Cocaine

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188 Cocaine

Cocaine abuse is one of the leading causes of drug-related emergency department visits and hospital admissions. Illicit use of this substance can lead to numerous medical complications, necessitating hospital admission and critical care and yielding significant mortality. Although cocaine use is more prevalent in young adults, complications of cocaine use should also be considered in older individuals.

Cocaine is obtained readily from the Erythroxylum coca plant, which is grown primarily in South America. Cocaine is extracted by soaking the leaves in organic solvents, and then precipitating the cocaine hydrochloride salt with the addition of hydrochloric acid. This form of cocaine can be snorted (inhaled through the nose), ingested orally, or intravenously (IV) injected. To smoke cocaine, the hydrochloride salt must be converted to a “free base” by dissolving it in an alkaline solvent. Allowing this product to dry into a rock-like state results in the popular street form of the drug, “crack cocaine.” The name comes from the cracking sound produced when this form of the drug is heated.

Testing for cocaine exposure is usually performed with urine assays, but almost any type of biological specimen can be tested. Because cocaine has a short half-life of about 1 hour, the metabolite, benzoylecgonine (half-life of 6 hours), is usually measured. Thus urine testing can usually detect cocaine use for approximately 1 to 2 days after an acute exposure. Chronic cocaine use may cause positive results days to weeks following last use of the drug.¹ There are no other drugs that can yield false-positive test results when benzoylecgonine urine assays are used.²

Mechanism of Action

Medicinal use of cocaine has fallen out of favor because other agents that lack potential for abuse and possess the medically useful local anesthetic and vasoconstrictive properties of cocaine have been found. The local anesthetic effects of cocaine occur because of its ability to block voltage-gated sodium channels in the neuronal membrane, resulting in blockade of neural conduction.³ The vasoconstrictive property of cocaine is mostly due to stimulation of α-adrenergic receptors in arterial wall smooth muscle cells. Increased endothelin-1 and decreased nitric oxide blood concentrations also may contribute to cocaine’s vasoconstrictive properties.⁴ Two major metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, may persist for over 24 hours and can be associated with delayed or recurrent coronary vasoconstriction.^5,⁶

The sympathomimetic activity of cocaine is caused by inhibition of the presynaptic reuptake of biogenic amines including norepinephrine, dopamine, and serotonin. Inhibition of reuptake of these neurotransmitters occurs throughout the body, including the central nervous system (CNS), as cocaine and some of its metabolites readily cross the blood-brain barrier. The resulting systemic effects of cocaine include increased heart rate and blood pressure and diffuse vasoconstriction. The CNS effects include marked euphoria and self-confidence at lower doses and agitation and delirium at higher doses. These CNS effects are most likely due to excessive dopaminergic activity.²

The thrombogenic activity of cocaine has been ascribed to increased plasminogen-activator inhibitor activity, increased platelet count, increased platelet activation, and platelet hyperaggregability. Additionally, because circulating elevated concentrations of C-reactive protein, von Willebrand factor, and fibrinogen are seen in cocaine users, it seems likely that the drug induces a proinflammatory state that enhances thrombosis.⁴

Cocaine and ethanol are frequently abused together, which may lead to added detrimental effects. Cocaine in the presence of ethanol is metabolized by the liver into cocaethylene, which has a longer duration of action than cocaine and is more toxic than cocaine or ethanol alone.^3,⁷ Additionally, ethanol inhibits cocaine metabolism, yielding higher cocaine concentrations.²

In addition to the toxic effects of cocaine itself, adulterants that are frequently added to cocaine may cause other undesirable effects. Commonly, talc and cornstarch are used as “fillers.” Other potential contaminants include benzocaine, quinine, and more recently, levamisole. Levamisole is an anthelmintic and antineoplastic drug that is not commonly used in humans because of an unacceptably high risk of agranulocytosis. The majority of cocaine tested from the United States is now adulterated with levamisole, and several cases of agranulocytosis have been linked to contaminated cocaine.⁸

Toxicities

Central Nervous System

The most significant CNS toxicity associated with cocaine use is stroke; both hemorrhagic and ischemic strokes can occur. Hemorrhagic strokes associated with cocaine use are hypothesized to result from acute elevations of blood pressure, coupled with platelet dysfunction and/or the presence of vascular malformations. The presence of vascular malformations, in particular, was suggested by several reports to be a significant predisposing factor. However, a large retrospective study failed to find a significant association between the presence of vascular malformations and cocaine-induced intracranial hemorrhage. Additionally, there was no predilection for cocaine to affect a particular area of the brain. The study noted that brainstem hemorrhage and intraventricular extension were associated with cocaine use.⁹ Ischemic stroke is also thought to be caused by cocaine use and is likely caused by cerebral vasoconstriction, which has been demonstrated experimentally and may be particularly associated with chronic abuse of the drug.¹⁰ Increased thrombogenic activity as described earlier also may play a role, especially with chronic use. All standard stroke care should be provided to patients with stroke related to cocaine use.

