the intestine, and the more widely distributed β receptors. Their purpose is to relax the smooth muscle in blood vessels and bronchi (Lands etal.1967).

The α receptors were found to consist, firstly, of post- synaptic α

receptors located in the tunica media (edge

of the tunica adventitia). Their vasoconstrictive action is triggered by the exogenous catecholamines carried in the bloodstream and the norepinephrine released by nerve endings. The pre- synaptic α

receptors in the sympathetic

nerve endings block the release of norepinephrine on activation. When located in the tunica intima of vessels they constrict the blood vessels on activation, similar to the response to exogenous catecholamines carried in the bloodstream (Langer1974; Langer and Hicks1984).

Today, information deriving from the isolation of the pure proteins comprising adrenoreceptors and functional pharmacological studies suggests the existence of subtypes

μg per 1.8- ml

cartridge

recep-

t.me/Dr_Mouayyad_AlbtousH

Table6.5 Potency andtoxicity oflevo over dextro isomers ofepinephrine, norepinephrine, andlevonordefrin.

membrane

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Catecholamines 89

Δ potency

Catecholamine

levo > dextro Reference Δ toxicity levo > dextro

Epinephrine 15–20 Cushny (1909)

Welsh (1955) Hondrum etal. (1993)

15–20 Launoy and Menguy (1920)

Reference

Launoy and Menguy (1922) Hondrum etal. (1993)

20 Tye etal. (1967)

Norepinephrine 25–33 Tainter etal. (1949) 10–15 Hoppe etal. (1949)

27 Luduena etal. (1949) 12–18 Luduena etal. (1949) 10–15 Welsh (1955) 40 Tye etal. (1967)

Nordefrin 100–200 Luduena etal. (1958) 10 Hoppe and Seppelin (1953)

35 Tye etal. (1967) Luduena etal. (1958)

Toxicity can be verified in Annex 18.

of α1 (α1a, α1b, α1c, α1d) and α2 (α2a, α2b, α2c) (Ruffolo Jr etal.1991; Bylund etal.1994; Hieble2000; Goldstein2001), as well as further β receptors, such as β Bylund etal.1994; Coman etal.2009) and β

(Goldstein2001;

(Hieble2000).

The identification of adrenoreceptor subtypes and the characterization of their functions may clear the way for the design of future drugs with an optimal pharmacological spectrum (Bylund etal.1994; Hieble2000).

Adrenoreceptors are transmembrane receptors with an alpha- helix structure that span the cell membrane seven times. They are G protein-

coupled receptors, i.e. they activate the G proteins, intracellular “switches” that help regulate cell function (Ostrowski etal.1992). The various parts of this helix structure are depicted schematically in Figure6.3 (Wolfe and Molinoff1988; Ruffolo Jr etal.1991; Ostrowski etal.1992; Coman etal.2009).

● The transmembrane segments or domains are the seven

“pieces” that span the cell membrane. They are shown as tubes because each one is two to four amino acids thick and labeled with indoarabic numerals (Figure6.3).

● Six hydrophilic connecting loops connect the seven

transmembrane domains, three of which are extracellular (E) and the other three intracellular or cytoplasmic (C). They are shown as lines because each chain is just one amino acid thick.

● The COOH terminal is intracellular and the NH

termi-

nal is extracellular.

● The extracellular segment has two glycosilation

zones (Y).

Each adrenoreceptor, with around 400–560 amino acids,

has a molecular weight of 45–70

kDa (Ruffolo Jr etal.1991;

Ostrowski etal.1992; Coman etal.2009). Adrenoreceptors

Figure6.3 Basic structural model common to

adrenoreceptors.

Extracell

Cell

Intracell

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E2 E3

COOH

Vasoconstrictors

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Table6.6 Vasoconstrictor affinity foradrenoreceptors

andrelative potency (values forlevo isomers).

Adrenoreceptor

Vasoconstrictor

Epinephrine + + + + 100 Norepinephrine + + +  25 Levonordefrin  + +  15

+, stimulates receptor;  does not stimulate receptor.

Relative potency (%)α1α2β1β

differ primarily in the composition of their C3 and cytoplasmic terminal zones (Ruffolo Jr etal.1991).

