Toxic Effects

Understanding the relationship between toxicokinetics and toxic effects, signs, and symptoms is crucial for effective clinical toxicology. Toxicokinetics describes how a substance moves through the body, while understanding the clinical manifestations of toxicity aids in diagnosis and treatment

Toxicokinetics: What the Body Does to the Toxin

Definition: The study of the movement of toxic substances within the body, encompassing absorption, distribution, metabolism, and excretion (ADME)
Relationship to Pharmacokinetics: Toxicokinetics is essentially the study of pharmacokinetics applied to toxic substances, providing insights into how the body handles these compounds

Absorption

Definition: The process by which a toxic substance enters the body
Routes of Exposure
- Ingestion: Oral intake of a toxic substance
- Inhalation: Breathing in toxic gases, vapors, or particulate matter
- Dermal Absorption: Absorption through the skin
- Injection: Introduction directly into the bloodstream or tissues
- Mucosal Absorption: Absorption through mucous membranes (e.g., nasal, oral, rectal)
Factors Affecting Absorption
- Route of Exposure: Intravenous (IV) exposure has 100% bioavailability
- Physicochemical Properties
  - Molecular weight, lipophilicity, and ionization affect the ease with which a substance crosses biological membranes
- Concentration: Higher concentrations increase absorption rates
- Surface Area: Larger surface areas (e.g., lungs, small intestine) enhance absorption
- Blood Flow: Increased blood flow at the absorption site increases absorption rates
- Physiological Factors: Gastric emptying time, intestinal motility, and skin integrity influence absorption rates

Distribution

Definition: The process by which a toxic substance is transported from the bloodstream to various tissues and organs in the body
Factors Affecting Distribution
- Blood Flow: Highly perfused organs (brain, heart, liver, kidneys) receive the toxic substance more rapidly
- Tissue Permeability
  - Lipid-soluble substances can easily cross cell membranes
  - Water-soluble substances may require transport proteins
- Protein Binding: Binding of toxic substances to plasma proteins (albumin, alpha-1-acid glycoprotein)
  - Only unbound (free) substance can exert toxic effects
  - Substances with high protein binding have limited distribution
- Volume of Distribution (Vd): A measure of the apparent space in the body available to contain the toxic substance
  - Vd = Amount of Substance in the Body / Plasma Concentration
  - High Vd: Indicates extensive tissue distribution
  - Low Vd: Indicates limited tissue distribution
- Tissue Binding: Accumulation of toxic substances in specific tissues (e.g., lead in bone, DDT in adipose tissue)
Barriers to Distribution
- Blood-Brain Barrier (BBB): Protects the brain from many toxic substances
- Placental Barrier: Protects the fetus from some, but not all, toxic substances

Metabolism

Definition: The process by which the body chemically alters a toxic substance, often to facilitate its elimination
Primary Site: Liver
Other Sites: Kidneys, intestines, lungs, and plasma
Phases of Metabolism
- Phase I Reactions: Introduce or expose a functional group on the toxic substance molecule
  - Oxidation, reduction, hydrolysis
  - Enzymes: Cytochrome P450 (CYP) enzymes, flavin-containing monooxygenases (FMOs)
- Phase II Reactions: Conjugate a polar molecule to the toxic substance molecule
  - Glucuronidation, sulfation, acetylation, glutathione conjugation
  - Enzymes: UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs)
Activation vs. Detoxification
- Detoxification: Metabolism can convert toxic substances into less harmful metabolites
- Activation: Metabolism can convert relatively harmless substances into more toxic metabolites (bioactivation)
Factors Affecting Metabolism
- Genetic Factors: Genetic polymorphisms in drug-metabolizing enzymes can affect the rate of metabolism
- Age: Infants and elderly individuals may have reduced metabolic capacity
- Disease States: Liver disease can impair metabolism
- Drug Interactions: Enzyme inducers and inhibitors can affect the metabolism of other substances

Excretion

Definition: The process by which the body eliminates a toxic substance or its metabolites
Primary Routes
- Kidneys: Most toxic substances are excreted in the urine
  - Glomerular filtration, tubular secretion, tubular reabsorption
- Liver: Some toxic substances are excreted in the bile and eliminated in the feces
Other Routes: Lungs, sweat, saliva, breast milk
Factors Affecting Excretion
- Renal Function: Glomerular filtration rate (GFR), tubular secretion, and tubular reabsorption affect renal excretion
- Liver Function: Bile flow and hepatic metabolism affect biliary excretion
- Substance Properties: Molecular size, ionization, and protein binding affect excretion
- Urine pH: Can affect the excretion of weak acids and bases
Clearance (CL): A measure of the body’s ability to eliminate a toxic substance
- CL = Rate of Elimination / Plasma Concentration

