Principles of Toxicology I & II 11 & 25 Nov 2024 PDF

PHARMACOLOGY AND TOXICOLOGY PRINCIPLES OF TOXICOLOGY I&II 11&25 NOV 2024 WO N G C H U N K E U N G 1 TOXICOLOGY Toxicology - The field of science that studies the harmful and adverse effects of chemicals, substances, physical agents or situations...

PHARMACOLOGY AND TOXICOLOGY PRINCIPLES OF TOXICOLOGY I&II 11&25 NOV 2024 WO N G C H U N K E U N G 1 TOXICOLOGY Toxicology - The field of science that studies the harmful and adverse effects of chemicals, substances, physical agents or situations, that have on living organisms, and the environment https://www.slideserve.com/chance/toxicology 2 UNDESIRABLE CONSEQUENCES OF DRUGS Adverse effects (or side effects) – Unwanted undesirable effects related to drugs – Vary from minor problems to life-threatening events such as liver damage, etc https://www.scirp.org/journal/PaperInformation?PaperID=83084 3 UNDESIRABLE CONSEQUENCES OF DRUGS (CONTINUE) Toxic Effects of Drug – Toxicity: Degree to which the chemical substance cause damage to an organism – Dose-dependent – Affect the entire system / specific organ in human body https://maken.wikiwijs.nl/100421/Drugs 4 AN EXAMPLE: DRUG-INDUCED LUNG DISEASE Drug-induced lung disease – Caused by different agents – Diseases range from adult respiratory distress syndrome to pulmonary fibrosis – Diseases can be caused by chemotherapy agents; immunosuppressive agents; cardiovascular agents; antibiotic agents, etc https://radiopaedia.org/articles/drug-induced-lung-disease-1 5 DRUG-INDUCED LUNG DISEASE (CONTINUE) Adult respiratory distress syndrome – Serious lung condition – Low blood oxygen – Fluid builds up inside the tiny air sacs of the lungs Pulmonary fibrosis – Tissue around alveoli thickened, damaged and scarred – Difficulty in breathing – Not enough oxygen in blood https://radiopaedia.org/articles/drug-induced-lung-disease-1 6 WHAT IS DRUG OVERDOSE? Taken more than the recommended amount of a drug Take a drug enough of having the harmful effect on body functions Taking too much of a substance Whether through prescription Legal or illegal Accidental or intentional https://srivatchanphd.blogspot.com/2015_07_01_archive.html 7 OVERDOSE ALSO OCCURS WHEN Overwhelmed with a toxic amount of a substance or combination of substances Involve different substances like medications, alcohol and other non-prescribed drugs May also involve herbal remedies 8 SYMPTOMS AND CONSEQUENCE OF DRUG OVERDOSE Application or ingestion of a drug in quantities greater than recommended Take a toxic (poisonous) amount of a drug or medicine. Symptoms Symptoms of drug overdose may occur rapidly Or individuals may experience a delay in symptoms of drug overdose Consequence Varies depending on individual situation Not all the situations of drug overdoses are life threatening or fatal Need to seek medical advice if overdose is suspected https://vitalfirstaid.com.au/news/what-to-do-if-someone-has-an-overdose/ 9 DRUG TOXICITY AND DRUG OVERDOSE Drug toxicity – Adverse effects brought about by drug use of therapeutic or non-therapeutic doses – Toxicity occurs after the accumulation of the drug Drug overdose – Taken more than the recommended amount of a drug, enough of having the harmful effect on body functions – Overdose may be on purpose for people attempting to end the life 10 DRUG-DRUG INTERACTIONS https://www.positivehealthwellness.com/diet-nutrition/the-all-in-one-guide-to-drug-interactions/ 11 WHAT IS DRUG-DRUG INTERACTIONS When the drug is taken together with a second drug and causing a change in a drug’s effect on the body Drug-drug interaction can result in either decrease, enhance or delay in absorption of either drug It may lead to increase or decrease in action of either or both drugs or cause adverse effects 12 DRUG ANTAGONISM Interaction between two or more drugs Have opposite effects on the body May lead to blocking or reducing the effectiveness of one or more of the drugs https://www.slideserve.com/zyta/drug-receptor-interactions#google_vignette 13 ACETYLCHOLINE AND NOREPINEPHRINE - DRUG ANTAGONISM ON BLOOD PRESSURE Acetylcholine on blood pressure Acetylcholine decreases blood pressure by stimulating vasodilation in resistance arterioles Norepinephrine on blood pressure Norepinephrine, or noradrenaline, plays an important role in the body's “fight-or-flight” response. Norepinephrine increases and maintain blood pressure in limited, short-term serious health situations 14 DRUG SYNERGISM An interaction between two or more drugs Causing the total effect of the drugs greater than the sum of the individual effects of each drug Drug synergism can be beneficial or harmful