Historical records of indigenous cultures in South America describe early stimulant use by chewing leaves of the Erythroxylum coca plant, a practice that continues today. Cocaine was first used therapeutically in 1884 for ophthalmologic procedures. Amphetamines were first synthesized in 1887, and in 1932 they were first marketed medicinally in an inhaler form as a bronchodilator. Use of methamphetamine to enhance physical and intellectual performance began in the 1930s. These drugs have limited therapeutic roles but are widely used as drugs of abuse. Clinical effects and toxicity are due to sympathetic nervous system stimulation.

COCAINE

Cocaine is the naturally occurring alkaloid found in E. coca, a plant indigenous to South America. The water-soluble hydrochloride salt is absorbed across all mucosal surfaces, including oral, nasal, GI, and vaginal epithelium; thus, cocaine can be topically applied, swallowed, or injected IV. The hydrochloride (salt) form is most often insufflated (snorted) or injected IV. The freebase form of cocaine can be prepared in several ways. A common method uses an alkali, such as sodium bicarbonate, to produce “crack cocaine,” a freebase form that is stable to pyrolysis that, when smoked, produces the popping sound that characterizes its name. The onset and duration of action vary with the route of administration (Table 187-1).

When cocaine is insufflated nasally, the delayed and prolonged effect is a result of vasoconstrictive properties that limit mucosal absorption as well as the swallowing of a portion of the insufflated cocaine, which is then absorbed from the stomach. GI absorption is also delayed by vasoconstriction, producing delayed peak effect.

Cocaine is primarily metabolized to ecgonine methyl ester by plasma cholinesterase. Relative deficiency of this enzyme may predispose affected patients to life-threatening toxicity.¹ Benzoylecgonine is the other major metabolite excreted in the urine and is the target compound detected in routine urine toxicology screens. Cocaethylene is a long-acting metabolite formed when cocaine is used in combination with ethanol. Cocaethylene has vasoconstrictive properties similar to those of cocaine.

Cocaine is both a CNS stimulant and a local anesthetic.^2,3 Central effects are mediated by enhancement of excitatory amino acids and blockade of presynaptic reuptake of norepinephrine, dopamine, and serotonin. The excess of neurotransmitters at postsynaptic receptor sites leads to sympathetic activation, producing the characteristic physical findings of mydriasis, tachycardia, hypertension, and diaphoresis, and predisposing to dysrhythmias, seizures, and hyperthermia. Cocaine use produces a euphoria associated with enhanced alertness and a general sense of well-being. It is thought that the psychological addiction, drug craving, and withdrawal effects are mediated by interference with dopamine and serotonin balance in the CNS. Subsequent dopamine depletion at the nerve terminals may account for the dysphoria and depression associated with long-term abuse.

Like other local anesthetics, cocaine inhibits conduction of nerve impulses by blocking fast sodium channels in the cell membrane. Cocaine also has quinidine-like effects on conduction, causing QRS-complex widening and QT-interval prolongation. Thus, in large doses, cocaine may exert a direct toxic effect on the myocardium, resulting in negative inotropy and wide-complex dysrhythmia.

AMPHETAMINES

Amphetamines comprise a broad class of structurally similar derivatives of phenylethylamine.⁴ The derivative methamphetamine, also known as “ice,” is abused by ingestion, IV injection, inhalation, or nasal insufflation. Absorption and peak effects vary with the route (Table 187-2). Modification of the basic amphetamine structure produces substances with additional psychoactive properties.⁴ Over 50 such “designer” amphetamines have been created (Table 187-3), primarily for hallucinogenic effects (see chapter 188, “Hallucinogens”). Methamphetamine and the designer amphetamines may have effects that persist for up to 12 hours or longer.

Synthetic (or substituted) cathinones, often termed “bath salts,” are designer drugs derived from naturally occurring amphetamine analogs found in the Catha edulis plant. Cathinones stimulate the release and block the reuptake of norepinephrine, dopamine, and serotonin at synapses in the brain, producing stimulant effects similar to cocaine and amphetamines.^5,6,7 Commonly abused substituted cathinones include mephedrone, methylenedioxypyrovalerone, and methylone, although the composition in bath salts sold for use by abusers varies widely. Stimulant medications for attention-deficit disorder, such as methylphenidate and dextroamphetamine, are available in both immediate- and extended-release formulations. Abusers may crush the extended-release tablet to separate the active agent from the extended-release matrix to achieve a rapid onset of action after insufflation or injection.⁸

Amphetamines enhance the release and block the reuptake of catecholamines at the presynaptic terminal and may also directly stimulate catecholamine presynaptic and postsynaptic receptors.⁹ Some amphetamine metabolites inhibit monoamine oxidase, increasing cytoplasmic concentrations of norepinephrine. Certain amphetamine derivatives can also induce release of serotonin and affect central serotonin receptors. These serotonergic effects account for the hallucinogenic properties of some amphetamine derivatives such as MDMA (3,4-methylenedioxymethamphetamine) and mescaline (3,4,5-trimethoxyphenethylamine). Downregulation of dopamine receptor activity with long-term use may contribute to the withdrawal phenomenon. Mortality from amphetamine toxicity is a result of hyperthermia, dysrhythmias, seizures, hypertension (intracranial hemorrhage or infarction), and encephalopathy.

