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Cocaine and Other Sympathomimetics


Key Concepts

  • Excessive use of stimulants can lead to sympathomimetic toxicity , manifesting as tachycardia, hypertension, mydriasis, diaphoresis, hyperthermia, hyperreflexia, and agitation. If untreated, sympathomimetic toxicity can lead to seizures, coma, and death.

  • Administration of benzodiazepines is the key therapeutic intervention for sympathomimetic toxicity. Ketamine, olanzapine, and butyrophenones are alternative adjuncts if the cause of severe agitation is not clearly sympathomimetic toxicity.

  • Worsening hyperthermia portends imminent death. Reduce body temperature rapidly by external cooling, sedation, and, if needed, paralysis.

  • Anti-hypertensives are adjuncts to benzodiazepines. Antihypertensives do not treat as many aspects of sympathomimetic toxicity as do benzodiazepines, however, and short-acting antihypertensive agents (e.g., phentolamine, nitroglycerin, nicardipine, clevidipine) are preferred.

  • Wide-complex rhythms secondary to stimulants (cocaine, bupropion) may respond to intravenous sodium bicarbonate administration.

  • Cocaine body packers who develop toxicity need emergent surgical intervention to limit bowel necrosis and life-threatening sequelae caused by leaking packets.

  • Novel psychoactive substances (e.g., MDMA, bath salts) combine stimulant, hallucinogenic, and psychedelic effects. They generally produce longer-lasting and more intense effects than cocaine or amphetamine.

  • Screen for hyponatremia in patients with sympathomimetic or serotonin toxicity.

  • If the clinical presentation does not fit the history (e.g., ingested cocaine but hypoxic and somnolent), consider a contaminant or alternate cause. Contaminants change rapidly and vary by geographic region. Consult a medical toxicologist or regional poison control center.

Foundations

Sympathomimetics are substances that activate the sympathetic nervous system ( Box 144.1 ). These substances stimulate release (amphetamine, phenethylamines) or decrease reuptake (cocaine, amphetamine, phenethylamines) of neurotransmitters (serotonin, norepinephrine, dopamine, epinephrine). As a result, these neurotransmitters remain in synapses longer and activate neuronal pathways more strongly and persistently. Stimulants cause an acute upper effect—euphoria and increased energy. Excessive use can lead to sympathomimetic toxicity—tachycardia, hypertension, mydriasis, diaphoresis, hyperthermia, hyperreflexia, and agitation. If untreated, sympathomimetic toxicity can lead to seizures, coma, and death.

BOX 144.1
Clinical Effects of Sympathomimetics

  • Central nervous system (CNS) excitation

  • Diaphoresis

  • Hypertension

  • Hyperthermia

  • Increased motor tone

  • Mydriasis

  • Tachycardia

This chapter reviews the epidemiology, pathophysiology, and treatment of stimulant toxicity. Over the past two decades, many designer chemicals have emerged with properties that combine traditional drug classes. Some are stimulants and hallucinogens. Others are stimulants and sedatives. Toxicity from a stimulant, whatever its pedigree, manifests as overactivation of the nervous and cardiovascular systems. The primary goals of clinical intervention are to decrease activation of the sympathetic nervous system by sedating the patient, identify end-organ toxicity, and involve a medical toxicologist to guide further management for more complicated cases.

Cocaine

Cocaine is the canonical ubiquitous stimulant drug of abuse. The indigenous people of South America chew the cocoa leaf (Erythroxylon coca) for energy. Spanish colonists initially banned chewing cocoa leaves, but soon acknowledged their ergogenic properties, legalizing and taxing cocoa leaf production in the 16th century. In 1855, Friedrich Gaedcke isolated pure cocaine. This three-century delay partly reflects the difficulty in keeping cocaine warm and dry while shipping it across the Atlantic Ocean. Soon after, cocaine became a popular ingredient in beverages, pharmaceuticals, and tonics. In the 19th century, physicians such as Carl Koller and William S. Halsted explored the use of cocaine as an anesthetic, exploiting its unique ability to block sodium channels and constrict blood vessels. Victorian literature mentions cocaine’s ability to “stave off the ennui of existence,” and it was notably used by the character Sherlock Holmes to keep him stimulated between cases. In 1914, the U.S. Congress passed the Harrison Narcotics Tax Act, which required a physician’s order to dispense cocaine and narcotics.