https://i.ytimg.com/vi/uCedXbih0es/maxresdefault.jpg 15 EXAMPLE OF DRUG SYNERGISM Aspirin and caffeine Good example of synergism With combination – giving greater efficacy and pain relief for patients with pain Without combination – Efficacy and pain relief not as high https://images.freshop.com/00310158109501/8078a2998a50df17d0df8d9fc55641d9_large.png 16 DRUG-FOOD INTERACTIONS https://medssafety.com/dangerous-food-drug-interactions-you-should-know/ 17 DRUG-FOOD INTERACTION The reaction between drug and food or beverage When food affects medications in the body – Food may affect the medicine in its proper working – May also affect the medicinal side effects Becoming better or worse Causing new side effects https://pharmafactz.com/wp-content/uploads/2016/02/important-food-drug-interaction.jpg On the other hand, the drug may change the way that the body uses food 18 COCA-COLA AND NSAID A significant increase in plasma concentration of ibuprofen when taken with Coca-Cola Showing an increased extent of absorption of ibuprofen Daily dosage and frequency of https://caogam.vn/sites/default/files/styles/anh_detail/public/2021-08/thuoc- nsaid_0.jpg?itok=8c90OOCo NSAID’s like ibuprofen should be well observed when Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines used for administered with Coca-Cola relieving pain, reducing inflammation, and bringing down a high temperature of the body 19 GREEN VEGETABLES AND WARFARIN Spinach is rich in vitamin K Vitamin K is important for the production of clotting factors that help prevent bleeding On the other hand, anticoagulants such as warfarin effects by inhibiting vitamin K Warfarin is clinically used for decreasing the tendency for thrombosis An increased intake of spinach thus may https://img.cndoct.com/upload/202112/17/202112171735256977.png prevent the warfarin from working 20 MILK AND TETRACYCLINES Milk, being the main component of dairy products, is rich in calcium Calcium can interact with certain antibiotics such as tetracyclines Tetracyclines may bind with calcium and forming insoluble substances The bioavailability of tetracyclines can be influenced Bioavailability refers to the extent a drug becomes completely available to its intended https://pngimg.com/uploads/milk/milk_PNG12726.png biological destination(s) 21 MATURED CHEESE AND PHENELZINE Mature cheese is the cheese product undergone with ripening process for a specific amount of time managed with temperature and humidity Aging cheese is important for changing the cheese's flavor and texture. As cheese ages, it loses moisture and concentrating its flavors Matured cheese contains the amino acid tyramine Tyramine interactions with phenelzine that is used for treating depressive disorders Eating mature cheese while taking phenelzine can raise the blood pressure to dangerous levels, causing life- threatening side effects Complications may included cardiac arrhythmias, https://www.pngmart.com/image/260742 cardiac failure, pulmonary edema, and death 22 GRAPEFRUIT AND STATINS Avoid eating grapefruit or drinking grapefruit juice while taking cholesterol lowering agents Such as statins: e.g. atorvastatin, lovastatin Grapefruit contain furanocoumarin chemicals causing an increase in statins potency Raising the level of the drug in bloodstream Increase the risk of side effects, such as leg pain and muscular weakness https://www.goodrx.com/classes/statins/why-cant-i-have-grapefruit- with-my-statin 23 MECHANISMS OF DRUG TOXICITY https://is4-ssl.mzstatic.com/image/thumb/Purple122/v4/86/06/53/8606534a-e202-e358-82a4-ed95261cbc1d/source/512x512bb.jpg 24  MECHANISMS OF DRUG TOXICITY Major drug toxicities commonly grouped into five categories on the basis of their underlying mechanism: On-target Hypersensitivity and immunological Off-target Biological activation Idiosyncratic 25 CLASSIFICATIONS IN THE CONTEXTS OF DRUG TOXICITY Type Example On-target Statins Hypersensitivity and immunological Penicillins Off-target Terfenadine Biological activation Acetaminophen Idiosyncratic Halothane https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ 26 MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Type Mechanisms Toxicity arising from interaction of the drug with the same target producing the desired pharmacological response Binding to its target is the same one On-target producing both the efficacious and toxic effects Difficult to handle since all classes of compounds developed to treat the disease may show the toxicity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ 27 MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Type Mechanisms Drugs (or their metabolites) react with proteins in the body (as