Introduction to Toxicology and Adverse Drug Reactions 2 - Spring 2025 PDF

Introduction to Toxicology and Adverse Drug Reactions 2 PRINCIPLES OF DRUG STRUCTURE AND ACTION SPRING 2025 AMAL ABURAHMA, PHD Objectives * At the end of this lecture, you will be able to: 1) Define allergy reactions...

Introduction to Toxicology and Adverse Drug Reactions 2 PRINCIPLES OF DRUG STRUCTURE AND ACTION SPRING 2025 AMAL ABURAHMA, PHD Objectives * At the end of this lecture, you will be able to: 1) Define allergy reactions and describe the cascade of allergic reactions occurrence 2) Define idiosyncratic reactions and describe their characteristics 3) Differentiate between mutagenicity and carcinogenicity and list the general types of tumors 4) Describe the different types of pharmacokinetic drug-drug interactions and illustrate how these interactions can lead to adverse drug reactions and toxicity 5) Describe the different types of pharmacodynamic drug-drug interactions and illustrate how these interactions can lead to adverse drug reactions and toxicity 6) Describe therapeutic drug monitoring (TDM) and understand the significance of TDM 7) Describe the principles of TDM  4) Allergy (hypersensitivity) reactions - Adverse reaction of the immune system to a drug in response to a previous exposure to that chemical or to a structurally similar one - Steps: a) Sensitization: prior exposure to the drug required to produce the subsequent adverse effects The chemical/drug In the following exposure, (named hapten) must first The antigen then the antigen is recognized interact with a native stimulates the immune by the antibody leading to protein to form an antigen system to form antibodies allergic response (hapten-protein complex) b) Allergy reactions occur after from exposure to the offending drug - Some allergic reactions can be dose-dependent - Some allergic reactions can be severe and occasionally fatal  FYI Types of allergic reactions 1) Type I (Immediate or IgE-Mediated Hypersensitivity) 2) Type II (Antibody-Dependent Cytotoxic Hypersensitivity) 3) Type III (Immune Complex–Mediated Hypersensitivity) 4) Type IV (Cell-Mediated Hypersensitivity) 5) Idiosyncratic reactions - Often rare and occur in 1 – 10,000 people - Although rare, it is considered one of the most common reasons for withdrawing a drug from the market - Are NOT predictable from the known pharmacology or toxicology of the dug (i.e., does NOT occur from the drug itself) - Are NOT produced experimentally in vitro and in vivo - Dose independent - Occurs from a unique set of patient characteristics including gender, age, genetic predisposition, and lack of drug-metabolizing enzymes Mutagenicity VS carcinogenicity * Mutagenicity is the ability of the chemical/drug to cause changes to DNA during cell division (production of gene mutants) * Carcinogenicity: the potential of the chemical/drug to cause tumors - A carcinogen is an agent, chemical or physical or biological (viruses), that causes or induces a cancer - The majority of drugs that could cause gene mutants could also lead to tumor development - Carcinogenicity assessment for drugs is a must in pre-clinical studies - Tumors are classified as: 1) Malignant: demonstrates invasive growth characteristics, capable of spreading not only through the organ of origin but also via metastasis to other organs 2) Benign: tumor stays in the primary tissue (does NOT spread) 6) Drug-Drug Interactions A) Pharmacokinetic interactions: * Pharmacokinetic drug-drug interactions occur when on or more of the components of ADME of one drug is altered by the other - The result of this alteration could be the increase or decrease of drug effects 1) Interactions affecting absorption: - Here, the presence of one drug changes the absorption of another drug (usually from the intestinal lumen) - These changes can occur due to an alteration in the GI pH or adsorption - Example of GI pH alteration: Ranitidine is an H2 receptor antagonist that increases GI pH which can lead to increasing the absorption of basic drugs like triazolam - Example of adsorption: the coadministration of levothyroxine with calcium-containing antacids leads to the decreased absorption of levothyroxine due to the adsorption of levothyroxine to calcium (calcium binds to levothyroxine surface and prevents it from being absorbed) 2) Interactions affecting distribution: * Involvement of transporters: - Interactions at transporters can alter drug absorption, distribution and elimination - Examples of clinically relevant transporters are P-glycoprotein (efflux transporter) - Inhibition of P-glycoprotein increases the absorption and bioavailability of drugs that are Pgp substrates * Interactions at Protein Binding Sites - Many drugs are highly protein bound in the plasma - Coadministration of these drugs results in competition for binding sites and displacement of one drug by another which alters the free concentrations of the drugs - Higher free concentration leads to higher bioavailability which could lead to toxicity 3) Interactions affecting metabolism: - Some drugs can affect the metabolism of other drugs specially by affecting CYP450 activity - Drugs that induce CYP450 enzymes, can increase the metabolism of drugs that are substrates of said enzyme and vice versa 4) Interactions affecting elimination: - Some drugs can alter the renal clearance of other drugs leading to toxicity - Example: Lithium (drug used to treat certain neuropsychiatric conditions like mania and bipolar disorder) is cleared via renal excretion - Drugs like NSAIDs that inhibit prostaglandin synthesis, decreases renal blood flow and clearance thus they lead to the decrease in renal excretion of lithium - The decreased renal excretion and clearance of lithium leads to increasing lithium levels in the blood beyond the therapeutic range leading to toxicity B) Pharmacodynamic interactions: - Pharmacodynamic drug-drug interactions occur due to activity at the same receptor or via physiological effect - Interactions that lead to an increase in effect are known as agonistic (can be additive, synergistic or