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Home , Antianginal, Cocaine, Local anesthetic

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 , monoamine oxidase inhibitors, phenothiazines and P-blockers. It reviews interactions and emphasizes potential detrimental systemic effects that contained in !ocal can have when administered concomitantly with these . Finally, special considerations are expressed concerning patients who abuse illicit drugs such as . (ORAL SURG ORAL MED ORAL PATHOL 1992;74:692-7)

he first two articles of this series reviewed and sion. Their efficacy in alleviating is well discussedthe “absolute” contraindications to the use established, but TCAs are also extremely effective in of vasoconstrictors in . This third and last the treatment of certain chronic 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 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 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 , dentists should be aware of the , 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 pressure after the intravenous infusion of lows for deep anesthesiaduring a sufficient period of very small doses of (0.022 pg/kg/ time. As a routine procedure, the local 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 . 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 (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 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

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Fig. 1. Action of TCAs and MAOIs. 1, Presynapticneuron; 2, synaptic cleft; 3, postsynapticneuron; 4, monoamineoxidase; 5, terminal vesiculesand ;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 severehypertensive 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 usedin antiarrhythmic properties but in overdose they be- the treatment of major depression, certain phobic- come arrhythmogeni.c, exposing the patient to reentry states and obsessive-compulsive disorders. and circus rhythms.1°-13On the basisof 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 of TCAs is genie amines in the by inhib- furthermore reflected by the report of suddendeath of iting their breakdown by the monoamine oxidase en- cardiac patients treated with amitryptiline and imi- zyme at the presynaptic 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 . 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 changesnor 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 diseasewho were receiving usual ther- fact, the metabolic degradation of exogenous cate- apeutic dosesof or .‘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- anesthesiaof adequate duration. ings have not been confirmed in any human study, &Blockers there seemsto be no restriction from a theoretical ba- P-Blocking agents are usually prescribed for their sis to use local anesthetic with vasoconstrictor other antihypertensive, antiarrhythmic, and ef- than phenylephrine in patients currently treated with fects. They are used lessfrequently for the treatment MAOIs. of vascular headaches and certain forms of involun- tary . P-blockers are either cardioselective or Phensthiazines nonselective depending on their affinity to preferen- The phenothiazines are a class of psychotropic tially inhibit pi cardiac receptors or block simulta- drugs primarily employed in the treatment of serious neously p2 peripheral receptors (Table I). There is a psychotic disorders. In addition, many drugs in this wide diversity of ,&blocking compounds, the proto- group have useful antihistaminic properties and the type being (Inderal). ability to potentiate and . Ortho- Epinephrine is known to have at least two distinct static is the most common cardiovascu- pharmacologic actions on the cardiovascular system. lar side effect reported with the phenothiazines. It is It causesvasoconstriction of arterial vesselsin many brought about through a powerful a-adrenergic re- organs through or-adrenergic stimulation and vasodi- ceptor blockade in the peripheral vasculature and in- lation of arterioles in skeletal muscles through ,&- hibition of centrally mediated pressor reflexes, which adrenergic stimulation. In addition, epinephrine stim- are not exclusive to chlorpromazine as initially ulates PI-adrenergic receptors in the heart, resulting thought3 Consequently this suppressesthe vasocon- in . The concurrent administration of stricting effect of epinephrine and unmasks its usually vasoconstrictor in patients treated with nonselective weak vasodilatory effect. Although the epinephrine P-blockers raises the likelihood of a serious elevation content of a single dental cartridge of local anesthetic of the blood pressurebrought about by an unopposed is small, accidental intravascular injection