1.7 Target organ toxicity

1.7 Target organ toxicity : 

1.7 Target organ toxicity Physical results of toxicosis

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COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been copied and communicated to you by or on behalf of the University of New South Wales pursuant to Part VA of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright or performers’ protection under the Act. Do not remove this notice. 2

Advance Reading : 

Advance Reading Hughes, pp 87-102 Shibamoto, pp. 49-51 NLM Toxicology Tutor, Toxic Effects-Organ Specific Toxic Effects, http://www.sis.nlm.nih.gov/enviro/toxtutor/Tox1/a34.htm Neurotoxicity http://www.sis.nlm.nih.gov/enviro/toxtutor/Tox3/a34.htm Enterohepatic Recirculation Animation http://www.agls.uidaho.edu/foodtox/resources/animations/flash_enterohepatic_recirculation/enterohepatic_recirculation.htm Cholinesterase Inhibition Animation http://www.agls.uidaho.edu/foodtox/resources/animations/flash_cholinesterase_inhibitors/cholinesterase_inhibitors.htm 3

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Suggested Reading American Liver Foundation - Liver Health http://www.liverfoundation.org/ National Institute of Diabetes, Digestive, and Kidney Diseases http://www2.niddk.nih.gov/ American Lung Association http://www.lungusa.org/ 4

Keywords : 

Keywords Acute tubular necrosis (atn) Agranulocytopenia Allergic contact dermatitis Anemia Anthracosilicosis Anuria Arterial blood gases(abgs) Asbestosis Berylliosis Blood urea nitrogen (bun) Bronchoscopy Central nervous system (cns) Chloracne Creatinine Dermatotoxicity Crythropoietin Forced vital capacity (fvc) Glial cells Neurotoxicity Neurotransmitter Obstructive uropathies Oliguria PAH clearance Pancytopenia Peripheral nervous system (pns) Phototoxicity Pneumoconioses Poietins Proteinuria Pulmonary fibrosis Pulmonotoxicity Radiopharmaceutical Silicosis Slow vital capacity (svc) Target organ toxicity Thrombocytopenia Glomerular filtration rate (gfr) Glycosuria Hematotoxicity Hematotoxins Hematuria Hemolytic anemias Hepatotoxicity Hypoxia Inulin Irritant contact dermatitis Leukemia Microcytic hypochromic anemia Myelin Nephritic syndrome Nephrotic syndrome Nephrotoxicity Nerve Neurons 5 Start a list of medical terms

Organs and blood circulation : 

Organs and blood circulation Look up human biology texts if this is new to you Arteries carry blood away from the heart. Veins carry blood towards the heart. Blood volumetric flow differs for each organ 6

Learning Objectives 1 : 

Learning Objectives 1 Define target organ toxicity. Explain the basis for specificity of organ toxicity. Contrast the toxicity mechanisms for: Hemotoxicity. Hepatotoxicity. Nephrotoxicity. Neurotoxicity. Dermotoxicity. Pulmonotoxicity. 7

Learning Objectives 2 : 

Learning Objectives 2 Each of these has its own medical specialisation. Describe examples of target organ toxicity. Discuss the characteristic evaluative procedures for determining toxicity in target organs. Explain the concept of oxidative stress and demonstrate an understanding of the action of antioxidant enzymes and redox cycling compounds. Physiological basis of antioxidants in the diet. Examine the molecular pathways of cholinesterase inhibition. 8

Target Organ Toxicity 1 : 

Target Organ Toxicity 1 Adverse effects or disease states manifested in specific organs in the body. High cardiac output = higher exposure. Organs each have specialized tissues and specialized cells. Differentiated cellular processes and receptors. Protein receptors match substrates. Toxicants and metabolites may have specific reactivepathways. 9

Target Organ Toxicity 2 : 

Target Organ Toxicity 2 Toxicants do not affect all organs to the same extent. Organs differ in cell structures and chemical/biochemical features (e.g. lipid content). A toxicant may have several sites of action and target organs. Multi-toxicant exposure may target the same organ. Synergy. The target organ may not be the site for storage. Toxicokinetic processes determine concentrations in target organs. 10

Blood : 

