Toxicology

INTRODUCTION TO TOXICOLOGY TOXICOLOGY - poison, adverse effect, treatment of disorder that they produce - adverse effect or unwanted effect of any agent on a biological system TOXICOLOGIST - trained to examine the nature of those effects and ssess the probability of the occurrence I. HISTORY  Smith Papyrus - 1600BC; use of charms against snake poison - Ebers Papyrus - oldest writing to known poison (hemlock, aconite, opium, etc) - Book of Jobs - poison arrows  Mithridates IV, King of Pontus - 1st developed an antidote - took 36 ingredients as protection against assassination - survived every poisoning attempt  Hippocrates - describe elemental concepts of bioavailability and overdose  Dioscorides - greek pharmacist - first attempt to classify poisons - De Materia Medica - 5 volumes, 600 plants, 1000 medications; first systemic pharmacopeia  Sulla - issued Lex Cornelia (law against poison)  Socrates - poison victim; executed by hemlock - coniine (active principle)  Maimonides - treat posion from snake, insects, dogs; bioav of milk, butter (delay absorp) - Treatise on Poisons & Their antidotes  Catherine de Medici - tested toxic concoction, onset, potency, specifiity  Philippus Aureolous Bombastus Theophrastus von Hohenheim Paracelsus - De Historia Planatarum - poisonus plants - All substances know to man are poison there is none which is not a poison and only the dose determines its effect  Paracelsus - revolutionary views on toxicology - On Miner’s Sickness…  Mathieu Joseph Bonaventure Orfila - Father of modern toxicology - autopsy material and chemical analysis as proof of poisoning (Forensic toxicology)  Magendie - MOA of emetine and strychnine  Claude Bernard - Experimental medicine  Oswald Schmiedeberg - trained 120 students  Ellenbog - toxicity of Hg and Pb  Bernardino Ramazzini - occupational toxicology (Doscourse on disease..) II. PRINCIPLES  Poison - “Corpus delecti” or body of evidence - cause injury, disease, death  Poisoning - accidental exposure  Toxin - produced by natural substance  Xenobiotics - foreign substance not found in the body  Intoxication - toxicity associated with chemical substance  Overdosage - intentional exposure with intent of causing self injury Risk - frequency of occurrence of adverse effect upon exposure Hazard - injury with occur in a given situation Toxicity - cause biological change, leading to adverse effect Safety - harm will not occur Toxidrome - collection of signs ans symptoms which characterizes a specific toxicants     III. AREAS OF TOXICOLOGY 1. Experimental Toxicology - investigation of toxic effect of substance on biological system - use of living organism (mice, rat, rabbit) ▪ LD50 - smallest dose that kills 50% of the population, any route except inhalation ▪ LC50 - smallest concentration that kills 50% of the population - administered through inhalation, aquatic exposure ▪ TLV - Threshold Limit Value - maximum amount of drug considered safe - low TLV = more dangerous ▪ ED50 - dose which produces the desired effect in 50% of subject; “Median effective dose” ▪ Therapeutic Index - measure safety; ratio of LD50 to ED50 2. Clinical/ Medical Toxicology - diagnosis and treatment of poisoning cases - with emphasis on medical scinces, including signs and symptoms (toxidrome) CLASS Antichloinergic Cholinergics Sympathomime tics Opiates 3. 4. TOXIDROME Dry, hyperthermia, mydriasis delirium, flushed skin DUMBBELSS/SLUDGE - Diarrhea, urination micturition bradycardia bronchoconstriction emesis mydriasis tachycardia hypertension hyperthermia seizure Triad: miosis (pinpoint) hypotension coma hyperventilation bradycardia EXAMPLE Atropine Organophosphat es, carbamates Amphetamine cocaine Morphine Heroin Environmental Toxicology - deleterious effect and impact of chemicals (air,soil,water) present as pollutants of environment to bring organism - Exotoxicology - impact of toxic in ecosystem Developmental toxicology - adverse effct due to exposure to chemicals substance (prenatal) - Teratology - study of defects conception to birth 5. Regulatory toxicology - establishment of standards for chemicals 6. Descriptive toxicology - concerned with sampling and toxicity testing which provide information for safety evaluation and regulatory requirements 7. Forensic Toxicology - medical and legal aspects or poisoning or harful effects of chemicals to human 8. Mechansticl toxicology - mechanism by which chemicals exert their toxic effect on organism application of genomic.evidence from various events but not very reliable 2. Occupational Toxicology .more than 3 months 4. Organophospahte s Strychnine.irritant to genitourinary system) 4. Symptomatic . dermal)  Ingestion . Specific effect POISON TYPE Irritants Neurotic Carcinogenic Asphyxiants Lacrimators Sternutators Asthenics Narcotics EFFECT Cause tissue necrosis on contact: caustic effect Affect CNS Stimulate proliferation of cancer cells Cause dyspnea. Post-mortem . EVIDENCES OF POISONING 1.effect after a long period of time (10-30yrs) Example: Carcinogens. NM blockers Opiods   Topical. components of benzopyrene (carcinogenic) 4.skeletal muscle relaxation (ester short acting) .use of tissue organs or body fluid 