Epidemiology

General statistics on drug use may not distinguish between people who have ever used cocaine, those who have used in the last year, or those who have used in the last week. As a result, these studies combine different populations: the regular user, the sporadic user, the heavy user, the sampler, adults, and adolescents. Any of these groups may experience an overdose of cocaine, although anecdotal experience suggests that inexperienced drug users with psychiatric comorbidities are the population most at risk for cocaine toxicity. Regular use of cocaine accelerates vascular pathology, including coronary artery arteriosclerosis. It is more useful for the clinician to consider incidence or prevalence in terms of the at-risk population. Most information on novel psychoactive substances comes from observational studies on social media, which rarely can identify the exposure or fully define the population.

The prevalence of people in the world who reportedly used cocaine was 13 million in 2012 (0.18%), increasing to 18 million (0.24%) in 2016. The fraction of 8th graders in the United States who reportedly used cocaine was 0.9%, nearly four times the global average. The fraction of 12th graders who used cocaine was 3.8%, again, nearly four times the global average.

In the emergency department (ED), cocaine use is associated with up to 20% of drug misuse-related deaths in the United States , and between 20% and 50% in the European Union. These data may underestimate the incidence of morbidity and mortality attributable to cocaine, especially in trauma patients. In 2017, drug overdose deaths involving cocaine increased by more than 33%, with almost 14,000 Americans dying from an overdose involving cocaine. From 2016 to 2017, the largest relative and absolute rate changes for cocaine-involved overdoses among racial/ethnic groups were highest among non-Hispanic Blacks. The highest death rate for overdoses involving cocaine in 2017 also occurred among Non-Hispanic Blacks.

Formulation

Unpurified cocaine paste is converted to more usable forms of cocaine. The crystallized freebase of the cocaine alkaloid is known as crack cocaine. It is inhaled with a “crack pipe” designed to tolerate the high temperature required to volatilize pure cocaine. The high lipid solubility and rapid transport from the lungs into the brain contribute to crack’s rapid onset of action ( Table 144.1 ). The water-soluble salts of cocaine (i.e., cocaine hydrochloride and cocaine sulfate) are available as a white crystalline powder that is inhaled intranasally or dissolved and injected intravenously. Oral administration is rare except for among those patients who are smuggling or concealing drugs.

TABLE 144.1
Cocaine Pharmacology by Route of Administration
Route Formula Onset of Action Peak Effect Duration
Inhalation “Crack” 8–12 s 2–5 min 10–20 min
Intranasal Cocaine HCl 2–5 min 5–10 min 30 min
Intravenous Cocaine HCl Seconds 10–20 min 60–90 min
Oral Cocaine HCl 30–60 min 60–90 min Unknown
“Skin popping” Cocaine HCl Unknown Unknown Unknown
HCl, Hydrogen chloride.

Pathophysiology

Cocaine decreases the clearance of dopamine, epinephrine, norepinephrine, and serotonin from synapses between nerve cells or between nerve cells and muscle cells ( Fig. 144.1 ). Decreased clearance allows these neurotransmitters to stay bound to post-synaptic receptors longer, leading to autonomic stimulation (all four neurotransmitters), euphoria (dopamine and serotonin), and a sensation that things are more salient, or important, than they might be otherwise (dopamine) (see Box 144.1 ). Norepinephrine causes vasoconstriction by stimulation of alpha-adrenergic receptors on vascular smooth muscle. Epinephrine increases myocardial contractility and heart rate through stimulation of beta 1 -adrenergic receptors. In addition to catecholamine release, the reuptake of these stimulatory neurotransmitters from synaptic clefts is inhibited, altering the normal balance between excitatory and inhibitory tones in the central nervous system (CNS). Subsequent stimulation propagates peripheral catecholamine release. Reuptake of serotonin is similarly inhibited and can cause serotonergic excess, as well.