Blood 11

Resting cardiac output%; 63kg male : 

Resting cardiac output%; 63kg male 12

Resting blood flow mL/min: 63kg male : 

Resting blood flow mL/min: 63kg male 13

Blood circulation : 

Blood circulation Stomach, intestine and liver 20% hepatic artery; 80% portal vein 14

Hemotoxicity : 

Hemotoxicity Blood cell components: erythrocytes, leukocytes, thrombocytes. Hemotoxicity occurs when the number or function of blood cells is toxicant impaired. O2 transport: NO3-, CN-, CO, H2S, Zn2+ Number: anæmia, leukemia, thrombocytopenia,agranulocytopenia. Evaluation. complete blood count, CBC arterial blood gases, ABG toxicant/metabolic product 15

Case Study: Methemoglobinemia 1 : 

Case Study: Methemoglobinemia 1 Case Study: Methemoglobinemia following unintentional ingestion of sodium nitrite, NY 2002 On May 16, 2002, Yonkers, New York, emergency personnel were called to a household in which five adults of Middle Eastern descent (three men aged 40, 43, and 44 years and two women aged 60 and 29 years) reported symptoms of dizziness, lightheadedness, and cyanosis almost immediately after sharing a meal. Two of the men also reported vomiting. A sixth person, a man aged 21 years, who did not eat the meal, was asymptomatic. On arrival, the first responders found the younger woman unresponsive; all others were awake and alert. En route to the hospital, both women had progressive respiratory distress and loss of consciousness and were intubated (tube into lungs to assist breathing); the older woman began having seizures. Mortality Morbidity Weekly MMWR (2002) 51(29);639-642 16

Methæmoglobinæmia : 

Methæmoglobinæmia Nitrite affects oxidation-reduction in cells Methaemoglobin is hæmoglobin that has been oxidized from the ferrous (Fe++) to the ferric (Fe+++) state, thus unable to bind oxygen. The NADH- methaemoglobin reductase enzyme reduces methæmoglobin to hæmoglobin. Methæmoglobin results from either inadequate enzyme activity, too much methæmoglobin production or poisoning. http://www.med-ed.virginia.edu/courses/path/innes/rcd/enzyme.cfm 17

Case Study: Methæmoglobinæmia 2 : 

Case Study: Methæmoglobinæmia 2 On arrival at the emergency department (ED), the five persons were markedly cyanotic and had oxygen saturation levels by pulse oximetry of 72%--96% (normal: >92%). Blood drawn for routine testing was described as black coloured. Empiric therapy with methylene blue (a reducing dye) was initiated for suspected methæmoglobinemia after consultation with a poison control center. Subsequently, the patients were found to have extremely high methæmoglobin levels (range: 21.1% to 87.0%) (normal: 1% to 3%). 18

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Methylene blue therapy for methæmo-globinæmia http://www.dartmouth.edu/~rpsmith/Oxygen_Transport.html 19

Case Study: Methæmoglobinæmia 3 : 

Case Study: Methæmoglobinæmia 3 Within 10--15 minutes after administration of methylene blue, cyanosis resolved and oxygenation improved. After therapy, the three men became asymptomatic, and the two women continued to require ventilatory support; the younger woman did not regain consciousness immediately. After overnight observation, the three men were discharged. The older woman was extubated on May 18, and the younger womanwas extubated on May 20; all patients recovered completely. Follow-up investigation suggests that sodium nitrite used for meat curing by an acquaintance was put into a bag marked Iodized Table Salt in English and Arabic. This nitrite salt was added during cooking. 20

Liver : 

Liver 21

Hepatotoxicity : 

Hepatotoxicity Functionally important organ for life processes. Biosynthesis, nutrient metabolism. Most important organ in detoxication and biotransformation. Site for toxication by metabolism. High cardiac output and first pass effects. Enterohepatic recirculation. Potential for re-exposure Liver tissue can regenerate but cannot withstand constant abuse (cirrhosis in alcoholism). http://www.germes-online.com/direct/dbimage/50178394/Frozen_Pork_Liver.jpg 22

Liver : 

Liver Infarction, necrosis, hemorrhage (bovine) 23

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Liver histology Many lobules – parallel processing Hepatocytes Hepatic artery Portal vein Bile duct 24

