US Pharm. 2008;33(2):HS-16-HS-25.

Cocaine is one of the most commonly used illicit drugs, and its abuse is a widespread problem in the United States and around the world. Approximately 13.8% (33.7 million) of Americans age 12 and older have reported trying cocaine at least once.1 Although the psychological effects of cocaine are widely known due to media exposure, most users know little about the medical consequences. This review will focus on cocaine-associated chest pain, the most common cocaine-related medical problem.2

Cocaine History
Cocaine (benzoylmethylecgonine) is an alkaloid isolated from the leaves of Erythroxylon coca, a plant indigenous to western South America.3 The use of the cocaplant dates back to early recorded history; archaeological evidence suggests that the chewing of coca leaves was practiced by the Incan civilization 5,000 years ago. The Incas purportedly used the plant for the relief of hunger and fatigue and as a local anesthetic.3,4 Cocaine was isolated by the German chemist Friedrich Gaedcke in 1855, and Albert Niemann is credited with being the first to purify and name it.5 The substance became popular in the United States in the late 1800s, when it was used in such products as cigarettes, toothache drops, and beverages (coca wines, Coca-Cola).3,6

Cocaine use was first restricted by the 1906 Pure Food and Drugs Act, which required the proper labeling of medications to list all constituents.7 The Harrison Narcotics Act, which followed in 1914, identified cocaine as a narcotic and limited its use to prescription medications.8 In 1970, the Controlled Substances Act further prohibited the manufacture, distribution, and possession of cocaine, except for limited medicinal use. Today, cocaine is classified as a Schedule II drug, indicating its high potential for abuse and its high incidence of psychological and physical dependence while also recognizing its medi!=cinal value.9 Currently, cocaine's only pharmacotherapeutic use is as a local anesthetic for topical application to the mucous membranes of the nasal, oral, or laryngeal cavities.

Forms of Cocaine
Cocaine is available as a hydrochloride salt, as "free base," and as "crack" cocaine. 6 The hydrochloride form is prepared by dissolving the alkaloid in hydrochloric acid to form a water-soluble powder or granule. This water-soluble form can be taken orally, IV, or intranasally; it cannot be smoked because it decomposes when heated.10 The free-base form is lipophilic and is produced by dissolving the cocaine in water and then extracting it using a solvent.10 This type of cocaine is smoked. Crack cocaine is molecularly the same as free base, but is prepared by the simpler method of alkalinizing the cocaine with ammonia or sodium bicarbonate (baking soda) and then heating it.10 It is heat stable and melts at 98C, thereby allowing it to be smoked.6 Because crack cocaine is inexpensive to make, it is easily accessible and thus a popular form of the drug.6

Since cocaine hydrochloride is well absorbed through all mucous membranes, cocaine users may achieve high blood concentrations via intranasal, sublingual, intra!=vaginal, or rectal administration (see TABLE 1).11 Compared with IV injection of the drug, mucosal administration has a slower onset of action, a delayed peak effect, and a longer duration of action.6 Intranasal administration causes local vasoconstriction, delaying absorption into the vasculature, which may contribute to the longer duration of action.6 When crack cocaine is smoked, it is rapidly absorbed by the extensive pulmonary vasculature, leading to euphoria within seconds. Due to its rapid and intense euphoric action, crack cocaine is considered to be the most potent and addictive form of the drug.3,6,12

Detection of active cocaine in the blood is difficult due the short serum half-life of 45 to 90 minutes. 10 Instead, cocaine metabolites are commonly used as an indicator of recent drug ingestion.6,10,12

Cocaine is metabolized by plasma and liver cholinesterases to the metabolite ecgonine methyl ester. 10 Nonenzymatic hydrolysis metabolizes cocaine to benzoylecgonine.10 Both metabolites are excreted in the urine.12 While these metabolites are generally thought to be inactive, research has shown that they may have pharmacologic activity and could be responsible for some adverse effects, including vasoconstriction.10,13 Interestingly, some research has shown that individuals with low plasma cholinesterase levels may be predisposed to the cardiotoxic effects of cocaine due to their poor ability to metabolize it into inactive compounds.14,15