Fig. 144.1, How cocaine increases sympathetic tone by increasing neurotransmitters in the synapse.

Cocaine is also a local anesthetic. It blocks sodium channels, slowing nerve impulses from neuronal pain fibers by prolonging the upstroke of the action potential. Along with adrenergic stimulation, this can precipitate tachydysrhythmias such as supraventricular or, with severe sodium channel blockade, ventricular tachycardia. A clinical marker for heart sodium channel blockade is the duration of the QRS on a 12-lead electrocardiogram (ECG). QRS durations longer than 100 ms in a patient with a previously unremarkable ECG suggests sodium channel blockade. The prognostic value of the QRS in patients with preexisting bundle branch blocks or who are actively paced is less known.

The half-life of cocaine is approximately 90 minutes. Cholinesterases in the plasma and liver metabolize cocaine to the inactive metabolites—ecgonine methyl ester and benzoyl ecgonine. In the presence of ethanol, cocaine is metabolized to cocaethylene, which has the same effects as cocaine, giving rise to the observation that ethanol prolongs rather than counteracts cocaine’s effects. Genetic differences in the phenotypic expression of plasma cholinesterases may explain the variation across individuals in susceptibility to cocaine toxicity. Most standard urine drug screens in the ED test for benzoylecgonine, which is a metabolite only of cocaine. It can be detected in the urine within 4 hours after using cocaine and remains detectable, depending on the laboratory threshold, for up to 7 days after use.

Amphetamine and Its Derivatives

Amphetamines are structurally distinct from cocaine even though they have similar effects. They are in fact structurally more similar to dopamine than cocaine. The word “amphetamine” is an abbreviation of a lpha- m ethyl ph en et hyl amine . Phenethylamine is the parent compound from which amphetamines, catecholamines, cathinones (bath salts), and novel psychoactive substances such as methylenedioxymethamphetamine (MDMA) can be derived.

Amphetamines were discovered while chemists John K. Smith and Mahlon Kline were trying to develop a cheaper alternative nasal decongestant to ephedrine. Beginning in 1929, dextroamphetamine was sold as Dexedrine. It was made a prescription drug in 1959, however, owing to concerns over its addictive potential. The racemic mixture is sold as Adderall. Amphetamine-based psychostimulants with abuse potential include illicit drugs, such as methamphetamine and ecstasy, and prescription stimulants, as well. Prescription stimulants, used to treat conditions such as attention-deficit/hyperactivity disorder (ADHD), are commonly misused.

Epidemiology

Rates of overdose deaths from all psychostimulants have been increasing since 2010. More than 10,000 Americans died from an overdose involving psychostimulants with abuse potential in 2017, which was a nearly 40% increase over the previous year. From 2016 to 2017, non-Hispanic whites had the greatest percent increase in the death rate for overdoses involving psychostimulants, while the largest absolute rate change in psychostimulant-involved overdoses was in American Indian/Alaska Native (AI/AN) populations. AI/AN also experienced the highest death rate for overdoses involving psychostimulants in 2017.

The highest rate increases of psychostimulant-related overdose deaths were in the Midwest region in 2017, while the overall rate was highest in the West. However, the highest overdose death rates were in West Virginia and Alaska.

Methamphetamine

Methamphetamine (methyl amphetamine) was discovered shortly after amphetamine, also as an alternative to ephedrine. Like amphetamine, it was extensively used during the Second World War, to the point that German soldiers called it “Stuka-Tabletten,” referring to the pilots of the Stuka dive bombers. The effects of methamphetamine, also known as “crank” and “crystal meth,” last longer. Some paranoid delusions persist for 24 hours. The production of methamphetamines requires metal salts. Lead toxicity from the drug being inappropriately produced has been reported. Injuries during illicit methamphetamine production or police raids include exposure to anhydrous ammonia, hydrochloric acid, sodium hydroxide, ether, and ephedrine, as well as burns and explosions in “meth labs.” Amphetamines are usually ingested orally as pills, but can be crushed and injected, as well.