haptens) to induce antibodies and immune responses Hypersensitivity and Haptens are small molecules eliciting an immunological immune response only when attaching to a large carrier such as protein; while the carrier may not elicit an immune response by itself 28 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Type Mechanisms Drugs may not be totally specific Drug is not specific in its interactions Off-target Binding to an alternate target is the cause of toxicity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ 29 MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Type Mechanisms Many drugs are converted to reactive products – Reactive metabolites These entities modify the proteins they react with and may cause toxicity One possibility - Some proteins are Biological activation modified and loss of function Another possibility - The modified proteins induce immune responses, linking with the second context of toxicity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ 30 MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Type Mechanisms Idiosyncratic means “unique to an individual” Not well understood Adverse events difficult to find even in Idiosyncratic large clinical trials Problematic as few animal models are very predictive https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707670/ 31 MECHANISMS IN THE CONTEXTS OF DRUG TOXICITY (CONTINUE) Example Functions of Drug Lower the level of low-density lipoprotein (LDL) cholesterol in the Statins blood Treat infections caused by bacteria by inhibiting enzymes involved in Penicillins building bacterial cell walls An antihistamine formerly used for the treatment of allergic Terfenadine conditions. Superseded by other drugs in the 1990s due to the risk of disruption of the electrical rhythms of the heart Acetaminophen A pain reliever and fever reducer Halothane A general anaesthetic used to induce or maintain anaesthesia 32 DRUG TOXICITY - A PROBLEM IN PHARMACOLOGY Toxicity is the topic of interest for almost all drug since Affecting patient care and management Leading to high cost of drug development Studies characterizing drug toxicity can be suboptimal with risk of incorrect conclusions Large number of pre-clinical toxicity (animal) and adverse events (human toxicity) cases 33 CELLULAR MECHANISMS OF TOXICITY Cell toxicity can be induced by both medicines and environment toxicant Main cellular toxicity mechanism includes: Mitochondrial Toxicity Reactive Oxygen Species and Oxidative Stress Reactive Metabolites Cell Cycle Mediated Toxicity Apoptosis Steatosis https://www.pngall.com/body-cell-png/ 34 MITOCHONDRIAL TOXICITY Inhibition of Protein Complexes Five protein complexes (Complexes I, II, III, IV and V) are located within the inner mitochondrial membrane and involved in ATP production Certain drugs, such as some antidiabetic and cancer drugs, etc are able to inhibit the protein complex Impair the mitochondrial ATP synthesis https://sitn.hms.harvard.edu/art/2018/mothers-mitochondria/ https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex- Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 35 MITOCHONDRIAL TOXICITY Inhibition of Mitochondrial Membrane Transporters Inhibition of transporters such as the adenine nucleotide translocator The proteins that exchange mitochondrial ATP for cytosolic ADP https://ohiostate.pressbooks.pub/app/uploads/sites/36/2017/07/Mitochondrion-structure-1536x783.jpg Cause substrate depletion and https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex- Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf reduced ATP production 36 MITOCHONDRIAL TOXICITY Inhibition of Krebs Cycle Enzymes and Fatty Acid Metabolism Inhibition of enzymes involved in the Krebs cycle (e.g., fluoroacetate) or Inhibition of enzymes involved in the fatty acid β-oxidation (e.g., tetracyclins) https://ohiostate.pressbooks.pub/app/uploads/sites/36/2017/07/Mitochondrion-structure-1536x783.jpg https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex- Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf Cause substrate depletion and reduced ATP production 37 MITOCHONDRIAL TOXICITY Inhibition of mitochondrial DNA (mtDNA) replication and mtDNA-encoded protein synthesis Some drugs (e.g., nucleoside reverse transcriptase inhibitors) able to – inhibit mtDNA replication or mtDNA-encoded protein https://ohiostate.pressbooks.pub/app/uploads/sites/36/2017/07/Mitochondrion-structure-1536x783.jpg https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex- synthesis Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 38 MITOCHONDRIAL TOXICITY Oxidative Stress An imbalance of free radicals and antioxidants in the body