Toxic Effects, Signs, and Symptoms: What the Toxin Does to the Body

Dose-Response Relationship: The severity of toxic effects is generally related to the dose of the toxic substance
Target Organs: Toxic substances can selectively target specific organs or tissues (e.g., liver, kidneys, brain)
Mechanisms of Toxicity: Toxic substances can cause damage through various mechanisms, including:
- Cellular Necrosis: Cell death
- Apoptosis: Programmed cell death
- Oxidative Stress: Damage caused by free radicals
- Mitochondrial Dysfunction: Disruption of energy production
- Inflammation: Activation of the immune system
- Neurotoxicity: Damage to the nervous system
- Carcinogenesis: Cancer development
- Teratogenesis: Birth defects
Signs and Symptoms: The clinical manifestations of toxicity vary depending on the toxic substance, the dose, the route of exposure, and individual factors
Common Toxic Syndromes (Toxidromes): A group of signs and symptoms associated with a particular class of toxic substances
- Cholinergic Toxidrome: Associated with exposure to organophosphates, carbamates, and other cholinergic agents
  - Symptoms: Salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis (SLUDGE)
- Anticholinergic Toxidrome: Associated with exposure to anticholinergic medications and plants
  - Symptoms: Dry mouth, blurred vision, dilated pupils, urinary retention, constipation, tachycardia, delirium
- Sympathomimetic Toxidrome: Associated with exposure to stimulants such as cocaine, amphetamines, and caffeine
  - Symptoms: Tachycardia, hypertension, diaphoresis, agitation, tremor, seizures
- Opioid Toxidrome: Associated with exposure to opioid medications
  - Symptoms: Respiratory depression, miosis (pinpoint pupils), altered mental status
- Sedative-Hypnotic Toxidrome: Associated with exposure to benzodiazepines, barbiturates, and other sedatives
  - Symptoms: Sedation, altered mental status, slurred speech, ataxia, respiratory depression

Specific Examples of Toxic Substances and Their Effects

Toxic Substance	Target Organ(s)	Mechanism of Toxicity	Signs and Symptoms
Acetaminophen	Liver	Formation of toxic metabolite NAPQI	Nausea, vomiting, abdominal pain, jaundice, liver failure
Salicylates	Multiple	Uncoupling of oxidative phosphorylation	Tinnitus, hyperventilation, metabolic acidosis, confusion
Opioids	Brain, Lungs	Respiratory depression, CNS depression	Miosis, respiratory depression, altered mental status, coma
Organophosphates	Nervous System	Cholinesterase inhibition	Salivation, lacrimation, urination, defecation, emesis, muscle weakness, seizures, respiratory failure
Lead	Multiple	Disruption of enzyme function	Abdominal pain, constipation, anemia, neurological symptoms, developmental delays
Mercury	Kidneys, Brain	Protein binding, oxidative stress	Tremor, memory loss, kidney damage
Carbon Monoxide	Brain, Heart	Binds to hemoglobin, reduces oxygen delivery	Headache, dizziness, nausea, vomiting, confusion, loss of consciousness

Key Terms

Toxicokinetics: The study of how a toxic substance moves through the body (ADME)
Absorption: The process by which a toxic substance enters the body
Distribution: The process by which a toxic substance is transported to tissues
Metabolism: The process by which the body chemically alters a toxic substance
Excretion: The process by which the body eliminates a toxic substance
Volume of Distribution (Vd): A measure of the apparent space in the body available to contain the toxic substance
Clearance (CL): A measure of the body’s efficiency in eliminating a toxic substance
Toxidrome: A group of signs and symptoms associated with a particular class of toxic substances
Dose-Response Relationship: The relationship between the dose of a toxic substance and the severity of its effects
Target Organ: The organ or tissue most affected by a toxic substance
Mechanism of Toxicity: The way in which a toxic substance causes damage
Signs: Objective evidence of a disease or condition
Symptoms: Subjective evidence of a disease or condition
Cellular Necrosis: Cell death
Apoptosis: Programmed cell death
Oxidative Stress: Damage caused by free radicals
Mitochondrial Dysfunction: Disruption of energy production
Inflammation: Activation of the immune system
Neurotoxicity: Damage to the nervous system
Carcinogenesis: Cancer development
Teratogenesis: Birth defects
Bioactivation: Metabolic activation of a substance to become toxic

Toxicokinetics

Metabolism, Excretion