Today catecholamines are believed to bind to the extracellular portion of the receptors between transmembrane domains 3 and 4 (Ostrowski etal.1992). The lipid solubility coefficient is consequently unimportant in vasoconstrictor sympathomimetics because contact is made on the surface of the membrane and not, as in local anesthetics, inside the sodium channel.

Not all receptors are stimulated by vasoconstrictive sympathomimetics, nor do all these vasoconstrictors exhibit the same potency. Table 6.6 summarizes their properties: as epinephrine is the most potent catecholamine and stimulates all four main receptors (α

), it is assigned an activity of 100%. It is fourfold

and β

, α2, β1,

more potent than norepinephrine (Furchgott 1972) and six to seven times more potent than levonordefrin (Robertson etal.1984). Adrenoreceptor distribution and the major effects of their stimulation are given in Table6.7 (Keiser2001; Goldstein2001). As these receptors tend to seek equilibrium (receptor dynamics), when large quantities of catecholamines are present in the blood for lengthy periods of time they adapt by becoming less sensitive to stimulation. In contrast, when the receptors are not exposed to catecholamines they tend to be overstimulated by adrenergic amines (Brown and Rhodus2005).

Systemic Effects

Of the many effects induced on the body by vasoconstrictive sympathomimetics (Keiser 2001; Goldstein 2001), the ones of greatest interest to dental clinicians are discussed below.

Heart

The heart bears adrenoreceptors α1, α2, β1, and β2. Receptors

and α2 constrict the coronary vessels while receptor β2

induces vasodilation. Receptors β

and β2 raise heart fre-

quency and strength.

Table6.7 Adrenoreceptors: distribution andkey responses.

Receptor Location Response

Source: Data from Goldstein (2001) and Keiser (2001).

Heart ↑ Contraction strength Vessels, smooth

muscle Liver Glycogenolysis,

Genitourinary smooth muscle

Uterus Pregnancy Sudoriparous glands ↑ Perspiration Vessels, smooth

muscle Pancreas (β cells) ↓ Insulin secretion Platelets Platelet aggregation Nerve endings ↑ Norepinephrine release Heart ↑ Contraction strength

Juxtaglomerular cells ↑ Renin secretion Heart ↑ Contraction strength

Vessels, smooth muscle

Liver Glycogenolysis,

Pancreas ↑ Insulin secretion Bronchi, smooth

muscle Skeletal muscle Glycogenolysis and K

Genitourinary smooth muscle

Uterus Pregnant or

Adipose tissue Lipolysis

Contraction

neoglucogenesis Contraction

→ contraction

Contraction

and frequency

and frequency Relaxation

neoglucogenesis

Relaxation

capture Relaxation

otherwise

→ relaxation

As epinephrine stimulates the four types of receptors it raises cardiac frequency or heart rate (tachycardia) and contraction strength (β deficit because the effect of β offset by α

and α2 vasoconstriction.

and β2), and generates an oxygen

- induced vasodilation is

Norepinephrine, and to a lesser extent levonordefrin, induce coronary vessel vasoconstriction by stimulating α

, and although they stimulate β1, as they do not bind

and α

to receptor β

the vasodilation effect is minor. The concom-

itant rise in blood pressure triggers the baroreflex, a feedback mechanism involving the baroreceptors located in the carotid sinus and aortic arch that ultimately reduces heart rate (bradycardia) (Annex 15).

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Catecholamines 91

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Circulatory System

The arteries and veins of organs, muscles, viscera (lungs, kidneys, genitourinary tract, etc.) have α receptors. As α

and α2 receptors prevail in most of these

, α2, and β2

vessels, they are constricted by sympathomimetic amines, raising (primarily systolic) blood pressure and peripheral resistance. Skeletal muscle and some abdominal viscera vessels bear readily stimulated vasodilating β

receptors

that tend to lower (primarily diastolic) blood pressure.

Epinephrine stimulates α

and α2 receptors, inducing

vasoconstriction and raising (primarily systolic) blood pressure. It also stimulates vasodilating β

receptors in

skeletal muscle, which tends to lower (primarily diastolic) blood pressure; by balancing systolic and diastolic, it tends to stabilize blood pressure (Annex 15). Systolic and diastolic blood pressure rise simultaneously only when large quantities of epinephrine are injected, stimulating skeletal muscle α receptors (Campbell1977).

