CLINICAL                                                                                                        PHARMACOLO...
CLINICAL PHARMACOLOGY                                                                                                inhib...
CLINICAL PHARMACOLOGYbeats in the fourth.                    TABLE 1   The potentiation of epineph-rine by imipramine and ...
CLINICAL PHARMACOLOGYpreciated only in the 1970s thatpropranolol qualitatively                                           M...
CLINICAL PHARMACOLOGY10-minute period. Subsequent                a patient who has received gen-             may additiona...
CLINICAL PHARMACOLOGYANTIPSYCHOTIC AGENTS                  α-adrenergic blocking activity,             the pharmacokinetic...
CLINICAL PHARMACOLOGYinteraction of minor severity.              Even so, a subset of patients               acting, exoge...
CLINICAL PHARMACOLOGY  The drugs listed by brand name in this arti-     concentrations and effects of noradrenaline       ...
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Adverse drug rxs vasoconstrictors jada 1999


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Adverse drug rxs vasoconstrictors jada 1999

  1. 1. CLINICAL PHARMACOLOGYADVERSE DRUG INTERACTIONS IN DENTAL PRACTICE: INTERACTIONSASSOCIATED WITH VASOCONSTRICTORSPART V OF A SERIESJOHN A. YAGIELA, D.D.S., PH.D. A B S T R A C T Background. Adrenergic vasoconstrictors tions involving adrenergic neuronal blocking drugs, are commonly used by dentists to enhance the pain- drugs with α-adrenergic blocking activity, local anes- relieving action of local anesthetics and to control thetics and thyroid hormones is much less com- local bleeding. Although normally considered safe for pelling, suggesting for the most part that clinically these applications, vasoconstrictors can participate in significant reactions may occur only when both the drug interactions that potentially are harmful to vasoconstrictor and the interacting drug are used in patients. excessive doses. In the case of monoamine oxidase in- Methods. The faculty of a March 1998 sympo- hibitors, there is no credible evidence of a significant sium entitled “Adverse Drug Interactions in interaction with epinephrine or levonordefrin. Dentistry: Separating the Myths From the Facts” ex- Conclusions. Potentially serious adverse tensively reviewed the literature on drug interac- drug interactions involving adrenergic vasoconstric- tions. They then established a significance rating of tors can occur in dental practice. In most circum- alleged adverse drug interactions pertaining to den- stances, careful administration of small doses of vaso- tistry, based on the quality of documentation and constrictors and avoidance of gingival retraction cord severity of effect. The author of this article focused on containing epinephrine, coupled with monitoring of the adrenergic vasoconstrictors epinephrine and vital signs, will permit these drugs to be used with no levonordefrin. risk or only minimally increased risk. Only in the Results. Vasoconstrictor drug interactions in- case of cocaine intoxication must adrenergic vasocon- volving tricyclic antidepressants, nonselective β- strictors be avoided completely. adrenergic blocking drugs, certain general anesthet- Clinical Implications. For optimal pa- ics and cocaine are well-documented in both humans tient safety, dentists must recognize potential drug and animals as having the potential for causing seri- interactions involving adrenergic vasoconstrictors ous morbidity or death. Evidence for adverse interac- and modify their use of these agents accordingly.Adrenergic vasoconstrictors are among the The ability of vasoconstrictors to retard the sys-most commonly administered therapeutic agents temic absorption of injected local anesthetic agentsin dentistry. They also participate in more drug such as lidocaine (Xylocaine, Astra) is the basis forinteractions than do any other dental drugs. their widespread use.1,2 This beneficial drug inter-Epinephrine (Adrenalin, Parke-Davis) and related action frequently increases the duration of localsympathomimetic amines are routinely injected anesthesia and even the incidence of successfulin combination with local anesthetics for pain re- nerve blockade.3,4 It also may result in lower plas-lief and, less frequently, are used alone in gingi- ma concentrations of the local anesthetic.5val retraction cord and in topical or injectable so- Although adrenergic vasoconstrictors normallylutions for hemorrhage control. cause no untoward effects when used for dental JADA, Vol. 130, May 1999 701 Copyright ©1998-2001 American Dental Association. All rights reserved.