can leads to cell damage For example, depletion of reactive oxygen species (e.g., acetaminophen) Lead to activation of cell death https://ohiostate.pressbooks.pub/app/uploads/sites/36/2017/07/Mitochondrion-structure-1536x783.jpg signaling and apoptosis (a series https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex- Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf of molecular steps in a cell lead to its death) 39  MITOCHONDRIAL TOXICITY Mitochondrial Permeability Transition Pore Some drugs (such as some anticancer drugs) may induce irreversible opening of the pore Leading to influx of water and osmotic swelling Resulting in drug induced https://ohiostate.pressbooks.pub/app/uploads/sites/36/2017/07/Mitochondrion-structure-1536x783.jpg mitochondrial toxicity https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex- Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 40 REACTIVE OXYGEN SPECIES AND OXIDATIVE STRESS Reactive oxygen species (ROS) Derived from molecular oxygen Classified into two groups – Radicals (Chemical species with one unpaired electron) – Non-radicals (Hypochlorous acid, hydrogen peroxide, aldehydes, etc) ROS accept electrons from antioxidants Balance between ROS and antioxidants important for maintaining vital cellular and biochemical functions Balance tips towards an excess of ROS over antioxidants is known as oxidative stress – Lead to macromolecular damage Excess of ROS and oxidative stress can be detrimental to the cell https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 41 SOURCES OF ROS AND ANTIOXIDANTS Sources of ROS can be – Exogenous Drugs, food, pollutants and other chemicals – Endogenous – Through white blood cells Antioxidants – Compounds in foods that scavenge and neutralise free radicals https://www.researchgate.net/publication/349917055/figure/fig1/AS:962672996675591@1606530536654/Imbalance-of-antioxidants-and-ROS.png https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 42  TARGETS OF OXIDATIVE STRESS Lipid membranes Damage to cellular membranes DNA Modification of DNA bases Damage to deoxyribose sugar Proteins Damage to specific amino acid residues Changes in structure Degradation and fragmentation resulting in loss of enzyme activity https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 43  DRUGS CAUSE OXIDATIVE STRESS Drug Toxicity related to Oxidative Stress Doxorubicin Cardiotoxicity Cisplatin Nephrotoxicity and Ototoxicity Azidothymidine (AZT) Skeletal Myopathy and Cardiotoxicity Diclofenac Nephrotoxicity and Hepatotoxicity https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 44  ROLE OF REACTIVE METABOLITES IN DRUG INDUCED HEPATOTOXICITY Liver injury believed to be initiated by Bioactivation of the drug to chemically reactive metabolites Which can modify the function of various critical cellular macromolecules Able to cause direct damage https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 45  REACTIVE METABOLITE MEDIATED TOXICITY Can either be dose dependent (such as acetaminophen) where the toxicity is usually predictable, or Idiosyncratic (such as sulphamethoxazole and diclofenac) where the toxicity is unpredictable and dose independent Liver is the main organ involved in drug metabolism Chemically reactive metabolites targets the liver mostly in terms of toxic effects https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 46 MECHANISMS OF REACTIVE METABOLITE MEDIATED TOXICITY Drug metabolism usually acts to detoxify drugs Then facilitate their elimination from the body Occasionally certain drugs may undergo bioactivation to a reactive metabolite Which, if not adequately detoxified, binds to biological macromolecules (such as protein or DNA) Subsequently cause drug-induced toxicity https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 47 MECHANISMS OF REACTIVE METABOLITE MEDIATED TOXICITY The Hapten Carrier Hypothesis  Haptens are small molecular weight compounds that generally not immunogenic by themselves Need coupled to a larger molecule, such as proteins, to produce an immune response Reactive metabolites can bind to proteins and act as the haptens  Altered proteins are treated as foreign by body and induce hapten- specific antigen presentation by T cells and antibody production Direct cellular injury by the metabolite https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 48 DRUGS ASSOCIATED WITH HEPATOTOXICITY Drugs associated with hepatotoxicity include but not limited to: Acetaminophen - A pain reliever and fever reducer Carbamazepine - Anti-epileptic drug and to relieve certain types of nerve pain Clozapine - Used to treat certain mental and mood disorders Diclofenac - Non-steroidal anti-inflammatory drug (NSAID) Rifampin - Used to treat tuberculosis Terbinafine - Belongs to the group of medicines called antifungals Tacrine - Used to treat the symptoms of mild to moderate Alzheimer's disease https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 49 CELL CYCLE MEDIATED TOXICITY The primary function of the cell cycle: Duplicate DNA in the chromosomes and Segregate the copies precisely into two genetically identical daughter cells https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 50  CELL CYCLE MEDIATED TOXICITY There are 4 main sequential phases of the cell cycle: G1 Phase (first growth phase) S Phase (synthesis phase) G2 Phase (second growth phase) M Phase (mitosis phase) https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 51  CELL CYCLE MEDIATED TOXICITY There are 4 main sequential phases of the cell cycle: G1 Phase (first growth phase) – Allows cells time to grow and to prepare for DNA synthesis S Phase (synthesis phase) –DNA duplication and synthesis occurs during this phase G2 Phase (second growth phase) –Allows cells time to grow and prepare for mitosis M Phase (mitosis phase) –Chromosome segregation and cell division occur https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 52  CELL CYCLE MEDIATED TOXICITY There are 4 main sequential phases of the cell cycle: https://teachmephysiology.com/biochemistry/cell-growth-death/cell-cycle/ 53  CELL CYCLE MEDIATED TOXICITY The M phase is subdivided into several processes: Prophase – Nucleus chromatin begins to condense. Centrioles begin moving to opposite ends of the cell Metaphase – Spindle fibres align the chromosomes along the middle of cell nucleus Anaphase – Spindle fibres shorten and the paired chromosomes separate and move to opposite sides of cell Telophase – Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei. The spindle fibres disperse Cytokinesis – Cytokinesis results when cytoplasm of the cell is pinched into two daughter cells https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 54  CELL CYCLE MEDIATED TOXICITY The M phase is subdivided into several processes: https://www.cusabio.com/statics/images/Cell-Cycle-1.png 55  CELL CYCLE MEDIATED TOXICITY Progress through the cell cycle is monitored at the following key checkpoints: G1 (Restriction)-S Checkpoint – decision point on whether the cell should divide, delay division, or enter a resting stage S Phase (Replication) Checkpoint – checkpoint determines progression through S-phase G2-M Checkpoint – decision point on whether to trigger the start of the M-phase Metaphase (Spindle Assembly) Checkpoint – checkpoint ensures chromosome alignment and spindle integrity before proceeding through mitosis https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 56  CELL CYCLE MEDIATED TOXICITY Progress through the cell cycle is monitored at the key checkpoints These checkpoints have 2 main functions: Ensure that each stage of cell cycle is completed before progression into the next stage Detect and respond to DNA damage by delaying or arresting DNA replication and mitosis pending repair of the damage https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 57  CELL CYCLE MEDIATED TOXICITY Examples of drugs affecting the cell cycle include: Etoposide – Inhibits DNA topoisomerase II, with greatest effect at the G2-M checkpoint 5-fluorouracil - Inhibits thymidylate synthase, which blocks synthesis of the nucleoside thymidine, and so affects DNA synthesis at the S phase https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 58  APOPTOSIS Apoptosis is the process of programmed cell death Can be a beneficial process: – As a natural process to remove unwanted cells or – To remove detrimental process, such as that of autoimmune diseases, cancer or inflammatory disease The morphology of apoptotic cells, after activation of proteolytic enzymes, are – Cell shrinkage and rounding – Nuclear chromatin condensation – DNA fragmentation – Membrane blebbing – Cytoplasm appears dense – Cell eventually breaks apart into several vesicles – Engulfed by phagocytoic cells and removed https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 59  APOPTOSIS Mechanisms Involved in Apoptosis Complex and controlled by diverse range of extracellular signals (e.g., toxins, hormones, growth factors, nitric oxide, chemicals, etc) A cell receives stimulus normally undergoes organized degradation of cellular organelles by activated proteolytic caspases – Caspases are a family of site-specific proteases that play important roles in most apoptotic death pathways Two major signalling pathways leading to apoptosis – Mitochondrial Mediated (Intrinsic