Introduction to Toxicology and ADRs 2

Introduction to Toxicology and Adverse Drug Reactions 2

• Course: Principles of Drug Structure and Action
• Instructor: Amal Aburahma, PhD
• Semester: Spring 2025
• Institution: Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy

Objectives

• Define allergic reactions and describe the cascade of allergic reactions.
• Define idiosyncratic reactions and describe their characteristics.
• Differentiate between mutagenicity and carcinogenicity and list general tumor types.
• Describe pharmacokinetic drug-drug interactions and their role in adverse drug reactions and toxicity.
• Describe pharmacodynamic drug-drug interactions and their role in adverse drug reactions and toxicity.
• Describe therapeutic drug monitoring (TDM) and its significance.
• Describe the principles of TDM.

Allergy (Hypersensitivity) Reactions

• Adverse immune response to a drug or similar chemical following prior exposure.
• Sensitization: Initial exposure to the drug leads to the formation of an antigen-antibody complex.
• Subsequent reaction: Exposure to the drug triggers antibody response, resulting in allergic response.
• Allergic reactions can be dose-dependent and range from mild to severe, even fatal.

Types of Allergic Reactions

• Type I (Immediate): IgE-mediated, rapid response.
• Type II (Antibody-Dependent): Antibodies directly attack target cells.
• Type III (Immune Complex): Immune complexes deposit in tissues, causing inflammation.
• Type IV (Cell-Mediated): Delayed-type hypersensitivity, T-cell response to antigens.

Idiosyncratic Reactions

• Rare adverse reactions not predictable from drug pharmacology or toxicology.
• Not due to the drug itself but to a unique patient characteristic.
• Not reproducible in laboratory settings (in vitro and in vivo).
• Dose-independent, meaning the severity isn't directly related to the drug dose.
• Factors include genetic predisposition, age, gender, and lack of drug-metabolizing enzymes.

Mutagenicity vs. Carcinogenicity

• Mutagenicity: Ability of a chemical or drug to alter DNA, causing genetic mutations.
• Carcinogenicity: Ability of a chemical or drug to induce tumors.
• Carcinogens can be chemical, physical, or biological (viruses).
• Tumors are classified as malignant (invasive, spreadable) or benign (stays in primary tissue).

Drug-Drug Interactions

• Pharmacokinetic interactions: Alterations in drug absorption, distribution, metabolism, or elimination affecting drug levels.

  • Absorption: Changes in GI pH or adsorption can affect the absorption.
  • Distribution: Interactions at transporters (e.g., P-glycoprotein) can alter drug distribution, absorption, and elimination.
  • Metabolism: Some drugs can affect the metabolism of other drugs via CYP450 activity. Induction increases metabolism, while inhibition decreases it.
  • Elimination: Renal clearance can be altered leading to toxicity, such as in cases with lithium and NSAIDs.

• Pharmacodynamic interactions: Interactions related to the pharmacological action of drugs at the receptor site or through physiological effects.

  • Agonistic interactions: Increased effect.
  • Antagonistic interactions: Decreased effect.

Therapeutic Drug Monitoring (TDM)

• Clinical laboratory measurement of drug levels to guide prescribing procedures.

• Crucial when drugs have narrow therapeutic ranges or their effects are not directly linked to plasma concentrations.

• Used to adjust dosage regimens based on patient factors and drug response, ensuring appropriate drug levels and minimizing adverse reactions.

• Examples: Warfarin, insulin, bronchodilators in asthma, cancer chemotherapy.