Your Family Physician

Introduction

Background

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 nearly twice the number of reports to the Drug Abuse Warning Network (DAWN) as does marijuana or hashish, the second leading cause.

Cocaine is the most common reason for illicit drug-related ED visits in the United States. Patients who present to the ED with cocaine toxicity often have a combination of other drugs and cocaine in their system; in fact, the combined use of alcohol and cocaine may be the major cause of drug-related deaths.

The ubiquity of the acute or chronic effects of cocaine may cause patients to voice complaints involving virtually every organ system. Trauma is often associated with cocaine use. Even the absence of cocaine may precipitate an ED visit because patients may seek care for problems resulting from cocaine withdrawal.

History of use and abuse

Use of cocaine spans thousands of years, with a duality of effects noted throughout its 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 NationalDrugThreatIntelligenceCenter 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. However, the clinician should always keep in mind the drug that patients believe they purchased may not be what they received and took.

The drug and its 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 blocking the sodium channels, 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 (insufflation or snorting), 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 insufflated 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 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 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 use of alcohol and cocaine 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. The potential for adverse effects is considerably compounded by the presence of adulterants and substitutes. 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. 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. Many of these substances cause pulmonary and systemic reactions when taken intravenously, by insufflation, or by smoking; therefore, they may substantially contribute to the toxicity of cocaine use.

Pathophysiology

Most acute cocaine-related nontraumatic deaths are the result of tachydysrhythmias. Other causes of sudden death associated with cocaine use include stroke, subarachnoid hemorrhage, hyperthermia, and the consequences of agitated delirium. MI can result from acute vasospasm, dysrhythmias, or chronic accelerated atherogenic disease.

Dysrhythmias

The cardiovascular effects of cocaine result primarily from direct actions on the heart and secondarily from effects on the CNS. Cocaine causes central and peripheral adrenergic stimulation by inhibiting the reuptake of norepinephrine and dopamine 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. The 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).⁴ 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 of cocaine markedly increased norepinephrine content of the left ventricle, raising the possibility that long-term cocaine users should they also accumulate excess norepinephrine may be at risk for a malignant arrhythmia. 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.⁴

Electrical conduction becomes disorganized in enlarged hearts, a finding that assumes added significance because cardiac enlargement is 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, which was indicative of left ventricular enlargement. Another study of asymptomatic patients in rehabilitation revealed that more than 40% had an echocardiographically demonstrable increased in left ventricular mass.⁴

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.⁵ 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 delays, 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 dysrhythmias.

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 unlimited 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).⁶

Patients with cocaine-related MI often have fixed atherosclerotic lesions. In addition to these lesions, which may themselves be of clinical significance, cocaine-induced elevations in pulse and BP increase myocardial work. The additional metabolic requirements that result 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.⁴

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.⁷ Autopsy studies of patients with cocaine-related MI revealed atherosclerotic lesions in more than one half of patients.⁷ 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.⁷ 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 the production of the potent vasoconstrictor endothelin, and simultaneously decreases the 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, a phenomenon that is particularly prominent in cocaine users. 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 a devastating consequence.

In healthy coronary arteries, endothelial cells release endothelium-derived relaxing factor (EDRF) and prostacyclin, which synergistically interact to relax vascular smooth muscle and to inhibit platelet adhesion and aggregation. Mild atherosclerosis and hypercholesterolemia impair endothelium-mediated vasodilation in coronary arteries, and evidence from animal studies suggests 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 of cocaine 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 in people who use cocaine than in control subjects. It 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, cytotoxicity of myocardial cells 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 one case report, Jouriles describes a 35-year-old woman who developed hypotension, seizures, and hypoxemia after smoking crack cocaine; she had an ejection fraction of 10%, as observed on echocardiography.⁸

Neurologic effects

Cocaine users have been found to have a 14-fold increase in risk of ischemic or hemorrhagic stroke when compared with 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.⁵

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-induced seizure is a severe manifestation of toxicity. 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.

The frequency of seizures ranges from a low as 1% to as high as 29%, perhaps a reflection of an increase in cocaine use from one time period to another or the 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 may occur in naive and long-term users and are mostly single tonic-clonic, resolving 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.⁹ 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, the continued use of cocaine may result in a net 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.⁹

Although heart weight, ventricular hypertrophy, and past MI are not risk factors, repeated binges of cocaine use are associated with fatal excited delirium. The frequency of use that increases risk has not, however, 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 cocaine 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 been implicated as an exacerbating 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.¹⁰ 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.⁹ 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.¹¹

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.¹² 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.¹² The true relevance of this percentage is best appreciated when it is contrasted with 1978 data showing that cocaine accounted for only 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 2003.¹³ 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

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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 The drug and its pharmacology).
• Men detect the effects of cocaine faster and report more episodes of intense good feelings (euphoria) or bad feelings (dysphoria) than women.

