Introduction

 
     
     Pharmacologic agents and illegal drugs may induce a wide range of serious cardiovascular effects, when taken in excess. There are many drugs that directly or indirectly affect the cardiovascular system. One of the most dangerous and commonly abused substance is cocaine, and its use has become widespread around the world. Cocaine induces a wide variety of cardiovascular symptoms such as tachycardia, hypertension, ventricular arrhythmias, cardiac ischemia, acute myocardial infarction (AMI), syncope, and peripheral vasospasm.

    There have been increasing reports of AMI in persons using cocaine. It is well known that physical and psychosocial stress can trigger the onset of acute myocardial infarction (AMI), but the mechanisms involved in cocaine-induced AMI are not well understood. The purpose of this article is to review briefly the underlying mechanisms implicated in AMI by cocaine.


Origins of Cocaine Abuse


    Cocaine is an alkaloid extracted from the leaves of the Erythroxylum coca plant. The Indians of South America have relied on its stimulating and medicinal properties for thousands of years. With the invasion and conquest of the Inca Empire, knowledge of the euphoric effects of coca-chewing became known in Europe, and coca-chewing became fashionable. Cocaine was isolated from the coca leaves in the 1880s (1), and Sigmund Freud described it as a medical panacea, a view shared by many of his contemporaries(2). The medical community recommended its use in the treatment of opiate addiction. The “wonder drug” soon began to be taken for hedonistic purposes.

    In the United States of America (USA), it was sold in various forms such as cigarettes, cigars, inhalants, coca liquors, inhalants, crystals, and solutions. There were no laws restricting the consumption or sale of cocaine. Cocaine was added to a variety of over-the-counter items and to alcoholic drinks and soda pop drinks, such as Coca-cola, which contained enough cocaine to produce euphoria. One pick me-up drink was sold simply as Dope (3). However, chronic cocaine abuse began to surface. The harmful effects of the drug became apparent and in 1914, the US Congress passed a law tightly regulating the distribution and sale of cocaine. This brought to an end the first cocaine epidemic in the USA (2).

    The second wave of large-scale cocaine use in the USA began at the end of the 1960s, and increased steadily but relatively slowly until the early 1980s when a rapid rise in consumption took place, which was largely due to the widespread availability of inexpensive crack cocaine. Cocaine-use continues to increase worldwide despite intensive efforts by governments to curb its use. Thus, an increase in the number of cocaine-related cardiovascular events and deaths can be anticipated because of the popularity and increasing availability of the drug.


Pharmacology


    In 1855, Albert Niemann isolated the psychoactive alkaloid from the leaf of the coca plant (2) and he named it cocaine. Freud, having tested the effects of cocaine on himself many times, produced the first major report on the effects of cocaine in 1884.

    Von Anrep published the pharmacological effects of cocaine in 1880. He noted that in addition to being a potent local anesthetic agent, cocaine was also a potent vasoconstrictor. It was introduced in 1884 as the first local anesthetic and it rapidly gained popularity in ophthalmology and dentistry. The local anesthetic effect of cocaine is due to its ability to block the initiation and conduction of electrical impulses within nerve cells by preventing the rapid increase in cell-membrane permeability to sodium ions during depolarization (4).

   The systemic effects of cocaine on the nervous system are probably mediated by alterations in synaptic transmission. It blocks the presynaptic reuptake of the neurotansmitters norepinephrine and dopamine, producing an excess of transmitter at the postsynaptic receptor sites (4). This results in activation of the sympathetic nervous system with consequent vasoconstriction, an acute rise in arterial pressure, tachycardia, and a predisposition to ventricular arrhythmias and seizures.

   The euphoria induced by cocaine appears to be due to stimulation of dopaminergic transmission by blocking the reuptake of dopamine. There is evidence though, that with long-term use, the nerve terminals may become depleted of dopamine, and it has been hypothesized that dopmanine depletion may contribute to the dysphoria that develops during withdrawal and the subsequent craving for more of the drug (1).


