ontraindicat to vasoconstrictor

entistry:
Pharmacologic interactions

Jean-Paul Goulet, DDS, MD,’ Rbnald Phusse, DMD, MD,’ and

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.‘72 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

i OO
0°0 o”o 5
1 o"o

2-o 0 0
d"

T;r

Fig. 1. Action of TCAs and MAOIs. 1, Presynapticneuron;2, synaptic cleft; 3, postsynapticneuron;4,

apsehave led to seriousmedical 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 seemsreasonable 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 asthe plasma concen-
tration of TCAs increasesor 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 anxiety states and obsessive-compulsivedisorders.
arrhythmias 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 cardiotoxicity of TCAs is genie amines in the central nervous system 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 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 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 chancesof a worsening of the conduction
phrine, which is metabolized by monoamine oxidase, anomaliesafter 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 useof vasoconstrictors in patients treated
sympathomimetic amines can be enhanced by with phenothiazine drugs, dentists should be prudent
MAOIs; however, these drugs are much lesseffective 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 antianginal 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 tremors. 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 propranolol (Inderal).
ability to potentiate sedatives and analgesics.Ortho- Epinephrine is known to have at least two distinct
static hypotension 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 tachycardia. The concurrent administration of
stricting effect of epinephrine and unmasksits usually vasoconstrictor in patients treated with nonselective
weak vasodilatory effect. Although the epinephrine P-blockers raisesthe 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 causedby the blockade of /32
tentially worsen the hypotension frequently associ- peripheral receptors. I932oWhen 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 anesthesia, several
ture. On the other hand, certain hypotensive episodes casereports 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
Propranolol (Inderal) Metoprolol (Lopressor)
physiologic activity of exogenously administered epi-
Nadolol (Corgard) Atenolol (Tenormin)
nephrine. Studies have revealed that P-adrenergic Timolol (Blockadren, Acebutolol (Sectral)
blockade reduces the clearance of intravenously in- Timolate, Timoptic, Betaxolol (Kerlone)
fused epinephrine,24> 25 raising the possibility that the Timoptol)
clearance of endogenous epinephrine might also be Pindolol (Visken)
Alprenolol (Aptine)
affected. It has also been reported that the kinetics of
Labetalol (Trandate,
epinephrine varies according to the type of P-blocker Normodyne)
administered. Hjemdahl et a1.25 observed no differ- Oxprenolol (Trasicor)
ential effect on the clearance of epinephrine and Sotalol (Sotacort)
norepinephrine by the cardioselective P-blocker me- Carte0101 (Cartrol)
Penbutolol (Levatol)
toprolol. However, ilmpairment of epinephrine kinet-
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- alkaloid 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 ophthalmology,
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 arrhythmia, angina,
before using local anesthetic with vasoconstrictor. and myocardial infarction. 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 adulterants 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
ORALMED ORAL PATHOL 1985;59:565-71.
disappear after 2 hours. 51 However, when the intra- 7. Jastak JT, Yagiela JA. Vasoconstrictors and local anesthesia:
nasal route of administration 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.
Adverse reactions to local anesthetic vasoconstrictor prepara-
prolonged for as long as 4 to 6 hours.32$ 51 Because of 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 antidepressant
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.
11. Glassman AH, Bigger JT. Cardiovascular effects of therapeu-
they have their dental appointment. Dentists should tic 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 dentist 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 amitriptyline. 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
report of two fatalities with electrocardiographic abnormali-
attention is given to certain diseasestates, especially 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. Gen Dent 1987;35:298-300.
20. Frishman WH. P-Adrenergic receptor blockers: adverse ef-
mendations are directed to patients with cardiovas- fects and drug interactions. Hypertension 1988;11:21-9.
cular diseases.Dentists should know about both the 21. Hansbrough JF, Near A. Propanolol-epinephrine antagonism
noncardiac conditions where the use of vasoconstric- with hypertension and stroke (Letter). Ann Intern Med
1980;92:717.
tors is contraindicated and the different drugs that 22. Kram J, Bourne HR, Melmon KL, Maibach H. Propanolol
could interact with these substances.A thorough un- (Letter). Ann Intern Med 1974;80:282.
derstanding of the pharmacologic interactions be- 23. Foster CA, Aston SJ. Propanolol-epinephrine interaction: a
potential disaster. Reconstr Surg 1983;72:74-8.
tween exogenously administered adrenergic drugs 24. Crver PE. Rizza RA. Havmond MW. Gerich JE. Eoinenhrine
and vasoconstrictors usedin dentistry is a prerequisite and norepinephrine are cleared through beta-adrenergic, but
to prevent untoward reactions in patients taking psy- not alpha-adrenergicmechanism in man. Metabolism 1980;29:
1114-8.
chotropic drugs or nonselective beta blockers, or in 25. Hjemdahl P, Akerstedt T, Pollare T, Gillberg M. Influence of
usersof illicit drugs such as cocaine. @-adrenoceptor blockade by metoprolol and propanolol on
plasma concentrations and effects of noradrenaline and adren-
aline during IV infusion. Acta Physiol Stand 1983;Suppl
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