Age

Table 3. Cocaine Use in Lifetime, Past Year, and Past Month, by Detailed Age Category: 2006¹¹

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*Low precision, no estimates reported.

Table 4. Crack Use in Lifetime, Past Year, and Past Month, by Detailed Age Category: 2006¹¹

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*Low precision, no estimates reported.

Table 5. 2005 DAWN Data Emergency Department Visits for Cocaine

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• 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.¹⁴ 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.¹⁵

Clinical

History

The factors addressed below focus on drug use. They supplement the questions and elements of the standard medical-history interview. A drug history is indicated in all patients and should be particularly complete in those presenting with drug reactions, acute anxiety, or other psychological problems, as well as in those with acute cardiovascular, pulmonary, or neurologic symptoms. If the patient is confused or unresponsive, query relatives, friends, or witnesses about antecedent activities, and seizures or syncope. This is crucial, especially if patients are carrying cocaine in their body, because they often have no stigmata of drug abuse.

• History of present illness
  • Did onlookers or other users apply any resuscitation measures that may cause complications?
  • What was used? (Do not accept denial unquestioningly. Street drugs often are not what they are marketed to be. Adulterants markedly increase the potential for complications.)
  • When was the substance used and for how long was it used? What is the patient's tolerance, cross-tolerance, and reverse tolerance? Is evidence of an abstinence syndrome present?
  • What was the total amount of cocaine used? How does this compare with the amount generally used? How long after cocaine use were symptoms noted?
  • By what route was it taken? How long has this route been used?
  • Does the patient have symptoms such as pain (eg, chest, abdominal), dyspnea, altered tactile sensation (eg, cocaine bugs, Magnan sign), or hallucinations (eg, lilliputian hallucination, halo lights around objects)? Do reports of seizures or altered mental status exist?
  • Is the patient pregnant (eg, decreased plasma cholinesterase)?
  • Is the patient a victim of domestic violence? (Substance abuse may develop or worsen as a result of domestic violence. Accordingly, it is appropriate to consider domestic violence when evaluating a patient for alcohol intoxication or drug toxicity and overdose.)
• Review of systems
  • Is the effect of cocaine increased secondary to liver disease or CHF? Is evidence of MI or coronary artery disease present? Is evidence of a dysrhythmogenic substrate (eg, myocarditis, cardiomyopathy, WPW) present?
  • When considering the extent of the review of systems (ROS), be mindful of the wide range of organ systems that cocaine and its routes of administration can affect.
• Medication and drug use history
  • What is the patient's average daily use? What is his or her history of cocaine and other drug use? (The mechanism of fatality differs for long-term cocaine users.)
  • Does the patient smoke (ie, does he or she have coronary vasospasm)? How many packs does the patient smoke per day? When did the patient smoke in relation to using cocaine?
  • Does the patient use alcohol (ie, is cocaethylene formation possible)? If so, did the patient drink before or during cocaine uses? How much alcohol was consumed?
  • What other substances were used? How much was consumed? What route of intake was used?
  • Does the patient have any other drug addictions? Were any drug combinations taken or were drugs taken to increase, prolong, or decrease the effects of cocaine?
  • Could medications taken by the patient potentiate the effects of cocaine? Is the patient in withdrawal?
  • What prompted the visit to the ED? DAWN data for 1998 reflect the reasons for cocaine-related ED visits:
    • Unexpected reaction - 21.9%
    • Overdose - 15.1%
    • Chronic effects - 13.8%
    • Accidental injury - 4.9%
    • Withdrawal - 3.2%
  • Does the patient want help in coping with cocaine use? DAWN data from 2004 reported that 46% of patients presenting to EDs did so for detoxification.¹⁶

Physical

Multisystem effects of cocaine

Cocaine has multisystemic effects, and virtually every organ system may be a site of action. Suspect cocaine use in patients, especially young patients, with altered mental status, new-onset seizures, hypertension, chest pain, myocardial ischemia or infarction, shortness of breath, intracranial hemorrhage, epistaxis, or psychiatric illness. Pay particular attention to the assessment of vital signs and to a detailed examination of the cardiac, pulmonary, and neurologic systems, as listed below.

