Cocaine Toxicity in Emergency Medicine 

The ancient Incas of Peru believed cocaine to be a gift from the gods. However, it is a modern-day curse to the emergency physician.^[1] Aside from alcohol and tobacco, cocaine is the most common cause of drug-related ED visits in the United States, accounting for 548,608 ED visits in 2006 (CI, 374,579 to 722,636), nearly twice the number according to the Drug Abuse Warning Network (DAWN) as marijuana or hashish, the second leading cause at 290,000 visits. Heroin-related visits are estimated at 190,000.

Patients who present to the ED with cocaine toxicity often also have other drugs present; in fact, the combined use of alcohol and cocaine may be the major cause of drug-related deaths.

Across the spectrum of acute and chronic effects, nearly every organ system can be effected. Trauma is often associated with cocaine use. Even the absence of cocaine may precipitate an ED visit due to withdrawal symptoms.

History of use and abuse

Use of cocaine spans thousands of years, with a duality of effects noted throughout history. Knowledge of its mind-altering function dates to at least 2000 BC. For centuries, indigenous mineworkers in Andean countries have used cocaine derived from the chewing of coca leaves as an endurance-enhancement agent. Spanish physicians reported the first European use of coca for medicinal purposes in 1596. Cocaine was not isolated from coca leaves until 1859. Nevertheless, by 1863, a wine fortified with 6 mg of cocaine alkaloid extract per ounce was marketed in France. By 1880, the US pharmaceutical company Parke-Davis sold a fluid extract containing 0.5 mg/mL of crude cocaine.

In 1884, William Stewart Halsted performed the first nerve block using cocaine as the anesthetic. Halsted subsequently became the first cocaine-impaired physician on record. That same year, Sigmund Freud published the essay "Uber Coca," in which he advocated the use of cocaine in the treatment of asthma, wasting diseases, and syphilis. As with Halsted, Freud also became dependent on cocaine. In 1885, John Styth Pemberton registered French Wine Cola in the United States. The popular product, which contained 60 mg of cocaine per 8-oz serving, was later renamed Coca-Cola.

By 1893, occasional reports of fatality were associated with cocaine use, and, in 1895, The Lancet reported a series of 6 deaths. By 1909, more than 10 tons of cocaine was being imported into the United States each year. Many over-the-counter medical products and elixirs had been created. One product for nasal application, called Dr. Tucker's Asthma Specific, contained 420 mg of cocaine per ounce.

The Harrison Narcotics Act of 1914 banned nonprescription use of cocaine-containing products. The resulting reduction in the use of cocaine marked the end of the first American cocaine epidemic. In the 1950s, amphetamine gradually replaced cocaine as the most common stimulant of abuse. However, this trend was reversed in the 1970s, with crack ushering in the second epidemic of US cocaine use in 1985.

Crack, which is generally sold in the form of "rocks," may also be sold in large pieces called slabs. These are approximately the size and shape of a stick of chewing gum and are sometimes scored to form smaller pieces. Users of cocaine in its crack form tend to be young adults aged 18-30 years who live in the central city and who are from low socioeconomic backgrounds. However, in 1986, the National Office of Drug Control Policy reported that young inner-city drug users were beginning to disdain crack as a ghetto drug. In Miami, for example, crack use had become unfashionable, and individuals continuing to use it, particularly African Americans, were trying to hide it from their peers.

Cocaine powder is currently marketed to adults from all ethnic backgrounds and socioeconomic groups, predominated by white men older than 30 years who live in the central city. In several locales, cocaine is mentioned as a club drug, but it is not as prominent as methamphetamine and some hallucinogens in the club environment.

Cocaine transported into the United States originates from coca plants in South America, 75% of which are in Columbia. In 2002, the National Drug Threat Intelligence Center reported that 353 metric tons of export-quality cocaine was available for US markets, with 75% passing through the Mexican–Central American corridor, 27% passing through the Caribbean, and 1% coming directly from South America.

In 2005, the US Government reported that retail-level prices for cocaine had increased, and purity had decreased. One gram of powder cocaine sold for an average of $100, although variation among major cities was noted: in New York City, for example, powder cocaine sold for $25-35 per gram, whereas in Detroit, a similar amount sold for $75-150. Crack cocaine, sold in the form of 0.1-0.2 g rocks, generally cost $10 per rock, with a price range of $2-40, depending on the size of the rock.

As reflected in the Synonyms, Key Words, and Related Terms, cocaine, alone or in combination, is known by a number of street names. The White House Office of National Drug Control Policy periodically updates street terms in its Drugs and the Drug Trade, a reference that may prove helpful when a patient uses an unfamiliar drug-related term. The clinician should always keep in mind that the drug a patient believes he or she purchased may not be what he or she received and took.

Pharmacology

The chemical name for cocaine is benzoylmethylecgonine. It is derived from the leaves of Erythroxylon coca, a shrub indigenous to Peru, Bolivia, Mexico, the West Indies, and Indonesia. Cocaine is a bitter crystalline alkaloid with the molecular formula of C₁₇ H₂₁ NO₄. Ecgonine, an important part of the cocaine molecule, is an ester-type local anesthetic that belongs to the tropane family, which also includes atropine and scopolamine.

The primary effect of cocaine is blockade of norepinephrine reuptake; its secondary effect is marked release of norepinephrine. These effects act synergistically to increase norepinephrine levels at the nerve terminal. Cocaine also causes moderate release and reuptake-blockade of serotonin and dopamine. Its marked local anesthetic effects are caused by sodium channel blockade, which inhibits the conduction of nerve impulses, decreasing the resting membrane potential and the amplitude of the action potential while simultaneously prolonging the duration of the action potential.

