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Abstract

Cocaine abuse remains a significant worldwide health problem. Patients with cardiovascular toxicity from cocaine abuse frequently present to the emergency department for treatment. These patients may be tachycardic, hypertensive, agitated, and have chest pain. Several pharmacological options exist for treatment of cocaine-induced cardiovascular toxicity. For the past 3 decades, the phenomenon of unopposed α-stimulation after β-blocker use in cocaine-positive patients has been cited as an absolute contraindication, despite limited and inconsistent clinical evidence. In this review, the authors of the original studies, case reports, and systematic review in which unopposed α-stimulation was believed to be a factor investigate the pathophysiology, pharmacology, and published evidence behind the unopposed α-stimulation phenomenon. We also investigate other potential explanations for unopposed α-stimulation, including the unique and deleterious pharmacologic properties of cocaine in the absence of β-blockers. The safety and efficacy of the mixed β-/α-blockers labetalol and carvedilol are also discussed in relation to unopposed α-stimulation.

Keywords

cocaine β-blocker unopposed α toxicity cardiovascular vasoconstriction

Introduction

Cocaine abuse represents a major public health problem with no end in sight. There are estimated 20 million cocaine users worldwide based on the most recent 2016 United Nations World Drug Report.¹ In the United States, the prevalence of frequent cocaine use remains steady, with an estimated 1.5% of the population reporting use in 2014.² Cocaine was also the most common drug of abuse resulting in hospital utilization, with 505 224 (40.3%) of drug-related visits to the emergency department in 2011.³ Patients abusing cocaine risk life-threatening consequences, including dysrhythmias, acute coronary syndrome (ACS), stroke, heart and renal failure, seizure, and fetal/maternal morbidity and mortality.^4,5 The best pharmacological treatment of hypertension, tachycardia, and vasospasm associated with acute cocaine cardiovascular toxicity is subject to debate, with inconsistencies among clinicians, specialties, regions, and countries.^6
-8 The phenomenon of unopposed α-stimulation after β-blocker administration for cocaine cardiovascular toxicity represents one of the most controversial topics in toxicology, cardiology, and emergency medicine for over 3 decades.^9

-15 In this clinical review, we examine the evidence behind unopposed α-stimulation, explore alternative explanations, and provide guidance on the use of β-blockers for cocaine cardiovascular toxicity.

Unopposed α-Stimulation

The clinical phenomenon of cocaine-associated unopposed α-stimulation is essentially the acute increase in blood pressure and/or worsening coronary artery vasoconstriction after administration of a β-blocker. The putative physiological mechanism behind unopposed α-stimulation seems simple at first. However, the autonomic nervous system regulation of blood pressure, heart rate, and coronary epicardial and microvascular blood flow is based on a complex relationship among the sympathetic α- and β-adrenergic system, parasympathetic acetylcholinergic system, endothelium-dependent coronary vasodilation, pressure-dependent autoregulation, and metabolic demand.¹⁶

Cocaine is an amphipathic molecule that can cross the blood–brain barrier and placenta and increase peripheral and central nervous system (CNS) levels of catecholamines such as norepinephrine, epinephrine, and dopamine.⁴ This primarily occurs via blockade of plasmalemmal monoamine transporters involved in reuptake.¹⁷ Peripheral catecholamine stimulation of postsynaptic α1- and α2-adrenoceptors results in smooth muscle contraction and vasoconstriction, whereas presynaptic α1- and α2-adrenoceptors are primarily involved in feedback inhibition of norepinephrine release.¹⁶ In the heart, both α1-and α2-adrenoceptors mediate microvascular vasoconstriction, which is a primary determinant of vascular resistance.¹⁸ However, only α1-adrenoceptor stimulation results in larger diameter epicardial vessel vasoconstriction.¹⁹ Vasodilation is also mediated through endothelium-dependent nitric oxide (NO) and endogenous adenosine in response to exercise or other hyperadrenergic state, and this has been shown to attenuate α-mediated vasoconstriction.^20,21 To further complicate this interaction, cardiac α1-adrenoceptor activation also causes release of endothelin, a potent vasoconstrictor, and adenosine, a vasodilator.¹⁶

Stimulation of β1-adrenoceptors increases heart rate, conduction, and contractility, whereas stimulation of β2-adrenoceptors leads to smooth muscle relaxation and vasodilation in select vascular beds.²² If a nonselective β-blocker, such as propranolol, is used that has both β1 and β2 effects, blockade of β2-adrenoceptors is associated with vasoconstriction, as the β2 vasodilator influence opposing α-adrenoceptor-mediated vasoconstriction is removed. This is the most commonly cited physiological explanation for unopposed α-stimulation. Another explanation of unopposed α-stimulation is based on the Frank-Starling Law—β1-adrenoceptor antagonism results in decreased heart rate, increased left ventricular end-diastolic pressure, and increased cardiac fiber length, with subsequent increased blood pressure and ventricular contraction.²³

What Is the Evidence?

The unopposed α-stimulation phenomenon is based on 2 small prospective studies, 1 case series, and 3 case reports.⁶ In 1985, Ramoska and Sacchetti reported the first case of unopposed α-stimulation in an agitated, cocaine-toxic patient.²⁴ After receiving propranolol, the patient’s blood pressure increased from 170/118 to 180/140 mm Hg, but heart rate decreased from 112 to 104 beats per minute (bpm). Despite this increase in blood pressure, no adverse event or outcome occurred. The patient’s agitation resolved, and he left against medical advice.

In 1990, Lange and associates published the first prospective human investigation of propranolol after cocaine administration, which is the study most cited by those opposed to the use of β-blockers in the setting of cocaine cardiovascular toxicity.²⁵ During cardiac catheterization, the investigators studied 30 volunteer participants divided into 2 groups who were administered either intranasal saline (n = 15) or 2 mg/kg cocaine (n = 15). Five of the saline control group received intracoronary propranolol with no change in measured cardiovascular parameters. In the cocaine group, cocaine predictably increased arterial pressure, rate-pressure product, myocardial oxygen demand, and coronary vascular resistance, whereas coronary sinus blood flow decreased and mild vasoconstriction of epicardial coronary artery segments was noted. Ten of the cocaine group then received intracoronary propranolol, which resulted in a slight reduction in coronary sinus blood flow by an additional 15% (120-100 mL/min; P = .04), and increased coronary vascular resistance by an additional 19% (1.05-1.20 mm Hg/mL × min; P = .023). Slight further vasoconstriction of the proximal, mid, and distal left anterior descending and circumflex segments was reported after propranolol, but only the change in the proximal left circumflex segment was statistically significant (2.62-2.52 mm; P = .011). In 5 participants (4 with coronary artery disease) with coronary vasoconstriction following intranasal cocaine administration, intracoronary propranolol further constricted 1 or more segments greater than 10% with 1 adverse event, when a participant experienced complete coronary artery occlusion and ST-elevation that resolved with nitroglycerin. Three years later, this same research group performed a similar study with the mixed β1-/β2-/α1-blocker labetalol.²⁶ Nine participants were administered 2 mg/kg intranasal cocaine, which increased their mean arterial pressure and decreased the coronary arterial area. In contradistinction to their previous study of propranolol, intravenous (IV) labetalol had no significant effect on coronary arterial area, and the α1-antagonism unique to this agent may have been responsible for these reported outcomes.

