Toxicology and Epidemiology Overview

Cholinergic Substances

• Organophosphates: These are often used as pesticides and include nerve agents like Sarin gas, which have severe neurotoxic effects.
• Neostigmine and Edrophonium: Both are utilized for treating myasthenia gravis and as anesthesia reversal agents.

Mechanism of Action

• These substances inhibit acetylcholinesterase, leading to an accumulation of acetylcholine at the neuromuscular junction (NMJ).
• Increased acetylcholine results in a hypercholinergic response, overwhelming neurotransmission.

Clinical Presentation

• Symptoms can be remembered with the acronym SLUDGEM:
  • Salivation: Excessive drooling due to overstimulation of salivary glands.
  • Lacrimation: Increased tear production, causing watery eyes.
  • Urination: Frequent urination resulting from bladder overstimulation.
  • Defecation/Diarrhea: Gastrointestinal hyperactivity leading to diarrhea.
  • GI Pain: Abdominal discomfort linked to overstimulation.
  • Emesis: Nausea and vomiting due to autonomic overdrive.
  • Miosis: Constriction of pupils, which can impair vision.
• Characterized by a "leaky" or wet appearance, reflecting fluid release from various body systems.

Immediate Threats

• Bradycardia: Slow heart rate which can lead to cardiovascular collapse.
• Bronchorrhea: Excessive bronchial secretions obstructing airways.
• Bronchospasm: Constriction of bronchial muscles, leading to breathing difficulties.

Treatment Protocol

• Decontamination: Critical first step to remove exposure to organophosphates or nerve agents, often requiring formal decontamination procedures.
• Supportive Care: Includes monitoring and managing vital signs and symptoms.
• Antidote Administration:
  • Mark 1 Kit/Duo Dote: Contains atropine and 2 PAM (Pralidoxime).
  • Atropine: Used to counteract bradycardia and glandular secretions.
  • 2 PAM (Pralidoxime): Reactivates acetylcholinesterase if administered promptly.
• Once initial symptoms are under control, both medications can be given via drops (gtts) for ongoing management.

Epidemiology of Toxicology

• Intentional vs Unintentional exposures
• 77% of all reported toxic exposures are unintentional
• Bimodal distribution indicates two peaks in the frequency of exposures

Cholinergic Substances

• Key agents include:
  • Organophosphates found in pesticides
  • Sarin gas and other nerve agents
  • Neostigmine and Edrophonium, used in myasthenia gravis treatment and as anesthesia reversal agents

Mechanism of Action

• Organophosphates and nerve agents block acetylcholinesterase
• Resulting accumulation of acetylcholine at the neuromuscular junction causes a hypercholinergic response

Clinical Presentation (SLUDGEM)

• SLUDGEM Symptoms:
  • Salivation
  • Lacrimation
  • Urination
  • Defecation/Diarrhea
  • GI Pain
  • Emesis (vomiting)
  • Miosis (constricted pupils)
• Symptoms reflect a “leaky” or wet condition in the body with excessive secretions

Immediate Threats

• Bradycardia (slowed heart rate)
• Bronchorrhea (excessive bronchial secretions)
• Bronchospasm (constriction of air passages)

Treatment Protocol

• Decontamination: Essential for pesticide and nerve gas exposure
• Supportive Care: Focused on stabilizing patient condition
• Antidote Options:
  • Mark 1 Kit or Duo Dote
  • Atropine: reduces secretions and mitigates bradycardia
  • 2 PAM (Pralidoxime): reactivates acetylcholinesterase
• Administer drops of both antidotes once initial symptoms are under control

Anticholinergics Overview

• Anticholinergics are substances that block muscarinic acetylcholine receptors, leading to various physiological effects.

Substances

• Atropine: Commonly used to treat bradycardia and as an antidote for organophosphate poisoning.
• Antihistamines: Certain types cause anticholinergic effects, useful in allergy management but with potential side effects.
• Tricyclic Antidepressants (TCAs): Used primarily for depression, they also possess anticholinergic properties, leading to side effects like dry mouth and constipation.
• Selective Serotonin Reuptake Inhibitors (SSRIs): While primarily influencing serotonin levels, some SSRIs can exhibit mild anticholinergic effects.
• Muscle Relaxers (e.g., Flexeril/Cyclobenzaprine): Often prescribed for muscle spasms, these can cause sedation and anticholinergic effects.
• Anti-Parkinsonian Medications: Certain drugs used to treat Parkinson's disease may have anticholinergic properties, affecting movement and cognition.
• Herbals (e.g., Jimson Weed/Amanita Mushroom): These substances can cause significant anticholinergic toxicity and may lead to serious health risks.