Another important metabolite, cocaethylene, is formed when cocaine and ethanol are ingested together, a common occurrence among cocaine users.16 Cocaethylene is an active metabolite with psychoactive effects similar to those of cocaine.17,18 Conversion of cocaine and ethanol to cocaethylene leads to less formation of the benzoylecgonine, an inactive metabolite, which may lead to increased adverse events.19 Importantly, cocaethylene may contribute to cardiovascular adverse events, possibly by blocking cardiac sodium channels. 20,21 Some animal research has shown that cocaethylene and cocaine have similar toxicities relating to the heart.17,22 Additionally, cocaethylene has a longer half-life than cocaine (2.5 hours versus 50 to 90 minutes), which may explain why many patients experiencing myocardial infarction (MI) after cocaine use have low plasma cocaine levels.22,23 However, some researchers disagree that cocaethylene contributes to the cardiovascular adverse events of cocaine.24

Cocaine is a potent central nervous system stimulant. When taken systemically, cocaine binds to catecholamine transport protein, altering synaptic transmission by blocking the presynaptic reuptake of norepinephrine, dopamine, and serotonin. This blockade results in an excess of neurotransmitters at the site of the postsynaptic receptors, leading to an increase in postsynaptic receptor stimulation.11 The inhibition of dopamine reuptake is primarily responsible for cocaine's euphoric action.6

When applied topically, cocaine acts as a local anesthetic by blocking the initiation and transmission of electrical signals. The action is due to cocaine's ability to inhibit membrane permeability to sodium ions during depolarization.25 Inhibition of norepinephrine uptake leads to increased alpha-adrenergic stimulation and thus can result in vasoconstriction.10

Pathophysiology of Cocaine-Induced Chest Pain
Of the many complications that are associated with cocaine use (see TABLE 2), the most frequent complaint is chest pain.3,26-31 The incidence among cocaine users who present to the hospital has been reported to be as high as 40%.2,32 Ischemia, including acute coronary syndrome (ACS), is the most common cocaine-associated cardiac disorder.2

Of all patients presenting with cocaine-associated chest pain, approximately 6% are experiencing MI and 15% have ACS. The risk of MI is 24-fold higher in the first hour after cocaine use, but has been documented for up to six weeks following cocaine withdrawal. 33 Demographic and historical factors are not reliable for predicting cocaine-associated MI, but most patients are young, male cigarette smokers without other risk factors for atherosclerosis.34 Patients, especially young ones, should be questioned about cocaine use if they present with chest pain, and anyone with potential cocaine toxicity should receive a complete evaluation.12,33

The pathophysiology of cocaine-induced myocardial ischemia is multifactorial. Proposed mechanisms are coronary thrombosis, coronary artery vasoconstriction, mismatch between myocardial oxygen demand and supply, and accelerated atherosclerosis.3,33 The extent to which the mechanisms may interact is unknown.

Coronary thrombosis can develop in the presence of normal or diseased coronary arteries, possibly as a result of alterations in platelet and endothelial functions. Studies have proven that cocaine increases human platelet activation and aggregation. Additionally, vascular spasm may cause damage to the endothelium, creating a nidus for platelet aggregation and fibrin deposition and resulting in thrombus formation.3,34

Coronary artery vasoconstriction or spasm results from alpha-adrenergic stimulation and may occur in patients without coronary artery disease. Although this mechanism is not completely understood, it is known that it differs from Prinzmetal's angina.3,34

Cocaine has sympathomimetic effects that induce tachycardia and hypertension, resulting in an increased myocardial-oxygen demand. When this demand exceeds the supply, myocardial ischemia occurs. These sympathomimetic effects most likely act synergistically with other mechanisms to cause ischemia and are exacerbated by concomitant cigarette smoking.3,34

Chronic use of cocaine may lead to premature atherosclerosis. In autopsies, coronary atherosclerosis has been found with increased prevalence in young cocaine users compared with age-matched non-using controls.3,34,35

The differential diagnosis of cocaine-associated chest pain is similar to that of chest pain unrelated to cocaine use, but may vary depending on the route by which the drug was ingested. The smoking of crack cocaine has been associated with alveolar rupture resulting in pneumothorax, pneumopericardium, and pneumomediastinum. An ailment known as "crack lung syndrome," which involves pulmonary hemorrhage, chest pain, pulmonary edema, and an interstitial lung process, can occur. In addition, asthma, pneumonia, and pulmonary vascular disease must be considered. In patients using IV cocaine, endocarditis should be ruled out, especially if the patient also has fever. Finally, although it is a rare condition, aortic dissection must be considered in any patient with chest pain and a history of cocaine use because of the high mortality rate of roughly 27%. 3,33

EKG interpretation in patients with cocaine-induced chest pain is problematic. Approximately 60% of patients with cocaine-induced MI have a nondiagnostic EKG, and 56% to 84% of patients with cocaine-associated chest pain have abnormalities present on EKG. Thus, in cocaine users, MI cannot be ruled out in the setting of a normal initial EKG, nor can it be concluded that a patient needs reperfusion therapy if abnormalities are present on EKG.3,33