potentiating) - Interactions that lead to a decrease in effect are known as antagonistic (can be physiological, chemical or receptor antagonism) - Additive pharmacodynamic interactions can be beneficial or can lead to severe toxicity - Example: nitrate vasodilators (e.g., nitroglycerin) produce vasodilation via increasing cGMP levels in the vascular smooth muscles. Sildenafil (used in erectile dysfunction) also causes vasodilation via inhibiting phosphodiesterase type 5 enzyme (PDE5 hydrolyzes cGMP in the vasculature) - The coadministration of nitroglycerin with sildenafil can cause catastrophic vasodilation and severe hypotension Therapeutic drug monitoring (TDM): Therapeutic drug monitoring (TDM): the clinical laboratory measurement of a chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures * Many drugs that have wide therapeutic range do not need therapeutic drug monitoring * Therapeutic monitoring of plasma drug concentrations is valuable if a relationship exists between the plasma drug concentration and the desired clinical effect or between the plasma drug concentration and an adverse effect * In certain drugs where the plasma drug concentration and clinical effects and not directly related, other pharmacodynamic or “surrogate” parameters may be monitored ** Keep in mind: - The therapeutic range for a drug is an approximation of the average plasma drug concentrations that are safe and efficacious in most patients - Thus, the clinician should never consider the therapeutic ranges as absolute values * Examples: - In patients on warfarin (anticoagulant), clotting time can be measured directly - In diabetic patients using insulin products, glucose concentrations are often monitored - For asthmatic patients using bronchodilators, forced expiratory volume (FEV1) can be used to assess drug efficacy - In cancer chemotherapy, dose adjustment for individual patients may depend more on the severity of side effects and the patient’s ability to tolerate the drug ** When administering potent drugs to patients, the plasma drug level must be maintained within a narrow range of therapeutic concentrations - Various pharmacokinetic methods (or nomograms) may be used to calculate the initial dose or dosage regimen - The initial dosage regimen is calculated based on body weight or body surface after a careful consideration of the known pharmacokinetics of the drug, the pathophysiologic condition of the patient, and the patient’s drug history including nonprescription drugs and nutraceuticals - Because of variability between patients in ADME as well as changing pathophysiologic conditions in the patient, therapeutic drug monitoring (TDM) or clinical pharmacokinetic (laboratory) services (CPKS) have been established in many hospitals to evaluate the response of the patient to the recommended dosage regimen Self-assessment questions 1) (True/false): Sensitization to a drug is required for allergic reactions to occur. 2) Idiosyncratic reactions are typically: A) Predictable from pharmacological profiles B) Unpredictable and dose-independent C) Dose-dependent and mediated by immune complexes D) Linked to the drug’s primary mechanism of action 3) Mutagenicity refers to: A) The ability of a substance to cause cancer B) The cumulative toxicity of a substance over time C) The ability of a substance to cause genetic mutations D) The effect of a drug on DNA synthesis rates 4) (True/false): Carcinogens always act through direct DNA damage. 5) Which of the following is an example of a pharmacodynamic interaction? A) Concurrent use of a beta-blocker and a calcium channel blocker, leading to bradycardia B) Inhibition of CYP3A4 by one drug C) Reduced renal clearance of a drug due to competition D) Decreased gastrointestinal absorption of a drug due to antacids 6) A pharmacokinetic drug interaction occurs when: A) Two drugs affect each other’s pharmacological action at the receptor site B) One drug affects the absorption, distribution, metabolism, or excretion of another C) Two drugs cause an additive therapeutic effect D) A drug produces toxic metabolites in the liver 7) Induction of cytochrome P450 metabolizing enzymes can result in: A) Increased drug levels and toxicity B) Decreased renal excretion C) Prolonged drug half-life D) Reduced drug levels and decreased therapeutic effect References Michaleas SN, Laios K, Tsoucalas G, Androutsos G. Theophrastus Bombastus Von Hohenheim (Paracelsus) (1493-1541): The eminent physician and pioneer of toxicology. Toxicol Rep. 2021;8:411-414. Published 2021 Feb 23. doi:10.1016/j.toxrep.2021.02.012 Ferner, R., & Aronson, J. (2019). Susceptibility to adverse drug reactions. British journal of clinical pharmacology, 85(10), 2205–2212. https://doi.org/10.1111/bcp.14015 Casarett & Doull's Toxicology: The Basic Science of Poisons, Seventh Edition (Casarett & Doull Toxicology) 7th Edition Stark C, Steger-Hartmann T. Nonclinical Safety and Toxicology. Handb Exp Pharmacol. 2016;232:261-83. doi: 10.1007/164_2015_16. PMID: 26489827. Schatz, S.N., & Weber, R.J. (2018). Adverse drug reactions. British Medical Journal, 363. Introduction to clinical toxicology. Fre´de´ric J. Baud and Pascal Houze´ Teitelbaum DT. Introduction to Toxicology: Occupational & Environmental. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw-Hill; 2021. Accessed November 29, 2024. https:// accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx?bookid=2988&sectionid=250603950 Johnson AR, Brown KM. Principles of Clinical Toxicology. In: Brunton LL, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill Education; 2023. https://accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx? bookid=3191&sectionid=268044850 Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009 Mar;24(1):1-10. doi: 10.3904/kjim.2009.24.1.1. PMID: 19270474; PMCID: PMC2687654. Bowers DR, Tam VH. Application of Pharmacokinetics to Clinical Situations. In: Ducharme MP, Shargel L. eds. Shargel and Yu's Applied Biopharmaceutics and Pharmacokinetics, 8e. McGraw-Hill Education; 2022. https://accesspharmacy.mhmedical.com/content.aspx? bookid=3127&sectionid=264443549