Toxicology Past Paper PDF

Inför tentan - Toxikologi What were Paracelsus theories? 1.Experiment is crucial - to understand how chemicals affect the body. Direct observation and testing is important to determine effects of toxicants 2. Distinction between therapeutic and toxic effects - a...

Inför tentan - Toxikologi What were Paracelsus theories? 1.Experiment is crucial - to understand how chemicals affect the body. Direct observation and testing is important to determine effects of toxicants 2. Distinction between therapeutic and toxic effects - a chemical can have both therapeutic and toxic effects, depending on how it is used. low dose - medication, high - toxic 3. Dose-dependent - dose makes the poison, all substances can be toxic in wrong amounts. 4. Specificity of effects - possible to identify specific effects of chemicals (toxic or beneficial), can be hard to identify. Mercury as treatment for syphilis, because of its antibacterial properties, despite its toxicity Confirming his theory , the right dose is therapeutic, despite toxicity. Which are the different types of dose responses? Linear - the effect increases proportionally with the dose Supralinear - the effect increases faster than dose Nonlinear monotonic (most common) - the effect increases or decreases with the dose (not constant) Nonlinear non-monotonic - the effect varies irregularly with the dose, increase or decrease doses. Hormesis - nonlinear relationship, low doses have beneficial effect, higher, harmful (u-shape) Threshold - no effects observed att low doses until threshold, after the effect increases linearly Binary - effect either on or off Terms LD50 (Lethal Dose 50%) - Dose that causes death in 50% of the test subjects. LC50 (Lethal Concentration 50%) - Concentration of a substance in air or water that causes death in 50% of the test subjects when inhaled or exposed. ED50 (Effective Dose 50%) - Dose that produces a specific effect in 50% of the test subjects. EC50 (Effective Concentration 50%) - Concentration of a substance that produces a specific effect in 50% of the test subjects. NOEL (No Observed Effect Level): The highest dose at which no observable effect occurs. NOAEL (No Observed Adverse Effect Level): The highest dose at which no observable harmful effect occurs. LOEL (Lowest Observed Effect Level): The lowest dose at which an observable effect occurs. LOAEL (Lowest Observed Adverse Effect Level): The lowest dose at which an observable harmful effect occurs. How does pKa and Kow affect the absorption? pKa - decide if a base or acid is charged/uncharged at a certain pH, and only uncharged molecules can easily pass the cell membrane. Kow - measure lipid solubility, indicate how well a molecule can dissolve in fat, high kow the easier to pass cell membrane and to be absorbed What is the difference between toxin, poisonous and venomous? Toxin - harmful when ingested, inhaled or in contact with. Poisonous - harmful when ingested or injected tex frogs Venomous - harmful when injected tex snake What does the exposure frequency depend on? - dose, time between exposure and time for metabolism, time for excretion Efficacy vs Potency Efficacy - maximum effect a drug can give, despite the dose. Potency - amount of dose to reach a desired effect. What is antagonism and what's the difference from agonsist? What type of antagonism are there and describe them? Antagonism - action of substance that block or reduces the effect of other substance Agonist - substance bind to receptor and activated it, mimicking the action of naturally occurring substance (hormone or neurotransmitter) Physiological, functional - two compounds with opposite functions (different receptors) reduce the overall response. Chemical - two compounds interact and reduce the reduce the response Dispositional - one compound alters distribution of another compound, By altering absorption, distribution, biotransformation , excretion. Receptor mediated - two compounds bind to the same receptor What are the main types of receptor-mediated antagonism? Competitive - both antagonist and agonist compete for the same binding site on the receptor, thereby blocking agonist, and no activation. Non-competitive - antagonists bind to different sites on the receptor, causing change in receptor that prevent agonist ability to activate. What is the difference between toxicokinetics and toxicodynamics? Toxicokinetics - (what the body does with the toxicant) Study of how a toxic substance moves and is processed in the body. To induce action of drug it must be present in a certain conc. Response could be good or bad. Toxicodynamics - (the effect of a toxicant) The molecular, biochemical, physiological effects of a toxicant and their metabolites in biological systems. The effects from interacting between toxin/metabolite and protein, enzyme, dna or a target molecule. What are the components of toxicokinetics (TK)? Absorption - How the toxicant enters by ex ingestion, inhaling, skin contact Distribution - How it spreads and reaches different tissues/organs? Metabolism - how the body chemically modifies toxicants, often in the liver, to metabolites to be easier to excrete. (can be less or more harmful) Excretion - how the toxicants/metabolites are eliminated from body (urine, feces, exhalation) In absorption, what are the routes and barriers? 4 types of routes: Enteral routes (GI) (3 slow) - oral - buccal (cheek/gum) - subliminal (under tongue) - rectal Parenteral (inject) (1 fast) - intravenous - in veins - intramuscular - into muscle - subcutaneous - under skin - intraperitoneal - i bukhålan Topical (apply) (4 slow) - skin, eye, ear, nose, lungs - vaginal - in vagina - rectal - in anus, in rectum - transdermal - affixed to the skin Inhalation (breathe) (2 fast) - mouth - nose Barriers: Cell membrane - regulate the passage for substances, lipid soluble substances pass easier. Cell wall - protect, need to pass to reach cell membrane (stomata, cuticles) Epithelial cells of GI - selective barrier to absorb chemical and nutrients in intestine to blood. Lipid soluble pass easier. Respirator surface - absorption of chemical, gas exchange Body surface - skin (barrier against chemicals), fur, fjädrar Physical barriers Plasma - blood component with protein that bind, transport and help distribution Intracellular fluid - fluid in cells, where metabolic process occur (limiting interaction) Intestinal fluid - fluid between cells, nutrient and waste exchange (transport,conc grad) Extracellular fluid - subdivided into plasma and Intestinal (transport, must cross cell membrane) How is a drug distributed? include first passage effect, enterohepatic circulation, bound drugs Drugs are transported in blood and intraintestinal fluid. Hydrophils move freely in aqueous environments but have difficulty crossing cell membranes, and vice versa. Important organs are The liver and kidneys for detoxification, liver is main biotransformation site and kidney one of main excretion sites First passage effect - drug is taken orally, it is absorbed by GI, transported to liver via portal vein before entering the circulation system. It reduces the amount of active drugs due to metabolic conversion in the liver. Important with dosing. Enterohepatic circulation 1. Drugs taken Orally and enter intestinal tract 2. May be absorbed from IT into portal circulation by hepatic uptake.