  2. 2. CLINICAL PHARMACOLOGY inhibitors fluoxetine (Prozac, 200 Dista) and paroxetine (Paxil, Before IT After IT SmithKline Beecham), tricyclics w q q are still used in patients intoler- 180 HR ant of or unresponsive to the w w Systolic BP newer drugs. They are also pre- v v Diastolic BP scribed for the treatment of se- 160 w vere anxiety disorders, neuro- RECORDING pathic pain, nocturnal enuresis 140 w and attention deficit hyperactiv- ity disorder. w w The tricyclic antidepressants 120w block the active reuptake of bio- w w w w genic amine neurotransmitters w w by nerve terminals from which 100 they were released. The net q q effect is a potentiation of the ac- q q q v tion of the affected neurotrans- q 80v q q q q v v q q mitters. Adrenergic vasocon- v v v strictors are subject to the same v v v v uptake process—and, therefore, 60 0 2 4 8 16 32 to the same potentiation by tri- cyclics—once they reach adren- EPINEPHRINE INFUSION (µg/min) ergic receptors in close associa- tion with sympathetic neurons.Figure 1. Cardiovascular response to epinephrine infusion in a healthy Tricyclic antidepressants alsoman before and after five days of imipramine therapy, or IT (25 mil-ligrams three times per day). Based on data from Boakes and col- block muscarinic and α1-adren-leagues.7 HR: Heart rate (in beats per minute); BP: blood pressure (in ergic receptors and directly de-millimeters of mercury); µg: micrograms; min: minute. press the myocardium. Theseprocedures, they have the po- cific drug interactions. actions can additionally modifytential to do so. Local reactions This article reviews drug in- cardiovascular responses to themay include tissue ischemia teractions known or suspected vasoconstrictors.and necrosis. Systemically, to involve adrenergic vasocon- Various experimental studiesepinephrinelike drugs can strictors used in dentistry. in humans and animals have con-cause a number of cardiovascu- Knowledge of these interac- sistently revealed a significant in-lar disturbances, from changes tions, and of any medications teraction between tricyclic antide-in arterial blood pressure to the patient may be taking, is es- pressants and adrenergiccardiac palpitation and dys- sential for the delivery of opti- vasoconstrictors.6-9 For example,rhythmias. While most sys- mal patient care. Figure 1 illustrates the potentia-temic reactions are short-lived, tion of the effects of epinephrine TRICYCLIC ANTIDEPRES-because of the rapid inactiva- SANTS infused intravenously in one oftion of the vasoconstrictor once four healthy volunteers studiedit is absorbed into the circula- Tricyclic antidepressants, such by Boakes and colleagues7 beforetion, permanent injury or even as imipramine (Tofranil, Geigy), and after the administration ofdeath may follow drug-induced amitriptyline (Elavil, Zeneca) imipramine. The most obviousventricular fibrillation, myocar- and doxepin (Sinequan, Roerig), change was the dramatic increasedial infarction or cerebrovascu- were the first drugs (in the in systolic blood pressure at thelar accidents. Factors that in- early 1960s) to gain widespread higher infusion rates. However,crease the likelihood of such use for the treatment of depres- the researchers also noted thatadverse events include patient sion. Although they have been each subject they studied experi-intolerance, acute overdosage, largely replaced in recent years enced an interaction-induced dys-rapid entry of vasoconstrictor by safer alternatives, such as rhythmia: sinus dysrhythmia ininto the bloodstream and spe- the serotonin-selective reuptake three subjects, multiple ectopic702 JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
  3. 3. CLINICAL PHARMACOLOGYbeats in the fourth. TABLE 1 The potentiation of epineph-rine by imipramine and related THE DRUG INTERACTION SIGNIFICANCE RATING SCALE.*tricyclic antidepressants admin-istered acutely is about three- SIGNIFICANCE SEVERITY RATING DOCUMENTATION RATING RATINGfold. Greater potentiations, six-to eightfold, occur with nor- 1 Major Established, proba- ble or suspectedepinephrine (Levophed, SanofiWinthrop), which is no longer 2 Moderate Established, proba- ble or suspectedused in the United States as avasoconstrictor in local anesthet- 3 Minor Established, proba- ble or suspectedics, and levonordefrin, which isthe vasoconstrictor in local anes- 4 Major or moderate Possiblethetic solutions that contain 5 Minor Possiblemepivacaine (such as Polocaine All Unlikelywith levonordefrin, Astra). * This rating scale was described in depth in the first article in this series.16 How often, or even if, this po-tentiation results in clinically tween the clear experimental administration of tricyclicsignificant adverse events is sub- proof of a tricyclic-epinephrine agents. As argued by Brown andject to debate. Boakes and col- interaction and the paucity of Lewis13 and supported by labora-leagues10 reviewed 15 reports of clinical reports verifying it in tory studies,14,15 long-term ad-adverse reactions to local anes- dentistry. ministration of these agentsthetics with norepinephrine as dFirst, epinephrine produces may result in desensitization tothe vasoconstrictor. Five of these both vasoconstrictive effects, adrenergic vasoconstrictors andcases involved patients taking mediated by α-adrenergic re- a diminution of the drugtricyclic antidepressants. ceptors, and vasodilative ef- interaction.Persson and Siwers11 prospec- fects, mediated by β2-adrener- A cautious but prudent ap-tively studied the effects of one to gic receptors. For dosages proach to the patient taking athree cartridges of 2 percent lido- normally used in dental prac- tricyclic antidepressant is to as-caine with 1:80,000 epinephrine tice, even a threefold potentia- sume the existence of a fully ac-in 21 patients taking tricyclic an- tion will result in modest tive drug interaction. Given thattidepressants. One patient re- changes in blood pressure, be- assumption, levonordefrinceiving a total of 45 micrograms cause these opposing receptor should not be used, because anof epinephrine (the amount of influences tend to counterbal- accidental intravascular injec-epinephrine in 2.5 cartridges of a ance each other. tion of a single cartridge of 2 per-1:100,000 solution) experienced a dSecond, the cardiovascular cent mepivacaine with 1:20,000headache and a concomitant in- status of dental patients is levonordefrin conceivably couldcrease in systolic blood pressure rarely monitored. Thus, result in acute hypertension andthat peaked at 45 millimeters of changes in heart rate or cardiac dysrhythmias.8mercury over baseline four min- rhythm may go unnoticed or, if Similarly, certain brands of gin-utes after injection. It should be obvious to the patient, be mis- gival retraction cord containnoted that this patient was also diagnosed as anxiety responses large amounts of epinephrine,taking a low dosage of propra- or hypersensitivity reactions. and the possibility of rapid drugnolol (discussed below). Cawson dThird, several interactions absorption by abraded crevicularand colleagues12 reviewed avail- have been identified but not tissue proscribes their use. Inable evidence in 1983 and con- published on the assumption the case of epinephrine in localcluded that there was “no clinical that the interaction was firmly anesthetic solutions, injecting noevidence of significant inter- established (J. Yagiela, D.D.S., more than a 1:100,000 concen-actions between tricyclic antide- Ph.D., unpublished data, 1980; tration in a dosage no more thanpressants and dental local anaes- J. Giovannitti, D.D.S., written one-third the normal maximumthetics containing adrenaline.” communication, 1990). for a given patient should pre- Several factors probably con- dFourth, experimental studies clude any problem that couldtribute to the discrepancy be- have relied on the short-term arise from a tricyclic drug inter- JADA, Vol. 130, May 1999 703 Copyright ©1998-2001 American Dental Association. All rights reserved.