Preparation and Forms


   The active product extracted from its natural source, the coca leaf, is cocaine hydrochloride, which is prepared by dissolving the alkaloid in hydrochloric acid to form a water-soluble salt, the form available for medicinal use. It is marketed in the from of crystals, granules or a white powder, which is slightly bitter and numbs the tongue and lips (1)

   The cocaine alkaloid or “free base” is soluble in alcohol, acetone, oils, and ether. It is a colorless, odorless, transparent crystalline substance that is almost insoluble in water.
Because cocaine hydrochloride is not volatile, heating results in degradation; however, the nonionized molecule vaporizes at low temperatures, allowing vapors to be inhaled. The nonionized form is known as crack. Abusers who inhale the vapor, which is rapidly absorbed by the lungs, can experience a rush similar to intravenous use, increasing the risk of acute cardiovascular complications (4).

   Crack cocaine is the more popular form because it is readily available and inexpensive. The most common method of smoking crack cocaine is with a glass or regular pipe, or mixing with tobacco or marijuana in cigarettes. The cocaine freebase can be mixed with tobacco and smoked, or heated in special cocaine pipes and inhaled.

   Cocaine is injected intravenously or intramuscularly. Because cocaine can be absorbed through any mucous membrane, it can be snorted or inhaled. Plasma half-life is short, ranging from 0.5 to 1.5 hours (5). The highest concentrations appear in the brain, spleen, kidney, and lung. Although cocaine is rapidly cleared from plasma, it is more slowly cleared from other tissues, and can be detected in the brain, ocular fluid, and liver for 8 or more hours after initial use.


Cardiac Ischemia and Myocardial Infarction


   Reports from case-series have demonstrated that cocaine use can trigger the onset of myocardial infarction in patients with and those without underlying coronary atherosclerosis.

   Although there are occasional clinical cases of AMI reported in the literature (7-10), the true incidence of cocaine-induced AMI is not known. Of the reported cases, cocaine users tended to be young (mean age in the 30s), male, current cigarette smokers, and minority group members. Most used the drug chronically, and only a few claimed to have been first time users. The route of administration is commonly intranasal, intravenous, or by smoking. The time from intake to onset of symptoms appears to be highly variable, ranging from minutes to several hours. A recent study (11) found that the risk of myocardial infarction onset was elevated 23.7 times over baseline in the 60 minutes after cocaine use. The elevated risk rapidly decreased thereafter.

   Besides myocardial infarction, ischemic chest pain without infarction also has been described. These episodes may be associated with ST-T wave abnormalities on the ECG. One study (12) found that this subgroup had normal epicardial coronary arteries on angiography, but marked thickening of the walls of the intramural coronary arteries. Other investigators (13) have documented frequent episodes of transient ST segment elevation (similar to that observed in patients with Prinzmetal’s angina) on ambulatory ECG monitoring of chronic cocaine users during the first two weeks of withdrawal from cocaine. 87% of these episodes were silent. Coronary vasospasm has been implicated as the underlying cause.

Triggers of myocardial infarction

   A proposed mechanism for triggering of AMI is that onset occurs when a vulnerable but not necessarily stenotic atherosclerotic plaque disrupts in response to hemodynamic stresses. Thereafter, hemostatic and vasoconstrictive forces determine whether the resultant thrombus becomes occlusive (14,15). Thus, there are several pathways through which cocaine may induce AMI.