(lipophilic can avoid (lymph system)) 3. travels to liver via portal vein, metabolized 4. Drug/metabolite are excreted into the bile and are stored until digestion 5. Released and reabsorbed in the intestinal tract, enter portal circulation again 6. Travel back to the liver via portal vein. Can be processed again, multiple times Bound drugs - drugs may be bound to plasma protein (ex albumin) making them inactive, bound drugs cannot pass cell membranes, interact with receptors. amount of drug bound is due to concentration, protein conc, affinity for binding sites Which are the different compartment models, and how do they eliminate drugs? One-compartment - body is treated as a single space, where drugs are distributed rapidly and evenly. Assumes that the conc in the bloodstream is the same throughout the body. Areelimated at a constant rate described by elimination rate (k), linearly. Two compartment: central compartment - includes blood, organs with high blood supply ( heart, liver, kidneys) peripheral compartment - tissues with lower blood flow, drugs distributed slower. Elimination occurs from the central compartment, drugs can move between compartments. K10 elimination rate from central compartment. K12/k21 rate constants representing transfer of drug between compartments. Tissue compartment - how drugs in detail distribute in various tissues (aspect of two compartment) vascular compartment - blood/ fluids in vessels interstitial compartment - fluid around tissues Intracellular compartment - fluid in cells Elimination is dependent on tissue-specific factors and may involve redistribution to the central compartment How do different organs/tissues store toxicants, and the effect of storage on toxicity? Fat as storage - lipophilic toxicants accumulate in fat rich tissues (easily dissolved). These compounds can remain stored in fat, long periods and released when fat is metabolized, can increase conc of toxicant in body Liver and kidney as storage - liver easily bind toxicants due to ligandin (protein), high affinity for organic acids and toxic chemicals. kidneys store metal ions by bindning them with metallothionein (protein), like zinc and cadmium. can prevent direct toxic effect but can accumulate to harmful levels Plasma proteins as storage - albumin , bind toxicants, and reduce free conc in blood, reducing toxicity, is reversible, and can cause delayed toxicity. Bone as storage - can store toxicant like fluoride, can replace hydroxide ions in bone matrix, can have long term effects as they are released slowly Effect of storage on toxicity - Lower ph accelerated excretion of weak bases, decreases excretion of weak acids, and vise versa for alkalization, influencing how toxicants are eliminated - increasing plasma pH cause weak acid toxins to move from CNS into plasma, reducing neurotoxic effects, and vice versa. What is the volume of distribution? Vd - describes the relationship between total amount of drug and concentration in the plasma. Gives an indication on how the drug is distributed in the body's tissues in relation to blood. High Vd - most distribution tissues, often lipophilic drugs Low Vd - most in blood, hydrophilic What is phase I and phase II regarding metabolism? Two phases of drug metabolism that help the conversion of drug/toxins into more hydrosoluble and easier excreted compounds Phase I - modify the chemical structure of a compound to make it more polar (water soluble). involves oxidation, reduction or hydrolysis. Most common is hydroxylation, performed by the enzyme cytochrome P450. As a result the compound is more reactive and redo for next step (sometime become more toxic) Phase 2 - conjugate (fästa) a polar molecule to an already modified compound from phase1. In phase 2 reactions are big and water soluble groups (like sulfat) added to the compound. makes it more water soluble. As a result the compound is inactive and soluble, to ease excretion via urine or bile. ex: methylation, acetylation, amino acid conjugation What is genetic polymorphism? Genetic polymorphism - two or more different alleles (versions) of a gene within a population. (variations in dna). These variations effects how people metabolites drugs, which have consequences for drug effectiveness and safety - Enzyme are involved in drugmetabolism, ex CYP450, they have genetic polymorphisms, can led to different levels of enzymes activity, meaning that the metabolism can be slower or faster - can lead to ineffective treatment due to too fast metabolism, or toxic effect due to slow - 4 types: poor, intermediate, extensive (normal), ultrarapid. Though which kinetic processes do excretion occur, why is it important, including half life? Kinetics refers to the study of rates at which drugs are eliminated from the body. Are 2 primary kinetic processes: Zero-order kinetics - the rate of drug elimination is constant and independent of the drug concentration. - Slope (-k), - conc vs time graph is linear - are no true half-time. First-order kinetics - elimination rate proportionate against drug concentration in blood. - elimination rate rise with drug increase - nonlinear, exponential decline - half-life is constant and independent of drug concentration Important - decide dose schedule, predict drug active in body, reassure drug levels are therapeutic Half life(t1/2) - the time it takes for conc of a drug in the body to reduce by half. important when determining the duration of drug action after single dose, influence time required to reach steady state, affect dosing. Calc: t1/2 =0,693/k What is clearance, referring to excretion, and what types are there? Clearance refers to the volume of blood in a defined region of the body that is cleared of a drug per unit time. Total body clearance is clearances from all organs (renal, hepatic, pulmonary). It varies due to body weight or degree of protein binding. Renal clearance involves: - Glomerular filtration. - Secretion from peritubular capillaries to the nephron. - Reabsorption from the nephron back to capillaries. What are the functions and structure of the liver including cell types? Structure: - largest gland in body, located below diaphragm and anterior to stomach - two lobes, which are divided into smaller lobules containing hepatocytes, bile canals, blood vessels - liver receives blood from hepatic portal vein (small intestine) or hepatic artery (lungs) - two liver ducts combine to form a hepatic duct which collects bile product in the liver, transport to duodenum. Functions: - Homeostasis - regulate blood sugar, lipid metabolism - Bile production - cholesterol formation - blood storage - plasma protein production - vitamin storage - hormone metabolism - Detoxification - remove harmful substance from blood and excreted via bile, kidneys  - regulatory: production of heat, regulation of lipid, amino acids, Cell types: Hepatocytes - perform detoxification, and concert compounds obtained from intestine (metabolic) is rich in lysosomes, granular endoplasmatic reticulum Duct cells - elongated cells with villi, epithelial tissue in bilegångar Ito Cells - store lipids, structural supporting function Endothelial cells - surround vein, arteries in liver, express most of the detoxification systems Kupffer cells - macrophages, contact with circulation, intrahepatic macrophages common, protect against infection. Sinusoidal cells (LSEC) -specialized endothelial cells makes border between blood cells and hepatocytes What are some liver diseases? Cirrhosis - formation of scar tissue because of a chronic liver damage, often alcohol or fatty liver disease. symptoms: jaundice, fatigue, and weight loss Cholestasis - condition where bile flow from the liver to the intestine is reduced or blocked, leading to bile acid accumulation in