  4. 4. CLINICAL PHARMACOLOGYTABLE 2 ADVERSE DRUG INTERACTIONS IN DENTISTRY: VASOCONSTRICTORS. POSSIBLE DRUG INTERACTION CUMULATIVE MECHANISM AND CLINICAL RATING* PRESENTATION Vasoconstrictor with tricyclic antidepres- 1 Sympathomimetic effects may be sant (levonordefrin with imipramine) enhanced. Epinephrine should be used cautiously; use of levonorde- frin should be avoided. Vasoconstrictor with nonselective 1 Hypertensive and/or cardiac reac- β-adrenoceptor antagonist (epinephrine tions are possible. Vasoconstrictor with propranolol) should be used cautiously; blood pressure and heart rate should be monitored. Vasoconstrictor with general anesthetic 1 Increased possibility of cardiac ar- (epinephrine with halothane) rhythmias exists with some gener- al anesthetics. Consultation with anesthesiologist is recommended. Vasoconstrictor with cocaine 1 Arrhythmias and hypertensive (epinephrine with cocaine) responses possible. Concurrent use should be avoided. Vasoconstrictor with antipsychotic or 4 Hypotension resulting from over- other α-adrenoceptor blocker dose of antipsychotic agent may (epinephrine with chlorpromazine) be worsened. Vasoconstrictor should be used cautiously. Vasoconstrictor with adrenergic neu- 4 Sympathomimetic effects may be ronal blocker (levonordefrin with guan- enhanced. Vasoconstrictor should adrel) be used cautiously. Vasoconstrictor with local anesthetic 4 Multiple effects on systemic toxici- (lidocaine with epinephrine) ty, which may be self-limiting. Vasoconstrictor with thyroid hormone 4 Summation of effects possible (epinephrine with thyroxine) when thyroid hormones are used in excess. Vasoconstrictor should be used cautiously if signs of hyperthyroidism are present. Vasoconstrictor with monoamine oxidase 5 No substantial evidence of an inhibitor (epinephrine with phenelzine) interaction. * This rating system was described previously.16 See Table 1.action. Additional injections β-adrenoceptor blockers or, more tered adrenergic drugs. β-block-then may be safely given 30 simply, β-blockers) are pre- ers can be categorized by theirminutes later. scribed for a variety of condi- specificity of action: propranolol According to the rating scale tions: acute panic symptoms, (Inderal, Wyeth-Ayerst) andadopted by Moore and col- angina pectoris, cardiac dys- nadolol (Corgard, Bristol-Myers)leagues16 for this series of arti- rhythmias, essential tremors, are examples of nonselective β-cles (Table 1), the tricyclic-vaso- glaucoma, hypertension, hyper- blockers, which block both β1constrictor interaction rates a 1 thyroidism, hypertrophic subaor- and β2 receptors; atenolol(Table 2) because it is “estab- tic stenosis, migraine headache, (Tenormin, ICI Pharma) andlished” and is “potentially life- myocardial infarction and metoprolol (Lopressor, Geigy)threatening or capable of caus- pheochromocytoma. They act by represent drugs with β1-selectiveing permanent injury.” competitively blocking the stim- antagonistic effects. ulation of β receptors by endoge- Although the ability of β-β-ADRENERGICANTAGONISTS nous catecholamines such as blockers to counter the cardiac epinephrine and norepinephrine. effects of adrenergic drugs hasβ-adrenergic receptor antago- They also block β-receptor acti- been known for more than fournists (otherwise known as vation by exogenously adminis- decades, it became widely ap-704 JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
  5. 5. CLINICAL PHARMACOLOGYpreciated only in the 1970s thatpropranolol qualitatively MEAN BLOOD PRESSURE (% INCREASE)changes physiologic responses 25 25to epinephrine. By blocking va- ssodilating β2 receptors in the HEART RATE (% DECREASE)blood vessels of skeletal muscle 20 20and other tissues, propranolol BP qcauses epinephrine to act vascu-larly as a pure α-adrenergic 15 15stimulant.17-19 Peripheral resis- s HRtance, which normally falls 10 q 10after moderate doses of sepinephrine are administered,rises and thus induces a dose- q 5 q 5dependent increase in blood spressure and a reflex slowing ofthe heart (Figure 2).17 Selectiveβ1-blockers such as metoprolol 0 s q 0 0 1 2 3 4are incapable of creating this ef- EPINEPHRINE INFUSION (µg/min)fect.17-19 However, both types ofβ-blockers decrease clearance ofepinephrine and norepi- Figure 2. Mean changes in heart rate, or HR, in beats per minute, andnephrine from the blood- mean arterial blood pressure, or BP (in millimeters of mercury), during low-dose epinephrine infusion in hypertensive patients (n = 5) taking anstream.18 This effect may par- average daily dose of 208 milligrams of propranolol. Based on data fromtially explain the modestly Houben and colleagues.17 µg: micrograms; min: minute.increased pressor responsive-ness to norepinephrine caused blockers and epinephrine.24,25 monitoring. As with