Pharmacology 1.4: Toxicology (Far Eastern University PDF)

FAR EASTERN UNIVERSITY NICANOR REYES MEDICAL FOUNDATION INSTITUTE OF MEDICINE | BATCH 2023 PHARMACOLOGY 1.4: TOXICOLOGY Hypersensitivity Reactions Lecturer: Celia R. Ravelo, MD, FP...

FAR EASTERN UNIVERSITY NICANOR REYES MEDICAL FOUNDATION INSTITUTE OF MEDICINE | BATCH 2023 PHARMACOLOGY 1.4: TOXICOLOGY Hypersensitivity Reactions Lecturer: Celia R. Ravelo, MD, FPPS INTRODUCTION WHAT IS TOXICOLOGY? - Study of the adverse effects of chemicals, physical and biological agents on living organisms and the ecosystem including prevention and amelioration of such adverse effects AGENTS THAT MAY CAUSE TOXICITY - Drugs - Insecticides/herbicides - Plant toxins - Animal toxins - Chemical weapons - Radioactive elements Toxicologist - examine and communicate the nature of those effects on human, animal, and environmental health 3 TYPES 1. Mechanistic toxicologist - identifies and understands the cellular, biochemical, and molecular mechanisms by which chemicals exert B. IDIOSYNCRATIC REACTIONS toxic effects on living organisms - genetically determined; may take the form of extreme 2. Descriptive toxicologist - concerned directly with toxicity testing, sensitivity or insensitivity which provides information for safety evaluation and regulatory o Ex. Succinylcholine - short acting muscle relaxant requirements 3. Regulatory toxicologist - decides on the basis of data provided by § Metabolized by butylrylcholinesterase descriptive and mechanistic toxicologists, whether a drug or other § SNP genetic polymorphism: less active chemical poses a sufficiently low risk (or, in the case of drugs, a enzyme favorable risk/benefit profile) to be marketed for a stated purpose § Prolonged muscle relaxation and apnea or subsequent human or environmental exposure resulting from its - Due to a combination of individual differences in the ability to: use 1. Form a reactive intermediate 2. Detoxify that reactive intermediate (usually through WHAT IS POISON? hydrolysis or conjugation) and/or - Any agent capable of producing deleterious response in a 3. Exhibit difference in immune response biological system, seriously injuring function or producing death C. IMMEDIATE OR DELAYED TOXICITY - Immediate – occurs immediately or rapidly after single exposure to a substance - Delayed – may take years to happen - Ex. Carcinogenic effect of DES observed in daughters of “All things are poison and mothers who took the said medication during pregnancy. nothing is without poison, o result: vaginal cancer approx. 20-30 years after in- only the dose permits utero exposure something not to be D. REVERSIBLE OR IRREVERSIBLE poisonous.” - depends on the type of tissue exposed Ex: liver which has a high ability to regenerate vs injury to the (?) Paracelsus, E. LOCAL VS SYSTEMIC TOXICITY Grandfather of Toxicology - Target organs most commonly involved in systemic toxicity: CNS, circulatory system, hematopoietic system, liver, kidneys, lungs ADVERSE DRUGS REACTIONS (ADRS) - Noxious or unintended responses occurring at therapeutic doses (WHO definition) — TOXIN – toxic substance produced by biologic systems such as - ~ 5% of all acute hospital admissions plants, animals, fungi or bacteria Eg. Zearalenone – produced by molds Effects Examples Type A related to known haemorrhage with — TOXICANT – toxic substance produced by or by-product of human (augmented) pharmacology, but anticoagulants activities ADRs undesirable respiratory depression with Eg, dioxin - produced during production and/or combustion of common, dose- opioids chlorinated organic chemicals related sedation with anxiolytic and predictable older antihistamine drugs SPECTRUM OF UNDESIRED EFFECTS Type B unrelated to known anaphylaxis with penicillin (bizarre) pharmacology allergic liver damage by A. ALLERGIC REACTION ADRs rare halothane — Chemical allergy- immunologically mediated adverse reaction unpredictable bone marrow suppression by to a chemical