Increased myocardial oxygen demand
and coronary vasoconstriction


     Within 15 minutes of intranasal administration of even low doses of cocaine, vasoconstriction has been shown to occur angiographically in both normal and diseased segments of coronary arteries through stimulation of a-adrenergic receptors (16). This adrenergic stimulation increases the heart rate, blood pressure, and left ventricular contractility, so that the metabolic requirement of the heart for oxygen increases (17). Concomitantly, myocardial oxygen supply declines because of cocaine-induced vasoconstriction of the coronary arteries. Most patients who present with AMI or sudden death are young or middle-aged men who are smokers and who smoke while using cocaine. Cocaine freebase is also mixed with tobacco and smoked in cigarettes. The majority of cocaine users who have had AMI or who died suddenly have angiographic or postmortem evidence of coronary artery disease (18). Studies have shown that cigarette smoking causes coronary vasoconstriction (19,20). In short, cocaine use and cigarette smoking each increase myocardial oxygen demand and simultaneously reduce oxygen supply. Since cocaine abusers often smoke while they are ingesting cocaine, the combination of cocaine use with smoking probably induce an even greater increase in myocardial oxygen demand and a more marked decrease in coronary arterial diameter, culminating in myocardial ischemia, infarction, or sudden death. Studies have shown that the magnitude of angiographic reduction in coronary artery diameter caused by simultaneous cocaine use and smoking is greater than that caused by either cocaine use or smoking alone (16).


Increased platelet aggregability


    Cocaine use has been associated with thrombosis of coronary as well as peripheral arteries. There is evidence that increased platelet activation may be the cause of cocaine-associated acute arterial occlusion and the accelerated, often atypical atherosclerotic lesion, which has been observed in cocaine users. Indeed, cocaine has been documented to cause an increase in platelet aggregability in vivo (21) and in vitro testing (22). Furthermore, angiographic studies have shown that some patients who had myocardial infarction after cocaine use had occlusive thrombi at nonstenotic sites within their coronary arteries (8,9,16,). Accelerated atherosclerosis has been detected in young cocaine users (9). It is possible that the development of such subclinical disease may contribute to the likelihood that a habitual cocaine user will have vulnerable atherosclerotic plaques present in their coronary vessels at the time of subsequent cocaine use.

   The mechanism by which cocaine causes platelet activation is not yet clear. It is believed that the increased catecholamine release such as norepinephrine and epinephrine might activate platelets directly or by induction of hemodynamic stress. Alternative theories implicate that the drug itself or its metabolites may induce platelet activation (21).


Endothelial dysfunction


    Little is known about the effect of cocaine on vascular endothelium, but it is speculated that the integrity of the coronary arterial endothelium may influence the vasomotor response that occurs with cocaine use,

    cigarette smoking, and their combination. Furthermore, each causes more intense vasoconstriction in diseased than non-diseased coronary segments, suggesting that the presence of functioning endothelium may attenuate cocaine-induced or smoking induced vasoconstriction (16).

    The direct vascular effects of cocaine are not fully understood. A recent study (23) suggests that cocaine increase endothelial release of endothelin-1, the most potent endogenous vasoconstrictor, which has been implicated in coronary vasoconstriction/vasospasm, myocardial ischemia, and infarction. As endothelin-1 has been found to increase the calcium sensitivity of human arteries, it may sensitize the vasculature to other vasoconstrictor stimuli and prolong coronary vasoconstriction or vasospasm, resulting in acute myocardial infarction without anatomic coronary stenosis (23). Animal models indicate that cocaine administration leads to a rapid rise in intracellular free Ca2 and a concomitant loss of intracellular Mg2 in vascular smooth muscle cells. These fluxes in in divalent cations may directly contribute to vasoconstriction (11).


CONCLUSIONS

 
    As cocaine abuse has become more common, reports of acute myocardial infarction after the use of cocaine have appeared with increasing frequency.

   Cocaine represents a potential hazard to anyone with underlying fixed coronary artery disease. The increased adrenergic stimulation caused by cocaine results in increases in heart rate, blood pressure, and myocardial oxygen demand. The pathophysiologic features of cocaine-related coronary occlusion remain uncertain, but current evidence suggests a transient focal coronary event, i.e., thrombosis or spasm.

   Cocaine is a risk factor for heart disease. Young patients who present with AMI, especially without other risk factors should be questioned regarding use of cocaine.



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