Toxicology

Cannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Endocannabinoids are endogenous neuropeptide neurotransmitters found in the human nervous system. Cannabinoids have a psychotropic effect, which leads to frequent recreational use, but the unique effects of cannabinoids on the CNS also provide pharmacological indications. Prescription cannabinoids treat pain, nausea, vomiting, and seizure disorders and also serve as appetite stimulants.

Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Chest computed tomography (CT) scan shows multifocal pleural thickening and pleural effusion. Pleural biopsy is required for confirmation and to rule out metastases from lung or breast cancer. Treatment is rarely effective, with an average survival time of < 1 year.

Ethanol is a chemical compound that is produced in small amounts within the small intestine and is also ingested from alcoholic drinks. Ethanol's digestion involves a complex catabolic pathway that mainly takes place in the liver. Ethanol is turned into acetaldehyde, then to acetate, and finally into acetyl-CoA, which becomes a substrate for the citric acid cycle and produces energy. Excessive ethanol intake can have pathologic metabolic consequences including alcoholism, liver disease, and cancer.

Carbon monoxide (CO) is an odorless, colorless, tasteless, nonirritating gas formed by hydrocarbon combustion (e.g., fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than oxygen, forming carboxyhemoglobin (COHb). Increased levels of COHb lead to tissue hypoxia and brain damage. Symptoms of CO poisoning include headache, nausea, weakness, chest pain, shortness of breath, seizures, coma, and even death. Oxygen therapy is key to the management of CO poisoning.

Opioid use disorder (OUD) is a substance use disorder characterized by pathologic consumption of opioids. Opioids are central nervous system depressants that are used medically as potent analgesics. However, they are often misused for their euphoric effects. Features of opioid intoxication include respiratory depression, drowsiness, and pinpoint pupils. Intoxication can be managed with administration of naloxone. If discontinued, patients may develop withdrawal symptoms such as irritability, piloerection, and stomach cramps. Withdrawal may be managed by methadone or buprenorphine. Chronic OUD is managed with psychotherapy as well as medications. Prognosis is poor without adequate management and prevention of relapse and overdose.

Cocaine use disorder is a substance use disorder defined by pathologic consumption of the recreational drug cocaine. Cocaine is an indirect sympathomimetic that blocks the reuptake of dopamine, serotonin, and norepinephrine from the synaptic cleft. This process causes stimulant effects on the body and mind such as euphoria, increased energy, irritability, psychosis, decreased appetite, and weight loss. Cocaine overdose can cause death secondary to cardiac arrhythmia, myocardial infarction, seizure, or respiratory depression. Prognosis is poor as there is no approved pharmacological treatment, but psychosocial interventions have been associated with improved outcome.

Amphetamine use disorder (AUD) is a condition characterized by pathologic use of psychostimulants. Amphetamines produce their effect by increasing the release and blocking the reuptake of neurotransmitters (dopamine, norepinephrine, serotonin). Medically, they are used for the treatment of ADHD and narcolepsy. Methamphetamines and so-called designer drugs have no clinical use. Intoxication results in euphoria, pupillary dilation, hypertension, skin excoriation, paranoia, and severe aggression. Fatal complications can arise from myocardial infarction and coma. The prognosis for AUD is poor, as there is no FDA-approved pharmacotherapy, but psychosocial interventions have been associated with improved outcomes.

Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia results from congenital defects or can occur after exposure to oxidizing agents. Symptoms depend on methemoglobin levels and vary from simple cyanosis to neurologic and cardiac presentations. The condition can be fatal in the case of significant elevation of methemoglobin (> 70%). Diagnosis is established by measuring methemoglobin levels in blood using co-oximetry. Treatment of methemoglobinemia is with methylene blue or ascorbic acid, as they hasten the conversion of methemoglobin to hemoglobin.

Hallucinogen use disorder is defined by the pathologic consumption of hallucinogenic substances that cause perceptual distortions (visual or auditory). Examples include psilocybin (mushrooms), lysergic acid diethylamide (LSD), and phencyclidine (PCP). These drugs are used for their psychedelic effects, i.e., a temporarily altered state of consciousness. Most hallucinogens produce nausea, vomiting, and mild sympathomimetic effects such as tachycardia, hypertension, mydriasis, hyperthermia, and diaphoresis. Although hallucinogens may cause hyperthermia in severe cases, they don’t result in dependence or withdrawal symptoms.

Inhalant use disorder is a substance use disorder defined by pathologic consumption of inhalant substances—such as glue, paint, or lighter fluid—in order to reach a euphoric feeling. Individuals administer inhalers through the mouth (commonly known as huffing) or sniff them through the nose. The effect lasts for only several minutes. Signs of acute intoxication range from intense transient euphoria up to loss of consciousness. The abuse of inhalants results in CNS inhibition and may lead to coma and even death during acute intoxication and long-term cognitive impairment with chronic use. Management varies depending on the type of inhalant and ranges from supportive measures, including psychologic counseling, to intensive medical treatment to address and prevent further organ damage.

Tobacco use is the leading cause of preventable death in the world. Tobacco use is directly related to a higher risk of chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and various cancers. Nicotine, the psychoactive component of tobacco, stimulates nicotinic receptors in the autonomic ganglia of the sympathetic and parasympathetic nervous systems. Nicotine is highly addictive through its effects on the dopaminergic system. Treatment includes medications to prevent cravings, nicotine-replacement therapy, and psychotherapy.