resulting from previous sensitization to that often idiosyncratic chloramphenicol chemical or to a structurally similar one individual allergy/genetic — Hapten - molecule that must combine with an endogenous basis protein to elicit an allergic reaction page 1 | 15  Type C dose-related hepatitis from isoniazid ACUTE TOXICITY TESTING (Chronic) time related OBJECTIVES unrelated to drug’s (1) provide an estimate of the intrinsic toxicity of the substance, pharmacology often times expressed as an approximate LD (eg, LD 50 ) Type D unrelated to known teratogenic drugs such as (2) provide information on target organs and other clinical (Delayed) pharmacology thalidomide that causes manifestations of toxicity effects appear at a phocomelia; vaginal cancer (3) identify species differences and susceptible species later time after drug from mothers who used (4) establish the reversibility of the toxic response use diethylstilbestrol during (5) provide information that will assist in the design and dose pregnancy selection for longer-term (subchronic, chronic) studies Type E (End effects occur after convulsion caused by of Use) abrupt cessation of phenobarbital withdrawal — SKIN AND EYE IRRITATION TESTS drugs causing Opiate withdrawal - Tests the ability of a chemical to irritate the skin and eye after withdrawal an acute exposure Type F dose related antimicrobial resistance - Usually determined in rabbits (Failure of Often due to drug tolerance - Draize test - dermal irritation test therapy) interaction Toxic response depends SUBCHRONIC TOXICITY TESTS 1. on the chemical and physical properties of the agent - 90 days is the most common test duration 2. the exposure situation - Principal goals: 3. how the agent is metabolized by the system 1. To establish a NOAEL (no observed adverse effect level) 4. the concentration of the active form at the particular target 2. To further identify and characterize the specific organ or site(s), and organs affected by the test compound after repeated 5. The overall susceptibility of the biological system or subject administration EXPOSURE — DEVELOPMENTAL TOXICOLOGY — Human exposure - Study of adverse effects on the developing organism occurring 1. Acute - occurring from a single incident or episode) anytime during the life span of the organism that may result 2. Subchronic - occurring repeatedly over several weeks from exposure to chemical or physical agents before or months conception (either parent), during prenatal development, or 3. Chronic - occurring repeatedly for many months or years postnatally until the time of puberty — Exposure of experimental animals 1. Acute - exposure to a chemical for less than 24 hours — TERATOLOGY 2. Sub-acute - repeated exposure to a chemical - Study of defects induced during development between for 1 month or less conception and birth 3. Subchronic - repeated exposure to a chemical for 1 -3 month — REPRODUCTIVE TOXICOLOGY 4. Chronic - occurring repeatedly for 3 months to 1 year - Study of the occurrence of adverse effects on the male or female reproductive system that may result from exposure to PRINCIPLES OF DESCRIPTIVE ANIMAL TOXICTY chemical or physical agents 1. Effects produced by a compound/chemical in laboratory animals, when properly qualified, are applicable to humans. MECHANISMS OF TOXICITY 2. Exposure of experimental animals to chemicals in high doses is Potential stages in the development of toxicity after chemical a necessary and valid method of discovering possible hazards exposure in humans. TOXICITY TESTING - Done on animals to identify potential hazards before administering to humans - Uses different species of animals - Could be short term or long term - Establishes organ /tissue targets of toxicity - Also determines whether toxic effects are reversible or not - Not always reliable due to differences in ADME - Toxicity tests are not designed to demonstrate that a chemical is safe but to characterize the toxic effects a chemical