Hepatotoxicity : 

Hepatotoxicity Cytotoxic. Lipid peroxidation (oxidative stress). Necrosis. Cirrhosis, fibrosis – chronic injury - scarring. Fatty liver - lipid in sinuses of liver – abnormal blood flow. Cholestatic. Flow of bile interrupted. Liver function indicators. Liver enzymes. High concentrations in the blood indicates liver damage. Gross tissue effects. Liver biopsy. 25

Focus Area: Oxidative Stress : 

Focus Area: Oxidative Stress All aerobes generate free radicals in normal respiratory function. Superoxide, O2•. Normal antioxidant enzyme system detoxifies the radicals. Antioxidant enzymes are inducible. Catalase. Superoxide dismutase (SOD) Glutathione peroxidase (GSH-px) 26

Redox Cycling Compounds 1 : 

Redox Cycling Compounds 1 Some xenobiotic compounds are readily oxidized and sequentially reduced by normal biochemical processes. Radical formation. Rechargeable cycle. Toxic endpoints. Lipid peroxidation. DNA strand breaks. 27

Redox Cycling Compounds 2 : 

Redox Cycling Compounds 2 Typical compounds are highly polar. Able to be oxidized by O2. Able to be reduced by flavin enzyme (FAD). Paraquat herbicide. Nitro aromatics. Chelated metals (Zn2+). 28

ROS, RNS examples : 

ROS, RNS examples Reactive oxygen species (ROS). Superoxide free radicals. O2- Hydroxyl free radicals. OH Peroxyl, alkoxyl free radicals RO2 , RO Reactive nitrogen species (RNS) Oxides of nitrogen free radicals NO , NO2 29

Reactive Radical Species : 

Reactive Radical Species Where do they come from? Breathing oxygen UV radiation Infection Oxidants, and redox cycling compounds found in diet and environmental exposure 30

Free Radicals : 

Free Radicals Highly reactive. Can initiate chain reactions - find electron rich molecules. Damage to cells, DNA. Factor in degenerative disease. Antioxidants are radical scavengers. Vitamin C and -Carotenequench reactive oxygen. Vitamin E and -Carotene break chain reactions. Se-GSH-peroxidase quenches peroxide-driven oxidation. 31

Beneficial Oxidative Processes : 

Beneficial Oxidative Processes Chemotaxis of cells with immunological functions. Chemotaxis is the movement of cells in response to a chemical stimulus Phagocytosis. Phagocytes engulf and digest microorganisms and cell debris Triggering of clotting mechanisms. Apoptosis Programmed cell death 32

Antioxidants: Mechanism of action : 

Antioxidants: Mechanism of action Decreasing ROS, RNS formation. Binding redox cycling metal ions. Scavenging ROS, RNS and precursors. Adaptive antioxidant enzyme response. Repairing oxidative damage to biomolecules. Enhancing repair enzymes. 33

Look these up : 

Look these up http://www.nap.edu/openbook.php?isbn=0309069351Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000) Institute of Medicine Good reading on range of data available http://jn.nutrition.org/cgi/content/full/134/11/3199SAssessment of Antioxidant Nutrient Intake and Status for Epidemiologic Research1 Susan T. Mayne2, Margaret E. Wright and Brenda Cartmel © 2004 The American Society for Nutritional Sciences J. Nutr. 134:3199S-3200S, November 2004 34

Oxidative stress : 

Oxidative stress Di Giulio, 1989 35

Endpoints of Oxidative Stress : 

Endpoints of Oxidative Stress Lipid peroxidation. DNA strand breaks. Enzyme inactivation. Covalent binding to nucleic acids. Covalent binding to proteins. 36

Enzymatic response : 

Enzymatic response These enzymes are inducible – levels increase when under toxic stress 37

Kidney : 

Kidney 38

Nephrotoxicity 1 : 

Nephrotoxicity 1 Processes of the kidney. Glomerular filtration. Tubular re-absorption. Tubular secretion. Toxic effects. Porosity, osmotic changes. Modification of tubular re-absorption. Water, electrolyte, nutrient loss in renal failure. Active transport loss. 39