the tricyclicby these agents.20 Finally, one case report links antidepressants, neither the Interactions between nonse- levonordefrin with hypertension 1:50,000 epinephrine formula-lective β-blockers and caused by a propranolol interac- tion nor epinephrine-containingepinephrine, as used in local tion.26 retraction cord should be usedanesthetic solutions, have been Given the potential danger of in a patient who is taking a non-shown to occur regularly in this interaction and the strong selective β-antagonist.medicine and dentistry.21-23 documentation of its existence, GENERAL ANESTHETICSAlthough local anesthetics with it richly deserves a “1” ratingepinephrine injected into skin (Table 2). Epinephrine or lev- Certain general anesthetics aregenerally produce mild interac- onordefrin may be used in pa- known to potentiate the dys-tions,21 intravenous infusion of tients taking nonselective β- rhythmogenic effect ofas little as 15 µg epinephrine adrenergic antagonists; epinephrine and, presumably,(equivalent to 5⁄6 of a cartridge however, the initial dose should of levonordefrin and othercontaining 1:100,000 be kept to a minimum, such as adrenergic agents. Of the in-epinephrine) results in pro- one-half of a dental cartridge halation anesthetics currentlynounced, if transient, bradycar- with 1:100,000 epinephrine, and in use, halothane (Fluothane,dia (mean heart rate ± standard injected carefully to avoid in- Wyeth-Ayerst) is the most prob-deviation: 38 ± 8 beats per travascular administration. lematic in this regard. In 1962,minute).23 Adverse responses, Monitoring the patient’s vital Katz and colleagues27 arguedincluding cardiac arrest occur- signs before injection and five that epinephrine could be in-ring after facial injection of the minutes afterward will dictate jected safely for hemostasis inequivalent of two cartridges of 2 further administration. If there patients anesthetized withpercent lidocaine with 1:50,000 is no change in cardiovascular halothane so long as the dose inepinephrine, also document the status, additional cartridges can adults did not exceed 10clinical relevance of the interac- be injected individually at five- milliliters of a 1:100,000 solu-tion between nonselective β- minute intervals with continual tion (or 1 µg/kilogram) over a JADA, Vol. 130, May 1999 705 Copyright ©1998-2001 American Dental Association. All rights reserved.
  6. 6. CLINICAL PHARMACOLOGY10-minute period. Subsequent a patient who has received gen- may additionally contribute towork by Johnston and col- eral anesthesia should inform exaggerated responses to inject-leagues28 demonstrated that the the anesthesiologist of the need ed vasoconstrictors.minimum dysrhythmic dose of to administer a vasoconstrictor Animal experiments andepinephrine injected into the and then follow the dosage lim- human reports have clearlysubmucosa of the mouth and/or its that are recommended. A re- demonstrated the potential fornose was about 2 µg/kg for ported death under halothane adverse drug interactions be-halothane, 3.5 µg/kg for enflu- anesthesia caused by tween adrenergic vasoconstric-rane (Ethrane, Anaquest) and epinephrine in gingival retrac- tors and cocaine.34 In one well-5.5 µg/kg for isoflurane (Forane, tion cord32 reinforces the general documented case, a healthyAnaquest). When 0.5 percent li- prohibition against using con- young man given topical cocainedocaine was injected with centrated forms of epinephrine for nasal surgery developed1:200,000 epinephrine, the min- when there is a significant po- angina and suffered a heart at-imum dysrhythmic dose during tential for drug interactions. tack after injection of lidocainehalothane anesthesia increased with epinephrine.35 Deaths into 3 µg/kg because of the lido- COCAINE dentistry and medicine also arecaine’s cardioprotective effect. Introduced into Western alleged to have been caused by Thiopental (Pentothal, medicine in 1884 as the first this drug combination.36 AnimalAbbott Laboratories), an ultra- local anesthetic, cocaine was studies indicate that normal re-short-acting barbiturate, also is mixed with epinephrine in 1903 sponsiveness to vasoconstric-capable of enhancing the dys- to improve its clinical efficacy. tors, as with tricyclic antide-rhythmogenic potential of By 1924, several dozen deaths pressants, may return duringadrenergic drugs. This fact was led to the abandonment of co- continuous exposure to co-not appreciated in previous caine with epinephrine as an in- caine.37 Even so, a 1 rating forstudies involving halothane,27,28 jectable anesthetic.33 Cocaine re- this interaction (Table 2) is jus-as thiopental often was used for mains a useful drug for topical tified because of its potentialinduction of anesthesia, and has anesthesia of mucous mem- lethality and the fact