Association with trauma

Trauma is becoming increasingly associated with use of cocaine. Cocaine can cause agitation, paranoia, distractibility, distorted perception, and depression. All of these may increase the likelihood of violence, suicide, or accidental injury. When cocaine is combined with alcohol, the frequency of ED presentations is substantially greater than when cocaine is used alone.

Differential diagnosis

Cocaine overdose may resemble serotonin syndrome, lithium toxicity, toxicity due to TCAs, neuroleptic malignant syndrome (NMS), thyroid storm, and other hyperadrenergic states.

Consider the diagnosis of phenytoin toxicity in cocaine users who present with lethargy or cerebellar findings. Signs of phenytoin toxicity are correlated with serum levels and include nystagmus, ataxia, dysarthria, lethargy, hypotension, and coma.

• Vital signs and general presentation
• Although bradycardia is reported as an initial effect, the classic presentation of a patient under the influence of cocaine is tachycardia and hypertension.
• When Hollander and Hoffman reviewed the literature concerning 91 patients with cocaine-induced MI, they found that as many patients were bradycardic as tachycardic, and one third were hypertensive.¹⁷ As a result of pathologic vasoconstriction, a patient with hemorrhagic trauma may present with a normal mean arterial pressure.
• Cocaine causes pathologic vasoconstriction, thus hypovolemia secondary to hemorrhage may be delayed in recognition because the patient maintains a normal mean arterial pressure. This combination of pathophysiologic factors, coupled with delayed recognition, increases the potential for cerebral insult.¹⁸
• Chronic cocaine use downregulates adrenergic receptors and decreases endogenous catecholamine stores in the heart. This may affect the patient's presentation, as was observed in a study of patients admitted to a trauma service. Of 84 patients with a systolic BP less than 100 mm Hg, 45% had relative bradycardia (heart rate <100>
• The patient's skin may be cool and clammy though the patient is hyperthermic; therefore, obtaining a rectal temperature is advisable.
• Cardiovascular findings
• Cardiopulmonary complaints are the most common presenting manifestations of cocaine abuse and include chest pain (frequently observed in long-term use or overdose), MI, arrhythmias, and cardiomyopathy.
• In individuals with cocaine-associated MI, median times to the onset of chest pain vary with the route or form of cocaine use: 30 minutes for intravenous use, 90 minutes for crack, and 135 minutes for intranasal use.
• Chest pain may be observed in as many as 40% of patients presenting to the ED after admitting to cocaine use. In a study of urban and suburban EDs, cocaine or its metabolites were found in 17% of patients presenting with chest pain. This starkly contrasts with the pretest estimated prevalences of 2-4% for the suburban study site and 10% for the urban sites. The mean age of patients with chest discomfort and positive assays for cocaine was 36 years.
• Include cocaine in the differential diagnosis of any acute vascular problem.
• Vascular spasm may cause blindness, renal infarction, limb ischemia, and intestinal ischemia.
• Limb ischemia may occur after intra-arterial injection. This may be accidental, or intentional due to the unavailability of veins because of sclerosis secondary to repetitive puncture, or due to the desired effects from arterial injection.
• Aortic dissection may also be associated with cocaine use.
• Hypertension occurs frequently.
• Other cardiovascular findings include the following:
• Dysrhythmias (premature ventricular contractions [PVCs], supraventricular tachycardia [SVT], ventricular tachycardias [VT], VF)
• Vasomotor collapse
• High-output heart failure
• Respiratory findings
• As reported in the literature, the primary acute pulmonary complaint associated with cocaine use is cough with black sputum (44% of patients). Chest pain is secondary, affecting 38% (pleurisy in 64% of patients with pain). Of patients with new-onset asthma who present to large urban EDs, 36.4% have urine screens positive for cocaine (compared with 13.6% of control patients without asthma). Hemoptysis accounts for 25% of pulmonary complaints, the result of pulmonary and bronchial constriction and ischemia resulting in interstitial and alveolar hemorrhage.
• Crack lung, a syndrome usually occurring 1-48 hours after cocaine smoking, is a hypersensitivity pneumonitis. It consists of the constellation of chest pain, cough with hemoptysis, dyspnea, bronchospasm, pruritus, fever, diffuse alveolar infiltrates without effusions, and pulmonary and systemic eosinophilia.
• Barotrauma, such as pneumothorax and pneumomediastinum, may result from smoking or snorting cocaine and then performing a prolonged Valsalva maneuver to increase the effect of the drug. The increased airway pressure ruptures an alveolar bleb, and free air dissects along peribronchial paths into the mediastinum and pleural cavities.
• The incidence of respiratory complaints in people who use cocaine is not known. The following respiratory toxic reactions are reported in association with cocaine use:
• Barotrauma (eg, pneumothorax, pneumopericardium, pneumomediastinum)
• Pulmonary hemorrhage or infarction
• Diffuse alveolar hemorrhage