Pathway) – Receptor Mediated (Extrinsic Pathway) https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 60  APOPTOSIS Mitochondrial Mediated (Intrinsic Pathway): Mitochondria play a key role in apoptosis In response to cell stress, mitochondria initiate or enhance cell death signalling An induction of mitochondrial outer membrane permeabilisation – Allowing water and other molecules to enter the mitochondria – Swelling and rupture of the membranes and release of mitochondrial pro-apoptotic factors – The pro-apoptotic factors being released and cross the outer membrane – Induce apoptosis by caspase activation and DNA fragmentation https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 61  APOPTOSIS Receptor Mediated (Extrinsic Pathway): Initiated by the engagement of ligands with surface receptors Formation of the death-inducing signalling complex Activation of initiator caspases Both the two signalling mechanisms described above are controlled by a highly complex array of different stimuli and signalling pathways https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 62  HEPATIC STEATOSIS It refers to intracellular accumulation of lipids and formation of lipid droplets in the cytoplasm of hepatocytes Steatosis is associated with enlargement of the liver https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 63  HEPATIC STEATOSIS Mechanisms of Drug-Induced Steatosis Impaired Mitochondrial Function – Drug-induced steatosis involves the inhibition of mitochondrial fatty acid oxidation leading to impaired mitochondrial function – Several drugs such as glucocorticoids can induce steatosis – Glucocorticoids are steroid hormones produced from the cortex of adrenal glands, with role of glucose, protein and fat metabolism of the body Impaired Hepatic VLDL (very low density lipoproteins) Synthesis and Secretion – When liver function is normal, excess free fatty acids are esterified to triglycerides and then secreted in the plasma as VLDLs – Drug-induced impairment of this process is thought to be caused by inhibition of the microsomal triglyceride transfer protein – Tetracycline are thought to act by this mechanism https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 64  HEPATIC STEATOSIS Mechanisms of Drug-Induced Steatosis (Continue) Direct Activation of Transcription Factors involved in Hepatic Lipogenesis – Certain drugs can stimulate hepatic lipid synthesis – Examples of drugs act in this mechanism include tamoxifen (a selective estrogen receptor modulator used to prevent breast cancer ), and nifedipine (calcium channel blockers works by relaxing the muscles of the heart and blood vessels. It is used to treat hypertension) Insulin Resistance – Impaired insulin signalling can result in insulin resistance (where normal amounts of the hormone are no longer sufficient to facilitate transport of glucose into the cell). It ultimately leading to hepatic lipid accumulation and steatosis – Examples of drugs act in this mechanism include glucocorticoids and some antipsychotic drugs https://www.evotec.com/uploads/download-files/Downloadable_Publications/Cyprotex-Guides/Cyprotex-Mechanisms-of-Drug-Induced-Toxicity-Guide.pdf 65 ORGAN AND TISSUE TOXICITY Use of many drugs, particularly when used repeatedly, may lead to an accumulation of the drugs, or Harmful byproducts from the metabolism of drugs, in tissues or organs Resulting in the accumulation of toxic chemicals May lead to organ and tissue damage In extremely cases can lead to organ failure https://d20khd7ddkh5ls.cloudfront.net/tissue.png and death 66 ORGAN AND TISSUE TOXICITY https://image1.slideserve.com/2159450/drug-toxicity-in-various-organ-systems-l.jpg 67  ORGAN AND TISSUE TOXICITY What is the most common organ of toxicity? Central nervous system is the target organ of toxicity most frequently involved in systemic effects The blood circulation system, liver, kidneys and skin, etc may be the target organs 68  ORGAN AND TISSUE TOXICITY Which organ dies first before death? Once human stop breathing Brain & nerve cells: Require constant supply of oxygen and will die within a few minutes The next to go will be the heart Followed by the liver Then the kidneys & pancreas, which may last for about an hour Skin, corneas, tendons & heart valves may still be alive after a day 69 ORGAN AND TISSUE TOXICITY Liver and kidney toxicity Liver and kidney are particularly susceptible to organ toxicity As they are the sites of toxin filtration and toxin metabolic breakdown Being the organs responsible for metabolizing and excreting toxic chemicals, the liver and kidneys are most likely affected by toxins For example liver and kidney, like other