In 1991, Sand and colleagues published a cohort of 7 patients with cocaine toxicity treated with esmolol, a short-acting selective β1-blocker.²⁷ Esmolol reliably decreased heart rate but had an inconsistent effect on blood pressure. There was 1 treatment failure with esmolol for control of hypertension, for which the dihydropyridine calcium channel blocker nifedipine was then successfully used. There were 3 adverse events. In 1 patient, esmolol caused a 15% rise in systolic blood pressure and 50% rise in diastolic blood pressure, which was then successfully treated with labetalol. Esmolol caused hypotension in another patient that required reversal with the α1-adrenoceptor agonist phenylephrine. The third patient had resolution of symptoms of cocaine cardiovascular toxicity with esmolol but subsequently developed vomiting and lethargy and was intubated.

Sixteen years later, Fareed and associates published a case report describing a patient with cocaine-induced ACS whose chest pain resolved with nitroglycerin, but tachycardia (115 bpm) persisted despite diazepam treatment.²⁸ Two doses of IV metoprolol, a lipophilic β1-specific blocker, were given. Ten minutes later, the patient developed chest pain, became unresponsive with systolic blood pressure 50 mm Hg and heart rate 120 bpm, and expired. In 2009, Izquierdo Gómez and colleagues reported a patient with ST-elevation ACS after cocaine use who then developed ventricular fibrillation.²⁹ He was successfully treated with electrical defibrillation, after which IV propranolol was administered for diaphoresis, tachycardia, and hypertension. Following this, the patient had another episode of chest pain, with higher elevation of the inferior ST segments and new reciprocal anterior ST-depression. Coronary angiography demonstrated a 60% stenosis in the mid-left circumflex artery, and he was later discharged.

A small number of animal studies have also been cited in support of unopposed α-stimulation.^7,8 In 1980, Guinn et al studied the effect of propranolol, diazepam, and chlorpromazine on 4 groups of 3 monkeys administered potentially lethal infusions of cocaine (0.5 mg/mL/min at a rate of 1 mL/min).³⁰ The 3 subjects in the control group experienced convulsions and died. Propranolol (3 mg/kg IV) decreased the cocaine-induced elevated heart rate and mean arterial pressure, but the 3 subjects had convulsions and died. No unopposed α-stimulation events were described in the propranolol group. In the diazepam group (0.5 mg/kg IV), 1 of the 3 subjects had convulsions and died, whereas in the chlorpromazine group (10 mg/kg), 2 of the 3 subjects had convulsions but all 3 survived. In 1991, Smith and coworkers gave 6 groups of 10 rats an LD₅₀ dose of cocaine (1.4 mg/100 g) and studied survival based on treatment with normal saline, propranolol, labetalol, diazepam, verapamil, and chlorpromazine.³¹ Five of the 10 subjects in the control group died as expected. Four in the diazepam and chlorpromazine groups died, 6 in the verapamil group died, and 9 in the labetalol group died. All 10 subjects in the propranolol group died, which was the only outcome to reach statistical significance. Interestingly, the authors discussed unopposed α-stimulation as a possible factor in mortality, but no hemodynamic parameters were recorded in their study. It is also important to note the doses of drugs administered in these animal studies were not applicable to clinical practice involving humans, but this may reflect important physiological differences in cocaine toxicity and responses to certain drugs between species. For example, monkeys averaging 4 kg were given 12 mg IV propranolol, and rats averaging 400 g in weight were given 4 mg IV propranolol and 12 mg IV labetalol. In 1991, Vargas et al studied the effect of cocaine on isolated porcine coronary arteries.³² Cocaine did not cause vasoconstriction but did so in the presence of propranolol. This effect was counteracted by the α1-blocker prazosin.

Alternative Explanations of the Phenomenon

The rarity of the unopposed α-stimulation phenomenon is surprising, given the millions of doses of β-blockers administered each year for hyperadrenergic-associated medical conditions such as acute heart failure, hypertension, stroke, thyrotoxicosis, subarachnoid hemorrhage, preeclampsia, alcohol withdrawal, burns, sepsis, head injury, and trauma.^{33

-43} A small number of prospective studies, case series, and case reports of β-blockers in the setting of cocaine use exist, and several large retrospective studies on β-blocker use for cocaine-associated chest pain with no mention of any unopposed α-stimulation-related adverse events (Table 1).^{44

-90} These studies also suggest many present-day clinicians are disregarding previously published warnings on the use of β-blockers with cocaine because of potential unopposed α-stimulation, or patients do not disclose their cocaine use on initial history. It may be possible there may have been many more cases of unopposed α-stimulation that were not published because of reporting bias. However, there are alternative pharmacological and physiological explanations for unopposed α-stimulation other than precipitation by β-blockers (Table 2).

Table 1.

Studies and Cases Involving Cocaine Use and β-Blockers to Date.