liver cells. Steatosis - Accumulation of fat (triglycerides) in liver cells. Can be caused by excessive intake of fatty acids, impaired breakdown of fats, or increased fat synthesis Necrosis - Cell death in the liver, often associated with inflammation or toxicity Hepatocellular carcinoma - cancer of hepatocytes What are the effects of ethanol and paracetamol on the liver? Ethanol - Causes 1.steatosis, decreased lipoprotein production, 2.fibrosis and 3.cirrhosis - Alcohol affects the detoxification system, down regulating enzymatic processes that metabolize toxins, leading to accumulation of reactive substances that can damage DNA and liver cells. - damage result in inflammation, and favorable carcinogenesis 1. ethanol is metabolized to acetaldehyde by ADH 2. is converted to acetic acid by ALDH - ALDH inactive there is accumulation of acetaldehyde - ANTABUS block ALDH - acetaldehyde causes nausea Paracetamol - metabolized to non toxic metabolites, but if CYP2E2 enzyme is active (like under ethanol metabolism) it will be toxic metabolite - GSH is antioxidant, neutralizing this toxic metabolite, If GSH levels are reduced, toxic metabolite accumulates = liver damage What are microbial toxins, what different types are there? What are the mechanisms? Give examples. Microbial toxins are substances produced by microorganisms such as bacteria, fungi, algae. They are not living , cannot replicate, or spread. They are harmful byproducts that can cause damage. Resistant to antimicrobial agents, just kill the microbe not toxin. Fungal toxins (mycotoxin) toxic secondary metabolites produced by fungi. Are chemical messengers that influence biological processes. Effects: - Carcinogenic - cancer - Hepatotoxic - liver damage - Nephrotoxic - kidney damage - Teratogenic - developmental abnormalities - Neurotoxic - brain and NS damage Ex: Aflatoxin - produced by Aspergillus spp - found in nuts, grain, spices - 14 types, B1 most toxic - Mechanism: Aflatoxins are metabolized in the liver into reactive epoxides, which interact with dna , lead to mutations (p53 gene - prevent cell cycle regulation = cancer). Protist toxins - produced by marine algae, are environmental toxins harmful for both humans and marine life. Associated with harmful algal blooms (red tides) Ex: Saxitoxins - Produced by Marine dinoflagellates, freshwater cyanobacteria - found in shellfish during algal blooms - Paralytic shellfish poisoning: numbness, tingling, paralysis, severe: respiratory failure, death. Mechanism: saxitoxin blocks voltage-gated sodium channels in neurons, preventing nerve signal transmission and leading to paralysis. Bacterial toxins - produced by bacteria, Two groups: exotoxins and endotoxins (liposaccharides in cell wall, released when death of bacteria) Exotoxins: 1. cytotoxic toxin, 2. Cytolytic toxins, 3. Superantigens - Cytotoxic - act on intracellular targets, AB toxins with a A domain (enzyme that disrupt host cell function) and B domain (bind cell receptors, allow entry for A) Ex: Cholera toxin - Produced by Vibro cholerae - diarrheal disease, contaminated water - Mechanism (ADP-ribosylating toxins): b bind to receptor on intestinal epithelial cells, A enter. A transfers a ADP-ribose to Gs component of g-protein coupled receptor, leading to increased cAMP levels, which activate ion channels and secretion of chloride ions in intestine, water and NA+ follow chloride, learning to cause diarrhea - Cytolytic - damage cell membrane, learning to lysis and death. Cytolysins damage nucleated cells by affecting cell membrane and leakage. Ex: RTX toxin - Gram Negative bacteria - consist of toxins and cytotoxins - destabilizes the membrane - has repeated sequences in protein structure. - ex: hemolysin produced by E.coli. - Superantigens - causes excessive activation of the immune system by bypassing the normal antigen presentation pathway. Overstimulation leads to immune responses like inflammation, multi-organ failure.  Ex: Toxic shock syndrome - - TSS toxin- 1 produced by staphylococcus aureus - mechanism: bypass antigen pathway , by being processed into small peptides and presented to T cells, result in activation of a large amount of t cells. - without target it will attach body Explain the cell cycle and how it is regulated? Include DNA repair mechanisms, what happens if DNA repair is ineffective? https://www.youtube.com/watch?v=nEMMKzYQf9A Cellcycle: stages that cell go through to grow and divide Interphase - G1 phase - cell prepares for dna replication by growing, producing proteins, synthesizing organelle - S phase - DNA is replicated, resulting in two copies of each chromosome. - G2 phase - The cell continues to grow and prepares for division by repairing any DNA damage Mphase - division of the cell’s nucleus and cytoplasm, resulting in two daughter cells G0 phase - resting phase Regulation of CC: Regulated by cyclins, CDK, tumor suppressor like P53 Cyclins - regulatory proteins that are active in different phases of cycle.’ CDK - enzymes that is activated by cyclins, phosphorylate target proteins to drive CC P53 - guardian of genome, detect dna damage and other stresses, If detected p53 activation and induce cell arrest, dna repair (p21- inhibits CDK), apoptosis, senescence (premenat arrest) Checkpoints: - late G1 - ensure cells ready for DNA replication - late G2 - ensure ready for mitosis - Middle M - ensure chromosomes are attached to spindle before anaphase. Dna repair mechanisms Proofreading - DNA poly correct errors during dna replication Mismatch repair - correct mismatched base pairs that escape proofreading Excision repair: BER - fix small mon helix base lesions, NER - remove bulky, helix lesions (thymine dimers) Mutations - mutations in regulatory genes - cancer - mutations in germ cells - genetic disorders Types of mutations: Base-pair mutation - transition - changes purine against purine, or pyrimidine -//- - transversion - changes purine against pyrimidine, vice versa Deletion - one/more nucleotides removed Insertion - one/ more added Frameshift mutations - missense - changes of amino acid - nonsense - changes codon into a stop codon  - Read through - ribosome still reads instead of stopping at stop codon Types of lesions Missing base - acid and heat Altered base - ionizing radiation,alkylating agents incorrect base - spontaneous deamination Deletion-insertion - acridines (mutagenic) dimer formation - uv strand break - chemicals, ionizing radiation interstrand crosslinks - chemical agents psoralen, mitomycin C tautomer formation - spontaneous and transient (temporary) Explain the stages of neoplasia and how they interact to result in the formation of cancer. Neoplasia - process where cells begin to grow uncontrollably, eventually learning to tumor, cancer 1. Initiation - dna damage occurs, often formation of dna adducts, mutations or deletions that alters the dna sequence. Irreversible because the genetic changes permanently alter cell dna. 2. Promotion - the altered cells are stimulated to grow and divide, reversible because it involves changes in gene expression rather than permanent genetic alterations. If promoting factors are removed, growth can be halted. 