Cocaine also blocks potassium channels. In some cellular membranes, it may block sodium-calcium exchange. The drug is fat soluble and freely crosses the blood-brain barrier. Cocaine appears to stimulate the CNS, with particular activity in the limbic system. There, it potentiates dopaminergic transmission in the ventral basal nuclei, producing the pleasurable behavioral effects that result in its widespread use.

Cocaine enters the United States in the form of a hydrochloride salt, having undergone numerous steps in refinement from the original coca leaf. In its hydrochloride form, cocaine may be absorbed topically across all mucosal membranes, including the oral, nasal, GI, rectal, urethral, and vaginal membranes. It may also be injected intravenously or ingested. Ingested cocaine is poorly absorbed from the stomach because it is a weak base with a pKa of 8.6, but it is readily absorbed from the duodenum. Cocaine may be inhaled through a straw or rolled-up paper currency, or a coke spoon, typically containing 5-20 mg of the drug, may be used to snort cocaine. A 1-inch line typically contains 25-100 mg of the drug.

Crack is produced when the hydrochloride molecule is removed by ether extraction, which frees the basic cocaine molecule, or "freebase". Heating does not destroy freebase, rather it melts at 98°C and vaporizes at higher temperatures. These physical properties allow it to be smoked.

Crack is lipid soluble and therefore rapidly absorbed in the pulmonary capillaries. The term crack describes the crackling sound heard when cocaine freebase is smoked. Crack may be smoked in a pipe bowl containing 50-100 mg or in a cigarette with as much as 300 mg. Smoking crack bypasses the vasoconstriction that results when cocaine is snorted; therefore, the effects are similar to taking cocaine intravenously. Crack smokers may aggressively inhale against a small pipe and then perform a Valsalva maneuver before exhaling against pursed lips or forcefully blow the drug into a partner's mouth. These techniques are reputed to enhance the euphoria of cocaine.

Table 1. Onset of Effects, Peak Effects, Duration of Euphoria, and Plasma Half-Life by Routes of Administration (Open Table in a new window)

All of the cocaine injected intravenously is delivered to the circulatory system, versus 20-30% of cocaine that is ingested or inhaled. With repeated use, tolerance develops so that the intensity and duration of effect decrease. People who use cocaine long term may dose themselves as frequently as every 10 minutes, binge as long as 7 days at a time and use as much as 10 g/d. Reverse tolerance, with onset of seizures and paranoid ideation at decreased doses, has been observed in animals and is thought to occur in humans as well.

Approximately 30-50% of cocaine is metabolized by hepatic esterases and plasma pseudocholinesterase, resulting in the formation of ecgonine methyl ester. Spontaneous nonenzymatic hydrolysis of another 30-40% results in benzoylecgonine. Both products are water-soluble, metabolically active, and capable of increasing blood pressure (BP). Benzoylecgonine, which has a half-life of 7.5 hours, can induce seizures, perhaps even hours to days after the last use.

Approximately 80-90% of injected cocaine is rapidly metabolized. Decreased hepatic perfusion, secondary to conditions such as hypotension or low-output congestive heart failure (CHF), results in prolonged elevation of cocaine levels. A similar result may be observed in pregnant women, fetuses, infants, patients with liver disease, and elderly men, because their plasma cholinesterase activity is decreased. In addition, some people have a genetic deficiency of plasma pseudocholinesterase or a nutritional predisposition to abnormally low pseudocholinesterase levels. Some have postulated that these patients may metabolize cocaine slowly and have increased sensitivity to small doses of cocaine, which places them at risk for increased toxicity and sudden death. Evidence supporting this postulate is scant.

Most of the remaining amount of cocaine is metabolized by hepatic N -demethylation into norcocaine, which is metabolically active. Pregnancy, during which circulating progesterone levels are high, or the exogenous administration of progesterone increase the activity of hepatic N -demethylation. This increased formation of norcocaine, which is more vasoconstrictive than cocaine, may result in women being more sensitive to the cardiotoxic effects of cocaine than men as a result of hormonal potentiation.

Approximately 1-5% of cocaine is excreted, unaltered, through the kidneys within 6 hours of use.

With the multiplicity of physiologic and pharmacologic modifiers cited above, the literature reflects tremendous variability in the reported lethal dose of cocaine in humans. The range is as little as 20 mg IV, to a mean of 500 mg ingested orally, to 1.4 g.

Drug interactions and polypharmacy

More than 38 pharmacologically active substances have reportedly been used with cocaine; alcohol and nicotine are the most common. Although alcohol and nicotine are individually well known for their potential sequelae, their use with cocaine may acutely increase morbidity and mortality risks.

Between 30% and 60% of individuals who take cocaine combine it with alcohol. Clinical data indicate that the concurrent use of alcohol and cocaine is associated with increased mortality and morbidity from cardiovascular complications, hepatotoxicity, and behaviors leading to personal injury. In 74% of cocaine-related fatalities in the United States, another drug, usually ethanol, had been co-ingested. The addition of alcohol to cocaine increases the risk of sudden death 25-fold.

The increased risk from the concomitant alcohol use is enhanced by the formation of a third active compound of toxicologic importance, namely, ethylbenzoylecgonine, commonly known as cocaethylene. Although its behavioral pharmacology and psychomotor stimulant effects are similar to those of cocaine, its toxicity is greater. The plasma half-life of cocaethylene is longer than that of cocaine, and inferential evidence suggests that the lethal dose to kill 50% of subjects (LD50) is lower.