organs or tissues in the human body, can be affected by antimicrobial toxicity https://www.lifelinescreening.com/wp-content/uploads/2021/10/kidney- – Due to the use of antibiotics, particularly liver-CRP1.jpg when used repeatedly 70 ORGAN AND TISSUE TOXICITY Liver absorbs toxins in the body Liver is the body's chemical factory Take up the materials absorbed by intestine and makes various chemicals needed for body function Detoxifies potentially harmful chemicals and numerous toxin Breaks down and secretes many drugs toxic to the body such as alcohol, nicotine, and https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/boo kshelf/thumbs/th-livertox-lrg.png prescription medicines These drugs have bad side effect of damaging liver cells 71 ORGAN AND TISSUE TOXICITY The organ of kidney: Kidney is highly susceptible to toxicants There is a high volume of blood flows through the organ It filters large amounts of toxins which can concentrate in the kidney tubules Nephrotoxicity is toxicity to the kidneys. It can result in systemic toxicity causing the decreased ability to excrete body https://upload.wikimedia.org/wikipedia/commons/0/01/Ki wastes dney_Cross_Section.png 72 ORGAN AND TISSUE TOXICITY The kidney can be damaged by: Poor blood flow Mitochondrial dysfunction Overload by high total level of toxins – Toxins may come from within, such as from an unhealthy gut – Toxins may come externally from many metals and chemicals https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718206/#:~:text=The%20kid ney%20can%20be%20damaged%20by%20%281%29%20poor,that%20are%20sp ecifically%20harmful%20to%20the%20kidney%20tissues. 73  SYMPTOMS OF TOXIC LIVER Fever Nausea Vomiting Jaundice Enlarged liver Right upper quadrant abdominal tenderness 74 SYMPTOMS OF TOXIC KIDNEY Loss of appetite Nausea Vomiting Shortness of breath Muscle cramps Swelling of feet and ankles  Urinating either too little or too much 75  WHAT DRUGS ARE LIVER TOXIC? Painkillers and fever reducers Include acetaminophen  A common cause of liver injury Particularly when Taking doses greater than those recommended Drink alcohol to excess 76  WHAT DRUGS ARE RENAL TOXIC? Antimicrobials such as: Aminoglycosides Antifungals (such as amphotericin B) Beta-lactams (such as cephalosporins, penicillins) Quinolones (such as ciprofloxacin) Rifampin (such as Rifadin) Vancomycin (such as Vancocin) Can lead to drug-induced acute renal failure 77 ORGAN AND TISSUE TOXICITY How toxins affect the organ of heart? Exposure to toxins may cause structural damage to the cardiovascular system and/or functional disturbances Chemical substances may produce adverse effects on the cardiovascular system by – Act on the myocardial cells or the autonomic nervous system and affect Heart rate Blood pressure or Cardiac contractility Cardiotoxicity make it hard for heart to pump blood, may lead to cardiomyopathy, a heart muscle condition makes it harder for the heart to pump blood 78  SYMPTOMS OF CARDIOTOXICITY Chest pain Dizziness Heart palpitations Shortness of breath Swelling and fluid retention (edema) in the legs Abdomen enlargement (abdominal distension) 79 WHAT DRUGS ARE CARDIAC TOXIC? Psychiatric medications: Some antidepressants Some sedatives Some neurological medications Damage the heart or increase blood pressure Illegal drugs: Cocaine Methamphetamine Increase heart rate and blood pressure damaging the heart 80 ORGAN AND TISSUE TOXICITY How toxins affect the Central nervous system ? Toxic damage to the nervous system occurs by the following basic mechanisms: – Direct damage and death of neurons and glial cells – Interference with electrical transmission – Interference with chemical https://www.researchandmarkets.com/reports/ neurotransmission 4856478/central-nervous-systems-therapeutic- drug 81  SYMPTOMS OF NEUROTOXICITY Dysfunction relating to the nervous system such as: Confusion Poor concentration Memory loss Personality changes Loss of sensation Muscle weakness 82  WHAT DRUGS ARE NEUROTOXIC? Examples of neurotoxic medications: Cyclosporine is an immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as rheumatoid arthritis Imipenem is a carbapenem antibiotic to treat a variety of infections Lithium citrate - Used as a mood stabilizer and for treatment of depression Examples of illegal drugs: Cocaine Amphetamines 83 TUTORIAL Causes Symptoms and Treatment of Drug Toxicity https://www.youtube.com/watch?v=CBCe-1Nrnkw B.C. Drug Toxicity Deaths Spike Again While Drug Testing Continues to Pose Challenges https://www.youtube.com/watch?v=eXRpisylBmA A Medicolegal Case of Drug Toxicity https://www.youtube.com/watch?v=zgVXMkiZ5bQ 84 PRINCIPLES OF TOXICOLOGY I & II 85