Author(s), Year	Type of Study/Trial	β-Blocker	Level of Evidence^a	No. of Subjects	Adverse Events	Summary
Lange et al,²⁵ 1990	Prospective, randomized, double-blind, controlled	Propranolol	I	10	1	Intracoronary propranolol increased coronary vascular resistance, decreased coronary sinus blood flow
Vongpatanasin et al,⁴⁴ 1999	Prospective, randomized, double-blind, controlled	Propranolol	I	11	0	Propranolol prevented increases in heart rate
Sofuoglu et al,⁴⁵ 2000	Prospective, randomized, double-blind, crossover	Carvedilol	I	12	0	Carvedilol prevented increases in blood pressure and heart rate
Sofuoglu et al,⁴⁶ 2000	Prospective, randomized, double-blind, crossover	Labetalol	I	12	0	Labetalol prevented increases in blood pressure and heart rate
Vongpatanasin et al,⁴⁷ 2004	Prospective, randomized, double-blind, controlled	Propranolol	I	24	0	Heart rate increase was attenuated by propranolol
Orr and Jones,⁴⁸ 1968	Prospective cohort	Propranolol	II	60	0	Propranolol pretreatment decreased heart rate; posttreatment decreased blood pressure, dysrhythmias
Sand et al,²⁷ 1991	Prospective cohort	Esmolol, labetalol	II	7	3	Inconsistent response to esmolol; rescue with labetalol and nifedipine in 2 cases
Boehrer et al,²⁶ 1993	Prospective, controlled	Labetalol	II	9	0	Labetalol reduced heart rate, blood pressure; no effect on coronary artery cross-sectional area
Hoskins et al,⁴⁹ 2010	Prospective cohort	Labetalol	II	30	0	Diltiazem and labetalol decreased blood pressure, heart rate
Brody et al,⁵⁰ 1990	Retrospective	Labetalol	III	18	0	Eighteen of the 233 cocaine patients required treatment, no adverse effects reported
Dattilo et al,⁵¹ 2008	Retrospective	Metoprolol, atenolol, labetalol, propranolol, carvedilol	III	60	0	β-Blockers associated with decreased incidence of myocardial infarction
Mohamad et al,⁵² 2008	Retrospective	β-blockers (unspecified)	III	364	0	β-Blockers associated with higher incidence of myocardial infarction
Rangel et al,⁵³ 2010	Retrospective	Metoprolol, atenolol, labetalol, propranolol, carvedilol	III	151	0	β-blocker use associated with greater reduction in blood pressure and death
Ibrahim et al,⁵⁴ 2013	Retrospective	Metoprolol, atenolol, labetalol, carvedilol	III	162	0	β-blockers did not change incidence of troponin elevation
Fanari et al,⁵⁵ 2014	Retrospective	Metoprolol, atenolol, labetalol, carvedilol	III	164	0	No difference in outcomes with β-blockers
Gupta et al,⁵⁶ 2014	Retrospective	β-blockers (unspecified)	III	600	0	Majority of cocaine-positive patients with myocardial infarction received β-blockers
Chibungu et al,⁵⁷ 2016	Retrospective	β-blockers (unspecified)	III	378	0	Thirty-one percent of cocaine-induced myocardial infarction treated with β-blockers
Rappolt et al,⁵⁸ 1977	Case series	Propranolol	IV	5	0	Resolution of hypertension, tachycardia after propranolol
Meyers,⁵⁹ 1980	Case series	Propranolol	IV	2	0	Resolution of tachycardia, dysrhythmia after propranolol
Rigg and Weibley,⁶⁰ 1990	Case series	Propranolol	IV	4	0	Control of ventricular tachycardia after propranolol
Minor et al,⁶¹ 1991	Case series	Metoprolol	IV	3	0	Successful treatment of myocardial infarction in patients with normal coronary arteries
Merigian et al,⁶² 1994	Case series	Esmolol, propranolol, labetalol	IV	5	0	Successful use of β-blockers for cocaine toxicity
Nicholson and Rogers,⁶³ 1995	Case series	Labetalol	IV	3	0	Resolution of tachycardia, hypertension, dysrhythmia after labetalol
Gay,⁶⁴ 1976	Case report	Propranolol	V	1	0	Resolution of tachycardia, hypertension after propranolol
Rappolt et al,⁶⁵ 1976	Case report	Propranolol	V	1	0	Resolution of hypertension, tachycardia after propranolol
Rappolt et al,⁶⁶ 1978	Case report	Propranolol	V	1	0	Resolution of hypertension, tachycardia after propranolol
Jonsson et al,⁶⁷ 1983	Case report	Propranolol	V	1	0	Resolution of dysrhythmia, tachycardia after propranolol
el-Din and Mostofa,⁶⁸ 1985	Case report	Labetalol	V	1	0	Resolution of dysrhythmia, hypertension after topical intranasal cocaine
Ramoska and Sacchetti,²⁴ 1985	Case report	Propranolol	V	1	1	Hypertension worsened after propranolol, resolution with nitroprusside
Dusenberry and Mariani,⁶⁹ 1987	Case report	Labetalol	V	1	0	Resolution of hypertension, tachycardia after labetalol
Ascher et al,⁷⁰ 1988	Case report	Metoprolol	V	1	0	Post myocardial infarction treatment
Gay and Loper,⁷¹ 1988	Case report	Labetalol	V	1	0	Labetalol resolved hypertension, tachycardia
Burton et al,⁷² 1989	Case report	Propranolol	V	1	0	Propranolol resolved hypertension, tachycardia in cocaine-dependent hyperthyroid patient
Pollan and Tadjziechy,⁷³ 1989	Case report	Esmolol	V	1	0	Esmolol resolved hypertension, tachycardia after failure with nitroglycerin and digoxin
Samuels et al,⁷⁴ 1991	Case report	Labetalol	V	1	0	Labetalol resolved hypertension, tachycardia
Merigian,⁷⁵ 1993	Case report	Propranolol, esmolol	V	1	0	Resolution of tachycardia, dysrhythmia with propranolol, esmolol
Malbrain et al,⁷⁶ 1994	Case report	Labetalol	V	1	0	Labetalol resolved hypertension, tachycardia
Singh et al,⁷⁷ 1994	Case report	Labetalol	V	1	0	Hypotension and pulmonary edema during general anesthesia, phenylephrine
Williams et al,⁷⁸ 1996	Case report	Esmolol	V	1	0	Esmolol resolved hypertension, tachycardia, dysrhythmia after preoperative intranasal cocaine
Inyang et al,⁷⁹ 1999	Case report	Labetalol	V	1	0	Failure of nitroglycerin, morphine, labetalol to mitigate chest pain, myocardial infarction
Laffey et al,⁸⁰ 1999	Case report	Esmolol	V	1	0	Resolution of tachycardia after esmolol
Missouris et al,⁸¹ 2001	Case report	Metoprolol	V	1	0	Successful treatment of unstable angina
Ortega-Carnicer et al,⁸² 2001	Case report	Labetalol	V	1	0	Ventricular tachycardia and ST-elevation resolved with both medications
Erwin and Deliargyris,⁸³ 2002	Case report	Metoprolol	V	1	0	Worsening hypertension and pulmonary edema after multiple medications given
Mégarbane et al,⁸⁴ 2004	Case report	Labetalol	V	1	0	Hypertension, tachycardia resolved after labetalol
Fareed et al,²⁸ 2007	Case report	Metoprolol	V	1	1	Diazepam, nitroglycerin failed to resolve tachycardia; cardiac arrest after metoprolol
Feldhendler et al,⁸⁵ 2007	Case report	Esmolol	V	1	0	Successful treatment of cocaine-induced aortic dissection
Izquierdo Gómez et al,²⁹ 2009	Case report	Propranolol	V	1	1	Propranolol worsened chest pain, ST-elevation
Javed et al,⁸⁶ 2011	Case report	Labetalol, esmolol	V	1	0	Dexmedetomidine resolved hypertension, tachycardia after failure of other attempted medications
Martinez-Quintana et al,⁸⁷ 2013	Case report	Propranolol	V	1	0	Resolution of hypertension, tachycardia with combined treatment including propranolol
Öcal et al,⁸⁸ 2015	Case report	Carvedilol	V	1	0	Resolution of tachycardia with carvedilol
Richards et al,⁸⁹ 2016	Case report	Labetalol	V	1	0	Resolution of tachycardia, hypertension with labetalol
Richards et al,⁹⁰ 2016	Case report	Labetalol	V	1	0	Resolution of tachycardia, hypertension with labetalol
		Total		2124	7