Pathophysiology

Amphetamines act by multiple mechanisms to increase norepinephrine, epinephrine, dopamine, and serotonin levels in the brain. They increase the amount of neurotransmitter released per action potential, decrease the rate of clearance from the synaptic cleft, and decrease the rate of enzymatic inactivation. The subsequent CNS stimulation results in sympathomimetic effects nearly identical to those from cocaine, but the effects generally last longer and are less intense. Patients are at risk for hyperthermia, hypertensive emergencies, dysrhythmias, myocardial ischemia, and hyperkalemia associated with rhabdomyolysis. In contrast to cocaine, amphetamines do not block sodium channels. Although urine drug screens can identify amphetamines, they are of little utility in the treatment of an intoxicated patient.

Phenylethylamines, which are closely related in molecular structure to amphetamines, include the “2C” and “NBOMe” drugs, named for the location of specific structural elements along the amphetamine backbone. These have powerful serotonergic, hallucinogenic effects, and patients can present with adrenergic toxicity and behavioral agitation. The brominated form (street-named “Bromo-DragonFLY” due to its structural similarity to a dragonfly) is associated with a necrotizing angiitis that can compromise blood flow to the limbs. Limb or digit pain in such patients warrants comprehensive monitoring and evaluation for vasospasm and tissue ischemia.

Ephedrine and Ephedra

Ephedra is a plant-based medicinal preparation from the herb Ephedra sinica. It is an evergreen shrub-like plant native to Asia and also grows in southwestern United States. Ephedra, also known as the Chinese herbal product Ma Huang, has been associated with strokes and deaths in adolescent users. People have used ephedra for centuries in China for colds, fever, flu, headaches, asthma, nasal congestion, and wheezing. Ephedrine is the main active ingredient in ephedra. In 1997, in response to mounting concern over cardiovascular side effects, the U.S. Food and Drug Administration (FDA) banned products containing 8 mg or more of ephedrine alkaloids and required all ephedra-containing products to disclose the health risks of heart attack, stroke, and death.

Ephedra is widely used by athletes as a performance-enhancing drug, despite a lack of evidence that it improves athletic performance. Its use has been completely banned from all sports competitions since 2003. Bitter orange is marketed as a “safer” herbal alternative to ephedrine. It contains p-synephrine, which is demethylated ephedrine. At the dose amounts generally available, bitter orange appears to have neither stimulant nor cardiotoxic effects. Ephedrine (and its diastereomer pseudoephedrine) can also be used as a precursor in the manufacture of methamphetamine by dehydrating it. Ephedrine and its stereoisomer, norpseudoephedrine, cross the blood-brain barrier and lead to the release of noradrenaline and dopamine in the substantia nigra.

Caffeine

Caffeine (1,3,7-trimethylxanthine) is a widely consumed psychoactive substance noted for its ergogenic and prokinetic effects. It is a common component of energy drinks and weight loss supplements. It is also a reported adulterant in cocaine, MDMA, and many novel psychoactive substances. In one analysis of 512 street samples of cocaine from Brazil, caffeine concentration ranged between 40% and 60% by weight. Caffeine potentiates the euphoric effects of cocaine in mice. Caffeine is an adenosine antagonist, binding to post-synaptic adenosine receptors throughout the body. Toxic doses of caffeine (greater than 100 mg/kg, or roughly one cup of coffee per kilogram) may induce status epilepticus and tachydysrhythmias refractory to standard treatment regimens requiring hemodialysis.

Novel Psychoactive Substances

Novel psychoactive stimulants are structural variants of amphetamine that combine hallucinogenic, euphoric, and stimulant properties to strike balances between auditory hallucinations, visual hallucinations, paranoia, euphoria, dysphoria, and dissociation. A general rule of thumb used by informal chemists is that aromatic substitutions increase the hallucinogen/entactogen effects and aliphatic substitutions increase the stimulant effects.

