TOXICOLOGY/CASE REPORT

Acute Myocardial Infarction After Over-the-CounterUse of Pseudoephedrine

Alex F. Manini, MD

Christopher Kabrhel, MD

Todd W. Thomsen, MD

From the Harvard Affiliated Emergency Medicine Residency, Harvard Medical School,Boston, MA (Manini); the Department of Emergency Medicine, Massachusetts GeneralHospital, Harvard Medical School, Boston, MA (Kabrhel); and the Department ofEmergency Medicine, Mount Auburn Hospital, Cambridge, MA, and Harvard MedicalSchool, Boston, MA (Thomsen).

Pseudoephedrine is a commonly used over-the-counter decongestant with sympathomimeticactivity. We present the case of a previously healthy young man who had an acute myocardialinfarction 45 minutes after ingesting the recommended dose of an over-the-counter cold remedycontaining pseudoephedrine. Elevations of cardiac-specific creatinine kinase and cardiac troponin Iconfirmed the diagnosis. Cardiac catheterization 8 hours later revealed normal coronary arteries,suggesting a mechanism of vasospasm. Cardiac magnetic resonance imaging confirmed findings ofregional myocardial infarction. This case highlights a potential danger of pseudoephedrine evenwhen used by otherwise healthy individuals. [Ann Emerg Med. 2005;45:213-216.]

0196-0644/$-see front matterCopyright ª 2005 by the American College of Emergency Physicians.doi:10.1016/j.annemergmed.2004.07.003

SEE EDITORIAL, P. 217.

INTRODUCTIONPseudoephedrine is a stereoisomer of ephedrine that

produces mixed adrenergic agonist effects and is commonlyused as a decongestant.1 At usual doses, the drug produces localvasoconstriction in the nose and mucous membranes. However,cardiovascular adverse effects can occur, including hypertension,arrhythmias, prolongation of the QT interval, and anginapectoris.2,3 Dangers of over-the-counter sympathomimetic useare illustrated by the recent ban on dietary supplementscontaining ephedrine alkaloids by the US Food and DrugAdministration (FDA) because of increased risk of suddendeath, acute myocardial infarction, and stroke.4,5 We describethe case of a previously healthy young man who experienced anacute myocardial infarction after taking the recommended doseof pseudoephedrine. Inferior ST-segment elevations were readilyapparent on the initial ECG (Figure 1), and cardiaccatheterization 8 hours later was normal. Only 4 previous casesof pseudoephedrine-associated angina have been described inthe medical literature.6-9 Confirmation of myocardial infarctioncaused by pseudoephedrine ingestion by cardiac magneticresonance imaging has never been reported.

CASE PRESENTATIONThe patient was a 32-year-old man from Nigeria who was in

his usual state of good health until 1 week before presentation,when he developed nasal congestion and rhinorrhea. To treat

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these symptoms, he took the recommended dose of 2 tablets ofan over-the-counter cold remedy containing 30 mg ofpseudoephedrine and 500 mg of acetaminophen per tablet. Thepatient developed severe substernal chest pain 45 minutes laterwhile he was at rest. The pain was dull and nonradiating; it wasassociated with shortness of breath and diaphoresis. The patientattempted to treat his pain with 2 tablespoons of bismuthsubsalicylate but had no relief. He presented to the emergencydepartment (ED) 30 minutes after the chest pain began. Hedescribed his pain as moderate on arrival.

The patient’s medical history was unremarkable. He deniedany history of heart disease, diabetes, hypertension, or dyslipi-demia. Other than the over-the-counter cold remedy, he was nottaking any medications or dietary supplements. He deniedtobacco or cocaine use. He reported no allergies to medications.There was no family history of coronary artery disease or suddendeath. He reported 1 episode of similar chest pain 1 week earlier,also after administration of the same over-the-counter coldremedy. His symptoms were less severe and resolved spontane-ously, so he did not seek medical attention at that time.

On arrival to the ED, the patient’s vital signs were bloodpressure 155/97mmHg, pulse rate 70 beats/min, respiratory rate20 breaths/min, and oral temperature 35.5 �C (95.8 �F). Heappeared generally well but somewhat uncomfortable. Head,eyes, ears, nose, and throat examination results were normal. Hewas in no respiratory distress, and breath sounds were clearbilaterally. Auscultation of heart tones revealed a regular rateand rhythm without murmurs, rubs, or gallops. Abdominal

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Acute Myocardial Infarction and Pseudoephedrine Manini, Kabrhel & Thomsen

Figure 1. Initial ECG.

examination revealed normal bowel sounds; no tenderness,guarding, or rebound; and no organomegaly. Skin examinationrevealed no rash or hypoesthesia. Neurologic examination wasnonfocal. The remainder of the patient’s examination results werenormal.

