ontraindicat to vasoconstrictor entistry: Pharmacologic interactions Jean-Paul Goulet, DDS, MD,’ Rbnald Phusse, DMD, MD,’ and Jean-Yves Turcotte, DDS, CD, MRCD, FICD, FADI,bSte.-Foy, Quebec, Canada SCHOOL OF DENTAL MEDICINE, UNIVERSITti LAVAL This article discusses the relative contraindications to the use of vasoconstrictor in patients currently medicated with tricyciic antidepressants, monoamine oxidase inhibitors, phenothiazines and P-blockers. It reviews drug interactions and emphasizes potential detrimental systemic effects that epinephrine contained in !ocal anesthetics can have when administered concomitantly with these drugs. Finally, special considerations are expressed concerning patients who abuse illicit drugs such as cocaine. (ORAL SURG ORAL MED ORAL PATHOL 1992;74:692-7) he first two articles of this series reviewed and sion. Their efficacy in alleviating depression is well discussedthe “absolute” contraindications to the use established, but TCAs are also extremely effective in of vasoconstrictors in dentistry. This third and last the treatment of certain chronic pain states including part deals with their “relative” contraindications, orofacial pain disorders.‘7 2 The TCAs act on the cen- which by definition do not preclude their use but dic- tral nervous system by blocking the reuptake and thus tate the exercise of great caution. The focus here is on the physiologic inactivation of certain neurotransmit- the potential drug interactions that may take place ters at the neuroeffector junction3 (Fig. 1). between vasoconstrictors injected with local anes- Among the drug interactions involving the TCAs, thetic and exogenously administered adrenergic dentists should be mostly concerned with the poten- drugs. It emphazises once more the importance of tial enhancement of the cardiovascular effects associ- careful assessmentof the general health and drug in- ated with exogenously administered catecholamines. take including illicit drugs. When treating any patient In normotensive subjects pretreated for 4 days with taking medication, dentists should be aware of the protriptyline, 20 mg three times daily, Svedmyr4 ob- potential medical complications and always use the served an important increase in the systolic and dias- least concentrated solution of vasoconstrictor that al- tolic blood pressure after the intravenous infusion of lows for deep anesthesiaduring a sufficient period of very small doses of norepinephrine (0.022 pg/kg/ time. As a routine procedure, the local anesthetic so- min). As for epinephrine infusion, similar hemody- lution should always be injected slowly with frequent namic changes were observed but at a dosage three aspiration to minimize the potential hazard of an ac- times greater (0.067 pg/kg/min). Other investiga- cidental intravascular injection. tors5, 6 have also substantiated these findings. It is clear from the results of these studies that the vaso- RELATIVE CONTRAINDICATIONS pressor effects of norepinephrine, epinephrine, and Tricyclic antidepressants presumably levonordefrin are seriously potentiated by The tricyclic antidepressants (TCAs) are drugs TCAs. Although this enhancement is fivefold to ten- widely used today in the treatment of major depres- fold for norepinephrine and levonordefrin, it is not as dramatic for epinephrine and phenylephrine (twofold to threefold) enhancement at concentration currently aAssociate Professor, Section of Oral Medicine. bDean, Professor, and Active Director, Section of Oral and Max- used in local anesthetic solutions.7 The powerful illofacial Surgery. interactions between adrenergic drugs and the bio- 7/17/38157 genie amines accumulated at the neuroeffector syn- 692 Volume 74 Contraindications to vasoconstrictors: Part III 693 Number 5 4 0°0 o”o 5 1 i OOo"o 2-o 0 0 d" 3 T;r Fig. 1. Action of TCAs and MAOIs. 1, Presynaptic neuron; 2, synaptic cleft; 3, postsynapticneuron; 4, monoamineoxidase; 5, terminal vesiculesand neurotransmitters;6, neurotransmitters.A, Normal synaptic junction. B, junction in patient receiving tricyclic drugs. C, Junction in patient receiving MAOI. apsehave led to serious medical complications. Series potentiation of the pressoreffect of epinephrine is two of severe hypertensive crises, one of which resulted in to three times lessthan that reported for norepineph- the death of a patient, were reported by Boakes et a1.8 rine or levonordefrin, the possibility of potential un- after the injection of small quantity of local anesthetic toward reactions should be taken into consideration. containing norepinephrine 1:25,000 in patients treated In that respect, Yagiela et al6 recommend reducing with TCAs. Although such complications are not fre- to 0.05 mg (5.4 ml local anesthetic with epinephrine quent, it should emphasize