Advantages

As noted, vasoconstrictors heighten local anesthetic effects and safety.

1. In dentistry that enhanced efficacy and potency translate into a higher percentage of successful anesthetization of dental pulp, the most difficult tissue to numb (Table 6.1). The mass‐volume‐time effect attributable to the 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 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 vasoconstrictor 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 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.

Dilutions and Concentrations

Vasoconstrictor dilutions are measured as a ratio of parts 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.

• 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

Table 6.4 lists examples of the vasoconstrictor concentrations most commonly used in dentistry, along with the maximum doses allowed.

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 (DL or ± or RS), i.e. 50% of their molecules are dextrorotated (D or + or R, rectus) and 50% levorotated (L 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.

Hereafter, all references to epinephrine and norepinephrine are understood to be to L‐epinephrine and L‐norepinephrine, while nordefrin is referred to throughout as levonordefrin.

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 β₁ receptors, located primarily in the heart as well as in adipose tissue and the intestine, and the more widely distributed β₂ 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 α₁ 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 α₂ 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 of α₁ (α_1a, α_1b, α_1c, α_1d) and α₂ (α_2a, α_2b, α_2c) (Ruffolo Jr et al. 1991; Bylund et al. 1994; Hieble 2000; Goldstein 2001), as well as further β receptors, such as β₃ (Goldstein 2001; Bylund et al. 1994; Coman et al. 2009) and β₄ (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 NH₂ terminal 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 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 (α₁, α₂, β₁, and β₂), it is assigned an activity of 100%. It is fourfold 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.

Vasoconstrictive Effect

Like the vessels in the skin and mucosa, those in oral tissue (gums, alveolar mucosa, submucosa, periodontium, etc.) have α₁ 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, contracting 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).