that mostled to the revised dosage guide- branes and still is commonly cocaine abusers take the drugline of 1 µg/kg epinephrine if mixed with epinephrine for ap- on an intermittent basis.halothane is used with thiopen- plication in nasal surgery. Of A unique problem regardingtal and 2 µg/kg epinephrine if it course, illicit consumption con- cocaine is that the patient mayis used alone.29 stitutes by far the greatest use not report its use. Therefore, the Although the mechanism by of cocaine. dentist must be suspicious whenwhich general anesthetics aug- Cocaine possesses a complex confronted with a patient show-ment the dysrhythmic actions of pharmacology. As a local anes- ing signs of potential cocaineadrenergic agents is unknown, thetic, it blocks nerve conduc- abuse, such as agitation, tremor,it appears to involve the simul- tion similarly to lidocaine. As a sympathetic arousal and dys-taneous stimulation of both α1 stimulant, it prevents the active rhythmias. Damage to the nasaland β receptors.30,31 Epinephrine reuptake of norepinephrine, septum or skin lesions on theand levonordefrin each are ca- dopamine and 5-hydroxy- forearms may indicate, respec-pable of activating both receptor tryptamine by presynaptic tively, the “snorting” or injectiontypes and eliciting dysrhyth- nerve terminals. This tricyclic of cocaine. Because cocaine itselfmias during general anesthesia. antidepressantlike action poten- may cause sudden death as a re-However, phenylephrine (Neo- tiates the effects of adrenergic sult of cardiac arrest, myocar-Synephrine, Sanofi-Winthrop), vasoconstrictors. There also is dial infarction or stroke, no elec-a selective α1 agonist, and iso- evidence that cocaine may en- tive dental treatment isproterenol (Isuprel, Sanofi- hance adrenergic neurotrans- advisable while the patient isWinthrop), a β agonist, similar- mitter release and intensify under its influence. In all cases,ly disrupt the cardiac rhythm postsynaptic responses to vasoconstrictors should be with-only if given together. epinephrinelike drugs. Blockade held for at least 24 hours after As shown in Table 2, this “es- of cardiac muscarinic receptors cocaine exposure to allow fortablished” interaction warrants and central alteration of auto- elimination of the drug and itsa 1 rating. The dentist treating nomic nervous system activity active metabolites.38706 JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
  7. 7. CLINICAL PHARMACOLOGYANTIPSYCHOTIC AGENTS α-adrenergic blocking activity, the pharmacokinetics of localAND OTHER α-ADRENER-GIC BLOCKERS so long as the patient has not anesthetics.41-43 In addition to been rendered acutely hypoten- the previously mentioned reduc-Antipsychotic drugs, such as sive by the medication. tion in the rate of systemic ab-chlorpromazine (Thorazine, sorption, epinephrinelike drugs ADRENERGIC NEURONALSmithKline Beecham), thiori- BLOCKERS may increase the entry of localdazine (Mellaril, Novartis) and anesthetics into the brain.41risperidone (Risperdal, Janssen), Guanethidine (Ismelin, Geigy) When the anesthetic solution ishave as a side effect the ability and guanadrel (Hylorel, Fisons) injected into tissues, the oppos-to block α-adrenergic receptors are examples of drugs that in- ing effects of epinephrine tendand cause orthostatic hypoten- hibit the release of norepi- to counteract each other.sion. Drugs specifically devel- nephrine from sympathetic However, with intravascular in-oped for their α-adrenergic nerve terminals. When used jection, only the detrimental ef-blocking activity, such as pra- long-term in the management of fect can occur, resulting in in-zosin (Minipress, Pfizer) and essential hypertension, postsy- creased local anestheticphenoxybenzamine naptic adrenergic receptors may toxicity.42,43 No corroborating(Dibenzyline, SmithKline be up-regulated by the body in data from studies in larger ani-Beecham), of course share this an attempt to restore normal mals or humans have been re-hypotensive property. When neurotransmission.40 An in- ported.chlorpromazine is given in over- crease in receptor number Lidocaine similarly exertsdose sufficient to produce frank and/or sensitivity should result two effects on epinephrine toxic-hypotension, a resuscitative dose in greater responsiveness to ity. The vasodilatory effect of li-of epinephrine will reduce the adrenergic vasoconstrictors. The docaine significantly increasesblood pressure further because neuronal blockers also may aug- the vasoconstrictor’s rate of ab-only the vasodilative (β2-adren- ment the effect of epinephrine- sorption. Dose-dependent ad-ergic) action of epinephrine can like drugs by a competitive inhi- verse systemic effects ofoccur.8 However, no interaction bition of the neuronal reuptake epinephrine, therefore, shouldhas been