• Pulmonary edema
• Wheezing secondary to bronchial muscle constriction
• Airway irritation via damage to bronchial epithelial cells, and stimulation of vagal receptors, inducing bronchospasm, exacerbating asthma
• Eosinophilic lung disease
• Recurrent transient pulmonary infiltrates with peripheral eosinophilia
• Chronic diffuse interstitial pneumonia with mild fibrosis
• CNS stimulant effects (eg, neurogenic pulmonary edema, respiratory depression in overdose or postictal state, abnormal hypoxic response in infants of cocaine-abusing mothers, sudden infant death syndrome (SIDS), and pulmonary hypertension)
• Crack lung or transient pulmonary infiltrates
• Nasal septum perforation and/or aspiration
• Bronchiolitis obliterans organizing pneumonia
• Granulomatosis
• Sinusitis
• Epiglottitis
• Bronchitis
• Cellulose granulomas in lung
• Panlobular emphysema
• Needle or other foreign body aspiration
• Alveolar accumulation of carbonaceous material
• Airway burns or tracheal stenosis
• Tachypnea, irregular breathing
• Respiratory arrest
• Acute lung injury (noncardiogenic [increased permeability] pulmonary edema)
• Eyes, nose, mouth, and throat findings
• Signs include reactive mydriasis, nystagmus (generally vertical but may be bidirectional), epistaxis, atrophic mucosa, ulcerated nasal septa, perforations, acute inflammation or scarring of the tongue, epiglottis, vocal cords, and trachea.
• Hoffman and Reimer list a variety of ophthalmologic complications from cocaine use¹⁹ :
• Cocaine-associated cerebral vasculitis, which may produce gradual decrease in visual acuity or acute blindness
• Central retinal artery occlusion
• Blurring of vision
• Endophthalmitis from systemic or local infection
• Foreign-body granuloma
• Foreign-body embolization
• Optic neuropathy, resulting from chronic sinusitis due to intranasal cocaine use and manifesting as decreased visual acuity
• Corneal ulcerations secondary to direct instillation of cocaine into the conjunctival fornix and vision loss caused by crack-induced corneal ulceration from direct irritation of the smoke, cocaine-induced epithelial disruption, and repeated mechanical disruption from rubbing
• Torticollis, trismus, and laryngospasm may endanger the airway.
• GI findings
• Vomiting, diarrhea, and hyperactive bowel sounds may be present. When evaluating a patient with a history of cocaine use and a complaint of abdominal pain, consider mesenteric ischemia in the differential diagnosis. Patients with abdominal pain must also be evaluated for renal infarction.
• The vascular supply to the intestine has many alpha-adrenergic receptors, and their stimulation may cause mesenteric ischemia. The clinical presentation of mesenteric ischemia includes abdominal pain and possibly tenderness, nausea, vomiting, and bloody diarrhea. Muscarinic receptor blockade results from high concentrations of cocaine, with anticholinergic effects on gastric motility that predisposes the person to ulceration from prolonged exposure to acid.
• Skin, thermoregulatory, and renal findings
• Patients may have sores or linear excoriations; crack pipe burns of the fingers or thumbs; thermal burns of the face and upper airway; and redness, swelling, and tenderness (secondary to phlebitis, vasculitis, cellulitis, and abscess formation).
• Search for track marks in the usual sites, such as the antecubital fossae, and unusual sites, such as under the tongue and on top of the feet.
• Excoriations from pruritus or hallucinations of crawling insects associated with cocaine use may also be found.
• Cocaine affects the anterior hypothalamus, which increases the thermoset point. Agitation secondary to intoxication or withdrawal results in increased motor activity, which causes increased heat production.
• Rule out occult infections in patients with fever.
• Evaluate patients with abdominal or back pain for renal infarction.
• Neurologic and psychiatric findings
• Altered sensorium and acute seizures are the most common cocaine-associated neurologic syndromes observed in the ED, accounting for 52% of related presentations. Other cocaine-related neurologic processes are toxic encephalopathy, ischemic and hemorrhagic stroke, neurogenic syncope, and movement disorders. Use of cocaine also decreases rapid eye movement (REM) sleep.
• Seizures, which can produce hyperthermia and lactic acidosis, are a major determinant of lethality.
• About 3-4% of all strokes occur in patients aged 15-45 years. Cocaine is a common cause of cerebrovascular events, including all varieties of stroke, in young patients. Cocaine-induced hypertension may lead to hemorrhage from cerebral aneurysms or ruptured arteriovenous malformations (AVMs).
• Extrapyramidal phenomena and other movement disorders, though uncommon, are reported in association with cocaine use. These effects are collectively referred to as "crack dancing." In a patient without a history of neuroleptic use such a presentation may be confusing to the ED physician.
• Headaches, some potentially resulting from inhibited serotonin reuptake, are common in people who use cocaine, whereas cerebral vasculitis is rare.
• Approximately 60% of people who regularly use cocaine report psychiatric complications of their drug use, and 18% have had visual or tactile hallucinations; a sensation of something crawling on the skin is most common.