Although most cocaine metabolism involves serum cholinesterase, some of the drug is metabolized in the liver by carboxylesterases. In the presence of alcohol, a nonspecific carboxylesterase catalyses ethyl transesterification of cocaine to cocaethylene. Cocaine is the rate-limiting substrate in this reaction. Cocaethylene can be detected in urine and blood within 100 minutes after a person uses alcohol and intranasal cocaine. Whereas the half-life of cocaine is approximately 40 minutes, the half-life of cocaethylene is 2.5 hours, which may explain why cocaine-related symptoms can continue for some time after cocaine is last used.

The human brain, heart, liver, and placenta bind cocaine and cocaethylene. As with cocaine, cocaethylene binds to dopamine and norepinephrine transporters and inhibits catecholamine reuptake (primarily norepinephrine) into nerve terminals. The increased "high" reported with the concurrent use of alcohol and cocaine may be the result of the additive effect of cocaine and cocaethylene. Yet another reason may be the relationship between these substances and serotonin. The binding of serotonin by cocaine may modulate the high and may be the cause of the dysphoric effects of cocaine. Cocaethylene, which is 40 times less potent than cocaine in binding to the serotonin receptor, does not share this negative property.

In dog studies, cocaethylene was a more potent precipitant of convulsions and cause of lethality than cocaine. This is probably because cocaethylene blocks sodium channels more potently than cocaine. Although the toxic level of cocaethylene in humans is not known, the LD50 in mice was 93 mg/kg for cocaine versus 60 mg/kg for cocaethylene. The process of cocaethylene formation continues for several hours, which may explain why sudden deaths may occur 6-12 hours after cocaine ingestion.

Cocaethylene, which is ultimately metabolized to benzoylecgonine, is not the only factor augmenting the effects of cocaine with ethanol.^[2] Consumption of ethanol before cocaine use also increases the bioavailability of cocaine.

Signs et al present an exception to the weight of the literature in a study based on 57 ED patients who tested positive for both alcohol and cocaine. In these patients, systolic and diastolic BP, heart rate, and body temperature did not significantly differ between those testing positive for both alcohol and cocaine and drug-free control subjects.^[3] This may be because chronic cocaine users reportedly develop tolerance to the cardiovascular effects of the drug. Signs et al concluded that the incidence of serious cardiovascular complications resulting from simultaneous use of cocaine and ethanol does not appear to be significantly higher than that observed in patients using only cocaine, only ethanol, or no drug.^[3]

Nicotine is the second drug most commonly combined with cocaine. Many of the physiologic effects of nicotine are identical to those of cocaine. Nicotine produces a hypertensive and tachycardic response that is mediated by stimulation of the sympathetic ganglia and the adrenergic medulla. This response is coupled with the discharge of catecholamines from sympathetic nerve endings. Cigarette smoking also causes arterial endothelial desquamation and ultrastructural changes, a reduction of endothelial-cell prostacyclin production, increased serum fibrinogen levels, activation of platelets with enhancement of adhesiveness and aggregability, diminished coronary flow reserve, and an alpha-adrenergically mediated increase in coronary artery tone in patients with coronary atherosclerosis.

Most patients with cocaine-induced myocardial infarction (MI) also smoke cigarettes, a finding which suggests that simultaneous use of cocaine and tobacco may enhance coronary vasospasm. Of patients with cocaine-induced MI, 38% had normal coronary arteries; 77% of this group (average age, 32 y) had an anterior-wall MI. More than two thirds were moderate-to-heavy cigarette smokers (>1-2 packs daily). The average number of additional coronary risk factors, however, was less than 1.

Combining cocaine and heroin into a "speedball" causes frequent complications, as evidenced by the high-profile cases of actors John Belushi, River Phoenix, and Chris Farley. Speedballing accounts for 12-15% of cocaine-related episodes in patients presenting to EDs in the United States. In speedballing, heroin is injected or snorted, followed immediately by smoking of cocaine. Cocaine is harder to purchase during the summer months than at other times, thus heroin users may speedball with crack in the summer. The effects of heroin last longer than do those of crack, and it modulates symptoms secondary to withdrawal from crack. In both cases, the second drug is used to supplement, rather than substitute, the primary drug.

Persons addicted to crack may also use heroin to dampen the agitation produced by extended crack use. Body packers—smugglers who use their GI tract as a hiding place for large quantities of carefully wrapped packages of cocaine—often use a similar approach. They may take benzodiazepines to prevent becoming too high should a package rupture. Some premedicate themselves with a constipating agent, such as diphenoxylate with atropine, to prevent themselves from having a bowel movement before they arrive at their destination.

Dissolving and injecting crack is less expensive than purchasing enough cocaine powder to produce the same effect. Some users dissolve crack in lemon juice or vinegar before injecting it intravenously, a practice that reportedly produces a more intense rush than smoking the same amount of crack. If the vein is missed, the result is pain and potential abscess formation.

Various agents can heighten the effects of cocaine and contribute to complications. Organophosphates may be taken to deplete pseudocholinesterase, prolonging the effects of cocaine. However, because it produces organophosphate toxicity, the risk of fatality is increased. Cholinesterase inhibitors, such as carbamates, have a similar effect. Another practice involves coabusing crack cocaine and phenytoin to enhance the intoxication. In this practice, unbound phenytoin causes persons with hypoalbuminemia to become symptomatic at lowered drug levels; if death occurs, it usually is the result of respiratory and subsequent circulatory collapse.