^aOxford Centre for Evidence-Based Medicine (CEBM) levels of evidence. I = properly powered and conducted randomized clinical trial, systematic review, or meta-analysis; II = well-designed controlled trial without randomization; prospective comparative cohort; III = case-control studies, retrospective cohort studies; IV = case series with or without intervention, cross-sectional studies; and V = opinion of authorities, case reports.⁹¹

Table 2.

Deleterious Characteristics of Cocaine: Potential for Unpredictable Cardiovascular Toxicity in the Absence or Presence of β-Blockers.

Excess catecholamines from reuptake inhibition in the CNS and peripheral circulation^4,17

α-Stimulation resulting in vasoconstriction^{4,17,92,93,94}

β-Stimulation resulting in tachycardia and increased risk of dysrhythmia^4,17,95

Blockade of sodium and potassium channels with increased risk of dysrhythmia⁹⁶

Increased risk of thrombosis from platelet activation⁹⁷

Increased intracellular calcium and increased risk of dysrhythmia^96,98

Inhibition of peripheral arterial baroreceptors with altered baroreflex^99

-102

Acceleration of coronary arterial disease and enhanced vasoconstriction in diseased segments⁹²

Enhanced coronary microvascular disease^94,103

Additive vasoconstrictive effects in the presence of cigarette smoking⁹³

Generation of reactive oxygen and nitrogen species altering autoregulation of cardiac blood flow^104,105

Stimulation of the vasoconstrictor endothelin^106,107

Inhibition of NO production and associated vasodilation^106,107

Damage to coronary endothelium with increased sensitivity to vasoconstrictors¹⁰⁸

Direct cardiomyotoxicity from membrane oxidative damage and early apoptosis^{104,105,109,110}

Alteration of parasympathetic response with decreased heart rate variability^111,112

Abbreviations: CNS, central nervous system; NO, nitric oxide.

Cocaine has many pharmacologic properties that are potentially lethal in the absence of β-blockers.¹¹³ The danger of cocaine cardiovascular toxicity was first published in 1911.¹¹⁴ Cocaine-induced catecholamine stimulation may lead to sudden and unforeseeable epicardial and microvascular vasoconstriction through α-adrenoceptor stimulation, and the contribution of β2-adrenoceptor-mediated vasodilation is minor compared to α-adrenoceptor-mediated vasoconstriction.¹¹⁵ The contribution of feedback inhibition of vasoconstriction from presynaptic α-adrenoceptors may be much more important in this regard.¹¹⁶ Thus, the unopposed α-stimulation effect from β2-blockade may be overemphasized. The activation of α-adrenoceptor has been shown to increase cardiac myocyte calcium levels, trigger delayed afterdepolarizations and induce dysrhythmias, further placing even a first-time cocaine user at risk of sudden death in the absence of β-blockers.⁹⁸

Cocaine-induced stimulation of β1-adrenoceptors results in tachycardia, which in and of itself may contribute significantly to the development of malignant dysrhythmias.⁹⁵ In addition to promoting coronary arterial disease, cocaine-induced vasoconstriction is more pronounced in atherosclerotic coronary artery segments than in normal segments.⁹² Cocaine use with cigarette smoking also has additive effects on vasoconstriction of coronary arteries.⁹³ Even in the absence of coronary epicardial disease, cocaine causes microvascular disease.^94,103 The effects of cocaine may also vary between individuals secondary to pharmacogenetics, in that polymorphisms between β1- and β2-adrenoceptors may lead to alteration of predicted responses to catecholamines.¹¹⁷

Hyperadrenergic states such as that induced by moderate to strenuous exercise increase myocardial oxygen consumption that is matched by increased coronary blood flow through endothelial and metabolic coronary vasodilation, mediated by endothelial adenosine, NO, adenosine triphosphate–dependent potassium channels, and many other vasoactive agents.^118,119 This autoregulation is independent of the sympathetic nervous system and may be altered from cocaine-generated reactive oxygen and nitrogen species.^104,105 Cocaine stimulates the release of endothelin, a vasoconstrictor, and inhibits production of NO, a vasodilator, within endothelial cells.^106,107 Cocaine users may demonstrate coronary endothelial dysfunction, which increases the sensitivity to the vasoconstrictive effects of catecholamines.¹⁰⁸ Cardiac oxidative stress may occur soon after cocaine use and lead to damage and early apoptosis from peroxidation of membrane phospholipids and depletion of nonenzymatic antioxidants, such as glutathione.^104,105 The cardiomyotoxicity of cocaine is believed to be a major factor in the development of cardiomyopathy and heart failure.^109,110

The autonomic nervous system modulates the homeostatic balance of blood pressure through its influence on the heart and vascular smooth muscle. Parasympathetic nerves, through muscarinic acetylcholine receptors, counteract the positive chronotropic effect of the sympathetic nervous system on the heart.¹²⁰ Parasympathetic stimulation also influences norepinephrine release through presynaptic receptors.¹¹⁶ Vascular smooth muscle tension, maintained by sympathetic nerve activity, is opposed by metabolic endothelial vasodilators such as NO. Afferent baroreceptor feedback to the CNS is an essential element of blood pressure homeostasis and is impaired in hypertensive disease, leading to elevated resting blood pressure, heart rate, and total peripheral vascular resistance.¹²¹ An elevated heart rate at rest has been shown to be a significant predictor of cardiovascular morbidity.¹²² Cocaine has been shown to disturb the balance between cardiac autonomic neural systems by decreasing heart rate variability, a marker of cardiac parasympathetic vagal tone.^111,112