• Psychiatric complications commonly associated with cocaine use include anxiety, depression, paranoia, delirium, psychosis, and suicide. Toxic psychosis might be misdiagnosed as paranoid schizophrenia.
• A crash follows cocaine binging and may result in extreme exhaustion (may be severe enough that the patient appears unresponsive), anxiety, psychomotor retardation, and increased appetite. Of note, the most common problem during a crash is depression that may reach suicidal proportions.
• In withdrawal, depletion of dopamine and norepinephrine leads to dysphoria, depression, and drug craving.
• In short, neurologic and psychiatric findings may include the following:
• Normal sensorium
• Altered mental status (a change in the level of consciousness or the content of consciousness)
• Confusion
• Restlessness
• Severe agitation
• An increase in purposeless psychomotor activity that may be exacerbated by nonspecific stimulation in the setting of cocaine use (commonly called cocaine leaps)
• "Overamped" or "wired" behavior
• Paranoia
• Delirium (a florid abnormal mental state characterized by disorientation, fear, and irritability with misperception of sensory stimuli)
• Headache
• Tremor
• Depression and extreme exhaustion associated with withdrawal following a binge
• Renal findings
• Vascular spasm may cause renal infarction.
• Cocaine may also exacerbate renal susceptibility to rhabdomyolysis by causing hyperthermia, vasoconstriction, and/or hypotension secondary to hypovolemia or MI.
• Endocrine and metabolic findings
• Acute toxic effects of cocaine may include acidosis, hyperkalemia, and hyperglycemia.
• Prolonged use of sympathomimetics, such as in a cocaine binge, may result in hypoglycemia.
• Musculoskeletal findings
• Cocaine use is among the drug-related causes of intrinsic muscle weakness.
• Wilson and Hobbs report a patient with Cori disease in whom cocaine unmasked subclinical skeletal muscle weakness, causing prolonged respiratory muscle insufficiency.
• Cocaine has also been implicated as a cause of impairment of neuromuscular transmission in a patient with myasthenia gravis.
• Packets of illicit drugs may be ingested or inserted into body cavities by "swallowers," "internal carriers," "couriers," or "mules" to intentionally transport drug, a practice called body packing. Another practice, body stuffing, involves swallowing relatively small amounts of loosely wrapped drug, or secreting packets in body cavities because of the fear of arrest. With suspicion of body packing or body stuffing, perform careful cavity searches of the rectum and vagina. Continued drug absorption is likely if toxicity continues for more than 4 hours.
• Altered mental status: A number of etiologic possibilities are possible, including toxic (eg, drug intoxication, withdrawal), metabolic, structural or traumatic, infectious, epileptic, or psychogenic causes.
• A simple toxicologic presentation is rare. Therefore, it is frequently necessary to differentiate agitation secondary to various intoxicants, withdrawal, or possibly both. In the agitated patient with extreme irritability, irrationality, and destructiveness, intoxication or withdrawal should be considered.
• Cocaine causes a sympathomimetic toxidrome, as do amphetamines, hallucinogens, and PCP; PCP causes the most persistent psychophysiologic reactions. Withdrawal from alcohol or sedative-hypnotics may cause the triad of hyperthermia, agitated delirium, and seizures.
• Phases of acute cocaine toxicity: Three phases are reported. In fatal cases, the onset and progression are accelerated, with convulsions and death frequently occurring in 2-3 minutes, though sometimes in 30 minutes. Cocaine stimulates the CNS in rostral-to-caudal fashion, with findings varying with the time since drug use.
• Phase I - Early stimulation
• CNS findings - Mydriasis, headache, bruxism, nausea, vomiting, vertigo, nonintentional tremor (eg, twitching of small muscles, especially facial and finger), tics, preconvulsive movements, and pseudohallucinations (eg, cocaine bugs)
• Circulatory findings - Possible increase in BP, slowed or increased pulse rate (possibly with ventricular ectopy), and pallor
• Respiratory findings - Increase in rate and depth
• Temperature findings - Elevated body temperature
• Behavioral findings - Euphoria, elation, garrulous talk, agitation, apprehension, excitation, restlessness, verbalization of impending doom, and emotional lability
• Phase II - Advanced stimulation
• CNS findings - Malignant encephalopathy, generalized seizures and status epilepticus, decreased responsiveness to all stimuli, greatly increased deep tendon reflexes, and incontinence
• Circulatory findings - Hypertension; tachycardia; and ventricular dysrhythmias (possible), which then result in weak, rapid, irregular pulse and hypotension; and peripheral cyanosis
• Respiratory findings - Tachypnea, dyspnea, gasping, and irregular breathing pattern
• Temperature - Severe hyperthermia (possible)
• Phase III - Depression and premorbid state
• CNS - Coma, areflexia, pupils fixed and dilated, flaccid paralysis, and loss of vital support functions
• Circulatory - Circulatory failure and cardiac arrest (VF or asystole)
• Respiratory - Respiratory failure, gross pulmonary edema, cyanosis, agonal respirations, and paralysis of respiration

