Medical Consequences of the Use of Cocaine and Other Stimulants

2015

Once thought to be a benign, nonaddicting drug, cocaine now has well-recognized adverse effects. These adverse effects are manifested in nearly all organ systems of the body. It is important to realize that an organ system breakdown in classifying the adverse effects of cocaine is artificial and that multiple organs are often affected by similar mechanisms. In particular, the effects of cocaine on the cardiovascular system help to explain many of the effects on other organs throughout the body. In addition, certain adverse effects may be dependent on the route of administration, or dose of cocaine. The adverse effects of two other stimulant drugs, methamphetamine and phenylpropanolamine, will be summarized at the end of this post.

History

The history of cocaine use has been well described by a number of authors. Peruvian Indians have a long history of chewing coca leaves to achieve euphoria, combat fatigue, and increase stamina. Sigmund Freud used cocaine and also prescribed it as treatment for alcohol or opiate addiction. At one time, cocaine was a common ingredient in many commercial products, including teas and patent medicines. Although no longer the case, when first introduced, Coca-Cola was formulated using extracts from coca leaves and actually contained a small amount of cocaine. In the late nineteenth century, cocaine use was popular and reports of addiction and adverse effects became known. The Harrison Narcotic Tax Act of 1914 prohibited the importation of cocaine and coca leaves, except for pharmaceutical purposes. This legislation helped curtail much of the burgeoning cocaine use. In 1970, passage of the Controlled Substances Act prohibited the manufacture, distribution, and possession of cocaine, except for limited medical purposes. However, within the past twenty years, the use of cocaine has made a huge resurgence, especially with the advent of crack cocaine. This epidemic has further revealed many adverse effects of cocaine, yet its use remains very popular.

Forms of cocaine

Many review articles describe in depth the various forms and properties of cocaine. Cocaine is an alkaloid extracted from the leaves of the Erythroxylon coca plant, grown predominantly in Central and South America. The two different chemical forms in which cocaine is abused are cocaine hydrochloride and cocaine alkaloid. Cocaine hydrochloride is produced by adding hydrochloric acid to cocaine base. The result is a water-soluble salt that is typically insufflated, but may also be administered intravenously. Freebase and crack cocaine are both cocaine alkaloids that are smoked, but are produced by different techniques. Freebase is a colorless, crystalline substance that is made by dissolving cocaine hydrochloride in water, alkalinizing the solution, and then adding ether as a solvent. Cocaine base dissolves in the ether layer and is extracted by evaporating the ether. Many adulterants are removed by this process, but the remaining flammable ether predisposes the user to burns. Crack cocaine is made by a simpler process that allows more adulterants to remain, but does not require the use of ether. Crack is made by dissolving cocaine hydrochloride in water, adding baking soda, and slowly heating it to allow the alkaloidal cocaine to precipitate. The name crack stems from the popping sound that is made when crack is smoked ().

All forms of cocaine produce the desired effect of euphoria. However, the onset and duration of effect differs between the different cocaine forms and mode of administration. Both smoking and intravenous use of cocaine produce a rapid euphoria. Cocaine smoke is rapidly absorbed by the pulmonary vasculature, reaching the brain in six to eight seconds and producing a euphoric effect for about twenty minutes. When used intravenously cocaine reaches the brain in about double the time of smoked cocaine. The euphoria achieved with cocaine insufflation takes longer (three to five minutes), but lasts one to two hours. With insufflation, cocaine causes local vasoconstriction of the nasal mucosa which both delays and prolongs its absorption. Coadministration of cocaine with alcohol also prolongs the euphoria since an active metabolite named cocaethylene is produced when they are used together. Although this metabolite does not seem to produce a greater euphoric effect, it does have a long half-life and may result in a more prolonged euphoria.

Prior to the late 1970s, cocaine hydrochloride was primarily used by nasal insufflation. At that time, intravenous use of cocaine hydrochloride became popular as well as smoking of freebase cocaine. Smoking of cocaine became even more popular with the introduction of crack cocaine in the 1980s.

Physiologic effects

The mechanism of action of cocaine helps to explain both the desired effects by users and also many of the adverse effects observed with use. The effects of cocaine are mediated through both the central and peripheral nervous system and have been reviewed in depth.

Centrally, cocaine blocks the reuptake of the neurotransmitters dopamine and serotonin into presynaptic neurons, which leads to their accumulation in synaptic clefts. Dopamine and serotonin receptors are stimulated and the desired effects of euphoria, enhanced alertness, increased energy, diminished appetite, and increased self-confidence are achieved. By suppressing activity of two specific parts of the brain, the pontine nucleus and locus ceruleus, cocaine also suppresses feelings of fear and panic. When used repetitively, however, dopamine stores become depleted, leading to the compensatory increased production of dopamine receptors. It is believed that the ensuing cocaine craving experienced by the chronic user results from the “starvation” of these receptors for dopamine.