Cocaine may not elicit hypertension and tachycardia due to direct catecholamine effects but instead by altering CNS-mediated parasympathetic acetylcholinergic responses, sympathetic nerve activity, and baroreflex inhibition.^99

-102 Sympathetic activation and sodium and potassium-channel blockade by cocaine increases propensity for life-threatening and unpredictable dysrhythmias, which may be an important factor in prehospital cocaine-related deaths.⁹⁶ Finally, cocaine increases platelet activation, von Willebrand factor and α-granule release, and microaggregate formation with potential for sudden, unpredictable coronary arterial thrombosis.⁹⁷

Combined β1-/β2-/α1-Blockers

No unopposed α-stimulation events have been reported with the use of the combined β1-/β2-/α1-blockers labetalol or carvedilol in the setting of cocaine use.* It is recognized that β-/α-blockade is advantageous to β-blockade alone in patients with ischemic heart disease.^123
-125 If we prudently assume there is a risk of unopposed α-stimulation with β-blockers, then treatment with combined β-/α-blockers makes sense. The use of labetalol for the treatment of cocaine- and methamphetamine-associated chest pain has been sanctioned in an update of the American College of Cardiology/American Heart Association guidelines for the management of patients with unstable angina and non-ST-elevation myocardial infarction as Class IIb: “Administration of combined alpha- and beta-blocking agents (e.g., labetalol) may be reasonable for patients after cocaine use with hypertension (systolic blood pressure greater than 150 mm Hg) or those with sinus tachycardia (pulse greater than 100 bpm) provided that the patient has received a vasodilator, such as nitroglycerin or a calcium channel blocker, within close temporal proximity (i.e., within the previous hour). (Level of Evidence: C)”¹²⁶

Conclusion

The most effective single-agent treatment of cocaine cardiovascular toxicity would safely and predictably mitigate tachycardia, hypertension, coronary arterial vasoconstriction, chest pain, and agitation. Based on a recent comprehensive systematic review of this topic, no such single-agent exists, and as such, the treating clinician must choose from a variety of drug classes.⁶ From their review, Richards and colleagues determined benzodiazepines, calcium channel blockers, α1-blockers, α2-agonists, and NO-mediated vasodilators were more effective for treatment of hypertension than tachycardia.⁶ β-Blockers were most effective for the treatment of concomitant hypertension and tachycardia.

Further research is needed to fully explain the significance of the unopposed α-stimulation phenomenon with β-blocker use. As with any drug, the pharmacology, expected outcome, potential unique adverse effects, and risk/benefit ratio must be taken into consideration by the prescribing clinician. Regarding the benefit of β-blocker treatment in cocaine cardiovascular toxicity, methodologically sound evidence supporting a beneficial effect on patient outcomes is lacking. Unopposed α-stimulation after β-blocker treatment of patients with cocaine toxicity is an inconsistent, unpredictable, and rare phenomenon. The myriad deleterious pharmacologic effects of cocaine alone may also be responsible for the outcomes of previously published case reports describing unopposed α-stimulation.

Footnotes

Acknowledgments

The authors would like to thank Gerd Heusch, University for Essen School of Medicine, Germany, for their expert assistance.

Author Contributions

J. R. Richards contributed to conception, design, acquisition, analysis, and interpretation and drafted the manuscript. J. E. Hollander, E. A. Ramoska, F. N. Fareed, I. C. Sand, and M. M. Izquierdo Gomez contributed to conception, design, analysis, and interpretation. R. A. Lange contributed to conception, design, acquisition, analysis, and interpretation. All authors critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Notes

References

United Nations Office on Drugs and Crime. World Drug Report 2016. http://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf. Accessed July 11, 2016.

Substance Abuse and Mental Health Services Administration. Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. http://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf. Accessed July 11, 2016.

Substance Abuse and Mental Health Services Administration. National estimates of drug-related emergency department visits. 2011. http://www.samhsa.gov/data/2k13/DAWN2k11ED/DAWN2k11ED.htm. Accessed July 11, 2016.

Stankowski

Kloner

Rezkalla

. Cardiovascular consequences of cocaine use. Trends Cardiovasc Med. 2015;25(6):517–526.

Cain

Bornick

Whiteman

. The maternal, fetal, and neonatal effects of cocaine exposure in pregnancy. Clin Obstet Gynecol. 2013;56(1):124–132.

Richards

Garber

Laurin

. Treatment of cocaine cardiovascular toxicity: a systematic review. ClinToxicol (Phila). 2016;54(5):345–364.

Albertson

Dawson

de Latorre

; American Heart Association; International Liaison Committee on Resuscitation. TOX-ACLS: toxicologic-oriented advanced cardiac life support. Ann Emerg Med. 2001;37(4 suppl): S78–S90.

McCord

Jneid

Hollander

; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117(14):1897–1907.

Gupta

Greller

Hoffman

. Beta-blockers and cocaine: still a bad idea. Arch Intern Med. 2010;170(20):1859–1860.

10.

Freeman

Feldman

. Cocaine, myocardial infarction, and beta-blockers: time to rethink the equation? Ann Emerg Med. 2008;51(2):130–134.

11.

Leikin

. Cocaine and beta-adrenergic blockers: a remarriage after a decade-long divorce? Crit Care Med. 1999;27(4):688–689.

12.

Page

II Utz

Wolfel

. Should beta-blockers be used in the treatment of cocaine-associated acute coronary syndrome? Ann Pharmacother. 2007;41(12):2008–2013.

13.

Finkel

Marhefka

. Rethinking cocaine-associated chest pain and acute coronary syndromes. Mayo Clin Proc. 2011;86(12):1198–1207.

14.

Mariani

. Beta-blockers following cocaine use: a reappraisal. Ann Emerg Med. 2008;52(1):89;author reply 89-90.

15.

Schurr

Gitman

Belchikov

. Controversial therapeutics: the β-adrenergic antagonist and cocaine-associated cardiovascular complications dilemma. Pharmacotherapy. 2014;34(12):1269–1281.

16.

Heusch

. The paradox of α-adrenergic coronary vasoconstriction revisited. J Mol Cell Cardiol. 2011;51(1):16–23.

17.

Pifl

Drobny

Reither

Hornykiewicz

Singer

. Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter. MolPharmacol. 1995;47(2):368–373.

18.

Chilian

Layne

Eastham

Marcus

. Heterogeneous microvascular coronary α1- and α2-adrenergic vasoconstriction. Circ Res. 1989;64(2):376–388.

