21. TOXICOLOGY.pptx

TOXICOLOGY PHARMACOLOGY (DAB 2087) DR. NADIA BINTI HALIB (PHD)  Descri Describe signs and symptoms of be carbon monoxide poisoning. Identif Identify the major organ system y toxicities of common solvents....

TOXICOLOGY PHARMACOLOGY (DAB 2087) DR. NADIA BINTI HALIB (PHD)  Descri Describe signs and symptoms of be carbon monoxide poisoning. Identif Identify the major organ system y toxicities of common solvents. Learning objective s Descri Describe signs, symptoms, and treatment of toxicity resulting from be cholinesterase inhibitor insecticides. Identif Identify the toxic effects of chlorinated hydrocarbons and y botanical insecticides.  Introduction Toxicology = the study of the adverse effects of chemicals on living organisms. All chemicals (including drugs) have some degree of toxicity. There is none which is not a poison. The right dose differentiates a poison from a remedy. Toxic Actions of Chemicals A. Common target tissues B. Nonselective actions C. Selective actions D. Immediate and delayed actions A. Common target tissues Most chemicals adversely affect more than one tissue. Generally : ◦Lungs - gases, vapors, & inhaled particles. ◦Liver - ingested chemicals ◦Tissues with a high blood flow (brain and kidney) - particularly vulnerable to the toxic chemicals ◦Heart - sensitive to toxin-induced disruption in ionic gradients. B. Nonselective actions Exposure to some chemicals (corrosive compounds) - leads to a local irritation and/or caustic effects that are nonselective in nature and occur wherever the site of application or exposure is located. Eg : exposure to strongly alkaline or acidic substances - cause injury by denaturation of macromolecules (such as proteins, cleavage of chemical bonds essential to the function of biomolecules). C. Selective actions Many chemicals produce their toxic effects by interfering of specific biochemical pathways. E.g : rodenticide warfarin inhibits the vitamin K dependent posttranslational modification of certain clotting factors by the liver. Toxic effects - apparent after the chemical has been absorbed and distributed within the body. * Nonselective actions - occur at the exposure site. D. Immediate and delayed actions Some chemicals - have toxic actions that appear immediately (inhibition of acetylcholinesterase by malathion will rapidly lead to symptoms of excess acetylcholine at synapses and neuroeffector junctions). Other chemicals may exert effects later - latency periods of as long as several decade (e.g : carcinogen asbestos can lead to formation of significant pulmonary pathology including cancer, 15 to 30 years after Occupational and Specific Environmental Toxins A. Halogenated hydrocarbons B. Aromatic hydrocarbons C. Alcohols D. Pesticides E. Rodenticides F. Heavy metals G. Gases and inhaled particles A. Halogenated hydrocarbons Halogenated hydrocarbons - usually volatile Exposure can be through ingestion or inhalation. They are lipid soluble and can pass through BBB. Most will depress the central nervous system (CNS) when acute exposures are high. (1) Carbon tetrachloride (2) Chloroform (1) Carbon tetrachloride Exposure through - consumption of contaminated drinking water. Transient, low-level inhalation of carbon tetrachloride can produce irritation of the eyes and respiratory system. Higher levels (inhaled/ingested) - produce nausea, vomiting, stupor, convulsions, coma, and death from CNS depression. Carbon tetrachloride undergoes a cytochrome P450 mediated metabolic activation to produce free radicals (oxidizing essential cellular components). A nonlethal acute exposure can occur within a period of several hours to several days and produce (2) Chloroform The adverse effects of chloroform - similar to carbon tetrachloride. Exposures - ingestion @ inhalation High levels - cause nausea, vomiting, dizziness, headaches & stupor. Chloroform can sensitize the heart to catecholamine-induced arrhythmias. Chloroform is hepatotoxic and nephrotoxic (effects of metabolic activation). B. Aromatic hydrocarbons Aromatic hydrocarbons tend to be volatile. Exposure – inhalation @ ingestion. Large acute exposures - cause CNS depression, and cardiac arrhythmias (sensitization of heart cells to catecholamines). Other effects can differ significantly from halogenated