A toxidrome is a group of clinical signs and symptoms associated with a toxic ingestion or exposure. There are 5 traditional toxidromes: anticholinergic, cholinergic, opioid, sympathomimetic, and sedative-hypnotic. Toxidromes often arise from ingestion of overdose amounts, accumulation of medications with resultant elevated serum levels, adverse drug reactions, or interactions between 2 or more medications. Rapid recognition of a toxidrome can help determine the specific poison or class of toxin that was ingested. On presentation of a suspected toxidrome, appropriate airway, breathing, and circulation assessment is initiated. Decontamination is performed, and the patient is stabilized. Diagnosis is accomplished with clinical findings based on medication and exposure history, vital signs, mental status, and physical examination. Testing generally includes toxicology and drug levels, electrolytes, and ECG. Management consists of supportive care and antidote administration if indicated.

Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Known for their remarkable efficacy, opioids induce their effects (analgesia, euphoria, and sedation) by interacting with opioid receptors (μ, κ, and δ) in the nervous system. Opiates/opioids have adverse effects that include respiratory depression, nausea and vomiting, decreased GI motility and constipation, tolerance, dependence, and addiction.

Herbicides are chemical substances used to kill or control the growth of unwanted plants. Important herbicides that can affect humans include paraquat, Agent Orange, glyphosate, and organophosphates. Different types of herbicides result in different clinical manifestations and have various toxicity levels. Paraquat ingestion is associated with multiorgan damage within a few hours and is fatal in large amounts. In contrast, glyphosate typically has low toxicity, but if a significant volume is ingested, serious adverse effects occur. Organophosphates, which are broadly used as pesticides, produce a cholinergic toxidrome. Agent Orange, containing 2,3,7,8-tetrachlorodibenzo-p-dioxin, a human carcinogen, carries both short-term (e.g., chloracne, liver toxicity) and long-term (e.g., cancers) complications. Exposure can be dermal or via inhalation or ingestion. In general, early detection is important to prevent serious sequelae. Initial management consists of stabilizing the patient and decontamination. An antidote is given, if available. Treatment of herbicide poisoning revolves around supportive care that depends on the involved organ system.

Insecticides are chemical substances used to kill or control insects, to improve crop yields, and to prevent diseases. Human exposures to insecticides can be by direct contact, inhalation, or ingestion. Important insecticides that can affect humans include organochlorines (dichlorodiphenyltrichloroethane (DDT)), organophosphates (malathion and parathion), and carbamates (carbaryl, propoxur, aldicarb, and methomyl). Because of DDT's long-term adverse effects on wildlife and the environment, it is now not used in many areas. However, it is still in use in areas with high rates of malaria infection. The chemical produces neurotoxicity and endocrine disruption. Organophosphates and carbamates produce cholinergic effects, given their similar mechanism of action of inhibiting acetylcholinesterase. Organophosphates, though, bind the enzyme irreversibly, while carbamates inhibit the enzyme for < 48 hours. Diagnosis is based on history and clinical findings, with tests available for confirmation. Management involves decontamination, supportive care, and symptom control. For the cholinergic toxidrome, atropine and pralidoxime are given to reverse the effects of cholinergic excess.

Sedative, hypnotic, and anxiolytic agents include benzodiazepines (BZDs), barbiturates, and other hypnotics. Symptoms of intoxication include ataxia, minor respiratory depression, and short-term memory loss. Withdrawal symptoms include insomnia, anxiety, psychosis, and seizures. These drugs are often taken in conjunction with other substances. Chronic use can be managed with medication taper as well as psychosocial interventions.

Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. However, acetaminophen is believed to exert its effects through indirect and reversible inhibition of cyclooxygenase (COX)-1 and COX-2. The effects are generally limited to the CNS. Acetaminophen is primarily metabolized by the liver; therefore, an overdose can lead to life-threatening hepatotoxicity. In adults, limiting the total acetaminophen dose (from all sources and routes) to < 4000 mg/day is highly recommended. Contraindications to acetaminophen use include hypersensitivity, severe hepatic impairment, or severe active hepatic disease.

Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Withdrawal from chronic alcohol use can have fatal consequences, including delirium and seizures, and is managed with benzodiazepines. Chronic AUD affects almost every part of the human body and has serious impacts on a person’s mental and physical health. Alcohol user disorder can be managed with psychotherapy as well as medications; however, the prognosis is usually poor, with high rates of relapse and complications.

Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one’s health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. There are several individual substance use disorders, and they are linked by their chronicity and the significant impairment they cause. Most substance use disorders have associated intoxication and withdrawal symptoms. Treatment options include pharmacotherapy and behavioral interventions; however, individuals with substance use disorders have frequent relapse/remission as well as low compliance with treatment.

Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Diagnosis is based on a history of alcohol abuse and confirmed by laboratory derangement with an AST/ALT ratio > 2. Alcoholic liver disease carries a high mortality rate if patients present with severe hepatitis. Management aims at alcohol abstinence for reversal (at certain stages) and addressing contributing factors (such as viral infections or drugs) to minimize damage to the hepatocytes. Approximately 10% of patients regress with alcohol abstinence during the hepatitis stage. Cirrhosis is frequently irreversible.

Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychologic exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). The medical history and physical exam of a patient presenting with dyspnea should be used to rule out certain conditions or suggest the most likely cause of the respiratory discomfort. Management focuses on treating the underlying condition.