Case Report

Cardiac arrest in the setting of diet pill consumption

Abstract

The obesity epidemic currently plaguing the United States has spurred the development of a vast number of drugs to assist in the battle against obesity and its associated complications. The need to loose weight often causes patients to loose sight of or even ignore the serious side effects of some of the most widely used weight-loss medications. Here we present the case of ventricular tachycardia/fibrillation arrest in an otherwise healthy 48-year-old woman who was taking no medications other than phentermine, a common appetite suppressant that functions as a central nervous system stimulant through activation of the noradrenergic pathway of the sympathetic nervous system.

A 48-year-old woman with no significant medical history was brought by ambulance to the emergency department after an episode of substernal chest pain radiating to her left arm, accompanied by palpitations, and lasting for approxi- mately 15 minutes. While in the ambulance being trans- ported to the hospital, the patient had an episode of ventricular tachycardia followed by ventricular fibrillation arrest requiring defibrillation and intubation. The patient had no previous cardiac history and was taking no medications other than phentermine, a common over-the-counter appetite suppressant used for weight loss. There was no significant family history of cardiovascular disease.

On admission to the coronary care unit, the patient was in normal sinus rhythm and was hemodynamically stable. Her initial electrocardiogram revealed normal sinus rhythm at 96 beats per minute with poor R-wave progression; inverted T waves in leads I, aVL, V₂ through V₆; and a prolonged QT interval (QTc = 493 milliseconds). blood work showed a peak Creatinine kinase of 716 U/L with a peak creatinine kinase-MB fraction of 36.1 U/L and a troponin I level of

17.9 ng/mL. Toxicology workup was negative for cocaine, barbiturates, and benzodiazepines.

Coronary angiography soon after admission revealed a left ventricular end diastolic pressure of 26 mm Hg and a left ventricular ejection fraction of 35% with mild diffuse nonobstructive coronary artery disease. A transthoracic echocardiogram revealed segmental left ventricular systolic

dysfunction with severe hypokinesis of the mid- and distal- anterior septum, anterior wall, and apex. right ventricular function was normal. On telemetry, the patient continued to exhibit ectopy with episodes of nonsustained ventricular tachycardia for more than 72 hours after her myocardial infarction. An electrophysiology study performed 5 days after presentation demonstrated an inducible sustained ventricular tachycardia. The patient subsequently received an implantable cardiac defibrillator and was soon discharged with appropriate medical therapy and follow-up for her myocardial infarction.

One of the most pressing issues currently threatening global health and well-being is the alarming incidence of obesity, particularly among the US population. The recent National Health and Nutrition Examination Survey of 2003 to 2004 estimated that 66% of US adults are either overweight or obese [1]. Given the constant admonitions by health care providers and government health agencies advising patients to lose weight, in an era of relative food abundance, increasing portion sizes, and elevated levels of saturated fat and cholesterol in everyday food, it is not surprising that patients are constantly searching for quick and easy ways to lose weight. Despite the obvious positive effects of losing weight on overall health status, many patients may be unaware of the dire consequences that may arise after the use of common weight-loss remedies, many of which, such as phentermine, contain potent sympathomi- metic components.

The use of medications for combating obesity in the modern era dates back to the early 1940s, when the US Food and Drug Administration approved the use of hydrin, an ephedrine analogue, for the treatment of obesity. Even at that point, federal legislators charged with protecting the public from harm associated with approved medications were concerned about the use of such potent agents for the treatment of obesity. For example, in 1946, the medical director of the FDA’s division overseeing medication approval wrote that the use of ephedrine in obesity “…is wholly irrational and exposes the patient unnecessarily to a potent drug [2,3].” Ever since the 1940s, the manufacturers of weight-loss remedies have struggled to meet the standards that all other medications on the market are expected to achieve. The primary reason for this struggle has been the persistent lack of any wide-scale studies demonstrating that

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the benefit associated with weight loss attributed to the use of these remedies outweighs the considerable risk associated with their use [4].

The patient presented in the case above was taking phentermine, an agent that became well known in the mid- 1990s because of the highly publicized withdrawal of the popular “Fen-Phen” (fenfluroxamine-phentermine) from the market in 1997 because of the association of the drug to the development of valvular heart disease [5]. As a result of later reports indicating that patients taking only fenfluroxamine or the closely related desfluroxamine also developed valvular heart disease, phentermine received much less scrutiny than these 2 agents and the drug is still available and remains one of the cheapest and more popular anorectics on the market. The medication is generally intended to be used by obese patients in conjunction with lifestyle modification and only on a short-term basis. Weight loss results in patients taking phentermine have been relatively positive, although no reported randomized controlled trials assessing the efficacy of the drug and the risk-benefit-ratio have been published since the late 1990s. In addition, meta-analyses examining the efficacy and the adverse effects associated with phentermine have demonstrated no widespread clinically significant side effects, although there have been scattered case reports describing strokes in patients taking the medication [5-7]. There have not been, to our knowledge, any reports describing myocardial infarction or ventricular tachycardia/fibrillation arrest in patients taking phentermine. Phentermine is an adrenergic reuptake inhibitor that promotes adrenergic stimulation in the central nervous system (CNS) and in peripheral tissues. The chemical formulation is a direct derivative of amphetamine. As an amphetamine analogue, phentermine influences both nora- drenergic and dopaminergic CNS neurotransmission. Phen- termine and chemically similar compounds generally promote the release of norepinephrine from neuronal terminals and thus enhance noradrenergic postganglionic neuronal stimulation. These agents may also have the ability to increase dopamine release and block the reuptake of norepinephrine from the interneuronal cleft, further enhan- cing the noradrenergic effect [7]. The precise means whereby noradrenergic stimulation actually promotes weight loss is still unknown, although it is believed to be associated with the activation of the central and sympathetic nervous systems. The overall result is a decrease in appetite and an

increased degree of basal energy expenditure [8].