Mechanism of Action

• Anticholinergics competitively antagonize muscarinic receptors, leading to decreased acetylcholine activity and various clinical manifestations.

Clinical Presentation

• “Dry as a bone”: Characterized by dry mouth, eyes, and skin due to inhibition of secretions.
• “Anhidrosis despite elevated temp”: Impaired ability to sweat, even with increased body temperature, resulting in hyperthermia.
• “Hot as a hades”: Patients often present with elevated body temperatures due to disrupted thermoregulation.
• “Red as a beet”: Vasodilation occurs, leading to skin flushing and redness.
• “Blind as a bat”: Non-reactive mydriasis (pupil dilation), compromising vision and responsiveness to light.
• “Mad as a hatter”: Symptoms include acute delirium, lethargy, and hallucinations, indicating central nervous system involvement.
• “Full as a flask”: Acute urinary retention can occur, significantly complicating clinical management in affected patients.

Note on Urinary Retention

• Urinary retention is not typically related to physiological obstruction but rather is a result of the anticholinergic effects on the bladder function.

Sedative/Hypnotics Overview

• Sedative/hypnotics encompass various substances that depress the central nervous system (CNS).
• They include barbiturates, benzodiazepines, opioids, and alcohols.

Substances

• Barbiturates
  • Example: Phenobarbital, used in epilepsy treatment.
  • Fioricet is indicated for migraine relief.
• Benzodiazepines
  • Common examples: Alprazolam and Lorazepam.
  • Flunitrazepam, known as Rohypnol, is associated with sedation and potential misuse.
• Gamma Hydroxybutyrate (GHB)
  • A depressant with potential for misuse.
• Opioids
  • Important to monitor Lomotil and Loperamide, as they can have CNS effects.
• Alcohols
  • Types include Ethanol (typical alcoholic beverages), Ethylene glycol (toxic), Isopropyl alcohol, and Methanol (can lead to poisoning).

Mechanism of Action

• Dependent on substance, most involve GABA receptor binding.
• Opioids specifically bind to Mu, Kappa, and Delta receptors.
• All these substances exhibit CNS depressant effects.

Clinical Presentation

• Symptoms exhibit a depressed state:
  • Slurred speech and nystagmus (involuntary eye movement).
  • Miosis is a hallmark sign of opioid ingestion.
  • Other symptoms: ataxia (lack of coordination), nausea/vomiting, and respiratory depression.
• Altered mental status (AMS) can occur, alongside potential hypoglycemia or hypothermia if the individual is incapacitated for extended periods.
• Severity can vary widely based on the level of intoxication or substance ingestion.

Treatment Approaches

• Supportive care is crucial, focusing on airway management and respiration support.
• IV hydration is recommended to assist with overall stability.
• Correct any electrolyte imbalances.
• Antidote use is substance-specific to counteract effects.
• Flumazenil, an antidote for benzodiazepines, should be used cautiously as it may provoke seizures.
• Disposition and further management depend on the specific substance involved and the patient's response to treatment.

Sympatholytic Overview

• Sympatholytic agents reduce sympathetic nervous system activity, often resulting in sedation or hypotension.

Key Substance

• Clonidine: A member of the imidazoline class, primarily used for hypertension and its sedative effects.

Mechanism of Action

• Acts as an alpha-2 adrenergic and partial opioid receptor agonist, leading to decreased norepinephrine release and reduced sympathetic tone.

Clinical Presentation

• Symptoms resemble those of sedative-hypnotic overdose.
• Unlike typical sedative overdoses, patients do not respond to standard Naloxone doses.

Management Strategies

• Naloxone Treatment: High-dose Naloxone may be required due to its insufficient effects at regular dosages.
• Continuous intravenous infusion (gtts) may be necessary for sustained treatment.

Hypotension Management

• Use vasopressors to counteract hypotension resulting from alpha-2 receptor effects.

Bradycardia Management

• Administer atropine or use the chronotropic effects of vasopressors to address bradycardia.

Acetaminophen Mechanism

• Acetaminophen (APAP) is metabolized in the liver to N-acetyl-p-benzoquinone imine (NAPQI).
• NAPQI is detoxified by glutathione until glutathione reserves deplete.
• Accumulation of NAPQI leads to hepatocellular death and potential liver failure.

Presentation of Acetaminophen Toxicity

• Early symptoms can be asymptomatic despite toxicity.
• Liver failure symptoms may develop slowly over time.
• Immediate assessment of elevated APAP blood levels is crucial, with rechecking at 4 hours.