hydrocarbons. (1) Benzene (1) Benzene Exposure to benzene - through tobacco smoke. Chronic benzene exposure in humans - hematopoietic toxicities (agranulocytosis and leukemia e.g acute myelogenous leukemia). Nonoccupational exposures to benzene - through combustion of fossil fuels (automobile gasoline & consumption of contaminated water). (2) Toluene Exposure – automobile emissions (principal source in ambient air) Indoors exposure – household products containing toluene-like degreasers, certain paints and primers, and furniture polish. Acute and chronic exposure – produce CNS depression (symptoms : drowsiness, ataxia, tremors, impaired speech, hearing, and vision). Chronic exposure – may produce some damage to the liver and kidneys. Deaths – have occurred at high levels of exposure. C. Alcohols (1)Methanol & ethylene glycol (2) Isopropanol (1)Methanol & ethylene glycol Primary alcohols – relatively nontoxic and cause mainly CNS sedation. However, methanol and ethylene glycol are oxidized to toxic products – Formic acid (methanol) & glycolic, glyoxylic, and oxalic acids (ethylene glycol). Fomepizole inhibits this oxidative pathway, preventing the formation of toxic metabolites, and allows the parent alcohols to be excreted by the kidney. Coma, seizures, hyperpnea, and hypotension – suggest that a substantial portion of the parent alcohols has been metabolized to toxic acids. (2) Isopropanol This secondary alcohol is metabolized to acetone via alcohol dehydrogenase. Acetone cannot be further oxidized to a carboxylic acids – therefore, shows only limited acidemia and toxicity. D. Pesticides (1) Organophosphosphate & carbamate insecticides (2) Pyrethroids (3) Rotenone (1) Organophosphosphate & carbamate insecticides Exert their mammalian toxicity through inhibition of acetylcholinesterase, with subsequent accumulation of excess acetylcholine. (2) Pyrethroids Exert their mammalian and insect toxicity – by extending the open time of sodium channels throughout central and peripheral nervous systems. Symptoms – loss of coordination, tremors, convulsions, burning and itching sensations. Pyrethroids can act as dermal and respiratory allergens Exposure can lead to contact dermatitis, or asthma- like symptoms. Death is usually due to respiratory failure. Fortunately, the pyrethroids are much more toxic to insects due to their limited ability to eliminate these compounds. (3) Rotenone Rotenone – used primarily as an insecticide. It acts by inhibiting the oxidation of the reduced form of nicotinamide-adenine dinucleotide. Symptoms – nausea and vomiting, with convulsions High exposures – death E. Rodenticides Insecticides - applied by spraying. Rodenticides – used in form of solid baits ingested by rodents. Toxic effects to human – through accidental or suicidal ingestion. The most commonly used rodenticides are the anticoagulants, such as warfarin. F. Heavy metals (1) Lead (2) Mercury ◦(a) Elemental mercury ◦(b) Inorganic mercury salts ◦(c) Organic mercury (3) Cadmium (1) Lead Sources of exposure - old paint, drinking water, industrial pollution, food, and contaminated dust. Most chronic exposure – inorganic lead salts in paint used in construction prior to 1978. Age-dependent – differ the absorption of ingested lead. Adults - absorb about 10%, Children - absorb about 40%. Inorganic forms of lead - distributed to soft tissues, slowly redistribute to bone, teeth, and hair. Lead will eventually redistributed to bone – then can be detected by x-ray examination. Blood half life - 1 to 2 months, Bone half-life - 20 to 30 years. (a) Lead - Central nervous system The CNS effects – termed as lead encephalopathy. Symptoms - headaches, confusion, clumsiness, insomnia, fatigue, and impaired concentration. Clonic convulsions and coma can occur. Death is rare (if lead intoxication treated with chelation therapy). Children are more susceptible than adults to the CNS effects. Blood levels of 5 to 20 μg/dL in children – (b) Lead - Gastrointestinal system Early symptoms can include discomfort and constipation (and, occasionally, diarrhea). Higher exposures - can produce painful intestinal spasms. Calcium gluconate infusion is effective for relief of pain. (c) Lead - Blood Effects on blood - hypochromic, microcytic anemia (shortened erythrocyte life span & through disruption of heme synthesis). Lead inhibits several enzymes involved in the synthesis of heme - leading to increased blood levels of protoporphyrin IX and aminolevulinic acid, thus increased urinary excretion of aminolevulinic acid and coproporphyrinogen. Elevated blood and urinary levels of these intermediates – useful diagnostic features (blood lead levels >25 μg/dL). Below that – heme intermediates cannot be observed. (2) Mercury Exposure - by industry, natural release from the oceans and the earth's crust, and through the burning of fossil fuels. THREE different forms of mercury can occur. (a) Elemental mercury Exposures of elemental mercury - usually occupational through inhalation of vapors. Symptoms - tremors, depression, memory loss, decreased verbal skills, and inflammation of the kidneys. High concentrations are corrosive and cause nonselective toxicity within the pulmonary system. (b) Inorganic mercury salts Exposures to inorganic salts of mercury, such as mercuric chloride - usually occupational. Inorganic salts are corrosive and can destroy the mucosa of the mouth if ingested. Renal damage - observed several hours after exposure. Hazardous exposures of the public to inorganic forms of mercury are uncommon. (c) Organic mercury Organic mercury - contains one covalent bond to carbon atom: more lipid soluble but less corrosive. Significant absorption results after ingestion. Exposure – consumption of foods, e.g : fish contaminated with methylmercury. Symptoms – appear several days to several weeks (after ingestion). Symptoms - visual disturbances, paresthesias, ataxia, hearing loss, mental deterioration, muscle tremors, movement disorders. Severe exposure - paralysis and death. In the elderly – sometimes misdiagnosed as Parkinson's disease or Alzheimer's disease. Organic mercury - most dangerous to foetus, because its (3) Cadmium Exposures – ingestion @ inhalation. Exposure to the public - ingestion of food contaminated (result of uptake by plants of cadmium from fertilizers and manure) and atmospheric deposition. Large inhalational exposures - occupational in nature. Low-level exposure - burning of fossil fuels. Cigarette smoke is also a source of cadmium. Cadmium absorption upon ingestion is poor – 5% bioavailability. Inhalation - 10% - 40% is absorbed. Most of the cadmium - will eventually distribute to the liver and kidneys (result of its binding to metallothionein). Half-life of cadmium is 10 to 30 years. G. Gases and inhaled particles (1) Carbon monoxide (2) Cyanide (3) Silica (4) Asbestos (1) Carbon monoxide Colorless, odorless, and tasteless - Hard to detect without a detector. Sources - combustion of carbonaceous materials, automobiles, poorly vented furnaces, fireplaces, wood-burning stoves, kerosene space heaters, and charcoal grills. CO binds to hemoglobin producing carboxyhemoglobin. The binding affinity to hemoglobin - 230 to 270 times greater than O 2 Bound CO increases hemoglobin affinity for O2 at the other O2 -binding sites - prevents the unloading of oxygen at the tissues, further reducing oxygen delivery. Symptoms - hypoxia, with the brain and heart showing the greatest sensitivity, headache, dyspnea, lethargy, confusion, and drowsiness. Higher exposure - seizures, coma & death. Management of a CO poisoning - prompt removal from the source, institution of 100 percent oxygen by nonrebreathing face mask or endotracheal tube. In patients with severe intoxication, hyperbaric oxygen therapy may be indicated. (2) Cyanide Cyanide quickly binds to many metalloenzymes – thus inactivate them Toxicity - a result of the inactivation of the enzyme cytochrome oxidase (cytochrome a3) Causing the inhibition of cellular respiration. Even in the presence of O2, - tissues e.g brain & heart, which require a high O2 demand are affected. Death - occur quickly due to respiratory arrest of central origin. Cyanide poisoning can be treated amyl nitrite pearls, sodium nitrite & sodium thiosulfate. (3) Silica Exposure - Workers in mines, foundries, construction sites, and stone cutters. Silicosis is a progressive lung disease - results in fibrosis and, often, emphysema. Silicosis - currently incurable & prognosis is often poor. However, with lower exposures, silicosis does not always end in death or debilitation. (4) Asbestos