Seizures can be induced by acute use of cocaine, as the drug lowers the seizure threshold. Additionally, seizures can be induced by withdrawal of cocaine. Most seizures are self-limiting and usually respond to administration of IV benzodiazepines. Refractory seizure activity may indicate a severe CNS injury or severe hyperthermia.

Hyperthermia can occur with cocaine abuse and may result in death, especially in overdose situations and in hot climates.¹¹ Cocaine-induced hyperthermia is thought to be related to dysfunction of CNS thermoregulatory centers as well as derangements in regional distribution of blood flow caused by the vasoconstrictor effects of the drug.³ In addition, most patients present with heat exposure and muscle hyperactivity as contributing causes.^11,¹² A syndrome of excited delirium manifested by agitation, paranoia, and psychosis sometimes accompanies hyperthermia. In these cases, body temperature can be markedly elevated (>40.6°C). Patients presenting in this manner often have accompanying complications such as disseminated intravascular coagulation, rhabdomyolysis, and/or renal failure.¹³ Other than supportive care and aggressive cooling measures, there are no other standard therapies. Benzodiazepines such as lorazepam (administered IV or intramuscularly) should be used liberally to control agitation and hyperactivity. Haloperidol should be avoided, as this agent can lower the seizure threshold and also itself induce hyperthermia. Evaluation of the agitated cocaine abuser always should include accurate determination of core temperature.

Pulmonary

Pulmonary diseases associated with cocaine use are varied and can range from acute bronchoconstriction to noncardiogenic pulmonary edema to barotrauma. Most reported pulmonary complications have been associated with smoking freebase cocaine. Bronchoconstriction has been shown experimentally to be associated with inhaled cocaine.¹⁴ An increased need for intubation and mechanical ventilation with asthma exacerbations also has been found in cocaine abusers.¹⁵ The term crack lung has been used to refer to pulmonary infiltrates related to cocaine use. The pulmonary infiltrates may be transient or associated with significant disease, especially acute respiratory distress syndrome (ARDS).¹⁶ Noncardiogenic pulmonary edema caused by cocaine use is frequently associated with alveolar hemorrhage.¹⁷ Alternatively, hemoptysis can be the only presenting complaint and usually remits with avoidance of further cocaine exposure. Talc in contaminated cocaine has been reported to cause granulomatous lung disease. This entity is primarily associated with IV administration of cocaine, but chronic inhalation of the drug also can produce a similar form of lung disease.¹⁸ Data are lacking to show that administration of corticosteroids is of benefit for addressing pulmonary abnormalities associated with cocaine abuse.

Pneumothorax and pneumomediastinum have also been associated with smoking crack cocaine and are likely caused by coughing triggered by the inhalation of the drug, or particular behaviors such as breath holding which are employed to enhance the desirable effects of the drug. The cause of pneumothorax also may be related to adulterants in the inhaled cocaine.¹⁹ Treatment is usually conservative with supplemental oxygen and serial imaging. Tube thoracostomy is reserved for moderate to large pneumothoraces. The presence of pneumomediastinum by itself is not an indication for hospital or intensive care unit (ICU) admission.

Cardiovascular

Myocardial ischemia and infarction (acute coronary syndromes [ACS]) related to cocaine use were first reported in 1982.²⁰ Since then, numerous studies have confirmed that cocaine abuse is an epidemiologically significant cause of myocardial ischemia and infarction and morbidity and mortality on this basis. Chest pain is the most frequent reason for cocaine users to present to emergency departments. Cocaine-induced ACS are not related to the amount of cocaine used, route of administration, or frequency of use. First-time users can develop myocardial infarction (MI).⁵ Cocaine-associated myocardial ischemia is likely related to the combination of increased myocardial oxygen demand caused by acute increases in heart rate, blood pressure, and contractility, on the one hand, combined with decreased myocardial oxygen supply caused by coronary vasoconstriction, on the other hand. In addition, coronary artery atherosclerosis can develop prematurely in young cocaine users. In combination with the ability of cocaine to promote a prothrombotic state, cocaine-induced coronary artery disease likely contributes to the risk for ACS among cocaine abusers.⁴ Cocaine-associated myocardial ischemia appears to occur most commonly in the first few hours after cocaine exposure; however, delayed infarction can occur several hours to weeks after exposure to the drug. The effects of the metabolites of cocaine (benzoylecgonine and ecgonine methyl ester) are thought to contribute to the delayed presentation.⁵