The risk of severe effects is increased when cocaine is combined with drugs such as monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), alpha-methyldopa, and reserpine. These drugs alter the metabolism of epinephrine and norepinephrine, potentiating their effects and, in the presence of cocaine, inducing an adrenergic crisis. Serotonin syndrome may result when serotonin selective reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), are taken concurrently with sympathomimetics.

Illicit drugs are frequently admixed with additional chemicals either to increase the apparent quantity of the street drug or to enhance its effect. For example, 8-20% of stimulants available on the street contain cocaine and methamphetamine hydrochloride.

Adulterants are added to cocaine intentionally or are left over from the manufacturing process. Substitutes are compounds that have pharmacologic properties similar to those of cocaine and that are used in its place. Many of these substances cause pulmonary and systemic reactions when taken intravenously, by insufflation, or by smoking; they may, therefore, substantially contribute to the toxicity of cocaine use.

Among the substances used to cut cocaine are local anesthetics (eg, procaine, lidocaine, tetracaine), other stimulants (eg, amphetamine, caffeine, methylphenidate, strychnine), lysergic acid diethylamide (LSD), phencyclidine (PCP), phenytoin, heroin, marijuana, and hashish.

Recent reports describe agranulocytosis following use of cocaine contaminated with the veterinary antihelminthic levamisole.^[4] Levamisole was found in every cocaine-positive toxicology case reported by a major forensic laboratory.^[5] The Drug Enforcement Administration reports that levamisole has been identified in cocaine seized in widely separated geographic areas ranging from New York, to Illinois, Florida, Kansas, and Missouri, as well as drug seizures in South America, and coroners specimens in the United Kingdom.^[6] Levamisole increases dopamine levels in the same areas of the brain as does cocaine, possibly accounting for its current ubiquity.^[4]

Other adulterants may include quinine, talc (ie, magnesium silicate), ascorbic acid, boric acid, chalk, laundry detergent, meat tenderizer, laxatives, plaster of Paris, cornstarch, and lactose.

Tachydysrhythmias cause most acute cocaine-related nontraumatic deaths. Other causes of sudden death include stroke, subarachnoid hemorrhage, hyperthermia, and the consequences of agitated delirium. Myocardial infarction (MI) can result from acute vasospasm, dysrhythmia, or chronic accelerated atherogenic disease.

Dysrhythmia

Cardiovascular effects result primarily from direct actions on the heart and secondarily from effects on the CNS. Central and peripheral adrenergic stimulation results from inhibition of norepinephrine and dopamine reuptake at preganglionic sympathetic nerve endings. By preventing catecholamine reuptake at presynaptic terminals, cocaine causes catecholamine to accumulate at the postsynaptic membranes.

Without presynaptic reuptake, the action of a neurotransmitter on its receptors becomes sustained. Effects of endogenous catecholamines are thereby potentiated, resulting in tachycardia, hypertension, vasoconstriction, and increased myocardial oxygen consumption. Although cocaine-related tachydysrhythmias result primarily from increases in catecholamine levels, the local anesthetic properties of cocaine can impair impulse conduction in the ventricle, providing a substrate for reentrant ventricular dysrhythmias.

People who abuse cocaine may be exposed to toxic levels of circulating catecholamines. In one study, 48 mg of cocaine more than doubled circulating levels of norepinephrine (420 pg/mL increased to 900 pg/mL).^[7] However, most cocaine-related dysrhythmic fatalities occur in patients with low or modest levels of cocaine use. This finding suggests that the mechanism of death may be different in long-term cocaine users, in whom sudden death is most likely the consequence of adrenergic effects and long-term catecholamine toxicity.

In rat studies, long-term use markedly increased norepinephrine content of the left ventricle. This theoretically suggests that long-term cocaine users could be at increased risk of malignant arrhythmia if excess norepinephrine also accumulates in the human left ventricle. Of note, coincident with the increase in ventricular catecholamine concentration, the rate of catecholamine synthesis was reduced, reflecting physiologic attempts to decrease sympathetic tone secondary to chronic cocaine stimulation.

Alterations in cardiac histology may produce an arrhythmogenic anatomic substrate. Independent of coronary artery disease or clinically documented MI, cocaine use may induce scattered foci of myocarditis, microfocal fibrosis, and contraction band necrosis, the severity of which is correlated with serum and urine concentrations of cocaine. Although common in the hearts of cocaine and other stimulant abusers, such findings are found in only a minority of hearts examined.

Other conditions providing an anatomic arrhythmogenic substrate include the accessory pathways resulting in Wolff-Parkinson-White (WPW) syndrome, and left ventricular enlargement.

In patients with an arrhythmogenic anatomic substrate, even low levels of cocaine can cause tachydysrhythmias. In a study of 19 people who had survived cocaine-related cardiac arrest, 8 had asystolic arrest (5 because of massive overdose) and the remaining 11 had arrest resulting from ventricular fibrillation (VF). Of the latter group, all had an anatomic substrate for the dysrhythmia: 2 patients had an MI, 3 had WPW, and 6 had left ventricular hypertrophy or cardiomyopathy. On subsequent electrophysiologic testing, several patients had dysrhythmias, which were induced only after they had been given cocaine.^[7]

Normal electrical conduction may become disrupted in cardiomegaly, which can be observed with chronic cocaine use. Rat studies have demonstrated that cocaine causes genetic changes in cardiac myocytes. Hemodynamic overload results in the production of high levels of atrial natriuretic factor (ANF). Increased levels of mRNA coding for ANF were measurable within 4 hours after rats were injected with 40 mg/kg of cocaine. When that same dose was administered to rats over 28 days, levels of mRNA coding for collagen and heavy-chain myosin increased, and left ventricular mass increased by 20%. Increased collagen production and increased left ventricular mass are independent risk factors for sudden death.

