Pharmacology - lecture 18 - Toxicology

Learning Objectives

  • Students should be able to:

    • Describe three important principles of toxicology.

    • Explain terms: dose, dose-response, LD50, and therapeutic index.

    • Distinguish between acute and chronic effects, and organ-specific and systemic effects.

    • Identify common sources of toxins and toxicants.

    • Explain toxic effects from alcohol, botulinum toxin, paracetamol, aspirin, thalidomide, and grapefruit juice.

    • List branches of toxicology and examples of toxicants and their mechanisms.

    • Describe the science of safety testing.

Definition of Poison

  • Paracelsus: "All substances are poisons; the right dose differentiates a poison from a remedy."

  • Concept: "The dose makes the poison" emphasizes the role of dosage in toxicity.

  • Poison: drugs that are likely to cause ill effects at doses likely to be encountered

Principles of Toxicology

  • Toxicant effects are proportional to exposure/dose.

  • Variability in sensitivity occurs between and within species.

  • Different mechanisms mediate acute and chronic toxic effects.

Understanding LD50

  • LD50 (Lethal Dose 50) is the quantity of a substance that can kill 50% of a test population.

    • Variability based on route of administration and species differences.

Dose-Response Relationships

  • Understanding efficacy and effectiveness illustrated with dose-response curves.

  • Key thresholds: LD50, ED50 (Effective Dose 50), TD30 (Toxic Dose 30).

Therapeutic Index

  • The ratio indicating the margin of safety between effective and toxic doses.

  • A larger TI indicates greater safety.

Toxicity Comparison

  • Drugs A and B may share an LD50 but differ in hazard level due to their dose-response profile.

Drug Disposition Dynamics

  • Importance of ADME (Absorption, Distribution, Metabolism, Excretion) phases in drug efficacy and toxicity.

Types of Toxic Substances

  • Examples of toxins:

    • Drugs: Paracetamol, Aspirin, Thalidomide.

    • Industrial Chemicals: Lead, asbestos.

    • Food Additives: Artificial sweeteners, botulinum toxin.

    • Pesticides and Natural Products: DDT, plant toxins.

    • Household Products: CO, alcohol.

    • Environmental Pollutants: Ozone, tobacco smoke.

  • Distinction between toxins (natural origin) and toxicants (man-made).

Alcohol Toxicity

  • Acute Effects: CNS depression, impaired motor functions, vomiting.

  • Chronic Effects: Liver cirrhosis, various cancers, brain damage.

  • Benefits of low-level consumption for cardiovascular health.

Botulinum Toxin

  • Produced by Clostridium botulinum, highly toxic, a soil bacterium that thrives in low acid, low sugar, low oxygen, environment.

  • Blocks neuromuscular transmission through decreased release of acetylcholine.

  • Symptoms: blurred vision, swallowing difficulties, can lead to paralysis.

  • Therapeutic uses include muscle spasm treatments and cosmetic applications.

  • Risks highlighted by recent case of botulism in food products.

Paracetamol Metabolism and Toxicity

  • Metabolized mainly by sulfate and glucuronic acid conjugation.

  • Minor metabolism by oxidation followed by conjugation with glutathione.

  • Overdose leads to liver damage via toxic metabolite formation.

    • Saturation of conjugation pathway so more oxidative metabolism and depletion of glutathione.

    • Leads to hepatic necrosis and death.

  • Alcohol can potentiate the liver damage by inducing levels of cytochrome P450 enzymes which increases toxic metabolic activation of paracetamol.

  • Antidote: N-acetylcysteine; efficacy decreases after 10-12 hours.

Aspirin Toxicity and Mechanism

  • Metabolized to salicylic acid then conjugated with glucuronic acid ot glycine, impacting mitochondrial function.

  • Leads to hyperventilation, increase in blood pH, then correction by elimination of sodium bicarbonate into the urine.

  • Overdose may cause metabolic acidosis and brain damage.

  • Lack of ATP to brain and heart may prove fatal.

  • Antidote: Bicarbonate infusion.

Thalidomide Diversity

  • Initially an anti-sickness remedy, later linked to severe birth defects.

  • Importance of chirality (enantiomer effects) in toxicity.

  • New therapeutic applications discovered for various conditions.

Grapefruit Juice Interaction

  • Contains furanocoumarins that inhibit cytochrome P450 3A4, affecting various drugs.

Branches of Toxicology

  • Types of Toxicology:

    • Clinical, Forensic, Industrial, Environmental, Ecotoxicology, Regulatory, Genetic.

Clinical Toxicology

  • Focuses on diagnosis and treatment of poisoning cases, including drug overdoses and adverse reactions.

Forensic Toxicology

  • Examines poisons like arsenic, mercury, and cyanide in legal contexts.

Industrial/Occupational Toxicology

  • Identifies industrial diseases and their causes (e.g. asbestos, cadmium).

Environmental Toxicology

  • Studies pollution effects on ecosystems and human health.

Ecotoxicology

  • Examines chemical pollutants on non-human species and ecosystems.

Vulture Crisis and Diclofenac

  • Diclofenac's toxicity to vultures led to population declines and ecological consequences.

  • Captive breeding programs initiated to prevent extinction.

Genetic Toxicology

  • Evaluates mutagenicity and carcinogenicity metrics.

  • Major mutagenicity endpoints:

    • Gene mutations (point mutation or deletions/insertions)

    • Clastogenicity (structural chromosome changes)

    • Aneuploidy (numerical chromosome aberrations)

  • Major carcinogenicity endpoint: tumour formation

Regulatory Toxicology

  • Assesses safety of chemicals based on testing methodologies and ethical considerations.

    • Emphasizes risk vs. benefit analysis.