demonstrated with lev- transport system. be potentiated. However, lido-onordefrin or doses of epineph- Perhaps because of their in- caine also protects the heartrine normally injected in den- frequent use, adrenergic neu- against epinephrine-inducedtistry, and there are no clinical ronal blocking drugs have never rhythm disturbances.28case reports of significant ad- been reported to be associated The essential lack of humanverse interactions between vaso- with clinically evident drug in- data regarding these interac-constrictors used in local anes- teractions involving adrenergic tions dictates a 4 rating forthetics and these drugs. vasoconstrictors. A 4 rating is these possible moderate reac- Thioridazine and several other assigned to reflect the “possible” tions (Table 2).antipsychotics also may impair nature of the reaction, but clini- Lastly, local anesthetics in-cardiac conduction and promote cians are advised to follow the jected into peripheral tissuestachydysrhythmias.39 It has been same recommendations de- are selectively toxic to skeletalconjectured that the added car- scribed previously for the tri- muscle. The damage is greatlydiac effects of a vasoconstrictor cyclic antidepressants. increased when the local anes-might precipitate an adverse thetic is administered with a LOCAL ANESTHETICSevent.38 Once again, there are no vasoconstrictor, and multiplesuch instances on record that Adverse interactions between injections of the combination inpertain to the dental setting. adrenergic vasoconstrictors and rats can result in permanent A rating of 4 reflects the lim- local anesthetics are rarely con- scarring.44 Humans appear to beited evidence of this drug inter- sidered. Nevertheless, animal similarly susceptible to theaction. With proper care to experiments and limited human myotoxic effect of local anes-avoid intravascular injection, data suggest that they may thetics.45 Were this interactionvasoconstrictors may be used occur. included in Table 2 (it was ex-without special reservation in Studies in rodents document cluded because of its localizedpatients who are taking anti- that adrenergic vasoconstrictors effect), it would have been as-psychotic or other drugs with can exert two opposite effects on signed a 3 rating as a probable JADA, Vol. 130, May 1999 707 Copyright ©1998-2001 American Dental Association. All rights reserved.
  8. 8. CLINICAL PHARMACOLOGYinteraction of minor severity. Even so, a subset of patients acting, exogenously adminis- with excessive amounts of thy- tered vasoconstrictors are pref-THYROID HORMONES roid hormone in the circulation erentially inactivated by the en-Hyperthyroidism, whether the will have developed cardiac ab- zyme catechol O-methyltrans-result of disease or of the inap- normalities as a result of the ferase. Repeated studies withpropriate use of thyroxine chronic overstimulation of myo- these drugs in humans7,52 and(Synthroid, Boots) or another cardial metabolism.51 Thus, it is animals8,9,53 consistently havethyroid hormone preparation, appropriate to use adrenergic shown no significant interactioncan cause a number of cardio- vasoconstrictors cautiously in attributable to inhibition ofvascular changes reminiscent of patients with evidence of exces- MAO. The continued listing ofepinephrine overdosage: tachy- sive thyroid stimulation. this interaction in the packagecardia and other dysrhythmias, insert for local anesthetics with MONOAMINE OXIDASEa widening of the pulse width, INHIBITORS vasoconstrictors is simply a tes-increased cardiac output and tament to the bureaucracy ofmyocardial ischemia. For many The monoamine oxidase, or the U.S. Food and Drugyears, it was believed that thy- MAO, inhibitors comprise the Administration.roid hormone and epinephrine antidepressants isocarboxazid CONCLUSIONinteracted synergistically to cre- (Marplan, Hoffman-LaRoche),ate these effects.46 Nevertheless, phenelzine (Nardil, Parke- The adrenergic vasoconstrictorsevidence has accumulated over Davis) and tranylcypromine epinephrine and levonordefrinthe last three decades to show (Parnate, SmithKline may participate in a variety ofthat hemodynamic responses to Beecham), the antimicrobial adverse drug interactions, theepinephrine and norepi- agent furazolidone (Furoxone, most important of which in-nephrine are not significantly Norwich Eaton) and the an- volve tricyclic antidepressants,altered in the patient with hy- tiparkinson drug selegiline nonselective β-adrenergicperthyroidism. (Eldepryl, Somerset). As a blocking drugs, certain general Aoki and colleagues47 evalu- group, the MAO inhibitors have anesthetics and cocaine. Withated responses to intravenous been implicated in a number of few exceptions, the appropriateepinephrine and norepineph- potentially life-threatening in- selection