Understanding the clinical implications of the acute and chronic toxicity of illicit drugs is essential for health care professionals because these substances can cause a spectrum of toxic effects.
Terminology of Illicit Substance Toxicity
The term xenobiotic applies to all substances foreign to the human body, including illicit drugs, plants, heavy metals, and occupational exposures. The terms xenobiotic and substance are sometimes used interchangeably.
Illicit substances include:
Amphetamines
Other abused substances (including diuretics, erythropoietin and darbepoetin, growth hormone, ipecac syrup, and laxatives)
A medical toxicologist is physician who specializes in the diagnosis, management, and prevention of poisoning and other adverse health effects from exposure to drugs, chemicals, biological agents, or radiological agents. The exposure may be intentional, if patients intentionally expose themselves to a xenobiotic to experience the effects of a substance, including if the intent is to harm themselves. The exposure may be unintentional, such as a child or older person ingesting a delta-9-tetrahydrocannabinol (THC)-containing edible because they mistake it for candy. Intentional exposures are associated with a higher likelihood of toxicity and may warrant a comprehensive evaluation in the acute phase. Unintentional exposures generally require less extensive evaluation and treatment in the acute phase, but may indicate an unsafe environment for the patient (eg, workplace exposure or caregiver neglect); in some instances, they may pose a risk of serious harm. In general, children younger than 5 years and older patients with moderate to severe cognitive impairment are not intellectually adept enough to have intentional exposures. These age limits are based on clinical experience and not on formal studies. Age limits do not apply to people with cognitive developmental delays or those who display compulsive behaviors leading to sizeable unintentional ingestions.
Poisoning, also called toxic exposure, refers to an exposure to a xenobiotic with clinically significant consequences. Overdose refers to consuming a supratherapeutic amount of a drug. A person can be poisoned without an overdose if the metabolism or excretion of the substance is decreased, for example if kidney failure leads to accumulation of lithium or colchicine.
Tolerance refers to a xenobiotic having a decreased effect with repeated use. Tolerance to each of the effects of a xenobiotic happens at its own rate. Regular consumers of alcohol may not experience anxiolysis and euphoria at their habitual dose but still have motor impairment. Dependence refers to the psychological need to consume the xenobiotic to "function normally" and the physiological derangements that occur if use of the substance is stopped (eg, difficulty concentrating before a regular user of coffee consumes their usual daily amount of coffee). Withdrawal refers to physiologic effects, symptoms, and behavioral changes that are caused by stopping or reducing the intake of a substance, canonically substance-craving and physiological rebound, such as lethargy after discontinuing stimulant use.
Tolerance, dependence, and withdrawal are specific to the substance and route of administration. A person's tolerance to smoking marijuana and consuming THC edibles are different because the two routes lead to different dynamics of THC concentrations. Injection and insufflation ("snorting") usually lead to dependence more rapidly because peak serum concentrations are achieved more rapidly by those routes. Routes of use include:
Ingestion
Inhalation (eg, smoking, vaping)
Transmucosal (intranasal [eg, insufflation], buccal, sublingual, rectal or vaginal [eg, if rupture occurs of packets of drugs that have been body packed and body stuffed])
Transdermal (eg, fentanyl patch)
Injection (subcutaneous, intramuscular, or intravenous)
Medical Toxicologist Evaluation or Consultation
Clinicians should consider consulting a medical toxicologist and/or an addiction medicine specialist when treating all but the most straightforward cases involving poisoning, including due to illicit substance use or other toxic exposures. Depending on the location and clinical setting, a medical toxicologist may a member of or available to the hospital staff or clinicians can consult a medical toxicologist by phone or digital resource. In the United States, telephone consultations are available through Poison Control (800) 222-1222 or webPoisonControl (web-based consultations are primarily designed to provide information to the public and identify low-risk ingestions).
Two fundamental concepts in evaluating a patient who has been poisoned, including due to illicit substance use or other toxic exposures are:
The dose makes the poison.
Pharmacokinetics is not toxicokinetics, and pharmacodynamics is not toxicodynamics.
As an example of the dose making the substance a poison,cocaine is generally considered more dangerous than acetaminophen. However, a small amount of cocaine may be less harmful acutely than a large amount of acetaminophen.
The second concept refers to when substances taken in overdose take longer to eliminate or metabolize than when taken in therapeutic doses. In overdoses, metabolic processes can become saturated. A clinically relevant consequence of these changes is that substances not amenable to dialysis at therapeutic concentrations may be amenable to dialysis in overdose. For example, phenytoin in the circulatory system is largely bound to albumin. In sufficient overdose, the amount of phenytoin exceeds the binding capacity of albumin, thus creating an unbound fraction in the plasma that can be extracted with dialysis (2). Another example is the metabolism of acetaminophen to the hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), which occurs only at doses exceeding 150 mg/kg (3).
Substances taken in overdose may bind to more receptors than they would at therapeutic concentrations. For example, dihydropyridine calcium channel antagonists have the greatest affinity for isoform of L-type calcium channels found in the smooth muscle of the vasculature but also have a small affinity for the isoform found in the heart. If the amount of drug absorbed exceeds the amount required to occupy all L-type calcium channels in the smooth muscle, the remainder will bind to the cardiac L-type channels (4). Clinically concerning overdoses of dihydropyridine calcium channel antagonists present with hypotension, bradycardia, and drug-induced cardiogenic shock. The clinical importance of this additional binding is that the presentation of an overdose of a substance may not be an intensification of its therapeutic effects, but it may act by a different mechanism and on different organs or systems. An authoritative reference for toxicokinetics and toxicodynamics is Casarett & Doull’s Toxicology: The Basic Science of Poisons.