The patient received a cardiac monitor and 2 L of oxygen bynasal cannula. Intravenous access was obtained. An ECG wasperformed that was notable for 3 mm of ST-segment elevationin leads II, III, and aVF and 1 mm of ST-segment elevation inleads V5 to V6 (Figure 1). A posterior-anterior chest radiographresult was normal.

Initial treatment included 325 mg of aspirin orally and 3doses of 0.4-mg sublingual nitroglycerin 5 minutes apart.A single dose of 2 mg of intravenous morphine sulfate was alsogiven. The patient’s symptoms resolved fully after 20 minutes oftreatment. He was subsequently treated with 5 mg ofintravenous metoprolol and a 4,000-unit bolus of intravenousunfractionated heparin, followed by a continuous infusion of1,000 units per hour.

Repeated ECG demonstrated partial resolution of theST-segment elevations (Figure 2). Repeated blood pressure was102/48 mm Hg after the patient was made pain free.

Laboratory evaluation was notable for a total creatininekinase level of 648 U/L, with an MB fraction of 5.8 ng/mL anda cardiac troponin I level of 1.80 ng/mL. Electrolytes,blood urea nitrogen, and serum creatinine levels and CBCcount were all within the normal range. The serum acetamin-ophen level was 10 mg/mL. Urine toxicology screen was negativefor cocaine, amphetamines, and methamphetamines.

Cardiology consultation was obtained, and an ECGperformed in the ED demonstrated normal systolic functionand no regional wall motion abnormalities. The patient wasadmitted to the cardiology service with telemetry monitoring.Eight hours later, the patient’s total creatinine kinase levelpeaked at 814 U/L, his MB fraction peaked at 5.03 ng/mL, andhis cardiac troponin I level peaked at 15 ng/mL. Eighthours into the hospital course, the patient underwentcardiac catheterization that demonstrated normal coronaryarteries.

Family members were asked to bring the cold remedy to thehospital for verification. The product shown to hospital staffwas Tylenol Sinus, an over-the-counter product purchased inthe United States. The active ingredients (500 mg ofacetaminophen and 30 mg of pseudoephedrine per tablet) wereread from the label.

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He was discharged home in good condition 48 hours afterpresentation, with a prescription for sublingual nitroglycerin asneeded. Follow-up cardiac-gated magnetic resonance imagingwith gadolinium was performed 2 days after discharge anddemonstrated a subendocardial resting perfusion defect anda small region of delayed hypoenhancement along the inferiorwall, indicative of myocardial infarction.

Six months later, he denied any further episodes of chestpain, shortness of breath, or exercise limitation. Follow-upblood pressure in primary care clinic was 110/80 mm Hg.

DISCUSSIONWe present the case of an otherwise healthy 32-year-old man

who developed an acute myocardial infarction after ingestingthe recommended dose of an over-the-counter cold remedycontaining pseudoephedrine. The patient’s ECG, creatininekinase level, cardiac troponin I level, cardiac catheterization, andfollow-up cardiac-gated magnetic resonance image were allconsistent with the diagnosis of myocardial infarction causedby acute vasospasm. The patient’s serum acetaminophen levelof 10 mg/mL validated the history of ingestion of only 2 tabletsof the cold remedy, whereas urine cocaine, amphetamine,and methamphetamine levels were negative. This result is alsoconsistent with the medical history given because the minimumdetectable amphetamine level in urine at our hospital laboratoryis 750 mg/mL. An ingestion of 60 mg of pseudoephedrinewould not be expected to generate a positive urine toxicologyscreen for amphetamines. On further medical history taking, thepatient described a previous episode of chest pain after takingthe same medication. However, after discontinuation of the useof the over-the-counter medication, the patient has been chest-pain free for 6 months. Therefore, we believe that the mostlikely explanation for our patient’s acute myocardial infarctionis pharmacologically induced coronary vasospasm caused bypseudoephedrine.