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Kidney histology Glomerulus Proximal tubule 40

Nephrotoxicity 2 : 

Nephrotoxicity 2 Nephrotic syndrome. Glomerular filtration injury – allow larger molecules through. Proteinuria. Lead toxicosis – pores become holes. Nephritic syndrome. Glomerular filtration injury. Hematuria. Acute tubular necrosis (ATN). Nephrons damaged. Epithelial cells plug holes in tubes. Acute renal failure. Tubular re-absorption effects. Obstructive uropathies. Kidney stones. 41

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Toxic Acute Tubular Necrosis ©2004-2005 Mihai Danciu Tubules are blocked 42

Kidney Function Indicators : 

Kidney Function Indicators Glomerular filtration rate (GFR). Creatinine in blood and urine Active tubular secretion of para aminohippurate (PAH) Removal of serum waste products. Blood urea nitrogen (BUN). Scaly white powdery skin Catabolism of protein. Creatinine. Muscle metabolism product 43

Lungs : 

Lungs 44

Pulmonotoxicity : 

Pulmonotoxicity Gas exchange function critical to life. Rapid exchange, high surface area and sensitivity of mucosal tissues make the respiratory system susceptible to damage. Bhopal (1984): Methyl isocyanate spill. Methacrylate polymerised in contact with water in the lung. Chemical irritants, carcinogens, allergens, mineral dusts, cytotoxic chemicals. Endpoints: Inflammation, œdema, necrosis, fibrosis, emphysema, carcinoma. Acute respiratory distress syndrome (ARDS)*, asthma, lung cancer, infarcts#, emphysema. * fluids leak into lung an #infarction is the process of tissue death (necrosis) caused by blockage of the tissue's blood supply. 45

Skin : 

Skin 46

Dermotoxicity : 

Dermotoxicity Irritant contact dermatitis. Allergic contact dermatitis. Phototoxicity. UV and a phototoxic compound. Integumentary cellular effects. Chloracne from halogenated hydrocarbons Phytophotodermatitis from Oil of Bergamot (found in citrus) 47

Nervous tissue : 

Nervous tissue Nerves and brain 48

Neurotoxicity 1 : 

Neurotoxicity 1 Central nervous system (CNS). Brain and spinal cord. Peripheral nervous system (PNS). Sensory and motor control. Neurons. Cell body, dendrites, axon. Glial cells; structure. Astrocytes, nutrient transport. Oligodendrites/Schwann cells, myelin sheath Microglia, immune function. 49

Nerve cells and glial cell : 

Nerve cells and glial cell Nervous tissue is composed of two main cell types: neurons and glial cells. Neurons transmit nerve messages. Glial cells are in direct contact with neurons and often surround them. http://www.cartage.org.lb/en/themes/Sciences/Lifescience/GeneralBiology/Physiology/NervousSystem/Neuron/Neuron.htm 50

Neurotoxicity, 2 : 

Neurotoxicity, 2 Active transport of Na+ (out) and K+ (in) creates an electrical potential across axonal membrane. Passive reverse transport initiates cascading depolarization. At the synapse, neurotransmitters are released to chemically transmit a depolarization to the next neuron. Neurotransmitters cross the synaptic cleft to receptors. 51

Neurotoxins : 

Neurotoxins •Can affect Na+/K+ channels. Inhibition; stimulation. Tetrodo toxins. Dinoflagellates (marine toxin lecture) Bind neurotransmitter receptor sites. Inhibit enzymes responsible for neurotransmitter catabolism. Damage myelin sheath. Morphological (membrane) damage. Necrosis. 52

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Case Study: Equine - Yellow Star Thistle Nigropallidal encephalomalacia Animals lose brain function 53

Acetylcholine esterase : 

Acetylcholine esterase Vital to proper nerve impulse transmission Destroys acetylcholine, the neurotransmitter or chemical messenger across the synapse Nerve impulse lasts too long – does not decay as it should You must understand this mechanism and recognise the words. I will be referring to it often throughout the course. 54

Cholinesterase inhibition : 

Cholinesterase inhibition Acetylcholine is the chemical mediator responsible for physiological transmission of nerve impulses across the synapse. 55