Stimulants such as methylphenidate, ephedrine, pseudoephedrine, and phenylpropanolamine produce toxic syndromes similar to those caused by cocaine and amphetamines.^{10,11,12,13,14,15} Ephedrine is derived from ephedra or ma huang (Ephedra sinica) and is an indirect-acting sympathomimetic that was advertised as a “natural” stimulant in health food supplements and promoted for dieting, energy, and maintenance of alertness. Cardiovascular and neurologic toxicity associated with psychosis, severe hypertension, and several deaths prompted the U.S. Food and Drug Administration in 2004 to ban the sale of ephedra in dietary supplements.

The clinical features of cocaine and amphetamine toxicity are the result of their sympathomimetic, vasoconstrictive, psychoactive, and local anesthetic properties affecting a variety of organ systems.^2,3,4,9

CARDIOVASCULAR

Cocaine induces dysrhythmias, myocarditis, cardiomyopathy, and acute coronary syndromes.¹⁶ Other vascular complications include aortic rupture and aortic and coronary artery dissection. Even at relatively low doses, cocaine induces vasoconstriction in coronary arteries, contributing to cocaine-induced chest pain.¹⁷ Coronary vasoconstriction is exacerbated by β-adrenergic blockade and antagonized by phentolamine, which suggests mediation through stimulation of α-adrenergic receptors.¹⁸ This effect is further potentiated by cigarette smoking. In addition to promoting vasospasm, cocaine potentiates acute coronary syndrome by increasing atherogenesis through increased platelet aggregation, thrombogenesis, and accelerated atherosclerosis.

The patient most at risk for cocaine-associated acute coronary syndrome is a male between 20 and 40 years old, who is a cigarette smoker and who regularly uses cocaine.^19,20 All routes of cocaine administration are associated with chest pain, acute coronary syndrome, ST-elevation myocardial infarction, and non–ST-elevation myocardial infarction. Atypical chest pain is common.

Acute coronary syndromes and aortic dissection are also reported in association with ephedrine, phenylpropanolamine, and amphetamine use.²¹ Mitral and aortic valve abnormalities associated with use of the amphetamine combination phentermine-fenfluramine prompted a voluntary recall of these drugs. Cardiopulmonary toxicity from other amphetamine diet aids has also been reported.

Dysrhythmias induced by cocaine can result from sympathomimetic stimulation, blockade of the sodium channel during depolarization, inhibition of the potassium channel during repolarization, and effects on calcium channel current.^16,22 Sympathomimetic-induced dysrhythmias are tachycardias, such as sinus tachycardia, reentrant supraventricular tachycardia, and atrial fibrillation and flutter. Sodium channel blockade produces a rightward shift of the terminal portion of the QRS complex as seen on the frontal plane ECG leads, a pattern similar to that of cyclic antidepressants.²³ Progressive toxicity may induce a complete right bundle-branch block or a prolonged QRS >120 ms that, when combined with sinus tachycardia, produces a wide-complex tachycardia. Cocaine can induce the ECG appearance of the Brugada pattern, although it is not clear whether this is strictly a toxic effect or if the sodium channel–blocking effect of cocaine unmasked an underlying genetic predisposition to the Brugada syndrome.²⁴

Potassium channel blockade impairs repolarization, prolonging the QT interval on the ECG.²³ The effects of cocaine on calcium channel current are dose dependent and complex, but at concentrations associated with clinical toxicity, prolongation of both depolarization and repolarization is seen, as well as enhanced dispersion in repolarization.²² Delayed repolarization and enhanced dispersion promote early afterpotentials that can trigger reentrant dysrhythmias, such as ventricular tachycardia and a variant, torsades de pointes.

Takotsubo syndrome, transient apical ballooning of the left ventricle, has been associated with cocaine use. The physiology is not clearly understood but has been attributed to the effects of a sympathomimetic surge on the myocardium after cocaine use.²⁵

CNS

Neurologic syndromes associated with cocaine abuse include seizures, intracranial infarctions, and hemorrhages. Hyperadrenergic tone induces severe transient hypertension, hemorrhage, or focal vasospasm, and, sometimes, exacerbation of underlying abnormalities of cerebral blood vessels. Cerebral vasoconstriction following cocaine administration has been observed using magnetic resonance angiography.²⁶

Other CNS manifestations reported after cocaine use include spinal cord infarctions, cerebral vasculitis, and intracranial abscesses. Choreoathetosis and repetitive movements (termed “crack dancing”) are associated with cocaine and amphetamine intoxication and appear related to dopamine dysregulation. Acute dystonic reactions following cocaine use and withdrawal are also observed. Unilateral blindness has been reported secondary to central retinal artery occlusion, and bilateral blindness can be caused by diffuse vasospasm. A syndrome of corneal abrasions and ulcerations secondary to smoke and irritation is known as “crack eye.” Keratitis caused by methamphetamine use has been described as well.

“Cocaine washout” is a syndrome that may occur in patients after a prolonged crack binge and results from depletion of neurotransmitters. Patients have a depressed level of consciousness but can be aroused to normal with stimulation. Resolution of lethargy can take up to 24 hours.

Amphetamine, phenylpropanolamine, and ephedrine use are associated with intracranial hemorrhage, infarction, encephalopathy, and seizures.^4,9 Amphetamines can also cause a CNS vasculitis resulting in focal neurologic deficits. A profound paranoid psychosis can be seen with long-term amphetamine abuse and withdrawal.

PULMONARY