Exposure - inhalation of the fibers. THREE (3) diseases associated with asbestos exposure - asbestosis, mesothelioma, and lung cancer. Symptoms - apparent after 15 to 30 years following exposure. Asbestosis - a chronic pulmonary disease characterized by interstitial fibrosis in the lungs and pleural fibrosis or calcification. Initial symptoms - shortness of breath that can develop into severe cough and chest pains. Asbestosis is a progressive disease with no specific treatment & can be fatal. Mesothelioma is a rare cancer, usually in the chest wall symptom - pain in the vicinity of the lesion, with dyspnea and cough. Pleural mesothelioma - Patients survival no longer than 2 years Antidotes A. Pharmacologically antagonize toxic action B. Accelerate detoxification of toxic agent C. Provide alternative target D. Reduce metabolic activation E. Restore altered target F. Chelators A. Pharmacologically antagonize toxic action Atropine (muscarinic-receptor antagonist) - used as an antidote for intoxication by the anticholinesterases. It works by blocking access of excess acetylcholine to muscarinic receptors. B. Accelerate detoxification of toxic agent Acetaminophen at very high doses - produce liver necrosis (metabolic activation by cytochromes P450). N-acetylcysteine - serve as a substitute for glutathione by binding & inactivate reactive metabolites of acetaminophen. Must be given as early as possible (8-10 hrs of ingestion of acetaminophen). C. Provide alternative target Cyanide poisoning treated with a two-step process. 1st step : Sodium nitrite - to induce the oxidation of hemoglobin to methemoglobin, (high binding affinity for cyanide) to produce cyanmethemoglobin. Amyl nitrite can also be used for this purpose. 2nd step : to accelerate its detoxification. Sodium thiosulfate - accelerate the production of thiocyanate, (less toxic than cyanide & quickly excreted in the urine).  In patients with smoke inhalation and cyanide toxicity, induction of methemoglobin should be avoided (unless the carboxyhemoglobin concentration is less than 10%). Otherwise, the oxygen-carrying capacity of blood becomes too low. D. Reduce metabolic activation The toxicity of methanol is mediated by formic acid, (metabolism of methanol by alcohol dehydrogenase). Fomepizole is an antidote to methanol, It inhibits alcohol dehydrogenase & slowing the rate of methanol metabolism. Reduced rate of formic acid production - protecting the patient from the toxic effects of formic acid. E. Restore altered target Acetylcholinesterase that has been inhibited as a result of phosphorylation by organophosphorus compounds often can be reactivated by the antidote pralidoxime. F. Chelators Chelators - drugs that form covalent bonds with cationic metals. The chelator-metal complex : excreted in the urine (thus facilitating the excretion of the heavy metal). Unfortunately, chelators are not specific to heavy metals, and essential metals, such as zinc, often can also be chelated. Some chelators have potentially serious adverse effects – thus their use in treatment of heavy metal intoxication is undertaken only when the benefits of chelation therapy outweigh the associated risks. (1) Dimercaprol Chelator for arsenic intoxication. Dimercaprol – also used to chelate mercury. Combination with edetate calcium disodium – used to treat lead intoxication. It is not effective after oral administration. Usually given intramuscularly. Use of dimercaprol is often limited by its capacity to increase blood pressure and heart rate. (2) Succimer Succimer (dimercaptosuccinic acid) is a derivative of dimercaprol. Effective upon oral administration. Advantage of succimer over dimercaprol - lack of increased blood pressure and heart rate during treatment. Succimer is currently approved for treatment of lead intoxication, but may be effective in chelation of other metals as well. (3) Edetate calcium disodium Edetate calcium disodium - used primarily for lead Intoxication. It is not effective after oral administration and is Usually given intravenously or intramuscularly. The calcium disodium salt of EDTA - must be the form utilized to prevent chelation of calcium(in the body). Edetate calcium disodium can cause renal damage – but it is reversible upon cessation of the drug. Thank you