3. Progression - further genetic changes that affect chromosomes, develop aggressive and malignant tumors. irreversible and enable cells to invade surrounding tissues and spread, forming metastases. Discuss the role of proto-oncogenes, oncogenes, and tumor suppressor genes in cancer development. Proto-oncogenes - normal genes important in growth and division, when these undergo mutation, they become oncogenes, promote uncontrolled cell growth (tumor formation) Oncogenes - mutated visions of proto-oncogenes that drive transformation of normal cells into tumor cells after reregulation (disrupt normal control of genes). These contribute to cancer by allowing cell to proliferate uncontrollably, bypassing normal regulatory mechanisms Tumor suppressor - protecting cells from progressing toward cancer. Function by regulating cell growth, repairing dna damage, apoptosis. Loss of function in these genes can remove checks, allowing cancer. tex P53 Describe the role of chemical carcinogens, such as PAHs and TPA, in the process of carcinogenesis. How do phase 1 and phase 2 metabolic reactions influence cancer risk? Chemical carcinogens - substances that can lead to cancer by causing mutations or alterations in dna. Can be found in tobacco smoke, chemicals, food, pollutants. Once entering it can interact with DNA , leading to changes in growth and result in cancer. Complete carcinogens - type of chemical carcinogens that have the ability to initiate and promote development of cancer. Partial carcinogens only do initiation or promotion. Ex:  - PAH - potent initiators in carcinogenic processes, cause mutations and damage, both initiator and progressor of cancer. Mutations by PAH are irreversible, and sets a stage for uncontrolled cell growth. - TPA - tumor-promoting substance (phorbol ester group), not directly carcinogenic unlike PAH, but promotes tumor growth after initiation. TPA activates enzymes that mickins effects of DAG, activator of PKC, TPA can alter cell behavior, protote growth, survival, and contribute to tumor development. Phase 1 - phase 1 create highly reactive molecules that are not detoxified in phase 2, change that metabolites create covalent binding with dna which increase mutations and cancer risk. Some metabolites can make dna adducts by reacting with dna, (mutation and cancer) Phase 2 - effective phase 2 reaction is crucial to prevent cancer because it helps eliminate potential harmful metabolites before they interact with dna. If P2 is reduced it can contribute to cancer development How do chemical processes such as alkylation, free radical formation, and UV damage contribute to DNA mutations. Discuss the challenges posed by processes like deamination, methylation, and depurination. Alkylation - chemicals like tobacco smoke, can alkylate dna by adding alkyl groups (metyl-, etyl-) on bases. It can disrupt normal base pairs and lead to mutations. CYP450 help breaking down chemicals Free radical formation - created by UV and cell metabolism,are reactive and can cause dna damage like conversion of thymine to thymine glycol (disrupt dna function) UV - cause dna damage like base damage, single strand brek, double strand break ex: when two thymine-pasepair bind together which can lead to mutations Deamination - removal of amino group from nucleotide (A-C), lead to mutations, many chemical agents include deamination Methylation - adds methyl group to dna bases, cytosine → 5 metylcytocine. high levels of methylation can silent genes like tumor suppressor, low can activate genes. Environmental toxins alter methylation patterns, which contribute to carcinogenesis. Depuration - loss of purine bases from dna strand, leading to gap, can result in mutations. carcinogens increase depurination rate, increased dna damaged. How do epigenetic mechanisms influence gene expression, and what role do environmental factors, such as pesticides and heavy metals like cadmium, play in epigenetic toxicology? Discuss how these factors may contribute to diseases like Non-Hodgkin's lymphoma and diabetes Epigenetics - include regulation of gene expression without altering underlying DNA sequence. Determine which genes to be active/inactive. Epigenetic toxicology - studies how environmental and chemical factors affect epigenetic mechanism, leading to toxic effects and disease Pesticides/ non hodgkin's lymphoma - pesticides has been linked to increase risk of lymphomas (blood cancer), pesticides can cause dna damage leading to genetic alterations and gene translocation, chromosomes swap place, can lead to overexpression of antiapoptotic proteins = tumor growth Cadium - heavy metal that cause dna breaks, trigger repair mechanisms, PARP-1 activated and releasing ADP-ribose, leading to signs of diabetes Explain the impact of transposons and retrotransposons in the context of environmental exposure and cancer risk? Transposons - DNA sequences that can change positions within the genome. Can disrupt normal gene function by inserting into or near essential genes, leading to mutation and altered gene expression. Pollutants, carcinogens can activate transposons Retrotransposons - replicate themself and insert copies at various locations within the genome, regulated by enzymes like reverse transcriptase. Increased activity can lead to genomic instability (disrupt tumor suppressors, activate oncogenes)and altered gene expression Dna transposons - move through cut and paste mechanism, facilitated by enzyme transposase What is reproductive toxicology, and what are the target sites for toxins? What are the alternatives for testing? Reproductive toxicology - structural, functional changes that affect the reproductive system of mature men and females. Target sites - gonads, endocrine glands (hormone production),reproductive tract, placenta (can cross placenta barrier), embryo. Adverse outcome pathway - describe biological events that occur for when an organism has been exposed to chemical to negative effects appear. Techniques: molecular docking and in vitro binding assay to simulate interaction without using animals. - Molecular initiating event - involves study of how a chemical interacts with specific biomolecules, like protein or DNA. - Key events - biological events - Adverse outcomes - can be harmful Traditional Biological Analysis - involve studying whole organisms or organs to understand biological processes. using 3D cultures to mimic human tissues. Molecular and Cellular Analyses - involve the molecular and cellular mechanisms behind biological processes. Techniques like DNA sequencing (DNA-seq), Polymerase Chain Reaction (PCR), and cell cultures. What are the disturbed gonad development diseases? How do they occur? Hypospadias - in males, urethral opening is located somewhere along the underside of penis. Due to incomplete development, often linked to exposure to chemicals, like EDC endocrine-disrupting chemicals, which interfere with androgen signaling, which is crucial for male development Cryptorchidism - one or both testes fail to descend into the scrotum before birth, testes develop in the abdomen and descend later. Due to disruption in hormone signals, like genetic mutations,smoking,chemicals (endocrine disrupter interfere with hormones responsible What is developmental development and why do toxins cause defects? Include toxic windows Developmental toxicology - studies of the adverse effects that environmental agents have on developing organisms. toxins cause defects by timing of exposure in certain stages (toxic windows, when it is particularly sensitive to disruption.depending on exposure time it will affect different things, early - structural, late organ/growth. Describe how exposure to teratogens can lead to specific developmental toxicities, highlighting the types of changes (Type 1 and Type 2) observed. Teratogenesis - process in which birth defects or malformations occur due to exposure to teratogenic agents during pregnancy. Their effects depend on toxic windows Type 1 