Novel psychoactive stimulants are often combined with ethanol or sedatives to mitigate anxiety or dysphoria, or to prolong the perceptual alteration. Novel psychoactive substances are a broader category including synthetic cannabinoid receptor agonists (K2, synthetic marijuana). This chapter does not discuss those substances as they are conceptually closer to cannabis than stimulants.

Data on the usage of most novel psychoactive substances are lacking. Epidemiologists have used wastewater analysis to quantify exposure, but it is difficult to estimate usage from this method. From questionnaires, the use of mephedrone, a bath salt (cathinone), seems more prominent in the United Kingdom than the United States, where 0.5% of people aged 16 to 59 reported using mephedrone at least once in 2015 to 2016.

There is a similar trajectory between derivatives of amphetamine overtaking amphetamine and derivatives of fentanyl overtaking the parent compound fentanyl. In both cases, the derivatives are often more potent than the unmodified compounds, have narrower therapeutic indices, and are generally not detected on standard drug screens. In addition, novel combinations such as methamphetamine contaminated with fentanyl (street named “goofballing”) are emerging.

Ecstasy

MDMA (ecstasy, Molly) is a derivative of amphetamine. It is the canonical entactogen. An entactogen produces experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy. The molecular structure of MDMA is in between amphetamine and serotonin, explaining its combination of sympathomimetic and serotonergic features. The term “Molly” (short for molecular) is used to describe a product with a higher concentration of MDMA, although these products may contain merely caffeine or placebos. User reports are, therefore, often unreliable in determining true exposure.

MDMA can precipitate hyponatremia via drug-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). MDMA and its metabolite increase the release of vasopressin (anti-diuretic hormone), which in the setting of high free water intake, results in free water retention. Patients with MDMA-induced hyponatremia demonstrate urine with high osmolality and sodium. Chronic use of MDMA and its variants (MDA) may cause irreversible neurologic damage to serotonergic neurons in mice.

Bath Salts

Bath salts are derivatives of cathinone, an active ingredient in the leaves of khat or qat (Catha edulis) . Cathinone is, itself, a phenethylamine derivative. Khat leaves also contain methcathinone, a similarly potent sympathomimetic.

Bath salts were first encountered in Japan in the early 2000s. The ease of synthesis and modification of specific functional groups of the parent cathinone make these drugs particularly difficult to regulate. , This led to a cat-and-mouse dynamic between internet vendors and regulatory agencies. Most initial bath salts contained mephedrone (4-methyl methcathinone). Once regulatory agencies developed tests for mephedrone, the composition of bath salts rapidly changed to include methylone, ethylone, butylone, pyrovalerone, methylenedioxypyrovalerone (MDPV), methcathinone, and ethcathinone. One cathinone, bupropion (Wellbutrin), is approved for medical use in the United States.

Bath salts may be ingested, inhaled, or injected and can result in severe agitation, sympathomimetic effects, hyperthermia, and rhabdomyolysis. One in vitro study suggests that cathinones and MDMA may have direct myotoxic effects by increasing the permeability of the outer mitochondrial membrane. Smoking khat typically results in little toxicity because cathinone is heat labile. Numerous fatalities have been reported, causing the U.S. Drug Enforcement Administration (DEA) to categorize these agents as illegal Schedule I substances. Synthetic cathinones are usually not detectable on routine urine drug screens. Treatment is similar to that of cocaine and amphetamine toxicity and includes adequate dosing of benzodiazepines for agitation with diazepam, lorazepam, or butyrophenone antipsychotic agents, such as haloperidol and droperidol (see Management, Pharmacologic Sedation for Agitation section).

Some users of synthetic methcathinone demonstrate an extrapyramidal syndrome similar to Parkinson disease with elevated manganese concentrations, presumably resulting from contamination during production. Chelation therapy is, in general, not useful in treating the parkinsonism associated with manganese toxicity.

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