In the peripheral nervous system, cocaine blocks the reuptake of catecholamines, specifically norepinephrine, by sympathetic nerve terminals, leading to accumulation in the synaptic cleft. Norepinephrine acts on both alpha- and beta-adrenergic receptors located on the heart and blood vessels. Stimulation of alpha-adrenergic receptors leads to constriction and in some cases spasm of blood vessels, whereas stimulation of beta-adrenergic receptors on the heart leads to increased heart rate. These effects of norepinephrine on the heart and blood vessels combined with other systemic effects are referred to as the sympathomimetic effect. The term sympathomimetic derives from the “fight or flight” effect of the sympathetic nervous system. The resulting sympathomimetic presentation may include hypertension (elevated blood pressure), tachycardia (elevated heart rate), hyperthermia (elevated temperature), mydriasis (dilated pupils), and diaphoresis (sweating).

The local anesthetic effect of cocaine is also well known. In fact, cocaine was introduced as the first local anesthetic in Vienna, Austria, in 1884. Cocaine competitively inhibits fast sodium channels in neurons that normally allow sodium to enter cells to initiate the propagation of neural impulses. Blockade of these channels prevents nerve impulse formation and explains the anesthetic effect of cocaine. This effect is still used therapeutically with the use of topical cocaine used to provide local anesthesia to mucous membranes and to reduce bleeding through local vasoconstriction. Sodium channels are also located in the cells of the heart and blockage may result in conduction delays and dysrhythmias (abnormal heart rhythms).

Adverse effects of cocaine

Other stimulants

Methamphetamine

Amphetamine was first synthesized in 1887 and introduced in the 1930s in the form of inhalers for treating rhinitis and asthma. Amphetamines and amphetamine derivatives are still prescribed for the treatment of attention deficit disorder and for the treatment of narcolepsy. Multiple drugs, both legal and illegal, have been synthesized by various modifications to the structure of amphetamine. Therapeutic medications include phenylpropanolamine and ephedrine. Illicit drugs include methamphetamine and the “designer” drug, Ecstasy (3,4-methylenedioxymethamphetamine), also known as MDMA.

Both amphetamine and methamphetamine have become common drugs of abuse. Methamphetamine differs from amphetamine by the presence of a methyl group on the amine portion of the molecule, which affords improved central nervous system penetration. Amphetamines are abused by various routes of administration including intravenous, oral, insufflation, and inhalation. Amphetamine and methamphetamine exert their clinical effects primarily by releasing the catecholamines dopamine and norepinephrine frompresynaptic nerve terminals. The resulting clinical effects are very similar to cocaine with a few notable exceptions. The duration of effect of amphetamines is up to twenty-four hours, which is much longer than cocaine. In addition, amphetamines lack the sodium-channel-blocking effect of cocaine and therefore may be less likely to precipitate cardiac dysrhythmias.

As predicted by the very similar mechanism of action and physiological response with cocaine, many of the reported associated adverse effects with amphetamines are also similar. Associated cardiovascular adverse effects include hypertension, tachycardia, myocardial infarction, cardiomyopathy, and aortic dissection. Central nervous system effects include intracerebral hemorrhages, intracerebral ischemic strokes, seizures, psychosis, and choreoathetoid movements. Ischemic colitis, rhabdomyolysis, hepatotoxicity, and various fetal anomalies have also been reported. The medical literature detailing the associated adverse effects of cocaine use is much more extensive than the literature detailing amphetamine use. Only time and, unfortunately, continued abuse of amphetamines, will reveal if this is truly the case.

Phenylpropanolamine

Phenylpropanolarnine is a synthetic stimulant that has a very similar structure to amphetamine. Until recently it was present in a multitude of both over-the-counter and prescription-only cold preparations, as well as weight loss formulations. Adverse effects associated with its use, misuse, and intentional overdose have been known for many years, leading many to recommend removing it from the market. In 2000, the FDA began taking steps to remove phenylpropanolamine from all drug products and requested that all drug companies discontinue marketing products containing the drug (FDA Talk Paper, 2000).

The major adverse effects associated with phenylpropanolamine are neurologic, particularly hemorrhagic, strokes that have been lethal. Less commonly reported adverse effects include hypertension, myocardial infarction, dysrhythmias, ischemic bowel, seizures, and psychosis. Most of the adverse effects are explained by the pharmacologic action of phenylpropanolamine. Phenylpropanolamine primarily works as a direct alpha-one agonist causing constriction of arterioles. Through this mechanism the commonly desired therapeutic effect of nasal decongestion is achieved. With slightly higher than therapeutic doses, however, the alpha-one agonism can cause potentially severe hypertension which may require treatment and lead to lethal complications such as hemorrhagic stroke.

Summary

Cocaine use is fairly common in the United States and is associated with a variety of serious adverse effects. Many of these effects seem to occur by means of the physiological effects of cocaine on the cardiovascular system. Methamphetamine is becoming a more popular drug of abuse whose mechanism of action and adverse effects are very similar to those of cocaine. Phenylpropanolamine is an amphetamine derivative that until recently was found in numerous over-the-counter and prescription medications. Recent recognition that the drug is associated with severe neurological effects led to recommendations that its use be limited.

 

Selections from the book: “Handbook of the Medical Consequences of Alcohol and Drug Abuse” (2004)