Pseudoephedrine is a synthetic congener (stereoisomer) ofephedrine that is regulated by the FDA.10 Pseudoephedrine hasboth a- and b-adrenergic activity, with a direct and indirectmechanism of action.10 It is a common component of cold andinfluenza remedies and is readily absorbed by the gastrointes-tinal tract. Its beneficial effects are derived from production oflocal vasoconstriction in the nose and mucous membranes.1

Adverse effects of pseudoephedrine are mainly cardiovascularand include hypertension, arrhythmias, prolongation of the QTinterval, and angina pectoris.2,3,11 Its effects on the coronary

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Manini, Kabrhel & Thomsen Acute Myocardial Infarction and Pseudoephedrine

Figure 2. Repeated ECG after initial therapy while pain free.

circulation are not well studied.12 The mechanism of toxicity ofpseudoephedrine is to increase the availability of naturallyreleased catecholamines in tissues by direct stimulation of a-and b-adrenergic receptors.10 Four to 5 times the recommendeddose of pseudoephedrine can reproducibly cause hypertension.11

An association with supraventricular tachycardia has beenreported with pseudoephedrine ingestions of at least 120 mgwhen coupled with exercise.3

Naturally occurring ephedrine alkaloids exist, such asephedra (ma huang), and have been sold as herbal supplements.In recent years, ephedra products had been extensivelypromoted to aid weight loss, enhance sports performance, andincrease energy.2 Ephedrine has 4 times the adrenergic receptoractivity of pseudoephedrine1,11 and has been associated withsudden death, myocardial infarction, and stroke.13,14 OnDecember 30, 2003, the FDA published a consumer alert toimmediately stop the purchase and use of dietary supplementscontaining ephedra,4 and a final rule published by the FDAbanned the sale of these products, effective April 12, 2004.5

Despite the fact that pseudoephedrine is the D-isomer ofephedrine and therefore shares the same mechanism ofaction,1,11 the FDA ban did not apply to products containingpseudoephedrine.

Classic ECG changes associated with coronary vasospasm aretransient ST-segment elevations lasting for minutes,15,16

identical to the profile of our patient. ST-segment depressionscan occur if spasm involves coronary arterioles.16 Transient Qwaves have also been described.16 Vasospasm can occur withoutECG changes, a phenomenon that has been explained by thepresence of mild disease or collateral circulation.15

Mainstays of ED management of suspected coronaryvasospasm are similar to typical initial management of acutecoronary syndromes, with some caveats. Nitroglycerin should begiven either sublingually or as a continuous infusion and titratedto pain. Case reports of drug-induced coronary vasospasm haveverified the utility of nitrates in this setting.6-9,15 Aspirin andheparin should be administered in the acute setting on the basisof the association of vasospasm with increased thrombusformation.15,17

Initially, patients with vasospasm may receive b-blockers asstandard therapy for acute coronary syndrome.18 However, ifthere is a known stimulant exposure (eg, cocaine or amphet-amines), b-blockers should be avoided because of paradoxicallyincreased coronary arterial tone and increased incidence ofarrhythmias.19 These effects appear to be the result of

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unopposed a-adrenergic stimulation. Once normal coronaryarteries are identified on subsequent angiography, calciumchannel blockers should be added because of their ability toalleviate ischemic symptoms15,18 and produce coronaryvasodilation.18,20

Thrombolysis for acute coronary syndromes with suspectedpharmacologically induced vasospasm is currently an area ofcontroversy. Consideration of thrombolytic therapy iswarranted on the basis of the clinical setting and the availabilityof percutaneous coronary intervention. However, some litera-ture suggests increased risks associated with thrombolysis inpatients with cocaine-associated acute coronary syndromes.21

In conclusion, acute myocardial infarction should be on thedifferential diagnosis of young, otherwise healthy patientspresenting with chest pain to the ED after exposure tostimulants, including over-the-counter medications such aspseudoephedrine. The temporal association between thispatient’s ingesting pseudoephedrine and his myocardial in-farction suggests a causal relationship. The absence of coronaryartery disease at catheterization, combined with the cardiacmagnetic resonance imaging findings, were consistent with anacute myocardial infarction caused by vasospasm fromadrenergic effects of the medication. This case highlightsa potential danger of pseudoephedrine even when used byotherwise healthy people. Clinicians should be aware of thisdanger and should advise caution when taking over-the-countersympathomimetics such as pseudoephedrine.

Funding and support: The authors report this study did notreceive any outside funding or support.

Publication dates: Received for publication May 5, 2004.Revision received July 2, 2004. Accepted for publication July7, 2004. Available online November 21, 2004.

Reprints not available from the authors.