Similar findings also are observed in humans. The hearts of cocaine users are 10% heavier than those of nonusers. In a study of 200 asymptomatic patients in a rehabilitation program who had used cocaine long term, one third had increased QRS voltage, indicative of left ventricular enlargement. Another study of asymptomatic patients in rehabilitation revealed that more than 40% had an echocardiographically demonstrable increased left ventricular mass.^[7]

An autopsy study conducted by Darke, Kay, and Duflou (2006) compared cardiovascular and cerebrovascular pathology in decedents dying of cocaine toxicity, opioid toxicity, and those dying of hanging who were toxicologically negative for cocaine or opioids.^[8] With gender, effects of age, and body mass index (BMI) having been controlled for, 1 in 7 cocaine users were found to have left ventricular hypertrophy, two and one-half times the odds of such a pathologic diagnosis being made in either comparison group. In patients with enlarged hearts due to long-term exposure to high levels of cocaine, even low cocaine levels can be lethal.

Cocaine also has quinidinelike direct cardiotoxic effects, causing intraventricular conduction delay, as reflected by widening of the QRS and prolongation of the QT segment. In large doses, blockade of the fast sodium channels prolongs the slope of phase 0 of the cardiac action potential, which may result in a negative inotropic response, bradycardia, and, often as a precursor to death, hypotension from decreased contractility and dysrhythmia.

With high blood levels of cocaine, such as those observed in a body packer or body stuffer when a cocaine packet ruptures, or in a binge user with large cocaine supply, the membrane-stabilizing effects of cocaine may cause cardiac arrest from asystole. In such cases, blood levels may exceed 50,000 ng/mL. Cardiac arrest is even more likely if the patient also has been consuming alcohol, with resultant production of cocaethylene. Tolerance rapidly develops to the euphoriant effects of cocaine but not to its local anesthetic effects of membrane stabilization.

MI and acute coronary syndromes

A 2001 nationally representative study of 10,085 American adults aged 18-45 years found that regular use of cocaine was associated with an increased likelihood of MI. Approximately 1 of every 4 nonfatal MIs was attributable to frequent use of cocaine (defined in this study as >10 uses in a lifetime).^[9]

Patients with cocaine-related MI often have fixed atherosclerotic lesions. Cocaine can induce increased heart rate and BP, resulting in increased myocardial oxygen demand. The additional metabolic requirements may convert an asymptomatic obstruction into one of clinical significance.

Substantial evidence indicates that cocaine use causes accelerated coronary atherosclerosis. According to a 1995 study of trauma fatalities among men with a mean age of 34 years and an incidental finding of cocaine metabolites, 25% had lesions in 2 or more vessels, and 19% had disease in 3-4 vessels. Of the control subjects, only 6% had 2-vessel disease, and none had 3- or 4-vessel disease. In another study of 22 long-term cocaine users with a mean age of 32 years, all of whom died suddenly with detectable serum cocaine levels, severe narrowing of more than 75% cross-sectional area was found in 1 or more coronary arteries in 36% of patients.^[7]

Hollander and Hoffman reviewed and analyzed the literature of 91 patients with cocaine-induced MI. Cardiac catheterization in 54 patients demonstrated that 31% had significant coronary atherosclerosis.^[10] Autopsy studies of patients with cocaine-related MI revealed atherosclerotic lesions in more than one half of patients.^[10] In another review of medical examiners' records, 495 deceased patients had positive toxicologic findings of cocaine; 6 of them, whose mean age was 29 years, had MI with total thrombotic occlusion primarily involving the left anterior descending coronary artery. All of the patients had significant coronary atherosclerosis, with 83% having lesions that caused luminal stenosis of more than 75% cross-sectional area in 1 or more vessels.

Of the patients reviewed by Hollander and Hoffman, 24% had a thrombotic occlusion in the absence of clinically significant coronary disease.^[10] Cocaine's effect of increasing levels of plasma plasminogen activator enhances clot formation. In addition, cocaine activates platelets both directly and indirectly by means of an alpha-adrenergic–mediated increase in platelet aggregation.

Cocaine increases production of the potent vasoconstrictor endothelin, and simultaneously decreases production of nitrous oxide, a powerful vasodilator. As a result of alpha-adrenergic stimulation, cocaine may exert a direct vasoconstrictive effect by increasing the influx of calcium across endothelial cell membranes. These factors may produce coronary artery spasm. Although this may occur even in patients who do not have significant coronary artery disease, spasm is most pronounced in portions of the coronary artery that are already narrowed. Therefore, in patients who do have high-grade obstruction, including patients whose stenoses were previously asymptomatic, coronary artery spasm of even modest degree can have devastating consequences.