changes - permanent - life threatening - few live births - more stillbirths - more resorption (fewer embryo survival) - more malformed fetuses Type 2 changes - non permanent - reduced birth weight - less postnatal survival (some not survive) - impaired growth, reproductive capacity ex of teratogens: thalidomide - limb deformities, disrupt blood vessel formation, dna damage, growth regulation DES - cancer risk daughters, testis abnormalities - genetic ethanol - retardation, facial anomalies,reduced intelligence, disrupt cell signaling, brian development pesticides - food, water, airborne, interfere with processes, endocrine function. Which are the inner barriers vs the other barriers for toxic substances? Outer Barriers: Inner Barriers: GI-system Cell membrane Lungs BBB - blood brain barrier Skin Placenta barrier Testis blood barrier What is the structure of the GI tract, including the layers and gut barriers? Discuss the defense against ingested toxins, For exemple metals Gut barriers - Microbial barrier - huge collection of beneficial microbes, maintain gut health - Extracellular barrier - goblet cells secrete mucus, trap pathogens - Functional barrier - control of motility, secretion, absorption  - Immunological barrier - immune cells (lymph nodes, phagocytes, TLR, paneth cells, dendritic cells) recognize and respond to pathogens. - Gut-vascular barrier - cells and junctions that regulate exchange between gut lumen and blood vessels (pericytes, enteric glial cells, tj and adherens j) - Liver barrier - kupffer cells (macrophages), stellate cells that detoxify substances absorbed from gut before entering circulation - Epithelial barrier - goblet cells (mucus-producing), enterocytes (absorptive cells), tj, adherens j, maintain integrity of epithelial lining and regulates permeability Defense 1. avoidance - taste smell help avoid potentially harmful substances 2. Nausea, vomiting - immediate reaction to expel toxins 3. CNS detection - brain detects and triggers vomiting 4. Diarrhea - reduces time toxin remain in body Metals from meat - directly absorbed (Fe2+) Heme iron Metals from plants - oxidized, less absorbed (Fe3+) Non-Heme iron Such as lead, cobalt, strontium, manganese, and zinc, use the same transport proteins as non-heme iron to enter the body. If you consume high levels of one of these metals, they may outcompete others, reducing their absorption What is the difference between RS and GI regarding toxins? What is hygroscopicity and how does it affect particle deposition in the respiratory tract? GI - absorption is heavy dependant on the chemical properties of the substance, acidic, basic or lipophilic, charged ions RS - absorption faster due to thin squamous epithelial, less important with chemical properties Hydrosopcity - particles ability to absorb moisture from the environment. High humidity - particles absorb moisture, large size - less likely to remain suspended in air,reduce airborne suspension - trapped in upper RT (mucus of nose, upper airways) Low Humidity - absorb less moisture, smaller - enhance dispersion - deeper penetration of RS - increased inhalation expose - can cause more damage due to reaching lower What are the mechanisms of airborne particle deposition in RT? Impaction - particles inertia (tröghet) make them change direction when they encounter an obstacle or change in airflow. Larger more inertia, more likely to impact and deposit Sedimentation - particles denser than air is affected by gravity, heavy particles tend to settle out of airflow when reaching alveolar level Diffusion - small particles (0,5 microm) experience random collisions with gas molecules, causes them to diffuse through air, can reach deeper Electrostatic attraction - positive or negative charged particles can deposit in RT through electrostatic attraction. Attract or repel each other/surfaces Interception - deposit particles when in close contact with surfaces like cilia and walls of bronchi. Important for fibers and elongated particles that can be intercepted even if they follow airflow. How are the airways cleared? video Upper RT. nasal hairs, sneezing Middle RT - mucociliary escalator Lower RT - Alveolar macrophages, dissolution, uptake by vascular system. Mucociliary escalator - mechanism of bronchi, bronchioles and nose to clear inhaled particles and pathogens, move upward throat - goblet cells - prince mucus to trap foreign microbes and particles. Mucus composed of two layers: sol layer - thin fluid layer under the gel allow cilia to move freely gel layer - thick, sticky layer to trap pathogens, contain antibodies, chemicals, immune cells. - epithelial wall, contain cilia, work forward stroke (contact gel and push mucus up) and backstroke ( move back, allow easier moving during forward stroke. Coughing - irritation in the airway, coughing helps expel mucus, particles, pathogens in RT. Alveolar macrophages - called dust cells, white blood cells that reside in pulmonary alveoli and interalveolar septum. first line of defense in lower RT, engulfing, digesting particles, pathogens that reach alveoli What are the ways of absorption through skin and the routes of drug absorption? Explain stratum corneum. 1. Through epithelium: epidermis, particular through stratum corneum allow substances to pass into deeper layer of skin Stratum corneum: - highly selective, meaning size, polarity, solubility has a role in how well it will penetrate the skin. - dead, keratinized cells - main physical barrier to penetration 2. Through glands: ex sweat glands, substances diffuse into these glans, less significant due to small surface area. - Intercellular route: lipophilic drugs move between the cells (stratum corneum). dissolve in lipid matrix between th cells. - Transcellular route: hydrophilic drugs move through the cells, drugs must cross lipid layer surrounding cell and aqueous environments inside cell, Fewer use this route What are the barriers of the skin? - Microbiome layer - microbes, for protection, skin health - Chemical barrier - moisturizing factor (urea, electrolytes, lactate), low ph(inhibit growth of pathogens), lipids (prevent water loss, protect against irritants), peptides (defend) - Physical barrier - langerhans cells, adherens j, tight junctions, t-cells  - Immune barrier - ILC, Mast cells, dermal, macrophages, iNKT cell, Dermal DC; Tcells What's dermal toxicology and what is the difference between irritants and corrosion? Dermal toxicology - study effects of substances in contact with skin. Irritation - mild, skin response after exposed to chemical, like gasoline, only affects upper layers, reversible Corrosion - severe reaction that lead to damage to skin, underlying tissues, ex strong acid, bases, affect deeper layer, long time to heal. What factors influence the ability of toxicants to penetrate the blood-brain barrier (BBB), and what role do astrocytes play in maintaining this barrier? BBB - selective protective barrier between the blood and the brain (CNS) Factors that affect ability to penetrate barrier: - Small molecules, easy to move between tight junctions - Lipid solubility, easy to cross BBB because of lipid bilayers. - Charge - neural and nonpolar pass easier, because that charged molecules attract more water - Transport mechanism - some require transport proteins making it harder to penetre - Efflux pumps - pumps toxic substances out of brain - Protein binding - toxicants bound to plasma proteins cannot cross BBB only free can diffuse Astrocytes - glial cells that remain integrity of BBB by regulating what substances to pass from blood into