Toxicology

• Toxins


  A substance that can cause harm to living organisms
• Toxicologist


  A scientist who works with chemicals to determine if they are toxic or harmful to humans and other living organisms
• Areas of toxicology


  • Regulatory: Assessing safety and setting standards
  • Clinical: Understanding toxicity in medical contexts
  • Forensic: Investigating toxins in legal cases
  • Environmental: Analysing toxins' impact on ecosystems
  • Occupational: Assessing workplace safety, studying substance toxicity
• Physiochemical properties


  • Lipid solubility
  • Ionisation
• Systematic routes of administration


  • Enteral: Via the GI tract
  • Parenteral: Injected directly into the blood or specific tissues
  • Topical: Applied to the skin
  • Inhalation: Inhaled into the respiratory system
• Specific/local routes of administration


  • Intranasal: Absorption through nasal mucosa
  • Intrathecal: Directly into the spinal canal
  • Intraperitoneal: Into the peritoneal cavity
• Factors affecting drug absorption


  • Physiological factors: Stomach emptying time, Intestinal mobility
  • Drug-related factors: Particle size, Formulation
• Bioavailability


  The fraction or a drug/toxin reaching systematic circulation
• Bioavailability


  • Influenced by absorption, first-pass metabolism, and drug formulation
• First-Pass Metabolism


  Bioavailability varies based on route of administration, significant differences observed between IV and oral administration due to influence of first pass metabolism
• Physiochemical Properties


  • pH and pKa affect drug/ion absorption
• Distribution of Drugs in the Body


  Passage of drug molecules to liquid compartments and tissues in the body via transportation across the membrane
• Fluid Compartments


  • Extracellular: Body plasma, interstitial Fluid, lymph
  • Intracellular: Fluid with all cells
  • Transcellular: Cerebrospinal, introcellular
• Patterns of Distribution


  • Distribution only in plasma
  • Distribution to all body Fluids homogenously
  • Concentration in specific tissues
  • Non homogenous distribution pattern
• Physiochemical Properties of Toxins

  • pKa, Lipid solubility, Molecular weight, Protein/tissue binding
• Volume of Distribution (VoD)

  Influenced by blood flow and barriers, determines the extent of drug distribution in the body
• Mechanisms of Drug Transport Across Cell Membranes

  • Passive Diffusion
  • Filtration
  • Facilitated Diffusion
  • Active Transport
  • Endocytosis
• Plasma Protein Binding


  Albumin, Lipoproteins, alpha1 and glycoprotein, only free drug expects pharmacological effect
• Storage Depots


  Fat, bone, liver, tissues act as reservoirs for drug accumulation
• Blood Perfusion


  Determines rate of drug delivery to tissues, influences drug distribution in well-perfused vs poorly perfused organs
• Capillary Structure


  • Continuous vs fenestrated capillaries, size and fenestrae size influence drug permeability
• Blood-Brain Barrier (BBB)


  Selectively allows certain substances to pass into CNS, tight junctions between capillary endothelial cells restrict passage
• Placental Barrier


  Influencing factors: Blood Flow, molecular size, drug solubility, fetal pH, allows diffusion of fat-soluble substances
• Volume of Distribution (VoD) Calculation

  Amount of drug administered/concentration of drug in plasma, helps determine loading dose and therapeutic plasma concentration
• VoD <3L: Drug distributed in plasma only, VoD >46L: Drug likely stored in tissue depot
• Understanding mechanisms of drug distribution is crucial for optimizing factors such as protein binding, tissue accumulation and barriers like the blood-brain barrier and placental barrier, to calculate loading dose and predict and avoid adverse effects
• Metabolism


  Irreversible biochemical transformation of drugs into metabolites to increase excretion from the body
• Metabolism


  • Mainly occurs in the kidneys, converts drugs into more water soluble compounds, metabolites often have different activity from the parent compound, less likely to bind to plasma proteins and less likely to be stored in fat
• Importance of Drug Metabolism

  Understanding pharmacological and toxicological activity of drugs, shortening the duration of action of toxins/drugs, complications of drug-drug interactions mainly depend on the induction or inhibition of metabolic enzymes
• Types of Metabolic Reactions

  • Active drug -> Inactive metabolites
  • Inactive drug + Active drug
  • Active drug -> Transformed to more active compounds after biotransformation -> Transformed to inactive metabolites after biotransformation (detontica)
• First Pass Metabolism


  Drugs taken orally pass through the liver before systemic circulation, metabolism or hepatobiliary secretion occurs during this pass, Phase 1 (oxidation, hydrolysis, reduction) and Phase II (conjugation) reactions occur, forms easily excreted polar compounds
• Phase 1 Metabolism (Non-synthetic reactions)

  Mediated predominantly via microsomal endoplasmic reticulum cytochrome P450 liver enzymes, includes oxidation, reduction and hydrolysis reactions
• Cytochrome P450 Enzyme


  Important in drug and toxin metabolism, polymorphisms in the CYP family impact drug fate and influence drug metabolism variability
• Phase II Metabolism (conjugation reactions)


  Couples agent to existing conjugation site on drug/metabolite, involves addition to smaller functional groups, including ethers, alcohols, amines (mostly formed in Phase 1)
• Glucuronidation


  UDP-glucuronosyltransferases catalyses the reaction, glucuronidation decreases lipid solubility of drugs, facilitating excretion
• Factors Influencing Drug Metabolism

  • Age
  • Gender
  • Disease states
  • Genetic differences
  • Species
  • Inducers/Inhibitors
  • Drug tolerance
  • Drug-drug interactions
  • Diet
• Genetic Polymorphism


  Genetic variations in enzymes can impact drug metabolism, examples include hydrolysis of succinylcholine, acetylation of isoniazid, and CYP2D6 polymorphism
• Age and Gender Effects

  Oxidation reactions are slower in the elderly, aging affects enzyme activity and metabolism rates, metabolism rates may vary with gender
• Log P


  Measure of lipid solubility
• Bioavailability (F)


  Mass of drug delivered to the plasma / Total mass of drug delivered