By stimulating only the α receptors, norepinephrine, and less intensely levonordefrin, induce a general rise in both systolic and diastolic blood pressure, given the absence or weakness of the compensatory vasodilating effect induced

(Annex 15).

by β

Respiratory Tract

Here the prevalent effect is receptor β2 stimulation, with relaxation of the bronchial muscles and increased air ingress in the lungs attendant on bronchodilation. That effect is induced by epinephrine almost exclusively because it is the sole catecholamine that stimulates these receptors effectively (Himms-

Endocrine System andMetabolism

Hagen1972).

Catecholamines stimulate bodily metabolism by raising the number of nutrients to the heart and skeletal muscle, increasing oxygen consumption by 15–30% via the β recep- tors to prepare the body for the fight-

or- flight response.

Catecholamines activate glycogenolysis in the skeletal muscles (β liver (α

) and glycogenolysis and neoglucogenesis in the

, β2), releasing glucose into the blood and raising

blood glucose levels, a condition that may be highly detrimental to uncontrolled diabetics. By stimulating the β receptors in the pancreas, catecholamines intensify insulin release and subsequent glucose entry into the cells, although high levels of epinephrine activate the α

receptors, notably

reducing insulin release (Table6.7) (Annex 16).

In adipose tissue, via α

, β1, and especially β3 receptors,

sympathomimetics induce lipolysis, with the release of glycerol, free fatty acids, and even ketone bodies.

Another effect of stimulating β

receptors stimulation is

hypokalemia, a reduction in plasma potassium levels. While under normal circumstances these actions are of no

consequence, in patients taking digoxin (a cardiac stimulant) they may favor heart arrhythmias (Meechan and Rawlins1988; Meechan etal.1991).

Uterus

This organ has α1 receptors that stimulate contraction and

receptors that favor relaxation, although it is highly

impacted by the menstrual cycle and pregnancy.

By acting on both types of receptors (contraction-

simulating α

and relaxation- stimulating β2), epinephrine

has a neutral effect on the uterus, inhibiting contraction during pregnancy.

As norepinephrine acts primarily on α

contraction-

stimulating receptors, it intensifies uterus contraction during pregnancy and with it the risk of premature labor or miscarriage (Stepke et al. 1994). As levonordefrin acts on neither receptor, it barely affects the uterus.

Vasoconstrictive Effect

Like the vessels in the skin and mucosa, those in oral tissue (gums, alveolar mucosa, submucosa, periodontium, etc.) have α

and α2 receptors (Goldstein 2001;

Keiser 2001). That, together with the paucity of β receptors, explains why the vasoconstrictive effect of sympathomimetic amines prevails in these areas. These pharmaceuticals induce vasoconstriction defined by a series of special characteristics.

1) They act on the entire microcirculatory system, contract-

ing arterioles, meta-

arterioles, precapillary sphincters, and venules (Berde and Cerletti1964; Altura etal.1965; Burcher etal.1977; Olgart and Gazelius1977).

2) They penetrate tissues, in particular the vasa nervorum

of nerve trunks, very effectively due to their low molecular weight (Burcher et al. 1977; Olgart and Gazelius1977).

3) The vasoconstrictive effect is immediate (Burcher

etal.1977; Lindorf1979), with the effect of epinephrine peaking in 3 minutes and lasting around 60 minutes (Lindorf1979).

4) Hypoxia occurs in infiltrated tissue usually due to the

rise in local oxygen consumption and decline in oxygen supply due to intense vasoconstriction (Klingenström and Westermar 1964). That in turn induces rebound vasodilation, mediated primarily by epinephrine and norepinephrine (Klingenström and Westermar 1964), which induces a response in 2–3 hours (Lindorf1979).

Epinephrine has a vasoconstrictive effect four times more potent than that of norepinephrine (Furchgott1972) and six to seven times more potent than that of levonordefrin (Robertson etal.1984) (Table6.6).

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Vasoconstrictors

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Catecholamine Metabolism

Neural sympathomimetic amines (epinephrine and norepinephrine) are released into the circulatory system in two ways.

1) Norepinephrine originates primarily in sympathetic

nerve endings, with only small amounts released by the adrenal medulla (Landsberg and Young 1980; Goldstein2001).

2) Epinephrine is supplied almost exclusively by the adre-

nal medulla (Kopin 1989; Goldstein 2001). Of the catecholamines released by the medulla, around 80–85% are epinephrine and the rest norepinephrine.