In healthy coronary arteries, endothelial cells release endothelium-derived relaxing factor (EDRF) and prostacyclin, which interact synergistically to relax vascular smooth muscle and inhibit platelet adhesion and aggregation. Mild atherosclerosis and hypercholesterolemia impair endothelium-mediated vasodilation in coronary arteries, and animal studies suggest that endothelial dysfunction predisposes a person to vasoconstriction and arterial spasm. Hypersensitivity to the vasoconstrictor effects of catecholamines has also been demonstrated in humans with endothelial dysfunction. Therefore, individuals with mild coronary disease who use cocaine may be predisposed to occlusive vascular spasm at the site of early atherosclerotic lesions.

The combination of intimal hyperplasia, accelerated atherosclerosis, and endothelial dysfunction create a prothrombotic milieu.

Cocaine also potentiates platelet thromboxane production and decreases protein C and antithrombin III production, as well as the production and release of prostacyclin. Aggregating platelets are an important source of serotonin. In patients with dysfunctional endothelium, serotonin causes intense vasoconstriction because of its unopposed effects on vascular smooth muscle.

Chronic use appears to deplete stores of dopamine in peripheral nerve terminals. In patients undergoing cocaine withdrawal, more than one third have frequent episodes of ST-segment elevation (similar to variant angina), as documented on Holter monitoring. Inhibition of dopamine-mediated coronary vasodilatation secondary to dopamine depletion has been advanced as the hypothetical cause.

Patients with cocaine-related ischemic chest pain, even those who have had MIs, tend to do well after they stop using cocaine.

The effects of cocaine on the heart also include myocarditis and dilated cardiomyopathy. Myocarditis may be 5 times more common among cocaine users than in control subjects. Myocarditis may be the result of microvascular injury, and it is a common autopsy finding in patients dying from cocaine toxicity. The mechanisms producing these effects are unknown, but hypotheses include a direct effect on lymphocyte activity, myocardial cell cytotoxicity secondary to an increase in the activity of natural killer cells, hypersensitivity reactions (suggested by eosinophilic infiltrate), and induction of focal myocarditis from catecholamine administration.

Cocaine causes a direct negative inotropic effect on cardiac muscle, resulting in transient toxic cardiomyopathy. In one small series, 8 of 10 subjects who used cocaine long term had chest pain without MI but left ventricular ejection fractions less than 50%. In a case report, Jouriles describes a 35-year-old woman with hypotension, seizures, and hypoxemia who had an ejection fraction of 10% after smoking crack cocaine.^[11]

Neurologic effects

Cocaine users have a 14-fold increase in risk of ischemic or hemorrhagic stroke compared to matched controls. In the study of Darke, Kaye, and Duflou, atherosclerosis of the basal vasculature of the brain was noted in approximately 10% of the cocaine toxicity cases autopsied versus less than 1% noted in either of the comparison groups.^[8]

Cocaine acts as a CNS stimulant by inhibiting presynaptic reuptake of norepinephrine, dopamine, and serotonin. It also causes release of epinephrine by the adrenal glands. The intensity and duration of the stimulant effects of cocaine are mediated by the rate at which blood levels of cocaine rise (a function of the route of administration) (see Table 1) and the peak of blood levels.

Cocaine may cause generalized tonic and clonic convulsions as well as focal seizures. Intense stimulation of sigma and muscarinic receptors by cocaine and increased synaptic concentration of serotonin have been proposed as causal. Cocaine lowers the threshold for seizures and may produce a kindling effect on neurons that promotes convulsions.

Seizure frequency ranges from 1-29%–perhaps reflecting variations in use and concurrent use of other drugs. Of 474 patients with medical complications of cocaine abuse, 8% experienced first-time seizures and, of these, 85% had seizures during administration of the drug.

Cocaine-associated seizures occur in naive users and among long-term users. Seizures are most frequently single tonic-clonic and resolve without intervention. However, status epilepticus may occur. The first stage of status epilepticus is manifested by generalized tonic-clonic seizures associated with hypertension, hyperpyrexia, and diaphoresis. After approximately 30 minutes, the second stage may occur, in which cerebral autoregulation fails, cerebral blood flow diminishes, and systemic hypotension occurs. During this phase, the only clinical manifestations may be minor twitching, though cerebral electrical seizure activity continues.

Drugs that increase intrasynaptic dopamine change the density and sensitivity of dopamine receptors, with different effects on different receptor subtypes in different areas of the brain.^[12] Excited delirium, cocaine-associated rhabdomyolysis (CAR), and neuroleptic malignant syndrome (NMS) share many common features that can be explained by aberrant dopaminergic function.

Long-term cocaine use decreases the density of dopamine-1 (D1) receptors throughout the striatal reward centers, but it does not affect the number of dopamine-2 (D2) receptors. Antagonism of nigrostriatal dopamine function may cause extrapyramidal motor dysfunction, including dystonic reactions, bradykinesia, akinesia, akathisia, pseudoparkinsonism, and catalepsy. Neuroleptic agents are the principal medications that cause dystonic reactions by means of their blockade of dopamine receptors in the nigrostriatal pathways. Cocaine may increase the risk of neuroleptic-induced dystonias, a problem compounded by the street marketing of substances, such as haloperidol, sold as cocaine.

Over time, continued use may result in depletion of dopamine. Therefore, cocaine may be an independent cause of dystonic reactions. Two biochemical events, dopamine receptor blockade by neuroleptics and dopamine depletion by cocaine, result in the same effect, namely, the absence of physiologic dopamine in the nigrostriatal area of the brain. These events may represent the pathophysiologic basis for cocaine-associated dystonias. Intrauterine exposure to cocaine has been suggested as a cause of dystonia in infants.