Treatment for Acetaminophen Overdose

• N-acetylcysteine (NAC) is the antidote for acetaminophen toxicity.
• It can be administered orally or intravenously, depending on the severity of the case.

Diagnosis of Acetaminophen Overdose

• Utilize the Rumack-Matthew Nomogram to assess toxicity risk.
• Relevant for patients over 12 years old with a single, acute overdose ingested.
• Blood acetaminophen levels should be measured 4 to 24 hours post-ingestion.
• Toxicity is indicated by severe liver damage in 90% of patients with levels exceeding 300 mg/ml at 4 hours or above 45 mg/ml at 15 hours.

Side Effects and Management of NAC

• Potential side effects of NAC include anaphylaxis (IV administration).
• Common reactions: rash, urticaria, pruritus, and flushing.
• Gastrointestinal issues may arise: nausea and vomiting.
• Respiratory issues could occur: bronchospasm with a risk of being fatal.
• Manage severe reactions with antihistamines, steroids, beta agonists, or epinephrine as necessary.

Benzodiazepines Overview

• Benzodiazepines enhance the effects of gamma-aminobutyric acid (GABA) by binding to benzodiazepine (BZD) receptors in the brain.
• Common clinical presentation includes sedation, altered mental status (AMS), and respiratory depression.

Treatment Strategies

• Initial treatment focuses on supportive care to stabilize the patient.
• Flumazenil is a competitive GABA antagonist used as an antidote but is rarely utilized due to potential complications.
• In the event of seizures following flumazenil administration, anticonvulsants like phenobarbital or diprivan (propofol) should be administered.

Contraindications to Flumazenil

• Chronic benzodiazepine use can lead to acute withdrawal symptoms when flumazenil is given.
• Should be avoided in patients with suspected tricyclic antidepressant (TCA) overdose.
• Co-ingestion with seizure-inducing agents or stimulants poses a risk for seizures.
• Flumazenil is contraindicated in individuals with a known seizure disorder or increased intracranial pressure.

Urine Drug Screening (UDS) Considerations

• Alprazolam, lorazepam, and clonazepam may not be detected in all urine drug screenings, complicating diagnosis.

Heavy Metals Overview

• Substances: Key heavy metals include Arsenic, Iron, Lead, and Mercury.

Sources of Heavy Metals

• Wood Preservatives: Often contain harmful metals, contributing to environmental contamination.
• Industrial Solvents: Commonly used in various industries, posing risks of heavy metal exposure.
• Elemental Iron: Found in some supplements and industrial products; excessive exposure can lead to health issues.
• Medications: Certain pharmaceuticals may contain heavy metals, requiring careful evaluation for safety.
• Paint Chips: Older paints, particularly those with lead, can be a significant source of exposure.
• Fuels: Some fuels may contain heavy metals as additives or contaminants, affecting air quality.
• Batteries: Batteries, especially lead-acid types, are significant sources of lead exposure.

Clinical Presentation

• Varied Symptoms: The health effects and clinical presentation vary greatly depending on the specific heavy metal involved.

Treatment Approaches

• Chelation Therapy: Utilizes agents that bind heavy metals and convert them into non-toxic, excretable compounds.
• Excretion Methods: Chelated substances can be removed from the body through urine or dialysis, aiding detoxification.

Calcium Channel Blockers: Mechanism and Presentation

• Dihydropyridines:

  • Primarily cause hypotension with reflex tachycardia due to peripheral vasodilation.
  • At high doses, lose peripheral selectivity and can lead to bradycardia.

• Non-dihydropyridines:

  • Induce bradycardia and hypotension through decreased chronotropic (heart rate) and inotropic (force of contraction) effects.

Treatment Protocol

• Calcium Gluconate: Administer 3g IV.

  • Dosage: 10-50 mg/kg/hr, titrated based on blood pressure.

• Insulin: Use at a rate of 1 unit/kg/hr to help manage blood sugar levels.

• Supplementation:

  • Concomitant administration of Dextrose and Potassium to support metabolic needs.

• Fluid Management:

  • Intravenous fluids (IVF) and vasopressors are necessary for blood pressure support.

Cyanide Poisoning

• Sources include burning plastics and polymers, especially during house fires impacting victims or firefighters.
• Can occur through chemical warfare or intentional poisoning.
• Prolonged infusion of nitroprusside for more than 48 hours can lead to cyanide toxicity.

Mechanism of Action

• Cyanide binds to cytochrome oxidase in mitochondria, halting the electron transport chain.
• This binding shifts cellular metabolism from aerobic respiration to anaerobic processes.