Address for correspondence: Alex Manini, MD, Department ofEmergency Medicine, Brigham and Women’s Hospital, 75Francis Street, Neville House, Boston, MA 02115; 617-267-7415, fax 617-582-6038; E-mail amanini@partners.org.

REFERENCES1. Empey DW, Young GA, Letley E, et al. Dose-response study of the

nasal decongestant and cardiovascular effects of pseudoephe-drine. Br J Clin Pharmacol. 1980;9:351-358.

2. McBride BF, Karapanos AK, Krudysz A, et al. Electrocardio-graphic and hemodynamic effects of a multicomponent dietary

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Acute Myocardial Infarction and Pseudoephedrine Manini, Kabrhel & Thomsen

supplement containing ephedra and caffeine. JAMA. 2004;291:216-220.

3. Bright TP, Sandage BW Jr, Fletcher HP. Selected cardiac andmetabolic responses to pseudoephedrine with exercise. J ClinPharmacol. 1981;21:488-492.

4. FDA announces plans to prohibit sales of dietary supplementscontaining ephedra. Available at: http://www.fda.gov/oc/initiatives/ephedra/december2003/. Accessed January 24,2004.

5. FDA announces rule prohibiting sale of dietary supplementscontaining ephedrine alkaloids effective April 12. Available at:http://www.fda.gov/bbs/topics/NEWS/2004/NEW01050.html. Accessed June 20, 2004.

6. Rosen RA. Angina associated with pseudoephedrine. Ann EmergMed. 1981;10:230-231.

7. Wiener I, Tilkian AG, Palazzolo M. Coronary artery spasm andmyocardial infarction in a patient with normal coronary arteries:temporal relationship to pseudoephedrine ingestion. CathetCardiovasc Diagn. 1990;20:51-53.

8. Derreza H, Fine M, Sadaniantz A. Acute myocardial infarctionafter use of pseudoephedrine for sinus congestion. J Am BoardFam Pract. 1997;10:436-438.

9. Pederson KJ, Kuntz DH, Garbe GJ. Acute myocardial ischemiaassociated with ingestion of bupropion and pseudoephedrine ina 21-year-old man. Can J Cardiol. 2001;17:599-601.

10. Sapru HN, Theoharides TC. Autonomic nervous system. In:Teoharides TC. Essentials of Pharmacology. 2nd ed. Boston, MA:Little, Brown; 1996:58.

11. Drew CD, Knight GT, Hughes DT, et al. Comparison of the effectsof D-ephedrine and L-pseudoephedrine on the cardiovascular andrespiratory systems in man. Br J Clin Pharmacol. 1978;6:221-225.

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12. Physicians’ Desk Reference. Oradell, NJ: Medical EconomicsCompany; 1980:740-741.

13. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascularevents temporally associated with ma huang, an herbal source ofephedrine. Mayo Clin Proc. 2002;77:12-16.

14. Shekelle P, Morton S, Maglione M, et al. Ephedra and Ephedrinefor Weight Loss and Athletic Performance Enhancement: ClinicalEfficacy and Side Effects: Evidence Report/Technology Assess-ment No. 76. Rockville, MD: Agency for Healthcare Research andQuality; 2003. AHRQ Publication No.03-E022.

15. Vandergoten P, Benit E, Dendale P. Prinzmetal’s variant angina:three case reports and a review of the literature. Acta Cardiol.1999;54:71-76.

16. Kerin NZ, Rubenfire M, Naini M, et al. Prinzmetal’s variant angina:electrocardiographic and angiographic correlations. J Electro-cardiol. 1982;15:365-380.

17. Sakata K, Hoshino T, Yoshida H, et al. Circadian fluctuations oftissue plasminogen activator antigen and plasminogen activatorinhibitor-1 antigens in vasospastic angina. Am Heart J. 1992;124:854-860.

18. Tun A, Khan IA. Myocardial infarction with normal coronaryarteries: the pathologic and clinical perspectives. Angiology.2001;52:299-304.

19. Williams JB, Keenan SM, Gan Q, et al. Hemodynamic responseprofile predicts susceptibility to cocaine-induced toxicity. Eur JPharmacol. 2003;464:189-196.

20. Bory M, Pierron F, Panagides D, et al. Coronary artery spasm inpatients with normal or near normal coronary arteries. Eur Heart J.1996;17:1015-1021.

21. Boniface KS, Feldman JA. Thrombolytic therapy and cocaine-associated myocardial infarction. Am J Emerg Med. 2000;18:612-615.

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