19.

Chen

Dai

Zimmerman

Bache

. Postsynaptic α1- and α2-adrenergic mechanisms in coronary vasoconstriction. J Cardiovasc Pharmacol. 1988;11(1):61–67.

20.

Jones

CJH

DeFily

Patterson

Chilian

. Endothelium-dependent relaxation competes with α1- and α2-adrenergic constriction in the canine epicardial coronary microcirculation. Circulation. 1993;87(4):1264–1276.

21.

DeFily

Patterson

Chilian

. Endogenous adenosine modulates α2- but not α1-adrenergic constriction of coronary arterioles. Am J Physiol. 1995;268(6 pt 2): H2487–H2494.

22.

Woo

Xiao

. β-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin. 2012;33(3):335–341.

23.

Bevilacqua

Savonitto

Bosisio

. Role of the Frank-Starling mechanism in maintaining cardiac output during increasing levels of treadmill exercise in beta-blocked normal men. Am J Cardiol. 1989;63(12):853–857.

24.

Ramoska

Sacchetti

. Propranolol-induced hypertension in treatment of cocaine intoxication. Ann Emerg Med. 1985;14(11):1112–1113.

25.

Lange

Cigarroa

Flores

. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med. 1990;112(12):897–903.

26.

Boehrer

Moliterno

Willard

Hillis

Lange

. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med. 1993;94:608–610.

27.

Sand

Brody

Wrenn

Slovis

. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med. 1991;9(2):161–163.

28.

Fareed

Chan

Hoffman

. Death temporally related to the use of a Beta adrenergic receptor antagonist in cocaine associated myocardial infarction. J Med Toxicol. 2007;3(4):169–172.

29.

Izquierdo Gómez

Domínguez-Rodríguez

Gálvez Rodríguez

Marrero Rodríguez

. Reflections on beta-adrenergic receptor blockers and cocaine use. A case in point. Rev Esp Cardiol. 2009;62(4):455–456.

30.

Guinn

Bedford

Wilson

. Antagonism of intravenous cocaine lethality in nonhuman primates. Clin Toxicol. 1980;16(4):499–508.

31.

Smith

Garner

Niemann

. Pharmacologic interventions after an LD50 cocaine insult in a chronically instrumented rat model: are beta-blockers contraindicated? Ann Emerg Med. 1991;20(7):768–771.

32.

Vargas

Gillis

Ramwell

. Propranolol promotes cocaine-induced spasm of porcine coronary artery. J Pharmacol Exp Ther. 1991;257(2):644–646.

33.

Yancy

Jessup

Bozkurt

; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16): e147–e239.

34.

Rosendorff

Lackland

Allison

; American Heart Association, American College of Cardiology, and American Society of Hypertension. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens. 2015;9(6):453–498.

35.

Jauch

Saver

Adams

Jr ; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947.

36.

Bahn Chair

Burch

Cooper

; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21(6):593–646.

37.

Committee on Obstetric Practice. Committee Opinion no. 514: emergent therapy for acute-onset, severe hypertension with preeclampsia or eclampsia. Obstet Gynecol. 2011;118(6):1465–1468.

38.

Ibrahim

Viswanathan

. Management of agitation following aneurysmal subarachnoid hemorrhage: is there a role for Beta-blockers? Case Rep Psychiatry. 2012;2012:753934.

39.

Flores

Stockton

Roberts

Muller

Paratz

. The efficacy and safety of adrenergic blockade after burn injury: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2016;80(1):146–155.

40.

Morelli

Ertmer

Westphal

. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310(16):1683–1691.

41.

Kähkönen

. Responses to cardiovascular drugs during alcohol withdrawal. Alcohol Alcohol. 2006;41(1):11–13.

42.

Alali

McCredie

Golan

Shah

Nathens

. Beta blockers for acute traumatic brain injury: a systematic review and meta-analysis. Neurocrit Care. 2014;20(3):514–523.

43.

Bukur

Lustenberger

Cotton

. Beta-blocker exposure in the absence of significant head injuries is associated with reduced mortality in critically ill patients. Am J Surg. 2012;204(5):697–703.

44.

Vongpatanasin

Mansour

Chavoshan

Arbique

Victor

. Cocaine stimulates the human cardiovascular system via a central mechanism of action. Circulation. 1999;100(5):497–502.

45.

Sofuoglu

Brown

Babb

Pentel

Hatsukami

. Carvedilol affects the physiological and behavioral response to smoked cocaine in humans. Drug Alcohol Depend. 2000;60(1):69–76.

46.

Sofuoglu

Brown

Babb

Pentel

Hatsukami

. Effects of labetalol treatment on the physiological and subjective response to smoked cocaine. Pharmacol Biochem Behav. 2000;65(2):255–259.

47.

Vongpatanasin

Taylor

Victor

. Effects of cocaine on heart rate variability in healthy subjects. Am J Cardiol. 2004;93(3):385–388.

48.

Orr

Jones

. Anaesthesia for laryngoscopy. a comparison of the cardiovascular effects of cocaine and lignocaine. Anaesthesia. 1968;23(2):194–202.

49.

Hoskins

Leleiko

Ramos

Sola

Caneer

Khan

. Effects of labetalol on hemodynamic parameters and soluble biomarkers of inflammation in acute coronary syndrome in patients with active cocaine use. J Cardiovasc Pharmacol Ther. 2010;15(1):47–52.

50.

Brody

Slovis

Wrenn

. Cocaine-related medical problems: consecutive series of 233 patients. Am J Med. 1990;88(4):325–331.

51.

Dattilo

Hailpern

Fearon

Sohal

Nordin

. Beta-blockers are associated with reduced risk of myocardial infarction after cocaine use. Ann Emerg Med. 2008;51(2):117–125.

52.

Mohamad

Kondur

Vaitkevicius

Bachour

Thatai

Afonso

. Cocaine-induced chest pain and beta-blockade: an inner city experience. Am J Ther. 2008;15(6):531–535.

53.

Rangel

Shu

Lazar

Vittinghoff

Hsue

Marcus

. Beta-blockers for chest pain associated with recent cocaine use. Arch Intern Med. 2010;170(10):874–879.

54.

Ibrahim

Maselli

Hasan

Hamilton

. Safety of β-blockers in the acute management of cocaine-associated chest pain. Am J Emerg Med. 2013;31(3):613–616.

55.

Fanari

Kennedy

Lim

Laddu

Stolker

. Comparison of in-hospital outcomes for beta-blocker use versus non-beta blocker use in patients presenting with cocaine-associated chest pain. Am J Cardiol. 2014;113(11):1802–1806.