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Cholinesterase Inhibition Animation http://www.agls.uidaho.edu/foodtox/resources/animations/flash_cholinesterase_inhibitors/cholinesterase_inhibitors.htm 56

Acetylcholinesterase, AChE : 

Acetylcholinesterase, AChE The function of acetylcholinesterase is to hydrolyze acetylcholine. The active site of AChE contains two sub-sites, the esteratic and the anionic. Nerve impulses release Ach which is rapidly destroyed by AChE; allows normal propagated impulse. Interferences of AChE activity leads to accumulation of the neurohormone ACh. 57

Hydrolysis of Ach by AChE : 

Hydrolysis of Ach by AChE 58 The enzyme Acetyl group

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Poisoning of AChE Phosphorylation of AChE Kills the insect Poisonous to all nervous systems Parathion Organophosphate (OP) insecticide X = Leaving group 59

View of AChE : 

View of AChE 60 OP Binding Serine Oxy-Anion Hole Brüggemann 60

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OP – ACh docking Brüggemann OP Binding to Serine: Acetylcholine Docking Prevented 61

2-PAM Antidote 1 : 

2-PAM Antidote 1 A cholinesterase reactivator, used as the chloride salt as an antidote in the treatmentof organophosphate poisoningand to counteract the effects of overdosage by anticholinesterases used in treating myasthenia gravis. A cholinesterase reactivator, effective against the nicotinic cholinergic effects of organophosphorus compounds; it also has limited value in counteracting carbamate-type cholinesterase inhibitors; abbreviated 2-PAM Pyridine aldoxime methochloride (Protopam® Chloride, 2-PAM, 2-PAM Chloride) 62

2-PAM Antidote 2 : 

2-PAM Antidote 2 It also binds to the enzyme, competing with the toxicant, but the binding is reversible. 2-PAM chloride (pralidoxime chloride) cleaves the neurotoxic agent from the cholinesterase enzyme and restores the enzyme’s activity. Most noticeable at tissues with nicotinic receptors vs. atropine which is effective at peripheral muscarinic sites. Immediate therapy or “aging” occurs. 63

Case Study: Anticholinergic Poisoning from Herbal Tea, New York City, 1994 : 

Case Study: Anticholinergic Poisoning from Herbal Tea, New York City, 1994 During March 1994, the New York City Department of Health investigated seven cases of anticholinergic poisoning in members of three families; three of the seven ill persons required emergency treatment for characteristic manifestations. For all cases, manifestations occurred within 2 hrs after drinking tea made from leaves purchased commercially and labeled as Paraguay tea - herbal tea derived from the plant Ilex paraguariensis, which is native to South America. MMWR (1995) 44(11);193-195 Ilex paraguariensisYerba mate 64

Anticholinergic Poisoning: Patient : 

Anticholinergic Poisoning: Patient On March 20, a 39-year-old man and his 38-year-old wife shared a pot of Paraguay tea. Within 30 minutes after drinking the tea, both developed acute symptoms (including agitation and flushed skin). They were transported by ambulance to a local hospital. In the emergency department, the man was disoriented and agitated. Findings on examination included fever (101.2˚F {38.4˚C}), dilated and nonreactive pupils, and dry skin and oral mucous membranes; bowel sounds were absent. Anticholinergic poisoning was diagnosed based on clinical findings. After treatment with two doses of intravenous physostigmine (reversible cholinesterase inhibitor obtained from the Calabar bean), signs and symptoms completely resolved. 65

Physostigmine: the antidote : 

Physostigmine: the antidote Physostigmine W. African Doomsday Plant Physostigma venenosum Calabar bean 66

Anticholinergic Poisoning: Deadly Nightshade : 

Anticholinergic Poisoning: Deadly Nightshade At the request of the NYCPC, the emergency department physicians obtained samples of tea from each family for analysis. Samples consisted of packages of dried and chopped leaves and stems wrapped in clear cellophane. From 1 μL of the liquid extract, the belladonna alkaloids atropine, scopolamine, and hyoscyamine were identified by gas chromatography/mass spectrometry. Atropa belladonna Deadly Nightshade 67

Acknowledgement : 

Acknowledgement Professor Greg Möller University of Idaho 68

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