In the circulatory system 50–60% of these amines bind to plasmatic proteins, primarily albumin (Landsberg and Young1980), and have a very short (1

minute) mean halflife in the plasma (Lund1951; Whitby etal.1961). They are inactivated in two ways (Landsberg and Young 1980; Trendelenburg1988; Goldstein2001):

1) Uptake 1. After the post- synaptic release of norepineph-

rine, the noradrenergic nerve endings recapture over two- thirds of the neurotransmitter (Kopin 1989; Eisenhofer etal.2004), storing it in cytoplasmic vesicles for reuse or metabolizing it by monoamino- oxidase (MAO)-

mediated deamination in the ribosome membrane. Small amounts of exogenous epinephrine and norepinephrine administered with local anesthetics are also metabolized along this pathway.

2) Uptake 2. Non- nervous cells originating primarily in

the liver, but also in the kidneys, lungs, intestines, and other organs, capture circulating catecholamines, which they metabolize by a number of pathways.

● As noted, deamination is mediated by ribosomal

MAO, converting catecholamines into aldehydes.

● O- methylation is catalyzed by the cytoplasmic

enzyme catechol-

O- methyltransferase (COMT). COMT acts directly on the catecholamines or their MAO- deaminated metabolites by methylizing one of the catechol- OH groups to produce new methoxy derivatives. This is the predominant catabolic pathway for exogenous catecholamines (Eisenhofer etal.2004).

● Conjugation takes place primarily in the gastrointesti-

nal tract and other mesenteric organs (Landsberg1976; Eisenhofer etal.2004).

Interestingly, levonordefrin, due to its methyl group in position 1 (Figure 6.1), is protected from MAO and can therefore only be inactivated by COMT (Jastak etal.1995). There are two pathways for eliminating catecholamines and their metabolites.

1) Liver gall is the minority pathway (Landsberg and

Young1980).

2) Urine via the kidneys is the prevalent pathway and, as

shown in Annex 12, only around 5% of epinephrine and norepinephrine are eliminated unchanged.

Annex 12 describes the metabolic pathways for epinephrine degradation and the formation of its metabolites, along with the enzymes involved, while Annex 11lists the major pharmacokinetic variables.

Epinephrine

Epinephrine was first isolated in 1901 by Jokichi Takamine and Thomas Aldrich (Takamine1901; Aldrich 1901) and began to be used as a vasoconstrictor in local anesthetics in 1903 by Heinrich Braun (Braun 1903). Epinephrine is a natural hormone and neurotransmitter found in the brain (Mefford etal. 1978) and produced and released into the blood by the adrenal medulla (Kopin1989; Goldstein2001). Initially denominated epinephrine by John Jacob Abel (Abel1899), it was renamed suprarenin by Austrian chemist Otto von Fürth (von Fürth 1900) and adrenalin by Takamine (Takamine1901). Today it is known in US pharmacology (USP38) as epinephrine, further to an American Medical Association Council on Pharmacy and Chemistry decision (Smith 1920), while in European pharmacology, the World Health Organization, and the International Union of Pure Applied Chemistry (IUPAC), it goes by the term adrenaline (Navarro2003).

The levo isomer (levo-

epinephrine =- epinephrine) is used in clinical settings, as for all other catecholamines, because it has been observed to be 15–20 times more potent than the dextro form (Cushny1909; Welsh1955; Hondrum etal.1993). Epinephrine stimulates α

, α2, β1, and β2 recep-

tors (Table6.8) intensely and in human beings it has been shown to induce metabolic and hemodynamic effects 10- fold more potent than norepinephrine (Clutter et al.

1980). Its vasoconstrictive effect in humans is around four times more potent than exhibited by norepinephrine. For that reason epinephrine is taken as the model and assigned a vasoconstrictive potency value of 100%, to which norepinephrine is normalized to 25% (Table6.6).

The rise in epinephrine in the blood during dentistry treatments is associated not with stress or pain, but rather essentially with the amount contained in local anesthetic injections (Annex 16). A close relationship can be observed between the number of cartridges injected and the levels of epinephrine in the blood because, like the natural events that raise epinephrine levels, exogenous epinephrine is associated with metabolic and hemodynamic responses (Annex 16).

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