Clinical Presentation

• Early Symptoms:
  • Headache and confusion indicating neurological involvement.
  • Tachycardia and hypotension reflecting cardiovascular response.
  • Tachypnea as a compensatory mechanism for hypoxia.
• Late Symptoms:
  • Nausea and vomiting as signs of severe systemic impact.
  • Bradycardia leading to arrhythmias and potential asystole.
  • Altered mental status (AMS) indicating severe toxicity.
  • Characteristics of arterial and venous blood gas analysis show narrow pO2, highlighting the metabolic shift.

Considerations

• Enclosed fire victims should also be evaluated for carbon monoxide exposure, which results in carboxyhemoglobinemia; high-flow oxygen should be administered.

Treatment Options

• Hydroxocobalamin is the primary antidote for cyanide poisoning, effective at chelating cyanide ions.
• Colorimetric testing for cyanide is unreliable for 72 hours post-administration of hydroxocobalamin.
• Manual complete blood count (CBC) is necessary as standard SP02 measurements may not be accurate.
• Carboxyhemoglobin levels cannot be obtained, and kidney function tests (SCr) and transaminases may also be unreliable.
• Sodium thiosulfate should be given at 1.65 mL/kg IV over 10 minutes as a secondary treatment.
• Sodium bicarbonate can be administered to correct metabolic acidosis.

Digoxin Overview

• Digoxin is a cardiac glycoside used primarily for heart conditions like atrial fibrillation and heart failure.

Mechanism of Action

• Inhibits the sodium/potassium ATPase pump in myocardial cells.
• Results in increased intracellular sodium and calcium, enhancing myocardial contractility (positive inotropic effect).

Presentation of Digoxin Toxicity

• ECG Changes: Classic findings may include downward-sloping ST segments and T wave changes.
• Bradycardia: Occurs due to increased vagal tone, leading to slower heart rates that can be dangerous.
• Cognitive Effects: Can cause confusion or delirium, particularly in elderly patients or those with renal dysfunction.
• Visual Disturbances: Patients may report seeing yellow halos around lights or experience scotomas, indicating a visual side effect of toxicity.
• Electrolyte Disarray: Hypokalemia may worsen digoxin toxicity, while hyperkalemia can occur as a consequence.

Treatment of Digoxin Toxicity

• Digoxin Immune Fab (Digibind): An antidote that binds to digoxin molecules, reducing their bioavailability and effects, used in severe cases of toxicity or when life-threatening symptoms are present.

Anticoagulants

• Heparin and Low Molecular Weight Heparin (LMWH) are commonly used anticoagulants.
• Protamine can reverse heparin effects; administer 25-50mg over 10 minutes.
• Warfarin requires careful management, especially in emergencies.
• For emergent cases of intracranial hemorrhage, use Prothrombin Complex Concentrate and IV Vitamin K, along with Fresh Frozen Plasma (FFP).
• In non-emergent scenarios with INR over 9, treat with IV or oral Vitamin K and consider FFP as needed.
• Novel Oral Anticoagulants (NOACs) may require Prothrombin Complex Concentrate for reversal.

Alcohols

• Ethylene Glycol is found in anti-freeze, brake fluid, hydraulic fluid, and solvents, while Methanol is found in windshield washer fluid and various solvents.
• Ethylene Glycol leads to central nervous system (CNS) depression and elevated osmolar gap; it is metabolized to oxalic acid and glycolic acid, causing acidosis.
• Methanol is converted to formaldehyde by alcohol dehydrogenase, which then slowly converts to formic acid, responsible for downstream lactic acidosis.

Presentation

• Ethylene Glycol:

  • Early symptoms of intoxication include CNS depression.
  • Intermediate symptoms (12-24 hours) consist of hypertension, tachypnea, and hypocalcemia.
  • Late-stage effects lead to renal failure; the substance fluoresces under Wood’s lamp.

• Methanol:

  • Symptoms include confusion, ataxia, altered mental status (AMS), and seizures.
  • Visual changes and tachypnea can occur due to anion gap acidosis, with a latent onset of 12-24 hours.
  • Toxicity is attributed to its metabolites.

Treatment

• Fomepizole is an effective treatment; administer a loading dose of 15 mg/kg to inhibit alcohol dehydrogenase, preventing the formation of toxic metabolites.