could po- cr-adrenergic stimulation caused by the blockade of /32 tentially worsen the hypotension frequently associ- peripheral receptors. I932o When this occurs it is usu- ated with the phenothiazines through an unbalanced ally followed by a secondary rellex bradycardia me- stimulation of vascular P-receptors. The risk of a se- diated by vagally innervated aortic arch and carotid rious complication is probably remote because no baroreceptors. Although no such complication has such case has yet been reported in the dental litera- been reported after dental local , several ture. On the other hand, certain hypotensive episodes case reports have been published in the medical liter- might have been falsely attributed to vasovagal reac- ature.21-23Foster and Aston observed a dramatic tions when small amounts of local anesthetic with increase in blood pressureand severebradycardia af- epinephrinewereinadvertentlyinjected into the blood- ter the injection of local anesthetic with epinephrine stream of patients taking phenothiazine drugs. in six patients undergoing eyelid plasty and currently Thioridazine (Mellaril) and other phenothiazines taking propranolol, a nonselective P-blocker. The re- can also induce repolarization abnormalities resem- actions occurred within few minutes with a quantity Volume 74 Contraindications to vasoconstrictors: Part III 695 Number 5 of epinephrine ranging from 0.04 to 0.32 mg, thus Table I. P-Blocker compounds equivalent to the injection of 4 to 32 ml of local an- Nonselective Cardioselective esthetic with epinephrine 1: 100,000. P-blockers P-blockers (01 P-Adrenergic blockade may also influence cate- (/31 and fl2 adrenoceptors) adrenoceptors) cholamine kinetics and contribute to amplify the physiologic activity of exogenously administered epi- Propranolol (Inderal) (Lopressor) (Corgard) (Tenormin) nephrine. Studies have revealed that P-adrenergic (Blockadren, (Sectral) blockade reduces the clearance of intravenously in- Timolate, Timoptic, (Kerlone) fused epinephrine,24> 25 raising the possibility that the Timoptol) clearance of endogenous epinephrine might also be (Visken) affected. It has also been reported that the kinetics of (Aptine) (Trandate, epinephrine varies according to the type of P-blocker Normodyne) administered. Hjemdahl et a1.25 observed no differ- (Trasicor) ential effect on the clearance of epinephrine and (Sotacort) norepinephrine by the cardioselective P-blocker me- Carte0101 (Cartrol) toprolol. However, ilmpairment of epinephrine kinet- (Levatol) ics was greater than that of norepinephrine by the nonselective P-blocker propranolol. In addition, com- pared with placebo the increase in plasma epinephrine dieting, cocaine is now recognized as one of the most level after propranoM infusion was greater than dur- dangerous illicit drugs in common use.36 Cocaine is an ing metoprolol blockade. Although the clinical sig- that has the quality of being both a local an- nificance of a sustained elevation of plasma epineph- esthetic and a sympathomimetic agent with powerful rine concentration by beta blockade has not been fully central nervous system effects. It was once used investigated, we must acknowledge the possibility of extensively as a local anesthetic in , untoward cardiovascular effects triggered by exoge- otolaryngology, and dentistry. Besides its striking nously administered epinephrine. On the other hand, systemic effect on the central and sympathetic ner- recent studies have sh[own that cardioselective P-block- vous systems, it has profound effects on the cardio- ers interfere very little with the normal hemodynamic vascular system. reactions to epinephrine infusion.26, 21 Cocaine is a sympathomimetic agent that stimu- From all the data available, no relevant evidence lates norepinephrine release and inhibits its reuptake precludes the use of local anesthetic with vasocon- in adrenergic nerve terminals.37-3g This action gives strictor for patients treated with cardioselective rise to a state of catecholamine hypersensitivity and ,&blockers. However, the risk of a potential compli- increases the adrenergic response in susceptible or- cation exists for patilents taking nonselective P-block- gans. Through its action on endogenous catechola- ing agents. Until more data are available, we believe mine balance, in sufficient doses cocaine may induce dentists should be cautious and avoid the administra- a sympathetically mediated tachycardia and hyper- tion of local anesth’etic with vasoconstrictor in pa- tension, resulting in greater cardiac workload and ox- tients currently taking nonselective /?-blockers. In a ygen requirements. 