Diagnosis of cocaine-associated MI should rely on the measurement of cardiac troponin I, as rhabdomyolysis and consequent elevation of total creatine phosphokinase concentrations can otherwise confound diagnosis.^21,²² Diagnosis using electrocardiogram (ECG) is difficult because the majority of patients who present with chest pain associated with cocaine use have ECG abnormalities. Even ST-segment elevation is difficult to interpret in these patients, because an early repolarization pattern is frequently present.²³

American Heart Association guidelines recommend percutaneous coronary intervention over fibrinolytic therapy for ST-segment elevation MI in the setting of cocaine use. Nitroglycerin and benzodiazepines are advocated as primary therapy aimed at ameliorating the coronary vasoconstriction and the increase in myocardial oxygen demand. Administration of aspirin and heparin is recommended unless contraindicated. Calcium channel blockers may be used in patients unresponsive to nitroglycerin and benzodiazepines.⁴ Beta-blockers, including labetalol, were thought to be associated with worse outcomes in patients with recent history of cocaine use. However, this topic provokes considerable controversy, since beta-blocker use was not found to be detrimental in two retrospective studies of patients with a recent history of cocaine use.^24,²⁵ Administration of beta-blockers might be beneficial for selected patients with ACS and a history of cocaine abuse.

Cocaine’s ability to block sodium channels yields acute type Ic antiarrhythmic properties including QRS prolongation and a variety of arrhythmias. Sinus tachycardia is the most common abnormal rhythm in cocaine users, and it responds to observation or benzodiazepines. Supraventricular arrhythmias are usually self-limited, but benzodiazepines also may be useful. Ventricular arrhythmias may respond to treatment with sodium bicarbonate, and addition of lidocaine may be necessary.²⁶ Arrhythmias due to cocaine-associated myocardial ischemia should be treated by correcting the ischemia. As always, treatment of life-threatening arrhythmias should follow Advanced Cardiac Life Support (ACLS) protocols. Aortic dissection is an important consideration when addressing cocaine-associated chest pain. Though many previous reports linked aortic dissection to cocaine use, a large international registry did not confirm the presence of a significant association.^27,²⁸

Musculoskeletal

The direct myotoxic effect of cocaine coupled with vasoconstriction-induced muscle ischemia are the likely contributors to rhabdomyolysis induced by cocaine use.²⁹ In addition, the various adulterants often added to cocaine may worsen the injury. Diagnosis is based on detection of elevated serum creatine phosphokinase (CPK) concentrations. In the absence of hematuria, evaluation for myoglobinuria with urine dipstick testing may aid screening for rhabdomyolysis.³⁰ It is prudent to consider the possibility of rhabdomyolysis in cocaine abusers with significant agitation or obtundation. Initial CPK concentrations may be normal, and repeat testing after a few hours, especially after volume administration, may identify significant rhabdomyolysis.

Treatment is aimed at preventing renal tubular damage caused by the nephrotoxic effects of myoglobin and some hemoglobin decomposition products. Treatment consists of providing aggressive IV hydration with crystalloid infusion. Recommendations for IV hydration include at least 1 to 2 L as an initial bolus, or achievement of a clinically euvolemic state followed by continuous infusion of 200 to 500 mL/h.^31,³² Recommendations for use of IV bicarbonate, mannitol, and forced diuresis are not supported by available clinical data. Frequent monitoring of electrolytes is imperative, as both the myocyte injury and associated renal injury can contribute to severe electrolyte abnormalities that require immediate intervention. Early acute dialysis may be necessary to treat persistent hyperkalemia.³³