56.

Gupta

Washam

Mountantonakis

. Characteristics, management, and outcomes of cocaine-positive patients with acute coronary syndrome (from the National Cardiovascular Data Registry). Am J Cardiol. 2014;113(5):749–756.

57.

Chibungu

Gundareddy

Wright

. Management of Cocaine-Induced Myocardial Infarction: 4-Year Experience at an Urban Medical Center. South Med J. 2016;109(3):185–190.

58.

Rappolt

Gay

Inaba

. Propranolol: a specific antagonist to cocaine. Clin Toxicol. 1977;10(3):265–271.

59.

Meyers

. Cocaine toxicity during dacryocystorhinostomy. Arch Ophthalmol. 1980;98(5):842–843.

60.

Riggs

Weibley

. Acute toxicity from oral ingestion of crack cocaine: a report of four cases. Pediatr Emerg Care. 1990;6(1):24–26.

61.

Minor

Jr Scott

Brown

Winniford

. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann Intern Med. 1991;115(10):797–806.

62.

Merigian

Park

Leeper

Browning

Giometi

. Adrenergic crisis from crack cocaine ingestion: report of five cases. J Emerg Med. 1994;12(4):485–490.

63.

Nicholson

Rogers

. Cocaine and adrenaline paste: a fatal combination? BMJ. 1995;311(6999):250–251.

64.

Gay

. Letter: Propranolol combats cocaine effects. JACEP. 1976;5(7):549.

65.

Rappolt

Gay

Inaba

Rappolt

. Propranol in cocaine toxicity. Lancet. 1976;2(7986):640–641.

66.

Rappolt

Sr Gay

Inaba

Rappolt

Jr . Use of Inderal (propranolol-Ayerst) in I-a (early stimulative) and I-b (advanced stimulative) classification of cocaine and other sympathomimetic reactions. Clin Toxicol. 1978;13(2):325–332.

67.

Jonsson

O’Meara

Young

. Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med. 1983;75(6):1061–1064.

68.

el-Din

Mostafa

. Severe hypertension during anaesthesia for dacryocystorhinostomy. Anaesthesia. 1985;40(8):787–789.

69.

Dusenberry

Hicks

Mariani

. Labetalol treatment of cocaine toxicity. Ann Emerg Med. 1987;16(2):235.

70.

Ascher

Stauffer

Gaasch

. Coronary artery spasm, cardiac arrest, transient electrocardiographic Q waves and stunned myocardium in cocaine-associated acute myocardial infarction. Am J Cardiol. 1988;61(11):939–941.

71.

Gay

Loper

. The use of labetalol in the management of cocaine crisis. Ann Emerg Med. 1988;17(3):282–283.

72.

Burton

Martin

Murray

Muniz

. Hyperthyroidism in a cocaine-dependent patient. J Clin Psychiatry. 1989;50(8):305–306.

73.

Pollan

Tadjziechy

. Esmolol in the management of epinephrine- and cocaine-induced cardiovascular toxicity. Anesth Analg. 1989;69(5):663–664.

74.

Samuels

Schwalbe

Marx

. Speedballs: a new cause of intraoperative tachycardia and hypertension. Anesth Analg. 1991;72(3):397–398.

75.

Merigian

. Cocaine-induced ventricular arrhythmias and rapid atrial fibrillation temporally related to naloxone administration. Am J Emerg Med. 1993;11(1):96–97.

76.

Malbrain

Neels

Vissers

. A massive, near-fatal cocaine intoxication in a body-stuffer. Case report and review of the literature. Acta Clin Belg. 1994;49(1):12–18.

77.

Singh

Dimich

Shamsi

. Intraoperative pulmonary oedema in a young cocaine smoker. Can J Anaesth. 1994;41(10):961–964.

78.

Williams

Kavanagh

Teo

. Pathophysiology and treatment of cocaine toxicity: implications for the heart and cardiovascular system. Can J Cardiol. 1996;12(12):1295–1301.

79.

Inyang

Cooper

Hodgkinson

. Cocaine induced myocardial infarction. J Accid Emerg Med. 1999;16(5):374–375.

80.

Laffey

Neligan

Ormonde

. Prolonged perioperative myocardial ischemia in a young male: due to topical intranasal cocaine? J Clin Anesth. 1999;11(5):419–424.

81.

Missouris

Swift

Singer

. Cocaine use and acute left ventricular dysfunction. Lancet. 2001;357(9268):1586.

82.

Ortega-Carnicer

Bertos-Polo

Gutiérrez-Tirado

. Aborted sudden death, transient Brugada pattern, and wide QRS dysrhythmias after massive cocaine ingestion. J Electrocardiol. 2001;34(4):345–349.

83.

Erwin

Deliargyris

. Cocaine-associated chest pain. Am J Med Sci. 2002;324(1):37–44.

84.

Mégarbane

Ekhérian

Couchard

Goldgran-Tolédano

Baud

. Surgery to save body-packers [In French]. Ann Fr Anesth Reanim. 2004;23(5):495–498.

85.

Feldhendler

May

Gandhi

. A triple-lumen aorta: an unusual manifestation of complex aortic pathology associated with crack cocaine abuse. J Cardiothorac Vasc Anesth. 2007;21(3):462–464.

86.

Javed

Benjo

Reddy

. Dexmedetomidine use in the setting of cocaine-induced hypertensive emergency and aortic dissection: a novel indication. Case Rep Med. 2011;2011:174132. doi:10.1155/2011/174132.

87.

Martinez-Quintana

Jaimes-Vivas

Cuba-Herrera

Saiz-Udaeta

Rodríguez-Gonzalez

Martinez-Martin

. Acute myocardial infarction secondary to catecholamine release owing to cocaine abuse and pheochromocytoma crisis. Int J Endocrinol Metab. 2013;11(1):48–51.

88.

Öcal

Çakir

Tellice

İzci

Alizade

Esen

. Successful treatment of cocaine-induced cardiotoxicity with carvedilol therapy. Herz. 2015;40(1):159–161.

89.

Richards

Lange

Arnold

Horowitz

. Dual cocaine and methamphetamine cardiovascular toxicity: rapid resolution with labetalol. Am J Emerg Med. 2017;35(3):519.e1–519.e4.

90.

Richards

Laurin

Tabish

Lange

. Acute toxicity from topical cocaine for epistaxis: treatment with labetalol. J Emerg Med. 2017;52(3):311–313.

91.

Oxford Centre for Evidence-Based Medicine. OCEBM Levels of Evidence. http://www.cebm.net/ocebm-levels-of-evidence/. Accessed October 8, 2015.