can produce. TOXICITY TESTS page 2 | 15 Presystemic Elimination - common in electrophiles and radical cations binding with - Elimination of toxicant biological macromolecules before absorption Targets: DNA, Proteins/peptides, lipids and Carbohydrates - reduces the toxic effects of chemicals that EFFECTS OF TOXICANTS ON TARGET MOLECULES reach their target sites - DYSFUNCTION OF TARGET MOLECULES – mimic endogenous ligands acting as agonist, blockers or interfere with Distribution - enhanced by cytoskeleton dynamics (1) the porosity of the - DESTRUCTION OF TARGET MOLECULES – altered primary capillary endothelium, structure of endogenous molecules; spontaneous degradation (2) specialized membrane of target molecules transport, - NEOANTIGEN FORMATION – covalent binding of xenobiotics (3) accumulation in cell with targets may evoke immune response organelles, and (4) reversible intracellular TARGET ORGAN EFFECTS binding. LIVER Hepatic response to insults depends on: Mechanisms Opposing (1) intensity of insult Distribution (2) population of cells affected 1. binding to plasma (3) exposure (acute vs chronic) proteins 2. Specialized barriers ZONE 1 –more 3. distribution to storage sites such as adipose tissue oxygenated, mitochondria 4. association with intracellular binding proteins rich zone, more glutathione 5. Export from cells. Zone 2 –Intermediate zone Zone 3 –hypoxic, greater TOXICATION amount of CYP enzymes - biotransformation to harmful products particularly CYP2E1 - Xenobiotics–converted to: Electrophiles free radicals nucleophiles MECHANISM AND TYPES OF TOXIN INDUCED LIVER INJURY redox –active reactants 1. Cell Death DETOXIFICATION - bio-transformations that eliminate or prevent the formation of the ultimate the toxicant 1. Detoxification of toxicants with no functional group; e.g. benzene, toluene - 2 phases: a.) functional group like hydroxyl, carboxy is added b.) addition of endogenous acid – glucuronicacid, sulfuric acid, amino acid - final product: inactive, highly hydrophilic organic acids 2. Detoxification of nucleophiles –by conjugation preventing its conversion to free radicals 3. Detoxification of free radicals –Superoxide dismutases (SOD) a. focal –randomly distributed death of hepatocyte or clusters of 4. Detoxification of protein toxins –extra and intracellular proteases hepatocytes inactivate toxic poypeptides ex. α-and β-bungarotoxin–inactivated b. zonal –death of hepatocytes in certain functional regions by thioredoxin which reduces their disulfide bonds c. panacinar–massive death of hepatocytes with or without survisors (widespread) TARGET MOLECULES — Mechanisms of toxin induced injury - NUCLEIC ACIDS (DNA) –most common a. lipid peroxidation - PROTEINS-enzymes b. binding to cell macromolecules - MEMBRANES c. mitochondrial damage d. disruption of cytoskeleton TYPES OF REACTION e. massive calcium influx 1. NON-COVALENT BONDING 2. Canalicular Cholestasis - hydrogen and ionic bonds - decreased bile formation or impaired secretion of solutes to - seen in toxicant binding with membrane receptors, intracellular the bile (bile salts, bilirubin) receptors ion channels and enzymes - manifest with jaundice - Non-covalent processes: - ex. of toxins: chlorpromazine, estrogen, Mn 3. Bile duct damage lipid peroxidation - also called cholangiodestructive cholestasis generation of toxic reactive species - elevated alkaline phosphatase as well as elevated bilirubin depletion of reduced glutathione and bile salts modification of sulfhydryl groups - maybe due to swelling of biliary epithelium, debris of 2. COVALENT BINDING damaged cells within the biliary tract, inflammatory infiltration - irreversible; permanently alters a molecule of portal tracts - Ex of toxins: amoxicillin page 3 | 15 4. Sinusoidal damage - dilatation or blockade of channels between hepatocytes that carry blood to the liver - leads to veno-occlusive disease - ex of toxins: anabolic steroids, cyclophosphamides 5. Disruption of cytoskeleton –ex of toxin: phalloidin (mushroom)and microcystin ( blue green algae) 6. Fatty liver – ex of toxins: ethanol, obesity, amiodarone, ethanol 7. Fibrosis and cirrhosis – CCl4, ethanol, vit A 8. Tumors –ex. Aflatoxin, androgen, vinyl chloride MAJOR FUNCTION OF THE LIVER AND CONSEQUENCES OF IMPAIRED HEPATIC FUNCTIONS TYPE OF EXAMPLE CONSEQUENCES OF FUNCTION IMPAIRMENT Nutrient Glucose storage and Hypoglycemia, confusion homeostasis synthesis hypercholesterolemia High Risk Patients & Factors increasing the hepatotoxicity of Uptake of cholesterol paracetamol Filtration of Products of intestinal Endotoxemia - Pregnancy –Paracetamol passes readily into the fetal particulates bacteria circulation. There is no contraindication to the use of N- Protein Clotting factors Albumin Bleeding acetylcysteine in pregnancy and a good prognosis in Synthesis Cholesterol Hypoalbuminemia, pregnancy depends on early treatment – however it does not ascites Fatty liver appear to cross the placenta in sheep and the ability to Bioactivation Bilirubin and ammonia Jaundice, prevent liver toxicity in the human toxicity in the human fetus is and Steroid hormone hyperammonemia uncertain Detoxification Xenobiotics related coma, loss of - Alcohol consumption –Chronic alcohol abuse secondary male characteristics, - Patients on microsomal inducing drugs – barbiturates, carbamezapine, rifampicin, isoniazid, omeprazole, oral ↓ drug metabolism, contraceptives, HIV medications ↓ detoxification - Patients likely to have glutathione depletion – recent severe Formation of Bile acid dependent Fatty diarrhea, fasting, acute illness with prolonged vomiting or dehydration, bile and uptake of dietary lipids malnutrition, anorexia nervosa, bulimia biliary and vitamins Bilirubin Vit E deficiency secretins and cholesterols Jaundice, gallstone, - Underlying hepatic impairment –viral hepatitis, alcoholic Metals (Cu, Mn) hypercholesterolemia hepatitis, NASH Xenobiotics Mn induced neurotoxicity - Other factors –HIV infection, Gilbert’s syndrome Delayed drug clearance PARACETAMOL (ACETAMINOPHEN) overdose: (i) enzymes saturation (ii) glutathione depletion PARACETAMOL SIGNS AND SYMPTOMS 67 - POISONING Phase 1 ( 95% of total lead in the body generate reactive radicals that result to cellular damage in the - Accumulate over a lifetime and released very slowly form of depletion of enzyme activities, damage to lipid bilayer and DNA - Biologic half-lives 4. Enzyme Inhibition o Blood (adults, short-term) 25 days, Lead - inhibits the action of aminolevulinic acid o Blood (children, natural exposure) 10 months dehydratase (ALAD) and ferrochelatase which are enzymes o Soft tissues (adult, short-term) 40 days involved in heme synthesis o Bone (labile, trabecular pool) 90 days o Bone (cortical, stable pool) 10-20 years LEAD - Bluish-white or silvery gray soft metal; strong reducing agent - Molecular weight: 207 daltons - Exposure: breathing air, drinking water, eating foods, and swallowing or touching dust or dirt COMPOUND MAJOR USE Lead Arsenate Insecticide https://www.researchgate.net/figure/Figure-depicting- the-mechanisms-of-lead-toxicity Lead azide Cartridge primers Lead carbonate Paint pigment (basic white lead) Lead chromate Paint pigment (chrome yellow) Lead oxide Paint pigment (red lead) commonly used as primer,for rust protection Lead silicate Glazes for china,porcelain,tiles Lead sulfide Most abundant lead ore, responsible for gingival MOLECULAR MECHANISM OF TOXICITY 243 lead line ENVIRONMENTAL LEAD SOURCES SOURCE REMARKS Leaded paint Especially pre-1978 homes Dust House dust from deteriorated lead paint Soil Yards contaminated by deteriorated lead paint,lead industry emissions, roadways with high leaded gasoline usage Water Leached from leaded plumbing, cooking utensils, water coolers Air Leaded gasoline, industrial emissions Food Lead solder in cans, “natural” calcium supplements, “moonshine” whisky, lead-foil covered wines, contaminated flour, paprika Exotic Folk