neural tissue. Maintain TJ, regulate blood flow (interact with vessels, neuron), detoxification (metabolize toxins) How do neurons meet their high energy demands for conducting electrical impulses, and how can toxicants like cyanide disrupt this process, leading to impaired axonal transport and neurotransmission? High energy demands - can conduct electrical impulse, done through aerobic metabolism in mitochondria, produces ATP, which is essential for maintenance ion gradients, axonal transport, neurotransmitter release. Toxicants (cyanide) - inhibit aerobic respiration by acting on mitochondria, lead to hypoxia, resulting in dysfunction in neurons. What is the structure and function of a neuron? and explain axonal transport. Neuron - lead electric impulses over long distances to fast react to environmental stimuli. Uses action potentials to lead these impulses, coveted into chemical signals at synapse. Structure: - Cell body - nucleus - Dendrites - receive signals - Axon - conduct electrical impulses - Synapse - site where neurotransmitters are released - Myelin sheath - insulates the axon - Node of ranvier - gaps in myelin, faster signal - Schwann cells - produce myelin, repair damage axons in PNS Axonal transport - move proteins/organelles between cell body and axon terminal Anterograde transport - (cell body to axon term) materials synthesized in cell body, processed in golgi and packed into vesicles, they travel along microtubules of the axon, mediated by kinesin Retrograde Transport - (axon term to cell body) neurotransmitter released, some vesicles recycled and transported back to cell body, mediated by dynein moving vesicles along microtubules. Neurotransmission - neuron communication, done through synapse, neurotransmitters (chemical messenger) released from one axon to cleft by action potential reaction terminal of presynaptic neuron. then bind to receptor of membrane of post neuron (second messenger) How can exposure to environmental neurotoxicants, such as lead or MPTP, contribute to the development of neurodegenerative diseases, and what role do genetic and epigenetic factors play in this process? Environmental neurotoxicants - can contribute to development of neurodegenerative diseases by causing long term, low dose neurotoxic effects ex: Lead Effects - brain damage leading to learning delays, cognitive deficits, children developmental issues Epigenetic changes - can alter dna methylation patterns which disrupt gene expression, which can lead to alzheimer later in life ex: MPTP Effects - induces parkinsonism by destroying dopaminergic neurons, mocking symptoms of parkingsons Genetics - certain genetic profiles are more susceptible to neurotoxicants exposure. ex those with specific mutations in genes related to oxidative stress/neural repair could be more vulnerable to neurodegenerative effects Epigenetics - environmental neurotoxicants can trigger epigenetic modifications (dna methylation, histone modifications) learning to dysregulated processes. Can alter expression but not dna , promoting neurodegenerative disease. What are some injuries caused by neurotoxicants (inc neuropathies, axonopathies and myelopathies) and what are the mechanisms of action? Give examples Neuropathies - disorders affect the PNS and CNS, resulting in damage to nerves, learning to weakness, sensory loss, autonomic dysfunction. Affect: directly, learning to apoptosis or necrosis or induce inflammatory responses Ex: lead induce oxidative stress and disrupt calcium homeostasis Organophosphates overstimulation of cholinergic receptors Axonpathies - damage to axons, may lead to axonal degeneration while preserving the neural cell body. Affect: disrupted axonal transport leading to accumulation of materials and delayed degeneration or trigger calcium influx causing cellular dysfunction axon damage. Ex: methylmercury sensorimotor deficits due to axon damage through calcium-mediated hyperexcitation and oxidative stress. Acrylamide cause distal axonopathy trough axonal swelling, disruption of neurofilament structure Myelopathies - damage to myelin sheath, can slow nerve impulses conduction and lead to neurological deficits. Affects: breakdown of myelin sheath, affecting transmission of impulses. can cause swelling within myelin layers leading to loss insulation and signal propagation. Ex: carbon disulfide lead to demyelination and neurological deficits Lead myelin damage leading to cognitive, motor dysfunction through oxidative stress and inflammation How do the kidneys work? Kidney function - to maintain homeostasis and eliminate waste products - Filtration blood from metabolites - Regulate water balance by adjusting amount of water reabsorbed - Regulate osmolarity by controlling concentration of solutes in blood - Regulate levels of electrolytes (sodium, potassium, calcium) - pH regulation - Excretion of metabolites, toxin, drugs - Secretion of hormones like renin (blood pressure) - synthesize glucose from non carbon sources. Why are the kidneys so susceptible to toxins? High blood flow - exposing them to large volume of circulating substances including toxicants contration function Concentration function - kidneys absorb water which can concentrate toxins and increase local exposed to toxins High metabolic activity - kidney has high energy demand and contain CYP450 enzyme involved in drug metabolism, making them susceptible to toxicants High oxygen consumption - outer medulla of kidneys is sensitive to hypoxia due to delicate balance between oxygen supply and consumption Large endothelial surface - increase interaction with toxicants (uptake) Enzyme systems - kidneys can convert drugs into reactive or toxic metabolites Transcellular transport - active transport facilitated accumulation of toxins within kidney cells Protein unbinding - impaired renal function may lead to unbinding of toxicants from plama proteins allowing free toxicants to exert harmful effects How is renal toxicity induced (mechanisms)? 1.Inducing acute (fast) or chronic (slow) responses 2.Accumulation - toxic substances build up in kidneys, not effectively eliminated from body 3.Accelerators - factors can increase risk of kidney damage when exposed to toxins Hemodynamic alterations - changes in blood flow and circulation through the vascular system, can impact kidney function. - Kidneys rely on adequate blood supply to filter blood and produce urine effectively. Alterations can affect glomerular filtration rate (GFR), the rate at which blood is filtered. - Autoregulation: can maintain stable GFR despite alterations in blood pressure by adjusting the diameter of afferent and efferent arterioles - afferent - vasodilation (större), more blood in, induce by prostagladins  - efferent - vasoconstriction (narrowing) to maintain pressure in glomeruli, induced by angiotensin II What are the symptoms? -Azotemia - condition characterized by elevated levels of nitrogenous waste product in blood Prerenal - caused by reduced blood flow to kidneys ex dehydration, heart failure Renal - due to direct damage to kidney tissue ex kidney failure, glomerulonephritis Postrenal - result from obstruction (blockering) in urine flow, ex kidney stones, tumors -Changes in urine production -Swelling -weakness - vomiting Drug detoxification?, CYP450 Drug detoxification - metabolic process that converts drug toxins into less harmful substances, often in liver CYP450 - enzymes that facilitate oxidation of organic substances making drugs more water soluble and easier to excrete. What are common neurotoxicants? Aminoglycoside antibiotics - can cause necrosis of tubular cells Metals - induce damage by ischemic effect Cyclosporine - indirect renal damage through vasoconstriction Amphotericin B - affect renal blood flow and have toxic effects Ethylene glycol - metabolites can induce metabolic acidosis and kidney damage What is steroidogenesis? Steroidogenesis - steroid hormones are synthesized from cholesterol adrenal gland/gonads. Steps: - cholesterol obtained - cholesterol to pregnenolone - pregnenolone can be converted to: progesterone, cortisol, aldosterone, testosterone and estrogens - complete steroid hormone are released in blood, bind to transport protein and carry out function What are the some proteins involved with endocrine toxicology and their mechanism of action? Chaperone proteins - help folding, transport of other proteins. Protect against misfolding and secure a correct 3D structure. Mechanism: - chaperones bind to synthesized unfolded proteins preventing misfolding - help fold correct by producing conducive environment - in cases of misfolding, they assist in refolding denatured proteins, unsuccessful they target these proteins for degradation G-proteins - bind to GTP, two stages active (bound to GTP) or inactive (bound to GDP). Activated G protein can interact with enzymes , ion channels, leading to cellular responses Like increased cAMP. Also regulates hormonal pathways What types of competition for binding between substances are there? what are their effect on Vmax and Km Competitive - compete for the same binding site on enzyme or receptor (both inhibitor and substrate) Vmax - no change because if substrate conc is high enough, it can outcompete inhibitor Km - reduced , indicating higher affinity of enzyme for substrate. Non competitive - inhibitors bind to different sites than substrate on the enzyme/receptor. Does not compete directly. Vmax - is reduced because the inhibitor effectively lowers the number of active enzyme molecules, regardless of substrate conc. Km - unchanged, initiating affinity of enzyme for substrate does not change, can bind to active site still. What are EDS and what are their functions? EDS (endocrine disrupting substances) - chemicals that interfere with the hormone system, leading to negative effects on development, reproduction, neurological functions Functions: 1.Receptor activators (agonist) - EDS can act as agonists meaning they bind to receptors and activate them, causing a response. ex: Bisphenol A, chemical that mimics estrogen by binding to estrogen receptors, activating them and leading to develop, reproduction issues 2.Receptor blockers (antagonists) - EDS can act as antagonists by binding receptor without activating them, blocking normal hormone signals. Ex: Tamoxifen, estrogen receptor antagonist in breast tissue, block estrogen effects in breast cancer treatment 3.Altering receptor conformation - EDS can change shape and function of receptors, affecting ability to bind hormones. ex: Dioxins, bind to aryl hydrocarbon receptors, altering their structure and influencing gene expression 4. Affecting hormone release - EDS can alter release of hormones, potentially affecting gene activation or deactivation ex: PCBs affect release of thyroid hormones disrupting hormonal balance 5. Cofactor production/function - EDS can interfere with production or function of cofactors required for hormone activation of enzyme function Ex: Dioxins affect the production of certain enzyme cofactor involved in hormone detoxification 6. Alteration in signal transduction - EDS can change how cells respond to hormonal signals by affecting signaling pathway ex: Atrazine disrupts pathways related to sex hormones, leading to reproductive health issues. 7. Increased/Decreased Levels of Transport Proteins - EDS can affect the levels of transport proteins that regulate hormone distribution. Ex:Parabens, alter levels of TP like albumin influencing hormone availability in body 8.Reduction of Enzymatic Activity - EDS can reduce enzyme activity such as iodination, affecting hormone production and function Ex: chlorinated pesticides reduce activity of deiodinase enzymes, affecting conversion of T4 to active T3 thyroid hormones. 9.Blocking Transport/Release -EDS can block the transport release of hormones,disrupting hormonal balance Ex:phthalates,can block androgen transport,negatively affecting male reproductive system. Organs? Which are the different types of anemia? Folate deficiency anemia - deficiency in folate Sickle cell anemia - genetic disease with abnormal shaped RBC Anemia of chronic disease - genetic disease with abnormal hemoglobin production Pernicious anemia - Is a type of megaloblastic anemia,caused by B12 deficiency dueto lack of intrinsic factor (absorption protein). It is an autoimmune condition that prevents your body from absorbing B12. Megaloblastic anemia - result from deficiency in B12 or folate, leading to impaired dna synthesis, myelin formation, RBC production. The bone marrow produces unusually large, structurally abnormal immature red blood cells. Iron deficiency anemia - when the body lacks iron to produce adequate levels of hemoglobin (which is responsible to transport o2). Lack of iron, not possible to synthesize heme, not enough hemoglobin, which reduces RBC in bone marrow = anemia Hemolytic Anemia - RBC are destroyed faster than they can be produced by bone marrow. cause can be inherited diseases, infection, autoimmune disorders, medication or heart valve replacement Idiopathic aplastic anemia - rare condition, when bone marrow fails to produce sufficient blood cells, leading to deficiency in RBC, WBC and platelets. What is allosteric regulation? Explain Homotropic effects and Heterotropic effects. Allosteric regulation - process in which the activity of an enzyme/protein is modified through binding of effector molecules at sites other than the active site. Causes a conformational change in protein, either activating or inhibiting its function. Homotropic effects - occur when the substrate itself acts as an allosteric regulator. Means that binding of one substrate molecule to an enzyme influences the binding of additional substrate molecules Mechanism: first substrate bind to active site, induces a conformational change that increases the enzyme affinity for subsequent (följande) substrate molecule Ex: Hemoglobin. One molecule of oxygen binds to hemoglobin, increase the affinity of the remaining binding sites for oxygen, facilitating the efficient transport of oxygen in the blood Heterotropic effects - occur when a molecule other than the substrate (allosteric effector) binds to the enzyme, influencing its activity. This effector can be an inhibitor or activator. Mechanism: Binding of allosteric effector induces a conformational change that alters the enzymes activity, depending on nature of effector, this can lead to increase or decrease in the enzyme affinity for its substrate Ex:effect of ATP and citrate on the enzyme phosphofructokinase in glycolysis. ATP serves as inhibitor while ADP and AMP serve as activators. Citrate also inhibits linking glycolysis and energy metabolism. Ex: an increase in CO₂ or H⁺ (lower pH) reduces hemoglobin's affinity for oxygen. Allosterisk reglering styr enzymaktivitet genom att molekyler binder till andra delar av enzymet. Homotropa effekter: Substratets bindning underlättar mer bindning. Heterotrofa effekter: Andra molekyler påverkar enzymaktiviteten, antingen positivt eller negativt. What is the difference between Oncosis and apoptosis? Apoptosis - programmed cell death that is regulated and occurs