40, 41 Such sympathetic activity recent warning to otolaryngologists Brummet2* sug- may decrease coronary artery perfusion and lead to gested discontinuing the medication for at least 3 days significant ischemia, ventricular , , before using local anesthetic with vasoconstrictor. and . Indeed, adverse cardio- Because of reports of serious worsening of the preex- vascular effects related to cocaine use have been ex- istent cardiac diseas’e and sudden death after abrupt tensively reported and well documented by several cessation of chronicp-blocker therapy,2g, 3othis should authors.42-50 Although the specific sequence of events be done only with th’e consent of the prescribing phy- that leads to sudden death is poorly understood and sician. If the medication cannot. be discontinued or might be amplified by chemical of street changed, a local anesthetic without vasoconstrictor cocaine preparation,31, 34, 5o an overdose has toxic ef- should then be used to prevent any potential drug in- fects on the central nervous system and the heart teraction. muscle. Undoubtedly cocaine users are at prime risk for all Cocaine abuse sorts of unpredictable cardiovascular complications. Use of illicit drugs, reached a dramatic level in peo- This risk is even greater if local anesthetic with epi- ple of all ages, races, and socioeconomic levels during nephrine is inadvertently injected into their vascular the 198O~.~l-~~ Once thought to be benign and nonad- system while the drug is still active. Peak blood levels 696 Goulef, P&me, and Twcotte ORALSURGQRAL MEDORALPATHOL November 1992 of cocaine are reached within 30 minutes and usually oconstrictors used in local anesthetic solutions. ORAL SURG 51 However, when the intra- ORALMED ORAL PATHOL 1985;59:565-71. disappear after 2 hours. 7. Jastak JT, Yagiela JA. Vasoconstrictors and : nasal is used, blood release is a review and rational use. J Am Dent Assoc 1983;107:623-30. slowed down and as a consequence the effect may be 8. Boakes AJ, Laurence DR, Love1 KW, O’Neil R, Verril PJ. prolonged for as long as 4 to 6 hours.32$ 51 Because of Adverse reactions to local anesthetic vasoconstrictor prepara- tions: a study of the cardiovascular responses to xylestesin and the potential medical risk they represent for dentists, hostacain with noradrenalin. Br Dent J 1972: 133: 137-40. precautions should be taken to identify any illicit drug 9. Burrows GD, Vohra J, Hunt D, Sloman JG, Scoggins BA, Davies B. Cardiac effects of different tricyclic users, especially those using cocaine and derivative drugs. Br J Psychiatry 1976;129:335-41. substances such as crack. These patients are walking 10. Lipscomb PA. Cardiovascular side effects of phenothiazines time bombs if they have used the drug the same day and tricyclic antidepressants. Postgrad Med 1980;67:189-96. they have their dental appointment. Dentists should 11. Glassman AH, Bigger JT. Cardiovascular effects of therapeu- doses of tricyclic antidepressants. Arch Gen Psychiatry educate them on the medical risks and never inject 1981;38:815-9. local anesthetic with epinephrine or use epinephrine- 12. Cassem N. Cardiovascular effects of antidepressants. J Clin Psychiatry 1982;43:22-8. impregnated retraction cords unless they declare that 13. Glassman AL, Pardell R, Woodring S. Cardiovascular effects they have not used the drug within the past 24 hours. of the standard tricyclic antidepressants. Clin Chem 1988;34: As a minimal precaution, when a is suspicious 856-8. 14. Moir DC, Cornwell WB, Dingwall-Fordyce I, et al. Cardiotox- about a patient’s statement, dental treatments should icity of . Lancet 1972;2:561-4. be postponed to a later day. 15. Fowler NO, Chou TC, Holmes JC, Hanenson IB. Electrocar- diographic changes and cardiac arrythmias in patients receiv- CONCLUSION ing psychotropic drugs. Am J Cardiol 1976;37:223-30. 16. Giles TD, Modlin RK. Death associated with ventricular ar- During the past few decades the advance of med- rythmia and thioridazine hydrochloride. JAMA 1968;205:108- icine has contributed significantly to increase life ex- 10. 17. Hollister LE, Kosek JC. Sudden death during treatment with pectancy. More people with chronic diseasesare vis- phenothiazine derivates. JAMA 1965;192:1035-8. iting their dentists. Although we have always been 18. Garfield Kelly H, Fay JE, Laverty SG. Thioridazine hydro- concernedwith medically compromisedpatients, more chloride (Mellaril): its effect on the electrocardiogram and a attention is given to certain diseasestates, especially report of two fatalities with electrocardiographic abnormali- ties. Can Med Assoc J 1963;89:546-54. when local anesthetic with vasoconstrictor is being 19. Kevorkian G. Adverse sequelae with combined use of beta- used. Most of the published guidelines and recom- blockers and epinephrine. 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