of a vasoconstrictorrine in subjects before and after teractions with various adrener- and its dosage and avoidance ofthey became hyperthyroid as a gic amines. Two actions of the gingival retraction cord con-result of the administration of MAO inhibitors account for taining epinephrine, coupledliothyronine (Cytomel, these interactions: with careful drug administra-SmithKline Beecham) and in dthe inhibitors prevent the tion and patient monitoring,spontaneously hyperthyroid pa- metabolism of drugs normally will allow the clinician to pro-tients before and after they metabolized by MAO; vide necessary dental care withwere rendered euthyroid with dthe inhibitors block the intra- little or no increased risk of ad-radioactive iodine.48 No clinical- neuronal breakdown of norepi- verse outcome. sly significant changes in cardio- nephrine in sympathetic nerves Dr. Yagiela is a professor and chair of thevascular responsiveness to by MAO, increasing the pool of Division of Diagnostic and Surgical Sciences,adrenergic vasoconstrictors neurotransmitter capable of UCLA School of Dentistry, Center for the Health Sciences, 10833 Le Conte Ave., Loswere noted. Subsequent studies being released by indirect-act- Angeles, Calif. 90095. Address reprint re-have confirmed and extended ing adrenergic drugs such as quests to Dr. Yagiela.these findings by demonstrating amphetamine, pseudoephedrine This article is based on material presentedno altered responses to epi- (commonly found in nasal de- March 4, 1998, in a symposium entitled “Adverse Drug Interactions in Dentistry:nephrinelike drugs in patients congestants) and tyramine (an Separating the Myths From the Facts,” pre-with hypothyroidism.49,50 amino acid present in various sented at the 27th General Session of the American Association for Dental Research inAlthough a cardiovascular in- food products). Minneapolis. The symposium was jointlyteraction between epinephrine However, there is no credible sponsored by the International and American Associations for Dental Research, theand thyroxine would be poten- evidence of a clinically signifi- American Association of Dental Schools andtially serious, the lack of docu- cant interaction involving the American Dental Association and was supported in part by a grant from Warnermentation of its existence caus- epinephrine or levonordefrin as Lambert it to be assigned a rating of 4. used in dentistry. These direct-708 JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
  9. 9. CLINICAL PHARMACOLOGY The drugs listed by brand name in this arti- concentrations and effects of noradrenaline 37. Bernards CM, Cullen BF, Powers KM.cle are given as examples only. Their listing and adrenaline during i.v. infusion. Acta Effect of chronic cocaine exposure on thedoes not imply any endorsement. Physiol Scand Suppl 1983;515:45-53. hemodynamic response to vasopressors in 19. Rehling M, Svendsen TL, Maltbæk N, sheep. J Trauma 1997;43(4):680-6. 1. Jastak JT, Yagiela JA, Donaldson D. Tangø M, Trap-Jensen J. Haemodynamic ef- 38. Goulet J-P, Pérusse R, Turcotte J-Y.Local anesthesia of the oral cavity. fects of atenolol, pindolol and propranolol dur- Contraindications to vasoconstrictors in den-Philadelphia: Saunders; 1995:61-4. ing adrenaline infusion in man. Eur J Clin tistry: part III. Pharmacologic interactions. 2. Malamed SF. Handbook of local anesthe- Pharmacol 1986;30(6):659-63. Oral Surg Oral Med Oral Patholsia. 4th ed. St. Louis: Mosby–Year Book; 20. Reeves RA, Boer WH, DeLeve L, Leenen 1992;74(5):692-7.1997:37-8, 46. FHH. Nonselective beta-blockade enhances 39. Jastak JT, Yagiela JA. Vasoconstrictors 3. Keesling GR, Hinds EC. Optimal concen- pressor responsiveness to epinephrine, nor- and local anesthesia: a review and rationaletration of epinephrine in lidocaine solutions. epinephrine, and angiotensin II in normal for use. JADA 1983;107(4):623-30.JADA 1963;66(3):337-40. man. Clin Pharmacol Ther 1984;35(4):461-6. 40. Emmelin N, Engström J. 4. Brown G. The influence of adrenaline, no- 21. Dzubow LM. The interaction between Supersensitivity of salivary glands followingradrenaline vasoconstrictors on the efficiency propranolol and epinephrine as observed in treatment with bretylium or guanethidine. Brof lidocaine. J Oral Ther Pharmacol patients undergoing Mohs’ surgery. J Am J Pharmacol Chemother 1961;16(5):315-9.1968;4(5):398-405. Acad Dermatol 1986;15(1):71-5. 