once more the importance 1: 100,000) the maximum amount of epinephrine that of assessingthe current drug intake and being aware patients receiving TCAs should receive in any given of the potential drug interactions. session.Until more data are available, this recom- As several investigators pointed out,9-‘3 patients mendation seems reasonable and appropriate. We currently taking TCAs may have numerous electro- must reemphasize, however, the pitfall of false secu- cardiographic changes. TCAs have the property of rity when one relies on a maximum recommended lenghthening the conduction time (PR, QRS, or QT dose of vasoconstrictor. We believe dentists should intervals) and inducing various anomalies of repolar- always administer the lowest dose of vasoconstrictor ization characterized by flattening of the P wave and compatible with effective pain control of sufficient the appearance of the U wave. Although infrequent at duration. In addition, local anesthetic should be low dosages, such changes have been observed at injected slowly with careful aspiration to avoid inad- therapeutic dosesin otherwise healthy personsbeside vertent intravascular injection. their depressive state. lo These phenomena can be Monoamine oxidase inhibitors more consistent and significant as the plasma concen- tration of TCAs increases or in patients with preex- The monoamine oxidase inhibitors (MAOIs) are isting cardiac disease.l3 Interestingly, TCAs possess another group of psychotropic drugs primarily used in antiarrhythmic properties but in overdose they be- the treatment of major depression, certain phobic- come arrhythmogeni.c, exposing the patient to reentry anxiety states and obsessive-compulsive disorders. arrhythmias and circus rhythms.1°-13 On the basis of Their action is targeted at organ systemsregulated by these reports, concomitant administration of adren- the sympathomimetic amines and 5-hydrox- ergic drugs and TCAs has the potential to provoke ytryptamine. They can potentiate the effects of bio- serious arrhythmias. The cardiotoxicity of TCAs is genie amines in the central nervous system by inhib- furthermore reflected by the report of sudden death of iting their breakdown by the monoamine oxidase en- cardiac patients treated with amitryptiline and imi- zyme at the presynaptic neuron level3 (Fig. 1). Thus pramine.14 traditionally, local anesthetics with vasoconstrictor Sufficient evidence exists to consider the use of lo- have been contraindicated for patients receiving cal anesthetic with norepinephrine or levonordefrin MAOIs becausethe possibility of seriouspotentiation dangerous in patients taking.TCAs. Even though the of exogenously administered catecholamines could 694 Goulet, Ptrusse, and Turcotte ORAL SURGQRAL MEDQRALPATKOL November 1992 eventually lead to hypertensive crisis. This recom- bling those produced by quinidine. These drugs have mendation no longer seemsto be substantiated in light been shown to decreaseconduction velocity and facil- of more recent work. itate reentry phenomena.3,lo, I5 We cannot predict In an animal study Yagiela et al.6 did not observe the clinical significance of these changes nor the pos- any significant interaction between epinephrine, nore- sible effect adrenergic drugs may have in such in- pinephrine, levonordefrin, and MAO. Only phenyle- stances.The chances of a worsening of the conduction phrine, which is metabolized by monoamine oxidase, anomalies after an accidental intravascular injection is likely to be potentiated severalfold by MAOIS.~ We of local anesthetic with vasoconstrictor must be con- now recognize that the risk of hypertensive crisis at- sidered. In fact, cases of major and even fatal tributed to vasoconstrictors in local anesthetic has arrhythmias have been reported in patients without been overestimated for patients taking MAOIs. In previous heart diseasewho were receiving usual ther- fact, the metabolic degradation of exogenous cate- apeutic dosesof thioridazine or chlorpromazine.‘5S’8 cholamines is largely regulated by the enzyme cate- Until more data are available to strengthen or re- chol-O-methyltransferase and by neuronal reuptake. fute our concern about potential untoward effects re- Undoubtedly the cardiovascular effect of a variety of garding the use of vasoconstrictors in patients treated sympathomimetic amines can be enhanced by with phenothiazine drugs, dentists should be prudent MAOIs; however, these drugs are much less effective and administer the smallest amount of anesthetic so- in potentiating or prolonging the action of exogenous lution with vasoconstrictor required to obtain deep catecholamines. Despite the fact that previous find- anesthesia of adequate duration. ings have not been confirmed in any human study, &Blockers there seemsto be no restriction