Like all adrenegic agonists, phentermine has the potential to induce tachycardia and hypertension. As a result of the increased concentration of catecholamines, there is a generalized increase in the stimulation of peripheral ?- and ?-adrenergic receptors. The overall result is an increase in the heart rate, peripheral vascular resistance, and blood pressure [9]. Amphetamines may also have the additional effect of competitively inhibiting monoamine oxidase, an enzyme that inactivates adrenergic neurotransmission and thereby further enhances the effect of epinephrine/norepi-

nephrine and increases the overall adrenergic stimulus [10]. In general, the cardiotoxic effects associated with ampheta- mines have been reported primarily in patients who abuse methamphetamine or one of its derivatives, including the increasingly popular recreational drug “ecstasy” (3,4-methy- lenedioxymethamphetamine). The cardiotoxic effects that have been reported include heart failure, cardiomyopathy, acute myocardial infarction, and various arrhythmias. Despite these scattered reports and widespread use of amphetamines as recreational drugs, amphetamine-related cardiotoxicity is still relatively rare [11-14].

There have been very few case reports documenting significant arrhythmias associated with amphetamine use/ abuse. A recent case series looking at the clinical effects of the recreational drug paramethoxyamphetamine revealed the presence of nonfatal arrhythmias (atrial fibrillation, multifocal ventricular ectopic beats, and supraventricular tachycardia) in 5 of the 22 cases of documented para- methoxyamphetamine toxicity [15]. Otherwise, reports of cardiac dysrhythmias associated with amphetamine deriva- tives have been relatively rare. The cases that have been reported occurred primarily in the setting of recreational drug abuse/overdose with ecstasy or paramethoxyamphetamine, for example. Ventricular fibrillation has been reported in a case documenting acute myocardial infarction after the intravenous injection of amphetamine [12]. Other known Cardiac effects of the use of amphetamines include prolongation of the QT interval as what occurred in our case (QTc = 493) [16]. Although it is not possible to unequivocably reach the conclusion that the patient pre- sented above developed a myocardial infarction and subsequent ventricular tachycardia/fibrillation arrest as a result of phentermine use, her case history indicates that this medication may have contributed to this event, particularly because the patient was relatively young and had no significant family history of cardiovascular disease. Her cardiac catheterization demonstrated mild diffuse nonob- structive coronary artery disease, suggesting that the patient may have had a myocardial infarction and subsequent ventricular tachycardia and fibrillation as a result of coronary arterial spasm and ischemic myocardial injury. There have been cases in the past documenting coronary artery spasm after the use of recreational amphetamines [17,18]. There have not, however, been any reported cases of Coronary spasm or myocardial infarction after the use of phentermine. In addition to the adverse impact of increased adrenergic stimulation upon cardiac function and the possible induction of coronary spasm, amphetamines have been found to have direct cardiotoxic effects as well. Experimental animal studies have demonstrated fibrosis, sarcolemmal damage, and loss of myoglobin in affected ventricular myocytes. Further areas of subendocardial damage were demonstrated as well in the hearts of rats with prolonged exposure to methamphetamine [19]. Although the precise impact of amphetamine exposure on the human heart cannot be precisely surmised from animal studies, there are enough

Case Report

data from these studies to indicate that these agents can, in fact, have a direct impact upon myocardial tissue. The

References

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potential for producing myocardial fibrosis increases the prospect of attributing a pro-arrhythmogenic effect to amphetamine and its analogues. It must be noted that most of the negative outcome studies that have been performed involved recreational drugs used in doses far exceeding those usually contained in diet medications. For example, although phentermine and 3,4-methylenedioxymethamphetamine (ecstasy) are both amphetamine analogues, phentermine is usually administered in doses no higher than 37.5 mg/d, whereas each single pill of ecstasy contains 50 to 200 mg of the drug, further highlighting the dangers of recreational methamphetamine abuse. Nevertheless, although no studies, to our knowledge, have been conducted analyzing the effect of phentermine upon the heart, the medication is an amphetamine analogue that shares many of the character- istics of the other members of this family, and its adrenergic impact as well as the prospect of a direct negative impact on myocardial tissue must be kept in mind when a patient starts taking the medication.

The previously feared obesity epidemic that has unfortunately become a reality in the United States warrants new and novel approaches to combat the Negative outcomes associated with being overweight. Despite the urgent need to encourage weight loss, however, the general population must be wary of remedies that promise quick results with little or no adverse effects. Although there have been no previous case reports documenting significant adverse Cardiovascular effects associated with the popular appe- tite-suppressant phentermine, our case demonstrates that this agent, which is a chemical analogue of the potent amphetamine class of noradrenergic stimulants, may have the ability to promote potentially fatal cardiac outcomes, particularly in patients who may already be predisposed to the development of such pathologic states due to under- lying structural heart disease. Patients should be aware of the possibility of developing such conditions and should discuss their options with their physician before proceed- ing. Emergency department physicians should be cognizant of the potential for these medications to exert significant adverse cardiovascular effects.

John N. Makaryus MD Amgad N. Makaryus MD Division of cardiology department of Medicine

North Shore University Hospital Manhasset, NY 11030, USA

Email-address: [email protected]

doi:10.1016/j.ajem.2007.10.040

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