41. Yagiela JA. Vasoconstrictors: their role 5. Cannell H, Walters H, Beckett AH, 22. Sugimura M, Hirota Y, Shibutani T, et in local anesthetic toxicity. J Jpn Dent SocSaunders A. Circulating levels of lignocaine al. An echocardiographic study of interactions Anesthesiol 1993;21(2):261-78.after peri-oral injections. Br Dent J between pindolol and epinephrine contained 42. Åström A, Persson NH, Örtengren B.1975;138(3):87-93. in a local anesthetic solution. Anesth Prog The effect of adrenaline on the toxicities and 6. Svedmyr N. The influence of a tricyclic 1995;42(2):29-35. absorptions of L67 (Citanest) and some otherantidepressive agent (protriptyline) on some 23. Mackie K, Lam A. Epinephrine-contain- local anaesthetics studied in mice and rab-of the circulatory effects of noradrenaline and ing test dose during β-blockade. J Clin Monit bits. Acta Pharmacol Toxicol 1964;21(12):161-adrenaline in man. Life Sci 1968;7(1):77-84. 1991;7(3):213-6. 71. 7. Boakes AJ, Laurence DR, Teoh PC, Barar 24. Hansbrough JF, Near A. Propranolol- 43. Yagiela JA. Intravascular lidocaine toxi-FSK, Benedikter LT, Prichard BNC. epinephrine antagonism with hypertension city: influence of epinephrine and route of ad-Interactions between sympathomimetic and stroke. Ann Intern Med 1980;92(5):717. ministration. Anesth Prog 1985;32(2):57-61.amines and antidepressant agents in man. Br 25. Foster CA, Aston SJ. Propranolol- 44. Benoit PW. Microscarring in skeletal mus-Med J 1973;1(5849):311-5. epinephrine interaction: a potential disaster. cle after repeated exposures to lidocaine with 8. Yagiela JA, Duffin SR, Hunt LM. Drug Plast Reconstr Surg 1983;72(1):74-8. epinephrine. J Oral Surg 1978;36(7):530-3.interactions and vasoconstrictors used in local 26. Mito RS, Yagiela JA. Hypertensive re- 45. Yagiela JA, Benoit PW, Buoncristianianesthetic solutions. Oral Surg Oral Med sponse to levonordefrin in a patient receiving RD, Peters MP, Fort NF. Comparison of my-Oral Pathol 1985;59(6):565-71. propranolol: report of case. JADA otoxic effects of lidocaine with epinephrine in 9. Wong KC, Puerto AX, Puerto BA, 1988;116(1):55-7. rats and humans. Anesth Analg 1981:60(7):Blatnick RA. Influence of imipramine and 27. Katz RL, Matteo RS, Papper EM. The 471-80.pargyline on the arrhythmogenicity of injection of epinephrine during general anes- 46. Pérusse R, Goulet J-P, Turcotte J-Y.epinephrine during halothane, enflurane or thesia with halogenated hydrocarbons and cy- Contraindications to vasoconstrictors in den-methoxyflurane anesthesia in dogs. Life Sci clopropane in man. 2. Halothane. tistry: part II. Hyperthyroidism, diabetes, sul-1980;27(25-6):2675-8. Anesthesiology 1962;23(5):597-600. fite sensitivity, cortico-dependent asthma, 10. Boakes AJ, Laurence DR, Lovel KW, 28. Johnston RR, Eger EI II, Wilson C. A and pheochromocytoma. Oral Surg Oral MedO’Neil R, Verrill PJ. 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Br K, Yamatodani A, Kuro M, Yoshiya I. cardiovascular effects of catecholamines inDent J 1983;154(8):253-8. Adrenoceptor mechanism involved in thiopen- patients with spontaneous hyperthyroidism. J 13. Brown RS, Lewis VH. More on the con- tal-epinephrine-induced arrhythmias in dogs. Pharmacol Exp Ther 1972;181(2):362-8.traindications to vasoconstrictors in den- Am J Physiol 1993;265(4):H1380-5. 49. McDevitt DG, Riddel JG, Hadden DR,tistry. Oral Surg Oral Med Oral Pathol Oral 31. Kamibayashi T, Hayashi Y, Takada K, Montgomery DA. Catecholamine sensitivityRadiol Endod 1993;76(1):2-3. Yamatodani A, Sumikawa K, Yoshiya I. in hyperthyroidism and hypothyroidism. Br J 14. Moyer JA, Greenberg LH, Frazer A, Adrenoceptor mechanism involved in thiopen- Clin Pharmacol 1978;6(4):297-301.Brunswick DJ, Mendels J, Weiss B. Opposite tal-induced potentiation of halothane- 50. Johnson AB, Webber J, Mansell P,effects of acute and repeated administration epinephrine arrhythmias in dogs. 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Anesthesiology 1990;73(3):518-31. BNC. Modification by monoamine oxidase in-dental practice: professional and educational 34. Lathers CM, Tyau LS, Spino MM, hibitors of the effect of some sympathomimet-limitations. JADA 1999;130(1):47-54. Agarwal I. Cocaine-induced seizures, arrhyth- ics on blood pressure. Br Med J 17. Houben H, Thien T, Laar AV. Effect of mias and sudden death. J Clin Pharmacol 1967;2(5544):75-8.low-dose epinephrine infusion on hemody- 1988;28(7):584-93. 53. Goldberg LI, Sjoerdsma A. Effects ofnamics after selective and nonselective β- 35. Chiu YC, Brecht K, DasGupta DS, Mhoon several monoamine oxidase inhibitors on theblockade in hypertension. Clin Pharmacol E. Myocardial infarction with topical cocaine cardiovascular actions of naturally occurringTher 1982;31(6):685-90. anesthesia for nasal surgery. Arch Otolaryngol amines in the dog. J Pharmacol Exp Ther 18. Hjemdahl P, Åkerstedt T, Pollare T, Head Neck Surg 1986;112(9):988-90. 1959;127(3):212-8.Gillberg M. Influence of β-adrenoceptor block- 36. Cohen N. Deadly dentistry. Medade by metoprolol and propranolol on plasma Malpractice Law Strategy 1991; 8(12):2. JADA, Vol. 130, May 1999 709 Copyright ©1998-2001 American Dental Association. All rights reserved.