Determining level of care
Determining the initial level of care for a patient after exposure to a xenobiotic can be challenging. The amount consumed of each substance, pattern of substance use, polymorphisms in metabolism, drug-drug interactions, and influence of comorbidities may not be known when the patient initially presents for medical care. Levels of care generally include either observation in the emergency department and then discharge to home or inpatient admission (sometimes to the intensive care unit). If indicated, psychiatric evaluation is requested. Some chronic exposures can be treated in a clinic. Treating clinicians should consider the general heuristics discussed here together with hospital policy and local guidelines.
The clinician should first identify poisoning or overdose as the reason for the clinical presentation. A toxic exposure should be considered when a patient is noted to have an abrupt change (eg, abnormal vital signs, altered mental status, nausea and/or vomiting, diarrhea, trouble breathing) and no other cause is identified, even if there is no report of an ingestion or other route of administration of a xenobiotic.
Once vital signs are obtained and a history and physical examination are performed, if the patient or someone accompanying the patient reports that a xenobiotic has been used, the emergency clinician should contact a poison control center or consult a medical toxicologist. Early consultation with a toxicologist is important because many laboratory tests and interventions for patients who are poisoned must be done at specific times relative to the ingestion.
Most patients with ingestion of illicit substances with symptoms of toxicity should be sent to the emergency department. The emergency clinician and, if consulted, the medical toxicologist should create a plan of care in the emergency department. The plan of care depends upon the substance used and the presence and severity of symptoms and signs of toxicity.
The minimum laboratory evaluation for patients for whom there is a concern for a clinically significant exposure includes: a complete metabolic profile; serum acetaminophen (paracetamol), salicylate, and ethanol concentrations; serum lactate and blood gas; urinalysis; and urine toxicology screen.
Based on increasing severity of the clinical presentation, general principles of escalation of management for patients who have ingested a toxic substance are based on the presence of symptoms, signs, and laboratory abnormalities, as follows:
No symptoms or signs of toxicity and no laboratory abnormalities: Patients are typically observed in the emergency department for 2 to 12 hours for any change in clinical status. (The wide range of duration of observation reflects the wide range of poisons, each with a unique time course.) If there is no change, they are usually considered to have no acute toxicity and further medical and psychiatric evaluation and treatment may proceed, as appropriate.
Altered mental status but no other symptoms or signs of toxicity and no laboratory abnormalities: Observation period is extended until the patient's mental status returns to baseline.
Clinical symptoms or signs of toxicity beyond a change in mental status and/or presence of laboratory abnormalities: Treatment of specific clinical abnormalities, sometimes requiring hospital admission.
An exposure should be considered a sign of an unsafe environment or underlying condition until proven otherwise. Once the patient is medically stabilized, the clinician should identify how the patient was exposed to the toxin. This evaluation may include referral to adult or child protective services if deemed appropriate. The goal is to prevent future exposures and toxicity and to identify underlying conditions that require treatment.
General references
1. Klaassen, CD. (2019) Casarett and Doull’s Toxicology: The Basic Science of Poisons. 9th Edition, McGraw-Hill Education, New York.
2. Ghannoum M, Troyanov S, Ayoub P, Lavergne V, Hewlett T. Successful hemodialysis in a phenytoin overdose: case report and review of the literature. Clin Nephrol. 2010;74(1):59-64. doi:10.5414/cnp74059
3. Welling PG. Differences between pharmacokinetics and toxicokinetics. Toxicol Pathol. 1995;23(2):143-147. doi:10.1177/019262339502300207
4. McKeever RG, Patel P, Hamilton RJ. Calcium Channel Blockers. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 22, 2024.
Treatment of Illicit Substance Toxicity
Depending on the substance and the route of exposure (eg, ingestion, smoking), treatment of toxicity may involve methods to prevent absorption,enhance excretion, or mitigate toxicity.
Approaches to preventing absorption or enhance excretion of toxic substances include:
Gastric decontamination: using activated charcoal, gastric lavage, or whole bowel irrigation to prevent gastrointestinal absorption of a xenobiotic. While administration of activated charcoal may be indicated in ingestions of substances that adsorb to charcoal, gastric lavage has not shown to be beneficial in the majority of ingestion cases and is rarely performed. Whole bowel irrigation is reserved for patients ingesting substances that do not bind to charcoal (eg, iron) or to accelerate the passages of packages in the intestines (as seen in cases of body packing).
Urinary alkalinization: using an isotonic infusion of sodium bicarbonate to hasten urinary excretion of an acidic xenobiotic
Urinary acidification may enhance excretion of alkaline xenobiotics. Acidifying the urine is not advisable because it also decreases serum pH, increases the absorption of other drugs, and disrupts physiological processes.
Mitigating toxicity is accomplished by using specific approaches based on the substance, patient's status, medications, and comorbidities.
Additional measures, sometimes referred to as supportive care, are often part of management. These measures include treatments as varied as watchful waiting, sedation in cases of agitation, airway and blood pressure support, and hemodialysis.
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