remedies,cosmetics, ingested foreign bodies, LEAD EFFECTS retained lead CHILDREN: Population at Risk - In acute, high exposure: encephalopathy, irritability, 1. CHILDREN: convulsions, coma, death - Those living in old houses with lead-based paints - Lower exposure: decrement in IQ, and other neuropsychiatric - Those belonging to families with low economic income defects “For every 10ug/dL increase in BLL, children’s IQ - Those belonging to ethnic minority groups dropped by 4-7 points.” - Those living near industrial zones - Neurologic effects may persist into adulthood: lower class - “Children are more sensitive than adults to lead exposure in a performance, greater absenteeism, reading disability, etc. given environment” 2. PREGNANT WOMEN & THEIR DEVELOPING FETUSES - at high-risk because lead readily crosses the placenta page 13 | 15 Signs and Symptoms of Lead Toxicity MERCURY - Quicksilver, metallic mercury, liquid silver, mercurio - Odorless, shiny, silvery liquid; non-flammable; produces poisonous gas in fire; - Evaporation of metallic mercury occurs to some extent at room temperature - High vapor pressure - Molecular weight : 200.59 daltons REPRODUCTIVE & DEVELOPMENTAL EFFECTS - Male: Decreased sperm count, motility, increased abnormal sperm frequencies - Pregnancy outcomes: Miscarriages, stillbirths, spontaneous abortions - Developmental: Animal teratogen, increased minor congenital malformation, higher proportion of learning disabilities - “A higher proportion of learning disabilities was found among school-aged children with biological parents who were lead poisoned as children 50 years previously.” CARCINOGENIC EFFECTS - EPA classification: elemental lead and inorganic lead compounds as Group 2B (probable human carcinogens) - NTP classification: lead acetate and lead phosphate as “may reasonably be anticipated to be carcinogens.” Elemental mercury Quicksilver LEAD POISONING Inorganic mercury Hg+ Hg+ Mercurous ion salts Mercurous ion salts HgCl Calomel Hg+2 Mercuric ion HgCl2 Mercuric chloride Organic mercury Methylmercury Ethylmercury Methoxyethylmercury Phenylmercury Potential Occupational Exposures to Mercury Elemental Salts Organic Amalgam Disinfectants Bactericide makers Barometers Dye makers Drugmakers Bronzers Explosives Embalmers Ceramic workers Fireworks makers Farmers Dentists Fur processors Fungicides Electroplaters Laboratory workers Histology technicians Jewelers Tannery workers Pesticides Mercury refiners Wood preservatives Paint makers Photographers Non-occupational Exposures to Mercury Medicinal Food Others Antiseptics Fish Button batteries Calomel teething Grains and seed, Chemistry sets powders treated Lightbulbs Dental amalgam Livestock, Self-injection Laxatives fed treated grain Preservatives Sphygmomanometers “Magico-religious” Thermometers use page 14 | 15 BIOLOGIC FATE OF MERCURY Elemental Inorganic Organic Primary route of Inhalation oral Oral exposure Primary tissue CNS, Kidney Kidney CNS, Kidney, distribution Liver Clearance Renal, GI Renal, GI Methyl: GI Aryl: renal, GI Half-life 30-60 days 30-60 days 70 dats PATHOLOGIC EFFECTS OF MERCURY - Covalently binds to sulfur, replacing the hydrogen ion in the body’s ubiquitous sulfhydryl groups; also phosphoryl, carbonyl and amide groups - Necrosis of proximal renal tubules (after mercuric salt intoxication): direct effect and immune mechanism - Organic mercury (methylHg): formation of reactive oxygen species producing neuronal and peripheral nerve degeneration Elemental Inorganic Organic Nervous Tremor Tremor, Paresthesias ataxia, system erethism tremor, tunnel vision, dysarthria Pulmonary +++ - - Gastrointestin + +++ + al (caustic) Renal + +++ (ATN) + Acrodynia + ++ --- End Padayon, doc! References: - 2020 PPT of Dr. Ravelo - Royce Tan & Kat M trans Disclaimer: - Doc said you need to read on the other metals. Yes po, apo. - Listen to recordings…. - I didn’t proof read this I’m tired already okie. Sorry for the errors L page 15 | 15