Agitated (excited) delirium

Agitated delirium, also known as excited delirium, is a common presentation in patients dying from cocaine toxicity. Of cocaine-associated deaths investigated by the Medical Examiner's Department of Metropolitan Dade County, Florida, between 1979 and 1990, excited delirium was the terminal event in approximately 1 of every 6 fatalities. Patients with excited delirium had an immediate onset of bizarre and violent behavior, which included aggression, combativeness, hyperactivity, hyperthermia, extreme paranoia, unexpected strength, and/or incoherent shouting. All of these were followed by cardiorespiratory arrest.^[12]

Although heart weight, ventricular hypertrophy, and past MI are not risk factors, repeated binges of cocaine use are associated with fatal excited delirium. However, the frequency of use that increases risk has not been determined. Individuals with excited delirium may be more sensitive to the life-threatening effects of catecholamine surges than other cocaine users. Excited delirium appears to be generated by increased intrasynaptic dopamine concentrations resulting from a defect in the regulation of the dopamine transporter. Cocaine recognition sites on the striatal dopamine transporter are increased in users without excited delirium compared with drug-free controls. Persons dying from excited delirium have no such increase; therefore, they may have problems in clearing dopamine from the synapses, a condition that can easily result in agitation and delirium.

Hyperthermia, which may also be caused by downregulation of dopamine receptors, increases the incidence of fatal excited delirium. Death from excited delirium is more common in the summer months than at other times (55% vs 33% for other accidental cocaine toxicity deaths); therefore, high ambient temperature and humidity may play roles in the development of hyperthermia. An independent risk factor for fatal excited delirium is a body mass index (weight in kilograms/height in square meters) in the upper 3 quartiles, with the risk appearing to increase after a threshold is exceeded rather than in a dose-response fashion.

Restraints have also been implicated as a contributing factor, particularly when the patient is prone. Sudden death occurring during prone restraint of a person in excited delirium appears to be induced by a combination of at least 3 factors that increase oxygen demand and decrease oxygen delivery:

1. The psychiatric or drug-induced state of agitated delirium coupled with police confrontation places catecholamine stress on the heart.
2. The hyperactivity associated with excited delirium coupled with struggling against the police and/or restraints increases oxygen demands on the heart and lungs.
3. A hogtied position impairs breathing by inhibiting chest-wall and diaphragmatic movement.

Hyperthermia

Temperature dysregulation is also a problem with cocaine intoxication, as demonstrated by Callaway and Clark, who reported that patients presented with rectal temperatures as high as 45.6°C.^[13] Hyperthermia is a marker for severe toxicity, and it is associated with a number of complications, including renal failure, disseminated intravascular coagulation, acidosis, hepatic injury, and rhabdomyolysis.

Because dopamine plays a role in the regulation of core body temperature, increased dopaminergic neurotransmission may contribute to psychostimulant-induced hyperthermia in cocaine users, including those with excited delirium.

D2 receptors are involved with processes that decrease core temperature. The number of D2 receptors in the temperature regulatory centers of the hypothalamus is substantially reduced in persons with excited delirium. These decreases in D2 receptors lead to unopposed increases in temperature mediated through D1 receptors, which are not affected in individuals who die from excited delirium.

Ruttenber et al hypothesize that hyperthermia may result from extensive muscular activity in the setting of warm ambient temperature and, perhaps, humidity in combination with aberrant thermoregulation in the hypothalamus and mesolimbic system.^[12] Antagonism of central and peripheral catecholamine receptors may be required to protect against psychostimulant-induced hyperthermia because peripherally released catecholamines may directly stimulate muscle or other thermogenic tissue.

Cocaine-induced seizures can also contribute to hyperthermia, though cocaine can induce hyperthermia in the absence of seizures. In animal studies, hyperthermia was the most significant parameter in the lethality of continuous cocaine infusion.

Agitation secondary to intoxication or withdrawal increases motor activity, which increases heat production. The patient's volume needs are thereby increased, and, when not met, they lead to decreased renal perfusion. Heat production may also contribute to increased muscle breakdown, resulting in myoglobinuria. Myoglobinuria, in conjunction with decreased renal perfusion, causes acute tubular necrosis.

Cocaine-associated rhabdomyolysis (CAR)

Excitement, delirium, and hyperthermia frequently precede the onset of CAR. If excited delirium and CAR have a similar cause, the spectrum of severity ranges from rhabdomyolysis with no excited delirium or hyperthermia to various combinations of these 3 conditions.

Long-term, rather than short-term, cocaine use is responsible for persistent changes in dopaminergic function that place users at risk for excited delirium and CAR. Elevations in muscle-enzyme levels are observed in asymptomatic people who use cocaine long term and in untreated persons with schizophrenia. This evidence lends support to the hypothesis that chronic alterations in dopaminergic function can affect the physiology of skeletal muscle.

Acidemia

Acidemia is seen in a clinically significant toxicity and may play an important role in cocaine-related death. In experimental studies, calcium delivery to myofilaments is decreased and contractile proteins become less responsive in the presence of lowered intracellular pH, resulting in depression of myocardial contractility.

Acidosis also potentiates dysrhythmias by repolarization and depolarization abnormalities that lead to reexcitation states. As pH decreases, calcium is spontaneously released from the sarcoplasmic reticulum, resulting in a transient depolarizing current that can precipitate dysrhythmias during diastole. In addition, acidosis decreases conductance between the gap junctions of cardiac cells, which slows propagation of the action potential. In the presence of cocaine, which diminishes sodium conductance, a severe reduction in conduction velocity may occur, increasing the likelihood of dysrhythmia production by means of reentry excitation.