naturally in the body. Heart failure, apoptosis contributes to gradual loss of heart muscle cells. Cell morphology: cell shrink, chromatin condense, apoptotic bodies form, nucleus undergoes karyorrhexis (fragmentation) Toxicity: is a controlled process, associated with chronic toxicity and tissue remodeling and does not cause inflammation Oncosis - form of accidental cell death caused by injury or toxicity, leading to swelling and rupture, ultimately resulting in necrosis (uncontrolled cell death) Cell morphology: swell, rupture, necrosis, nucleus dissolve through karyolysis (without fragments) Toxicity: linked to acute toxicity and more inflammatory, important for evaluating immediate toxic effects and tissue damge What is Hematopoiesis and what are the toxic effects on the heart and the blood cells? include ion homeostasis Hematopoiesis - process by which blood cells are formed from hematopoietic stem cells in bone marrow Toxic effects on Erythrocytes (red blood cells): - Toxic substances affect production of RBCs leading to imbalance in alpha, beta globin chains, alterations in globin shan synthesis, disturbance in heme production - Anemia  - Alteration in respiratory functions of hemoglobin: homotropic effects /heterotropic effects - Alterations in erythrocyte survival: like hemolytic anemia where RBC are destroyed prematurely - Erypotosis - programmed cell death triggered by oxidative stress, hyperosmotic, anemia, infections. Characterized by shrinkage, blebbing and phospholipid membrane scrambling Toxic effects on Granulocytes (white blood cells) Granulocytes have a role in immune response by defending against infections. When toxic substances affect, immune systems ability is weakened - Effect on proliferation - toxicants can inhibit proliferation, leading to decreased production of granulocytes. Ability to fight infections weakened - Effects on function - alcohol/drugs can impair ability of neutrophils (granulocyte) to engulf, destroy pathogens. Toxins disrupt production of ROS which is necessary for pathogen destruction. - Idiosyncratic toxic neutropenia - condition where individual experience drop in neutrophil count due to unpredictable reaction to chemical or drug Toxic effects on thrombocytes (platelets) Thrombocytes are essential for blood clotting, toxins can disrupt, leading to bleeding disorder. - Effect on proliferation - reduce bone marrow activity, reduces producing of megakaryocytes the cell that generate platelets - Effect on function - toxins can inhibit platelets aggregation, the process of clotting, makes it harder to stop bleeding. Toxins interfere with proteins that promote clotting and alter expression of platelets receptors, affecting ability to interact. - Idiosyncratic toxic thrombocytopenia - low number of platelets caused by reaction to drug/chemical = excessive bleeding. Toxic effects on heart The heart relies on a balance of ions to maintain electrical activity and contractility. Ion Homeostasis - ion channels in heart cells regulate sodium, potassium, calcium, cricual for electrical signals (heartbeat) - NA+/K+ -ATPase inhibition - pump maintain gradients and inhibition lead to altering of ionic flux, impacting heart excitability and contractility - NA+ channel blockers- inhibit sodium ion flux, slowing action potential conduction in heart causing arrhythmias. - K+ channel blockers - prevent potassium from exiting the cell, prolonging action potential, causing abnormal heart rhythms. - Ca2+ channel blockers - inhibit influx calcium ions, essential for contraction, leading to reduced heart function Ros is generated due to toxin disrupt calcium handling in heart, leading to arrhythmias and contribute to long term cardiac remodeling Toxic on vascular system Vascular system responsible for transport blood, nutrient, waste Membrane damage -toxins increase permeability, slurping vessel integrity Oxidative stress - ROS cause vascular damage, affecting gene regulation, antioxidant defenses Bioactivation, accumulation - toxins convert into harmful forms in vessels. Toxic effects on blood Hepatotoxicity - chemicals affect blood cells , causing hypoxia, bleeding and infection risk. Xenobiotic-induced aplastic anemia - reduction in blood cells production because bone marrow fail to produce blood cells due to chemical Xenobiotic-induced agranulocytosis - depletion of neutrophils caused by toxin exposure Xenobiotic-induced thrombopenia - low platters, due to destruction or production decrease Toxic effects on cardiovascular system The cardiovascular system includes the heart and vessels and toxins can affect electrical activity and vessels. Toxicants can alter: - heart rate - contractility - conductivity -. electrical signals - excitability - increase sensitivity to electrical signal Which are the 5 toxidromes and how do they affect the body? Give examples! Toxidromes - combination of specific signs and symptoms that reflect drug effects Anticholinergic toxidrome - caused by blocking action of neurotransmitter ACh at synapses in central and peripheral NS. Inhibit Ach at muscarinic receptors leading to suppression of parasympathetic NS. Inhibiting movement of smooth muscles (gi, urine,lung, sweatglands) Symptoms - dry skin, dry mouth, blurred vision,urinary retention, increased heart rate, hypothermia. ex: Atropine - nonselective muscarinic antagonist (competitive), blocking action of ACh affecting central and parasympathetic receptors. - Compete with acetylcholine for cholinergic receptor sites on SA and AV nodes and by blocking AChatropine speed up heart. ex: Belladonna - plant with atropine Cholinergic toxidrome - result from excessive stimulation of cholinergic receptors due to acetylcholinesterase (breakdown ACh) inhibition, causing increase in ACh. Muscles stop responding to the high synaptic levels of ACh leading to paralysis, respiratory failure Symptoms: SLUGE (salvation, lacrimation, urination, defection, gI upset, emesis(vomiting) slow heart, miosis. ex:Pilocarpine - cholinergic agonist that mimics action of ACh activating cholinergic receptors Opioid toxidrome - substance binds to opioid receptors in brain, spinal cord to produce pain relief, euphoria. Opioids stimulate specific G-protein coupled receptors and reduce cAMP, decrease neural activity and modulates pain perception Overdose occurs when there is overactivation of the receptors learning to respiratory depression, lack oxygen in brain, neurotoxicity Symptoms: small pupils, unconsciousness, miosis, bradycardia (slow), hypotension (low blood pressure) ex:Heroin - metabolized to morphine and binds to receptors in brain feeling pain relief, depresses CNS. Sympathomimetic (adrenergic) toxidrome - excess stimulation of the adrenergic nervous system caused by increase in adrenaline and noradrenaline in the blood. Symptoms: rapid heart beat, hypertension, risk of heart attack or stroke, dilated pupils, sweating, seizures Ex:Cocaine - block reuptake of dopamine, norepinephrine, serotonin , high levels neurotransmitters. Sedative-hypnotic toxidrome - CNS depression caused by overconsumption sedative-hypnotic drugs that enhance GABA activity or reduce excitatory neurotransmission Symptoms: confusion, respiratory depression, hypotension, bradycardia, muscle relaxation. ex: Benzodiazepines, diazepam, lorazepam - alcohol enhance effects ex: Barbiturates: veronal - sleeping aid - depressant drug from barbituric acid - agonists of GABAA receptors, linked with inhibitor GABA, they enhance GABA results in hyperpolarization of neuron making less likely to fire action potential