Nikola Burić, 
Miloš Tijanić

Faculty of Medicine, Dental clinic, Orofacial surgery

Introduction

 Vasoconstrictive agents (VC) are added to local anesthetics (LA), used in orofacial surgery and dentistry for elimination of negative effect of LA on local circulation in the place of anesthesia administration. Since almost all LAs are vasodilatators (except for cocaine)¹ according to their structure, the result of their biological effect is enabling increased blood flow in the place of acting. The final result is possible toxic reaction to LA due to impetuous and uncontrolled increase of blood LA con-centration. Also, stronger intraoperative bleeding can be, by itself, a cause of the inadequate final outcome of the surgery, for the reduced vision within the operative field as well as the decreased anesthetic effect of LA. As the significance of VC in LA is greatly favored, in 1964 the workshop-conference of the American Dental Association and the American Heart Association was held with the conclusion that VCs were allowed for usage in LA without contraindications in patients with cardiovascular disease if administrated cautiously and with prior aspiration.²

Based on the above facts, vasoconstrictive agents are added to local anesthetics for:

 1. reduction of plasma concentration of local anesthetics;

2. reduction of minimal concentration of local anesthetic necessary for arresting the nerve impulse;

3. reduction of blood loss during surgery and optimal visualization of the operative field and,

4. prolonged effect of local anesthesia. 

All vasoconstrictive agents are divided into: 1. sympathomimetic amines and 2. synthetic vasopressins. Sympathomimetic amines act by expressing their effect on a1 and a2 adrenergic receptors in the arteriole wall exactly in the place where they are injected (in the submucosal tissue). Adrenalin is acting on b2 receptors which (apart from vasoconstrictive effect on a-adrenergic receptors in the arteriole wall where it is injected) causes vasodilatation, for example in the muscular tissue. Also, in the tissue with equally present concentrations of a and b receptors, the effects of adrenaline exogenously provided express on b receptors for their susceptibility to adrenalin. In clinical practice, the following vasoconstrictors are used as addition to local anesthetics¹:

1. adrenaline (epinephrine)

2. nor-adrenalin (norepinephrine)

3. levonordefrin (Neo-Cobefrine)

4. nordefrin (Cobefrine) and

5. phenylephrine (Neo-synephrine) 

Concentrations of vasoconstrictors in local anesthetics that affect the cardiovascular system 

Adrenalin (3,4-dihydroxy-a-ª(methyla-mino)methylº  benzyl alcohol is a sympatho-mimetic hormone  synthesized by the adrenal medulla. The amount of adrenaline exogenously added, standard for local anesthetics is low, although sufficient to cause the final b1 effect on the heart by increasing the heart activity, stimulated myocardium, and reinforcing the heart contraction. Adrenaline directly causes vasoconstriction of the blood vessels in the skin and mucosa, and relaxes the smooth muscles. It possesses bronchodilatory activity as well. In LA (Carpule of 1,8 ml) concentration of adre-nalin varies and amounts to 1:50000 (0,02 mg/mL), 1:100000 (0,01 mg/mL), and 1:200000 (0,005 mg/mL). Total dose of adrenaline in one ampoule of LA, on the average, is ten times lower than the therapeutic dose amounting to 0,2-0,3 mg. In one ampoule of the standard LA Lidocaine 2%-Adenalin of 2 ml (Galenika a.d. Belgrade), adrenalin is in concentration of 0,025 mg (1:80000)³. Intravenously administrated, adrenaline  has the half-life of 1-3 min.