The most useful diagnostic tool for detecting cardiac injury in this patient population is serum biochemical markers. Cardiac troponin I and T are the most specific, and are preferred. Elevations in creatine kinase (CK) and CK-MB occur in the absence of myocardial ischemia due to cocaine-induced skeletal-muscle injury. It has been reported that, after using cocaine, approximately half of patients have elevated serum CK with or without myocardial injury.33,36

Urine drug testing also may be useful, especially in patients who initially deny using cocaine. The metabolite benzoylecgonine can be detected for up to 48 to 72 hours after cocaine use.33

The treatment of patients with cocaine-related ischemia or MI varies only slightly from the traditional treatment of ACS. All patients should be administered oxygen and placed on a cardiac monitor. Based on extensive investigation in patients with ischemic heart disease unrelated to cocaine, a favorable safety profile, and theoretical considerations, aspirin should be given to prevent the formation or extension of thrombi if there are no contraindications (i.e., allergy or suspected subarachnoid hemorrhage).33,36

Initial therapy also should include nitroglycerin. Nitroglycerin has been shown to reduce infarct-related complications and limit the extent of acute MI in patients with ischemia unrelated to cocaine. Studies also indicate that nitroglycerin alleviates cocaine-induced vasoconstriction and relieves symptomatic chest pain. 37-39

Benzodiazepines, in particular lorazepam, also have established benefits. Early use may decrease cocaine's cardiovascular toxicity by decreasing its central stimulatory effects.40 The combination of lorazepam plus nitroglycerin appears to be more efficacious than either agent alone for relieving chest pain associated with cocaine use.41 The same was not proven for diazepam in a similar study, however.42

Although they are used in the treatment of coronary ischemia that is not related to cocaine use, beta-blockers are contraindicated for cocaine-associated ischemia. Presumably through unopposed alpha-adrenergic stimulation, beta-blockers enhance coronary vasoconstriction and increase blood pressure.3,43 They also increase the likelihood of seizures and may decrease survival.40 Although labetalol has been used safely in some patients, it is not recommended based on controlled studies performed in animals and humans. Labetalol has combined alpha-beta antagonism, but the beta antagonism is far more potent.33,40

Owing to conflicting data, the role of calcium-channel blockers in the treatment of cocaine-associated ischemia has not been established. Cardiac-catheterization studies in patients with cocaine-induced coronary vasoconstriction found that verapamil reverses the vasoconstrictive effects of cocaine, but large-scale clinical trials have shown no benefit in acute MI unrelated to cocaine use.33,44 The American College of Cardiology/American Heart Association's 2007 guidelines for the management of patients with unstable angina/nonñST-elevation MI recommend calcium-channel blockers in combination with nitroglycerin for patients with chest pain after cocaine use.37

Phentolamine, an alpha-adrenergic antagonist, also can be used to achieve vasodilation in patients who continue to have chest pain after administration of oxygen, aspirin, benzodiazepines, and nitrogly!=cerin.33 One case report describes a 38-year-old man with cocaine-associated chest pain refractory to oxygen, diazepam, and nitroglycerin that resolved after low-dose phentolamine. 45 To avoid hypotension while maintaining the anti-ischemic effects, phentolamine 1 mg was recommended for such patients.45

Thrombolytic therapy should be considered in patients having ST-segment elevation MI only when cardiac catheterization is impossible. Although cocaine's known thrombogenic properties make thrombolytic therapy attractive in theory, adverse outcomes have been documented in several case reports. When it is balanced against the low mortality seen in patients with cocaine-associated MI, thrombolytic therapy's risks most likely outweigh its benefits in this patient population. 33

Secondary Prevention
The key to secondary prevention of cocaine-related chest pain is the cessation of cocaine use. Sadly, 60% of patients use cocaine again during the year following an episode of chest pain.46 Cocaine-related death, MI, and recurrent chest pain are extremely rare in patients who stop using cocaine. Tobacco should be avoided as well, as it is a major contributor to the risk for coronary artery disease; it also is associated with a faster onset of chest pain and vasoconstriction after cocaine use.47 Patients likely will benefit from modification of other traditional risk factors for heart disease such as high cholesterol, high blood pressure, and obesity. The use of aspirin to prevent platelet aggregation also may be beneficial for secondary prevention. The role of calcium-channel blockers and nitrates remains unproven, and beta-blockers should be avoided in any patient who may use cocaine again.46,47

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