Other Complications

Ischemic injury due to cocaine also can affect the gastrointestinal (GI) tract. Bowel ischemia, infarction, and perforation have been reported following ingestion, IV injection, or inhalation of cocaine.³⁴^–³⁷ Although most cases of ischemia involve segments of the small bowel, ischemic colitis also can occur.^36,³⁷ Most patients tend to be younger with no predisposing risks for ischemia. Gastroduodenal perforation also has been described.³⁵ Vasoconstriction and/or thrombosis of mesenteric vessels are proposed mechanisms for bowel ischemia. Patients can present with acute or chronic abdominal pain, and peritoneal signs are often present. Management often includes surgical exploration, but nonoperative approaches with bowel rest and antibiotics may be appropriate in some patients. In some cases, preoperative angiography identified occlusion of celiac or mesenteric vessels that prompted revascularization interventions.³⁸

Acute renal injury due to cocaine may be precipitated by rhabdomyolysis, but other etiologic factors can include vasoconstriction or thrombosis of renal vessels, accelerated hypertension, thrombotic microangiopathy, interstitial nephritis and/or glomerulonephritis.³⁹ Renal infarction should be considered in cocaine users who present with significant persistent abdominal or flank pain that is often accompanied by nausea, vomiting, and fever.^40,⁴¹ The right kidney is more commonly involved, based on published reports. Diagnosis is facilitated by imaging and assessment of the renal vasculature. Management of renal infarction due to cocaine includes administration of aspirin, anticoagulation, thrombectomy, if indicated, and supportive care.

The effects of cocaine in pregnant women are similar to the effects of the drug in other groups of patients. In addition, however, cocaine-induced vasoconstriction decreases uterine blood flow and consequently oxygen delivery to the fetus. Obstetrical conditions associated with cocaine use include placental abruption, placenta previa, spontaneous abortion, premature rupture of membranes, and uterine rupture.^42,⁴³ Standard obstetrical management is indicated for these conditions.

Drug Transporters

Cocaine or other illicit drugs are sometimes ingested or inserted into body orifices for the purpose of transport or concealment.⁴⁴ Body “stuffers” swallow or otherwise hide small amounts of (wrapped or unwrapped) drug to avoid detection. In this circumstance, toxicity is frequent because the drug is not prepared to limit absorption, usually during passage through the GI tract. Quantities of drug are smaller, so toxicity is usually mild. In contrast, body “packers” swallow larger quantities of drug in packets that are specially prepared to withstand transit through the GI tract.⁴⁵ Plain abdominal radiographs often show the location of packets, but a negative result does not rule out body packing. An abdominal computed tomography (CT) scan may be needed to visualize the packets.

Asymptomatic transporters of cocaine packets can be managed conservatively until the packets have been completely evacuated.^45,⁴⁶ Activated charcoal given every 4 to 6 hours can reduce the lethality of cocaine absorption. Whole-bowel irrigation or mild laxatives such as lactulose may assist with passage of the packets. Surgical intervention is required in patients with clinical manifestations of cocaine toxicity, suspected rupture of packets, or symptoms compatible with GI obstruction or perforation.⁴⁵ Patients requiring surgical procedures may have a higher incidence of wound infections.^47,⁴⁸

Cocaine Withdrawal

Psychological and biochemical dependency occurs with cocaine use. Withdrawal symptoms are likely related to dopamine deficiency in the CNS after a period of abstinence.⁴⁹ Clinical manifestations of withdrawal include depression, fatigue, irritability, insomnia, psychomotor agitation or depression, and craving for more cocaine. Prolonged somnolence (“washout syndrome”) can occur after binge use and often leads to extensive evaluations for other etiologies.⁵⁰ Patients should be referred for drug counseling.

Annotated References

Goldstein RA, DesLauriers C, Burda AM. Cocaine: history, social implications, and toxicity—a review. Dis Mon. 2009;55:6-38.

A thorough review of cocaine’s uses, abuses, pharmacology, drug interactions, and toxicities.

Knuepfer MM. Cardiovascular disorders associated with cocaine use: myths and truths. Pharmacol Ther. 2003;97:181-222.

A review of the various cardiovascular disorders associated with cocaine use.

McCord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117:1897-1907.

The American Heart Association statement that describes the various cardiology recommendations in the care of patients with cocaine-associated chest pain and myocardial infarction.

Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351-358.

An important review article that describes the various cardiovascular complications of cocaine use and the scientific understanding of the disease processes.

Martin-Schild S, Albright KC, Hallevi H, Barreto AD, Philip M, Misra V, et al. Intracerebral hemorrhage in cocaine users. Stroke. 2010;41:680-684.

A large retrospective study addressing the location, pathology, and outcome of patients with cocaine-associated intracerebral hemorrhage.

References