Noradrenalin, ( -b-ª3,4 dihydroxyphe-nylº-a-aminoethanol) and levonordephrine, are direct sympathomimetics and thus directly effect the adrenergic receptors. These sympa-thomimetics have qualitatively lower effect on b2 adrenergic receptors. Noradrenalin is used in high concentrations (for it is weaker than adrenalin) in local anesthetics and amounts to 1:30000 (0,033 mg/mL) on the average. Total single dose must not exceed 10 mL solution in mentioned concentration (0,33 mg). Levonordephrine, on the market, can be found for usage in dentistry, (in USA specially) in concentration 1:20000 (0,05 mg/mL) in local anesthetic 2% mepivacaine with 1:20000 levonordephrine.⁴ Levonordephrine conce-ntration of 1:20000 equals the concentration of adrenalin of 1:100000. There are data pointing that this concentration of levonordephrine effect the cardiovascular system in the same way as adrenalin concentration of 1:100000⁵; other data obtained in the animal model, point out that this concentration can cause more harmful effect on cardiovascular system than the standard concentration of adrenalin.⁶

Phenilephrine (1:20000 or 1:50000) is the adequate substitute for adrenalin in cases when the application of adrenalin is contraindicated as a VC in patients with thyrotoxicosis. Phenilephrine causes peripheral vasoconstriction without final cardiologic effect. Nordephrine also causes local vasoconstriction, however it is suppressed by previously described vasoco-nstrictors.

Synthetic vasoconstrictors (vasopressins) 

These vasoconsrictors are used when there is a need to exclude the adverse effect of vasoco-nstrictors from the group of sympatho-mimetics in LAs. One of the major representatives of synthetic vasoconstrictors is ornipressin (8-ornito-vasopressin), better known in clinical practice as POR-8^Ò, which has special effect on peripheral circulation. After the application of POR-8^Ò, the prolonged ischemia occurs thro-ugh vasoconstriction of arterioles and capi-llaries, but without tissue necrosis, reactive hyperemia and systemic effect on CVS. This preparation is applied locally, or by instillation in the ratio of 1 i.j. to 10 ml of anesthetic and this solution is applied immediately. Phelipressin (Octapressin) is a synthetic vasoconstrictor, si-milar to vasopressine (antidiuretic hormone) ADH. Also, it is similar to oxytocin, secreted in the posterior hypophysis; oxytocyn increases the frequency and strength of the uterus contraction, and therefore it is contraindicated in pregnant women. Concentration of phelypre-ssine in LA prilocaine is 0,03 ij/ml (Citanest-Octapressin/Astra). ³ 

Advantages and disadvantages of vasoconstrictive agents 

Clinical practice reveals the opinion acco-rding to which the presence of VC in LA reduces the resorption of LA in the systemic circulation for the vasoconstrictive effect of adrenalin in the form of its stimulation of a1 receptor in the mucous membrane.⁷ Nevertheless, some studies showed that there were no differences in ma-ximal concentration of local anesthetic in the plasma after applying 2% lidocaine with 1:100000 adrenalin and 2% lidocaine without VA.⁸ In addition, although VCs provide prolonged effect of LA, there are variations in providing the prolonged effect of LA in dependence on concentration of VC and type of LA. For example, if the concentration of adrenalin in LA with 1:200000 is increased to 1:100000, then the effect of anesthesia is prolonged as well.⁹ On the other hand, there are data reporting that the concentration of adre-nalin of 1:250000-1:300000 prolongs the effect and depth of LA as well as adrenalin concentration of 1:50000.10 According to these data, it is clear that there are still variations in results and final effect of VC on the depth and duration of anesthesia. From the viewpoint of intraoperative hemostasis, positive hemostatic effect of VC on the blood loss is established. The application of 2% lidocaine with adrenalin 1:100000 causes doubled intraoperative blood loss than the application of 2% lidocaine with adrenalin 1:50000.11

Significantly, the amount of endogenous adrenalin released in blood during stress or inadequate anesthesia is higher than the amount of adrenalin injected with local anesthesia.12 In healthy patients, such a course is regular. In chronic patients with heart disease, hyper-tension or hypocalcemia, VC in LA can cause adverse effects. The data show that disturbance in the rhythm of the heart is possible in 16% of patients in the course of intervention when 2% lidociane with adrenalin 1:10000013 is used, e.i., adrenalin concentration 1:80000 causes the increase of heart contraction, heart frequency and cardiac output. These homo-dynamic disorders are much more serious in older pa-tients. However, nowadays it is considered that in the standard procedure of anesthetization (anesthesia technique, amount of anesthetic, vasoconstrictor selection), the routine admi-nistration of VC in LA is possible.¹

