The pharmacologic effects of cocaine are complex, and they include direct blockade of the fast sodium channels, increase in norepinephrine release for the adrenergic nerve terminals, interference with neuronal catecholamine reuptake, and increase in excitatory amino acid concentration in the central nervous system (CNS). Blockade of the fast sodium channels stabilizes axonal membranes, producing a local anesthetic-like effect and a type I antidysrhythmic effect on the myocardium. The increase in catecholamine levels produces a sympathomimetic effect. The result of increased excitatory amino acid concentration in the CNS is increased extracellular dopamine concentration.

Cocaine is well absorbed through the mucosa of the respiratory, gastrointestinal, and genitourinary tract, including less common routes of absorption such as the urethra, bladder, and vagina. The cocaine hydrochloride salt is the form most often abused nasally or parenterally. Crack cocaine and cocaine freebase are alkaloid forms of cocaine that are produced by an extraction process. These forms are heat stable, can be smoked, and are absorbed through the pulmonary system. When intravenously administered or inhaled, cocaine is rapidly distributed throughout the body and CNS, with peak effects in 3 to 5 minutes. With nasal insufflation, absorption peaks in 20 minutes.

Cocaine has a half-life of 0.5 to 1.5 hours. It is rapidly hydrolyzed to the inactive metabolites ecgonine methyl ester and benzoylecgonine, which account for 80% of cocaine metabolism. These compounds have half-lives of 4 to 8 hours, with effects similar to those of cocaine. Minor cocaine metabolites include ecgonine and norcocaine. Urinary toxicology screens for recreational drugs typically assess for the presence of benzoylecgonine, which is usually present for 48 to 72 hours after cocaine use [3].

Cocaine is frequently abused in combination with other drugs. In particular, ethanol is a frequent coingestant [2]. This may be a popular combination because ethanol antagonizes cocaine’s stimulatory effects. The metabolism of cocaine in the presence of ethanol produces cocaethylene, which has additional cardiovascular and behavioral effects [4]. Cocaethylene and cocaine are similar with regard to behavioral effects. However, cocaethylene has been more likely to result in death in animal studies. Human studies demonstrate that cocaethylene produces milder subjective effects and similar hemodynamic effects when compared with cocaine. Cocaethylene also has a direct myocardial depressant effect [4].

Cocaine toxicity is due to an exaggeration of its pharmacologic effects, resulting in myriad consequences that have an impact on every organ system. The widespread effects of cocaine are related to its ability to stimulate the peripheral and central sympathetic nervous systems, in addition to local anesthetic-like effects. Cocaine-induced seizures are most likely due to excess catecholamine stimulation.

Cocaine causes vascular effects through multiple pathophysiologic mechanisms that have been best described in the heart [5,6,7]. These include arterial vasoconstriction, in situ thrombus formation, platelet activation, and inhibition of endogenous fibrinolysis. In addition, myocardial oxygen demand is increased by cocaine-induced tachycardia and hypertension [5,6,7,8]. The direct local anesthetic-like effect of cocaine or secondary cocaine-induced myocardial ischemia [5,9] may be responsible for cardiac conduction disturbances [9] and dysrhythmias.

Clinical manifestations of acute cocaine toxicity may occur in a number of different organ systems. Most severe cocaine-related toxicity and cocaine-related deaths are manifested by signs of sympathomimetic overdrive (e.g., tachycardia, hypertension, dilated pupils, and increased psychomotor activity). This increased psychomotor activity causes increased heat production and can lead to severe hyperthermia and rhabdomyolysis [10].

Cocaine-induced cardiovascular effects are common. Of cocaine-related emergency department visits, chest pain is the most common complaint. Although most of these patients do
not have serious underlying etiology, myocardial infarction due to cocaine is a well-established entity and needs to be excluded [11,12]. It occurs in 6% of patients presenting with cocaine-associated chest pain [13]. The risk of myocardial infarction is increased 24-fold in the hour after cocaine use. In patients aged 18 to 45 years, 25% of myocardial infarctions are attributed to cocaine use [14]. Cocaine-associated myocardial infarction typically occurs in patients aged 18 to 60 years without apparent massive cocaine exposure or without evidence of cocaine toxicity. Patients with cocaine-associated myocardial infarctions frequently have atypical chest pain or chest pain that is delayed hours to days after their most recent cocaine use [5,11].

Cardiac conduction disturbances (e.g., prolonged QRS and QTc) and cardiac dysrhythmias (e.g., sinus tachycardia, atrial fibrillation/flutter, supraventricular tachycardias, idioventricular rhythms, ventricular tachycardia, torsade de pointes, and ventricular fibrillation) may occur after cocaine use [15,16,17]. Aortic dissection and endocarditis associated with cocaine abuse are uncommon [18].

The neurologic effects of cocaine may be manifested in a number of ways. Altered mental status and euphoria are typically short lived and without serious sequelae. The stimulatory effects of cocaine can lead to seizures, cerebral infarction, intracerebral bleeding, subarachnoid hemorrhage, transient ischemic attacks, migraine-type headache syndromes, cerebral vasculitis, anterior spinal artery syndrome, and psychiatric manifestations [19,20,21]. Cocaine is associated with a sevenfold increased risk of stroke in women [22].

Cocaine-induced seizures are typically single, brief, generalized, self-limited, and not associated with permanent neurologic deficit. These seizures may occur in the presence or absence of concurrent structural disease, such as infarction or hemorrhage. Multiple or focal seizures are usually associated with concomitant drug use or an underlying seizure disorder [19].

Cocaine has a number of direct and indirect effects on the lungs, and they are associated with how the drug is used [23]. These effects include asthma exacerbations, pneumothorax, pneumomediastinum, noncardiogenic pulmonary edema, alveolar hemorrhage, pulmonary infarction, pulmonary artery hypertrophy, and acute respiratory failure [24,25]. Asthma exacerbations are more common with crack cocaine usage, most likely due to particulate by-products of combustion [26]. Inhalation of cocaine is typically associated with deep Valsalva maneuvers to maximize drug delivery and can cause pneumothorax, pneumomediastinum, and noncardiogenic pulmonary edema.

The intestinal vascular system is particularly sensitive to cocaine effects because the intestinal walls have a wide distribution of α-adrenergic receptors. Acute intestinal infarction has been associated with all routes of cocaine administration [27].

The most deadly gastrointestinal manifestation of cocaine usage is seen in the patient who presents after ingesting packets filled with cocaine. These patients have been termed body packers or body stuffers. Body packers are patients who swallow carefully prepared condom or latex packets filled with large quantities of highly purified cocaine for the purposes of smuggling this drug into the country. In contrast, body stuffers are typically “street” drug dealers who swallow packets of cocaine while fleeing the police. These packets were generally prepared for distribution to individual customers and not to protect the body stuffer from absorbing cocaine. It was previously thought that cocaine ingested orally was metabolized in the gastrointestinal track and did not lead to systemic toxicity. This is clearly not the case and toxicity can develop in body stuffers and packers from cocaine leaking out of the swallowed packets. The dosage of cocaine exposure in body stuffers is generally substantially less than that of a body packer. However, toxicity is more likely to occur in the setting of body stuffers. Although massive exposure to leakage from a condom or latex-filled packet of a body packer can occur, most body packers identified by airport immigration officers, do not develop clinical toxicity. However, any patient identified as a body packer who has developed any signs of systemic cocaine toxicity (tachycardia, hypertension, diaphoresis, etc.) can rapidly develop worsening symptoms including life-threatening ones. These patients, when identified, have a high potential for progressively worsening toxicity and mortality [28].