Frequency

United States

The 2006 National Survey on Drug Use and Health found that 35.3 million Americans older than 12 years have used cocaine at least once, with 8.5 million having used cocaine in its crack form. Figures for annual use of cocaine were 6.1 million, of which 1.5 million had used crack. Reports indicate that 2.4 million Americans used cocaine within the previous 30-days, with 702,000 reporting the use of crack.^[14]

Since the early 1970s, in an ongoing national survey of approximately 600 hospital EDs, DAWN has reported the number of episodes of patients seeking treatment related to their use of an illegal drug or their nonmedical use of a legal drug. Although drug-related ED visits declined 6% from 1995-1996, they had previously risen by 65% from 1978-1995, compared with a 24% overall increase in ED visits during the same period.^[15] Although the increase in drug-related emergencies may partly result from an increased use of drugs in combination (particularly alcohol), changes in the route of administration, and changes in the amount of drug used per administration, the primary cause appears to be cocaine.

Cocaine-related ED visits increased 78% from 1990-1994, remained statistically level from 1994-1996, and then increased 33% as of 2002.

According to DAWN, in 2005, cocaine was associated with 31% of ED visits related to drug misuse or abuse.^[15] Data from 1978 indicate cocaine accounted for 1% of ED visits.

International

In the late 1990s, cocaine was reported to be a major public health issue in at least 3 of 6 major cities in Canada. In Mexico, cocaine was the primary drug of choice reported by patients in drug-treatment programs in 16 cities. In 5 of 7 capital cities of Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama, and the Dominican Republic, cocaine use increased.

Mortality/Morbidity

DAWN monitors fatalities reported by Medical Examiners/Coroners (ME/C) in 40 metropolitan areas in the United States. Cocaine was the most frequently reported substance associated with drug abuse or misuse deaths in the DAWN ME/C data for 2003.^[16] Cocaine was reported in 39% of such drug deaths, ranging from 8-70% in various areas. In 75% of the cocaine-associated deaths, 1 or more other drugs were involved.

Sequelae of intravenous injection may cause morbidity.

A "pocket shot" is an attempted injection of the internal jugular vein by directing the needle into the depression in the neck superior to the clavicle and lateral to the sternocleidomastoid. Such attempts can lacerate the apical pleura and/or vasculature resulting in pneumothorax, hemothorax, or hydropneumothorax. This is usually observed in the left side because most people have right-hand dominance, and it is easiest for them to attempt injection into the left side of the neck.

Intravenous injection may cause aneurysm or pseudoaneurysm of central veins or arteries, and rupture may result in intrathoracic or intra-abdominal hemorrhage, vascular obstruction, and arteriovenous fistulae. A necrotizing angiitis similar to periarteritis nodosa may develop, frequently with severe effects upon the kidneys, such as microaneurysm formation, segmental stenoses, and thromboses. The result is severe hypertension and oliguric renal failure. Similar lesions may occur in the small bowel, liver, and/or pancreas.

Other sequelae that may be observed with intravenous drug use include AIDS, thrombophlebitis, cellulitis, abscesses, viral and talc-induced hepatitis, subacute bacterial endocarditis (SBE), foreign-particle pulmonary emboli, tetanus, malaria, and cotton fever.

See also the Physical section below.

Race

Table 2. DAWN Data, 2005 (Open Table in a new window)

Sex

DAWN reports for 2005 reflect that men accounted for 292,402 cocaine-related ED visits, and women, 155,985. This disparity may have a physiologic basis.

Compared on a milligram-per-kilogram basis, women who use cocaine intranasally have significantly lower plasma cocaine levels than men. Women using cocaine in the luteal phase of their menstrual cycle have peak plasma levels lower than those observed during the follicular phase of the cycle. Notwithstanding these differences, be mindful of the potential for increased cocaine cardiotoxicity in women previously discussed (see Pharmacology).

Men detect the effects of cocaine faster and report more episodes of euphoria and of dysphoria than women.

Age

Table 3. Cocaine Use in Lifetime, Past Year, and Past Month, by Detailed Age Category: 2006^[14] (Open Table in a new window)

Table 4. Crack Use in Lifetime, Past Year, and Past Month, by Detailed Age Category: 2006^[14] (Open Table in a new window)

Table 5. 2005 DAWN Data Emergency Department Visits for Cocaine (Open Table in a new window)

Since 1988, cocaine-related episodes have almost tripled among people older than 35 years. In 1994-1996, the number of cocaine-related ED visits recorded among people aged older than 35 years increased by 21%. In that same period, no significant differences were found in any other age group. The reasons for the increase are not known. However, older people may be seeking emergency care for drug-related problems more often than they have before, or they may be making more frequent visits to EDs than in the past because aging increases their susceptibility to a wide variety of health problems that are exacerbated by drug use, particularly prolonged use and its cumulative effects.

In a study reported by Hollander et al, the frequency of cocaine positivity for patients aged 41-50 years was 18%. Of patients aged 51-60 years, 3% had positive results for cocaine. The prevalence of cocaine use in older persons was significantly higher than expected in population-based surveys.^[17] Older patients are at greatest risk of myocardial ischemia caused by cocaine. Query patients in all age groups about their cocaine use.

Advanced age does not preclude cocaine as the cause of a patient’s emergent presentation, as is demonstrated by the death of Ike Turner. The Medical Examiner ascribed the 76-year-old musician’s death to acute cocaine toxicity.^[18]