3.C/I to sulfa drugs (Sulfonamides).allergic state  Situation when pre-exposure of chemical is required to produce toxic effect:  Allergic reaction  Sensitization reaction 2. coma. Route & Site of Exposure .toxicity with n 24 hours  Delayed .more toxic  Multiple dose .months or years VI. respiratory depression EXAMPLE Acid & alkali Hallucinogens Nitorsamines Aflatoxin CO.industrial setting: major route of poisoning (inhalation) IV. Carbamates.the effect is produced in an area other than the site of application 3.chemical allergy  immunologically medicated adverse reaction to a chemical  resulting from previous sensitization to a chemical (or structurally similar one)  Hypersensitivity .lungs Immediate vs Delayed Response Immediate .1 month or less  Subchronic . Allergic reaction . oral. stupor. Remote effects .IR: Prolonged muscle relaxation (long acting) G6DP deficient .affected organ undergoes repair Example: Paracetamol affects liver (regenerating ability) .repeatedly over weeks or months  Chronic . Frequency of Exposure (Workplace)  Acute . Teratogens. Duration of exposure  Acute . SPECTRUM OF UNDESIRABLE EFFECTS 1. dermal .1 to 3 months  Chronic .after an autopsy is performed.Toxicogenomics .detection of suspected substance via analysis of sample body fluid collected 5.GIT  Inhalation . <4 (Inhalation)  Subacute .poisoning signs and symptoms observed VII.administering suspected substance to living animal and noting the effect or symptoms 4. after death . Experimental .chemical idiosyncrasy  refers to genetically determined abnormal reactivity to chemical  oversensitivity to smallest dose or no effect even at high doses 3.  Reversible vs Irreversible Toxic effects Reversible . antimalarial drugs (developed hemolytic anemia)  Example: Anaphylactic Shock . percutaneous.effect is continued to the area of administration Example: Corrosive (Acids) . POISONING EFFECT 1.descending order of effectiveness ( inhalation.<24hrs. intraperitoneal.tar in cigarette (smoke).blistering) Systemic (Aphrodisiac .less toxic 2.deals with chemical found in workplace .. Veratrine Tubocurarine. Methane Cholinergic. IM. trascriptomic. SQ. Mutagens Smokers .industrial andagricultural workers usually affected .the impression made by the poison to the body part it made contact .High Conc = High Toxicity  Single dose . cause complete suspension of respiration Stimulate the flow of tears from the lacrimal glands Stimulate excessive sneezing Produce musculat weakness “Exhaustive” Produce mental weakness & depression. ID.skin Parenteral 3. CHARACTERISTICS OF EXPOSURE 1. Local Effect .H2SO4 on cornea Coagulative (Solidification Necrosis Caustic (Alkali) .the poison posses both local and remote effects Example: Atropine PO → Blurred vision Example: Phosphorous: Local (Cutaneous burns) Systemic(Hepatic&Renal failure) Cantharidine: Local (Vesicant . Idiosyncratic reaction . CLASSIFICATION OF TOXIC AGENTS VI. Chemical . Concentration .H2SO4 on cornea Liquefactive (Perforation) Necrosis → → 2.lower BP vasodilation.worst form of allergy . Example: Succinylcholine . bronchoconstrict Corrosive H2SO4 V. 9. Circumstantial .single episode/ incident  Subchronic . Combine . often not the site of highest concentration of chemical  Order of frequency of involvement in systemic toxicity  CNS  Circulatory system  Blood & hematopoietic system  Visceral Organs (Liver.Principle: High dose/ conc = high toxicity c.Smokers & Chronic alcoholics . Route of administration . Poison-related a.vehicle . PO (used as tonics) IV ( toxic. Tolerances . skin)  Muscle & Bone . Solubility .Geriatric: decrease metabolizing rates. Habit .fatal since the poison is absorbed and distributed in the body -Requires absorption and distribution of toxicant to entry point Ex: Tetraethyl Lead . Nicotine: a true poison. so. but due to constant exposure. etc. the human body has welltolerated the poison.from skin to CNS and other organs  Target organ .Ex: Nerve gases (Absorbed via skin & inhalation) 2.apparent state of decreased responsiveness to a pharmacologically active agent from repeated exposure to the agents.seldom target tissue for systemic effect VIII. lungs.genetic defects may lead to toxicity . Patient-related a.affected organ does not undergo repair Example: Ethanol affects brain cells (differentiated cells) 5. renal function compromised compare to aged 20-40 b.Principle: Injected poison (IV-absorbed completely) is more toxic than orally administered poison (PO-1st pass effect) .lung tissue  Systemic .Ex: G6DP deficient: develop hemolytic anemia with sulfonamides.  Local vs Systemic Local .Ex: Saponins b. Age of patient .enzyme induction.Pediatric: liver (other organ system) are not fully developed = high toxicity . kidney. increasing their threshold levels Idiosyncrasy/ Unknown cause .Ex: Nitrates: “Monday disease” d.occurs at the site of first contact Ex: Acids . decrease effect of drug c. .coagulative necrosis Base . quinine.must increase the dose to have the same effect .Principle: High lipid solubility = high toxicity . Irreversible . FACTORS AFFECTING THE EFFECT OF POISON 1.liquefactive necrosis Gases (Chlorine gas) . . hemolytic agents) Concentration .