             Reaction of cardiovascular system to vasoconstrictors  

One of the basic questions in the application of VC is if they cause the reaction of cardio-vascular system, and if that reaction is within of physiological response limitations. Adrenalin exogenously added in the amount of 18mg (Car-pule with 1,8ml 2% lidocaine with adrenalin 1:100000), after a 5 minute interval causes the increase of plasma adrenalin concentration from (normal concentration) 98±38pg/mL to 240±69 pg/mL; the same amount of lidocaine without adrenalin did not cause concentration jump of adrenalin in the plasma. In healthy patients, the heart frequency and arterial pressure show no significant increase.¹⁴ Application of 5,4mL (54mg) 2% lidocaine with adrenalin 1:100000 in anesthetizing tooth extraction, after 5 minutes, causes 5 times higher plasma adrenalin concentration; such an increase of adrenalin in the plasma significantly increases the heart frequency and systolic blood pressure15; using 5 mL 2% lidocaine with 1: 50000 adrenalin and 5IU/mL of vasopressin causes no ischemic changes in patients with cardiovascular system diseases.16 In addition, there are no suggestions to limit the adrenalin concentrations to 40mg in patient with moderate CVS disease, i.e. to concentration of 20mg in patients with severe CVS disease.17 Such results show that in healthy patients, 1 anesthetic ampoule of 2% lidocaine with adrenalin 1:100000 (18mg) increases pla-sma adrenalin concentration up to two times, ho-wever with no significant physiological response or disturbance of  CVS; adrenalin of 54 mg given through LA can cause significant cha-nges in CVS, but these results are not always directly related to this adrenalin concentration endogenously added. The latest data point out that 1,8 mL of anesthetic (1 Carpule) with adrenalin is the safe amount in anesthesia and causes no consequences to CVS patients, whereas the adrenalin concentration of 22,5mg in LA is well endured even by serious CVS patients.¹⁸ 

Interaction of vasoconstrictor with other drugs 

Vasoconstrictor agents can chemically interact with other drugs and produce adverse effects. This is of significance having in mind that the patients anesthetized with LA in the course of dental or surgical interventions belong to the elder population in high percent. Vaso-constrictors mostly react with tricyclic anti-depressants and b blockers. Chemical effect of tricyclic anti-depressant results in the inhibition of neuron acceptance of catecholamine; such reaction causes increased catecholamine concentrations in sympathic-neuroeffective junction, i.e. there comes to the irritation of CVS. Such reaction is possible if the dose of adrenalin exogenously added exceeds 0,005mg in patients treated with tricyclic anti-depre-ssants. Experimental data point to the increase of effect of adrenalin in animals administrated with 2-4 times higher dose of tricyclic anti-depressants; potency of noradrenalin and levonordefrin is increased by 7-8 times in these experimental animals.¹⁹

In patients treated with b blockers, the conditions are provided for strong   expression of vasocontrictive a-adrenergic effect of adrenalin for, compensatory vasodilatation is not possible. Adrenalin in these patients almost certainly causes significant increase of arterial pressure.²⁰ Levonordephrine and nor-adrenalin are contraindicated in patients treated with tricycline anti-depressants. Yagiela in 2002²¹, published as the fact that the application of adrenaline is possible in patients treated with inhibitors of monoamine oxidases as well.

 Conclusion

In clinical practice, it is highly significant that the minimal dose of vasoconstrictors in local anesthetics that would cause favorable effect is used. In this way, the possibilities for toxic effect of local anesthetic, i.e. uncontrolled irritation of the CVS by the vasoconstrictors are reduced. Since the variations in concentration of VC in LA are still present, the aim of these investigations is to introduce the anesthetic with vasoconstrictive effect to clinical practice as well, what would reduce the usage of vasoconstrictors to rare clinical cases.

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