Beta Blockers

• Beta blockers are medications that inhibit the action of catecholamines on beta-adrenergic receptors, reducing heart rate and blood pressure.
• Non-selective beta blockers affect both beta-1 and beta-2 receptors, while selective beta-1 blockers primarily target the cardiac beta-1 receptors.
• Common adverse effects include:
  • Bradycardia: A significant decrease in heart rate, potentially compromising cardiac output.
  • Hypotension: Low blood pressure that can lead to dizziness or fainting.
  • Delirium: Confusion or altered mental status, particularly noted with Propranolol.
  • Seizures (SZ): Can occur with certain beta blockers like Propranolol.
  • Hypothermia: A reduction in body temperature due to impaired thermoregulation.
  • Hypoglycemia: Low blood sugar levels, affecting glucose metabolism.

Treatment for Beta Blocker Toxicity

• Administer Glucagon (5 mg IV push) to stimulate adenyl cyclase, increasing heart rate and contractility independently of beta receptors.
• Use Calcium gluconate (3 g IV) to help stabilize cardiac membranes and support muscle contractions.
• Insulin (1 unit/kg/hour) aids in managing hyperglycemia and potentiating cardiac function.
• Provide concomitant Dextrose and Potassium supplementation to counteract hypoglycemia and support electrolyte balance.
• Manage fluid status and blood pressure with intravenous fluids (IVF) and vasopressors as necessary.

Sulfonylureas (e.g., Glipizide)

• Sulfonylureas are oral antidiabetic medications that stimulate insulin release from pancreatic beta-cells, improving blood glucose control.
• Presentation of sulfonylurea overdose is primarily hypoglycemia, which can have serious consequences if not addressed promptly.
• Treatment for acute hypoglycemia includes:
  • Dextrose 50%: Rapidly raises blood sugar levels.
  • Octreotide: Can be used to inhibit further insulin release from the pancreas.
• Patients experiencing severe hypoglycemia typically require admission for monitoring and management of blood glucose levels.

Valproate

• Mechanism involves increasing GABA effects through competitive agonist action.
• Presents with CNS Depression, hypotension, and respiratory depression.
• Treatment options include Naloxone, with an unclear mechanism, potentially due to non-selective opioid agonist effects of valproate.
• Other treatment includes levo-carnitine with a loading dose of 100 mg/kg and dialysis for severe cases.

Opioids

• Mechanism is a competitive agonist at opioid receptors, affecting pain and sedation.
• Presents with CNS depression, respiratory depression, and miosis (pupil constriction).
• Treatment primarily involves NARCAN (Naloxone), with initial doses ranging from 0.4 mg to 2 mg administered IV push, adjusted based on symptom severity.
• Anecdotal dosing protocol includes 1 mg IV push every 2-3 minutes until the patient's GCS (Glasgow Coma Scale) increases to 13-14.
• Onset of NARCAN action occurs within 1-2 minutes.
• Rapid IV push or high doses may lead to severe withdrawal symptoms; it's advised to avoid this practice.
• When using a drip method, the "wake-up" dose is calculated as two-thirds of the total dose per hour.

General Workup for Poisoning

• Importance of obtaining a thorough history and physical examination to assess the patient's condition.
• ECG (electrocardiogram) is essential for monitoring cardiac function and identifying potential arrhythmias.

Laboratory Tests

• Point-of-Care (POC) glucose levels to assess for hypoglycemia or hyperglycemia.
• Complete Blood Count (CBC) to identify signs of infection or anemia.
• Comprehensive Metabolic Panel (CMP) for evaluating liver and kidney function, electrolyte balance.
• Magnesium levels to monitor for electrolyte imbalances.
• Creatine Kinase (CK) levels to assess muscle injury or rhabdomyolysis.
• Lactic Acid levels for detecting metabolic acidosis, commonly seen in toxicity.
• Ethanol levels to check for alcohol intoxication.
• Acetaminophen (APAP) levels to ascertain potential overdose.
• Salicylate levels to evaluate for toxicity from aspirin or related drugs.
• Urinalysis (UA) for identifying drugs or toxins.
• Urine Drug Screen (UDS) for detecting the presence of various drugs.
• Drug-specific levels may be required depending on the suspected poison.
• Pregnancy tests to rule out gestation, as some treatments can have implications for pregnant patients.

Supportive Care

• Continuous supportive care is critical until antidotes or metabolic byproducts can be administered.
• Involvement of poison control for expertise in managing toxicology cases and clinical support.

High-Risk Substances

• "One pill can kill" warning highlights the dangers of specific substances, particularly in children:
  • Clonidine
  • Quinine
  • Suboxone (buprenorphine/naloxone)
  • Calcium Channel Blockers (CCBs)
  • Sulfonylureas
  • Tricyclic Antidepressants (TCA)