92.

Flores

Lange

Cigarroa

Hillis

. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol. 1990;16(1):74–79.

93.

Moliterno

Willard

Lange

. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med. 1994;330(7):454–459.

94.

Weber

Hollander

Murphy

Braunwald

Gibson

. Quantitative comparison of coronary artery flow and myocardial perfusion in patients with acute myocardial infarction in the presence and absence of recent cocaine use. J Thromb Thrombolysis. 2002;14(3):239–245.

95.

Kent

Smith

Redwood

Epstein

. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation. 1973;47(2):291–298.

96.

Hoffman

. Treatment of patients with cocaine-induced arrhythmias: bringing the bench to the bedside. Br J Clin Pharmacol. 2010;69(5):448–457.

97.

Heesch

Wilhelm

Ristich

Adnane

Bontempo

Wagner

. Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart. 2000;83(6):688–695.

98.

Terzic

Pucéat

Vassort

Vogel

. Cardiac alpha 1-adrenoceptors: an overview. Pharmacol Rev. 1993;45(2):147–175.

99.

Buccafusco

Davis

Shuster

Buccafusco

Gattu

. The importance of brainstem cholinergic neurons in the pressor response to cocaine. J Pharmacol Exp Ther. 2005;312(1):179–191.

100.

Tuncel

Wang

Arbique

Fadel

Victor

Vongpatanasin

. Mechanism of the blood pressure—raising effect of cocaine in humans. Circulation. 2002;105(9):1054–1059.

101.

Andresen

Yang

Nelson

Steinsland

. Cocaine inhibits baroreflex control of blood pressure by actions at arterial baroreceptors. Am J Physiol. 1990;258(4 pt 1): H1244–H12449.

102.

Trouvé

Nahas

Arnaoudov

Latour

. Effects of antidotes to cocaine on the deregulation of the baroreflex by the alkaloid. Proc Soc Exp Biol Med. 1996;212(3):239–242.

103.

Kelly

Sompalli

Sattar

Khankari

. Increased TIMI frame counts in cocaine users: a case for increased microvascular resistance in the absence of epicardial coronary disease or spasm. Clin Cardiol. 2003;26(7):319–322.

104.

Kovacic

. Role of oxidative metabolites of cocaine in toxicity and addiction: oxidative stress and electron transfer. Med Hypotheses. 2005;64(2):350–356.

105.

Cerretani

Fineschi

Bello

Riezzo

Turillazzi

Neri

. Role of oxidative stress in cocaine-induced cardiotoxicity and cocaine-related death. Curr Med Chem. 2012;19(33):5619–5623.

106.

Wilbert-Lampen

Seliger

Zilker

Arendt

. Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: reversal by coincubation with sigma-receptor antagonists. Circulation. 1998;98(5):385–390.

107.

Singh

Arruda

Dunea

. Role of nitric oxide in cocaine-induced acute hypertension. Am J Hypertens. 1998;11(6 pt 1):708–714.

108.

Havranek

Nademanee

Grayburn

Eichhorn

. Endothelium-dependent vasorelaxation is impaired in cocaine arteriopathy. J Am Coll Cardiol. 1996;28(5):1168–1174.

109.

Tazelaar

Karch

Stephens

Billingham

. Cocaine and the heart. Hum Pathol. 1987;18(2):195–199.

110.

Diercks

Fonarow

Kirk

; ADHERE Scientific Advisory Committee and Investigators. Illicit stimulant use in a United States heart failure population presenting to the emergency department (from the Acute Decompensated Heart Failure National Registry Emergency Module). Am J Cardiol. 2008;102(9):1216–1219.

111.

Billman

Lappi

. Effects of cocaine on cardiac vagal tone before and during coronary artery occlusion: cocaine exacerbates the autonomic response to myocardial ischemia. J Cardiovasc Pharmacol. 1993;22(6):869–876.

112.

Newlin

. Effect of cocaine on vagal tone: a common factors approach. Drug Alcohol Depend. 1995;37(3):211–216.

113.

Degenhardt

Singleton

Calabria

. Mortality among cocaine users: a systematic review of cohort studies. Drug Alcohol Depend. 2011;113(2-3):88–95.

114.

Price

Leakey

. Grave and prolonged cardiac failure following the use of cocaine in dental surgery. Lancet. 1911;1(4569):797–799.

115.

Heusch

. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153(8):1589–1601.

116.

Boehm

Kubista

. Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol Rev. 2002;54(1):43–99.

117.

Leineweber

Heusch

. Beta 1- and beta 2-adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol. 2009;158(1):61–69.

118.

Tune

Gorman

Feigl

. Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol (1985). 2004;97(1):404–415.

119.

Costa

Carvalho

Bastos

Carvalho

Remião

. Contribution of catecholamine reactive intermediates and oxidative stress to the pathologic features of heart diseases. Curr Med Chem. 2011;18(15):2272–2314.

120.

Berg

Jensen

. Simultaneous parasympathetic and sympathetic activation reveals altered autonomic control of heart rate, vascular tension, and epinephrine release in anesthetized hypertensive rats. Front Neurol. 2011;2:71.

121.

Palatini

Julius

. The role of cardiac autonomic function in hypertension and cardiovascular disease. Curr Hypertens Rep. 2009;11(3):199–205.

122.

Tjugen

Flaa

Kjeldsen

. The prognostic significance of heart rate for cardiovascular disease and hypertension. Curr Hypertens Rep. 2010;12(3):162–169.

123.

Taylor

Silke

Nelson

Okoli

Ahuja

. Haemodynamic advantages of combined alpha-blockade and beta-blockade over beta-blockade alone in patients with coronary heart disease. Br Med J (Clin Res Ed). 1982;285(6338):325–327.

124.

Opie

. Role of vasodilation in the antihypertensive and antianginal effects of labetalol: implications for therapy of combined hypertension and angina. Cardiovasc Drugs Ther. 1988;2(3):369–376.

125.

Feldman

Prida

Lambert

Hill

. Systemic and coronary hemodynamics of labetalol in normotensive patients with ischemic heart disease. Cardiovasc Drugs Ther. 1988;2(3):355–361.

126.

Anderson

Adams

Antman

. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(23):e290.

β-Blockers,Cocaine,and the Unopposed α-Stimulation Phenomenon

Abstract

Keywords

Introduction

Unopposed α-Stimulation

What Is the Evidence?

Alternative Explanations of the Phenomenon

Combined β1-/β2-/α1-Blockers

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

Notes

References