Toxicology Past Paper PDF

Topic 8 [ Toxicology] [Toxicology] - Toxicology deals with toxic effects (unwanted harmful effects) of drugs and other chemicals - **Poison:** Any substance, including any drug, that can harm a living organism - Almost all drugs have a threshold dose beyond which they become po...

Topic 8 [ Toxicology] [Toxicology] - Toxicology deals with toxic effects (unwanted harmful effects) of drugs and other chemicals - **Poison:** Any substance, including any drug, that can harm a living organism - Almost all drugs have a threshold dose beyond which they become poisonous - Even excess carbs -- have been proven to be a sweet poison - "What is there that is not poison? All things are poison, and nothing is without poison. Solely the dose determines that a thing is not a poison" -- Paracelsus - The incidence of serious and even fatal adverse drug reactions is estimated to affect about 2 million hospitalized patients very year in the US - About 100,000 of these are fetal - Adverse drug effects due to dosing errors affect as estimated 775,000 people each year and cost \$1.5 to 5.5 billion annually [Types of effects of drugs and chemicals] A diagram of effects Description automatically generated [Pharmacological toxicity] - **Pharmacological toxicity:** An extension of therapeutic effect due to an increase in the dose to toxic levels or an increase in duration of treatment - **Type A reactions:** Expected from pharmacological actions of a drug - Examples: - CNS depression produced by very high doses of barbiturates such as phenobarbital - A severe fall in blood pressure produced by very high doses of sodium nitroprusside - Extrapyramidal motor disorder (Parkinson-like muscle rigidity) produced by prolonged treatment with certain antipsychotics etc. [Pathological toxicity] - The toxic effect of certain drugs is manifested as pathological effects in the body - A classic example is the liver damage produced by acetaminophen overdose - Another example is the antifungal drug amphotericin B and the antibiotic gentamicin can cause nephrotoxicity [Genotoxicity] - Drugs, chemicals, and ionizing radiation damage the DNA and cause genotoxicity - Many cancer chemotherapeutic drugs are genotoxic - They are designed to damage the DNA of cancer cells and kill them, but they also damage normal body cells - Ex. Nitrogen mustards, nitrosoureas, alkyl sulfonates, cisplatin [Mechanisms of drug toxicity] 1. "On target" adverse effects are the result of drug binding to its intended receptor, but at an inappropriate concentration, with suboptimal kinetics, or in the incorrect tissue - Eg. Sedative side-effect of certain antihistaminics administered for allergies are due to H1 receptor binding in the CNS - Increased prolactin secretion and galactorrhea due to the antipsychotic drug haloperidol is due to inhibition of dopamine D2 receptors in the pituitary  2. "Off-target" adverse effects are due to drug binding to an unintended receptor - Eg. The cardiac Ikr (hERG) potassium channel is not very specific in its binding to drugs and inhibition of K+ currents by many drugs leads to cardiac arrhythmias including torsades de pointes and sudden death (all new drugs are tested for binding to this channel (hERG assay)) - Another common example of "off-target" binding is seen with B1 and B2 receptors when their agonists and antagonists are used for specific organ/tissue stimulation or inhibition A diagram of a drug Description automatically generated with medium confidence 3. Adverse effects (type B -- idiosyncratic or unexpected) mediated by the immune system -- hypersensitivity responses (allergic reactions) and autoimmune reactions - **4 types of hypersensitivity responses:** a. Type I: Immediate hypersensitivity or anaphylaxis - Mediated by IgE - Mechanism: Mast cell degranulation to which the antibodies bind - Upon first exposure, allergens stimulate B cells to produce IgE antibodies - These antibodies bind to mast cells - Upon subsequent exposures, allergens cross-link IgE on mast cells, triggering mast cell degranulation (the release of histamine and other inflammatory mediators) - Symptoms: Bronchoconstriction, vasodilation, and inflammation - Timing: Occurs within minutes of exposure - Ex. Penicillin b. Type II: Cytolytic reactions - Antibody mediated cytotoxicity - Mechanism: Lysis of certain cells in the body - Drug binds to cells (usually RBCs) and is recognized by an antibody (IgG) which causes cell lysis - Type II can cause anemia - Ex. Heparin-induced thrombocytopenia c. Type III: Immune Complex-Mediated Hypersensitivity - Antibodies (IgG or IgM) bind to soluble antigens and form complexes, which are deposited in tissues (kidneys, joints, etc.) where inflammation follows - Mechanism: A soluble antigen antigen-antibody complex is formed and then it can go and deposit in different organs or tissues and cause local inflammation at that site - The antigen and antibody are totally separate, not bound to anything - Then the antibody binds to antigen and forms a complex which is soluble so it can circulate and deposit anywhere in the body - Wherever it deposits it will cause inflammation locally - Ex. Serum sickness d. Type IV: Delayed type-hypersensitivity due to activation of T~H~1 and cytotoxic T cells - Mechanism: T-cell-mediated response - NOT mediated by antibodies (medicated by T cells instead) - Normally symptoms appear 48-72h after exposure to a drug - Ex. Contact dermatitis due to poison ivy, psoriasis, fixed drug eruptions, drug reaction with eosinophilia and systemic symptoms (DRESS) - Skin rashes following a drug, ex. the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening (SCARS -- severe cutaneous adverse reactions) are type IV - "Red man syndrome" is due to a direct effect of drug on mast cells causing degranulation without the mediation of IgE antibodies (pseudoallergy) [Poisoning cases stats from two countries]  [Common substances involved in poisoning] American association of poison control centers US 2020 data: - \>2.1 million human exposures - 42% of cases were children \