Causes

• The National Institute on Drug Abuse (NIDA) estimates that 10% of individuals who begin using cocaine progress to serious, heavy use. After having tried cocaine, people cannot predict the extent to which they continue using the drug. According to 1999 DAWN data, patients visiting EDs for a drug-related cause provide the following reasons for using cocaine:
  • Dependence (49%)
  • Recreational use (37.6%)
  • Other psychic effects (19.7%)
  • Suicide (8.7%)
• A positive family history of substance abuse is related to the speed of developing dependence on cocaine and an earlier age of onset.
• Evidence suggests that cocaine dependence, similar to alcoholism, may have 2 subtypes, A and B (ie, type I and type II in the literature on alcoholism typology). Type A persons may develop cocaine dependence as a function of environmental influences, whereas type B persons may have certain premorbid risk factors that predispose them to a virulent form of cocaine abuse. Ball et al studied 399 patients with cocaine abuse or dependence in the first multidimensional subtyping study of cocaine users.²⁰ The most common presentation, observed in 67%, was type A. Women and African Americans most commonly had type A dependency, whereas men and whites most commonly had type B dependency.
  • Compared with persons with type A dependency, those with type B dependency had more severe abuse of alcohol and other drugs, addiction-related psychological impairment, antisocial behavior, and comorbid psychiatric problems.
  • Persons with type B dependency were more likely to be separated or divorced, to live alone or in an unstable situation, to have a family history of substance abuse, and to have had greater severity of childhood disorder than individuals with type A dependency. They also scored higher than those with type A dependency in assessments of sensation seeking, aggression, criminality, and violence.
  • Those with type B dependency had an early age of onset for antisocial personality disorder and early age of first use, first binge, first regular use, and first daily use of cocaine and alcohol. The quantity, frequency, duration, and severity of cocaine abuse and adverse effects (eg, loss of consciousness, chest pain, misperceived reality, violence, and use to relieve to stress) are greater with type B than with type A.
  • Although the groups do not differ in family history for psychiatric disorders, people with type B dependency had lifetime histories of major depression, suicide attempts, and total treatment episodes for psychiatric disorders as well as for abuse of alcohol and other drugs that were significantly greater than those with type A dependency.
  • No significant differences were found between the subtypes in terms of employment, education, referral source, number of close friends, age, time between the first use and the onset of symptoms of dependence, route of use, previous periods of abstinence from alcohol or other drugs, or the number of strategies used to control use.
• Rivara et al maintain that one half of those who abuse illicit drugs also have a mental disorder. Indeed, cocaine users, along with persons with alcoholism and those who abuse opiates, have elevated rates of antisocial personality, depression, anxiety, and polysubstance abuse. These traits also have been found in their first-degree relatives.²¹

Source : http://emedicine.medscape.com/article/813959-overview