Principles of Toxicology: The Study of Poisons Lecture Notes

PRINCIPLES OF TOXICOLOGY: THE STUDY OF POISONS Dr. Abdullah Alnuqaydan Associate Professor & Consultant of Toxicology [email protected] What is a Poison? All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy. Paracelsus...

PRINCIPLES OF TOXICOLOGY: THE STUDY OF POISONS Dr. Abdullah Alnuqaydan Associate Professor & Consultant of Toxicology [email protected] What is a Poison? All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy. Paracelsus (1493 -1541) What is toxicology?  The word toxicology is derived from two Greek words; toxikon , meaning poisonous substance into which arrow heads were dipped and logos , meaning study  It is the science of poison! Paracelsus (1493 AD)  He viewed a poison in the body would be cured by a similar poison but the dosage is very important  Paracelsus summarized his concept in the following famous phrase “All substances are poisons; there is none that is not a poison, The right dose differentiates a poison from a remedy” The 20th century  Toxicology has now become much more than the use of poisons  There are marked improvements in toxicological diagnosis (that ranges from screening to confirmatory tests), & management (production of antidote for them) What is toxicology? Toxicology is now formally described as the study of adverse effects of chemical, physical or biological agents on the ecosystem and living organisms, how they could harm us and what mechanisms can prevent that harm (ToxLearn 2015). The definition of toxicology can be expanded to other areas such as pharmacology, which studies the side effects of new medicinal drugs (Gilbert 2004).  The adverse effects under study can range from obvious ones such as cancer or death, to the unexpected outcomes of high doses of caffeine that result from drinking too much coffee every day. The study of the adverse effects of a toxicant on living organisms  Adverse effects  any change from an organism’s normal state  dependent upon the concentration of active compound at the target site for a sufficient time.  Toxicant (Poison)  any agent capable of producing a deleterious response in a biological system  Living organism  a sac of water with target sites, storage depots and enzymes Epidemiology of Toxicology  It is mostly a description of the epidemiology of unintentional poisoning.  Today, 7% of all emergency room visits are the result of toxic exposures.  Household cleaner, and prescription drugs and cosmetics are the most frequent human toxic exposures. American association of poison control center Epidemiology of Toxicology  During adolescence and young adulthood the exposures are more likely to be intentional, either through suicide attempts or experimentation with drugs or alcohol .  More than 72.4% of all poison exposures occur in children and adolescents less than 17 years of age.  Exposures are equally reported in males and females.  Adult men have been reported to be more at risk of occupational exposures than adult woman .  Route of entry of exposures reported was by mouth in most cases: 77% were the result of ingestion, 7.0% were transdermal , 5.9% were ophthalmic; and 5.5% were by inhalation . Refer to: American association of poison control center Epidemiology of Toxicology  Most poison exposures do not result in clinical toxicity.  In general, nearly everyone is at risk of acute and chronic toxic exposures to hazardous substances in the ambient environment Refer to: American association of poison control center Toxicologic terms and definitions  A) Important toxicological terms  Toxin - a poison of natural origin  Poison (Toxicant) - a chemical that may harm or kill an organism  Antidote - a medicine taken or given to counteract a particular poison. Toxicity  Toxicity – is the ability of a chemical agent to cause injury. So, it depends on the amount of chemical absorbed, severity of the exposure, dose & time  It can be: acute (toxic event which occurs for short time over 1 or 2 days.) or chronic (apply to an event which occurs many weeks, months or years after exposure) Hazard  Hazard – is the likelihood that injury will occur in a given situation or setting: the conditions of use and exposure are primary considerations Risk  Risk – is defined as the expected frequency of the occurrence of an undesirable effect arising from exposure to a chemical or physical agent. Acute & Chronic exposure  Acute exposure is a single exposure – or multiple exposures occurring over 1 or 2 days  Chronic exposure is multiple exposures continuing over a longer period of time  B) Presence of mixtures: Humans normally come in contact with several (or many) different chemicals concurrently or sequentially.  The resulting biologic effect of combined exposure to several agents can be characterized as synergistic, additive, Potentiation & antagonistic Synergism  Synergism - when the effect of two chemicals is greater than the effect of individual chemicals  e .g carbontetrachloride + alcohol= more toxic to the liver than the sum of the individual drugs Additive effect  Additive effect - when the total pharmacological action of two or more chemicals taken together is equivalent to the summation of their individual pharmacological action.  e.g. Combination of aspirin and paracetamol in the treatment of pain and fever . Potentiation effect  Potentiation effect - The action of a substance, at a dose that does not itself have an adverse action, in enhancing the effect of another substance  e .g Disulfiram at non -toxic doses potentiate the toxicity of alcohol & used in the treatment of alcohol abuse Antagonism  Antagonism -is the phenomenon of opposing actions of two chemicals on the same system  e .g paracetamol causes serious liver damage when given with alcohol or barbiturates, both of which induce drug metabolizing enzymes Classification of toxicology I. Based on research methodology A. Descriptive toxicology B. Mechanistic toxicology C. Regulatory toxicology D. Predictive toxicology Classification of toxicology II. Based on specific socio -medical issues A) Occupational toxicology Occupational toxicology Deals with chemical found in the workplace B) Environmental toxicology It is concerned with the toxic effects of chemical and physical agents on living organisms C) Clinical toxicology Clinical toxicology deals with diagnosis and treatment of the normal diseases or effects caused by toxic substances of exogenous origin i.e. xenobiotics. D) Forensic toxicology  Forensic toxicology closely related to clinical toxicology  It deals with the medical and legal aspects of the harmful effects of chemicals on man, often in post mortem material, for instance, where there is a suspicion of murder, attempted murder or suicide by poisoning III Based on the organ/system effect  Cardiovascular toxicology  Renal toxicology  Central nervous system toxicology  Gastrointestinal toxicology  Respiratory toxicology etc Classification of toxicology Toxicokinetics and Toxicodynamics  Toxicokinetics deals with absorption, distribution, biotransformation and excretion of chemicals  Toxicodynamics deals with the biochemical and physiological effects of chemicals to the body and mechanisms of their actions Toxicokinetics  Absorption: Absorption is the process by which the chemical enters the body  It depends on the route of administration, dissociation (to become ionized), dissolution (ability of solid dosage form to become soluble), concentration, blood flow to the site, and the area of the absorptive site.  The common sites of absorption are  Oral route (digestive tract ))  Dermal route (Skin contact)  Inhalational route (respiratory tract) e.g noxious gases  Other route of exposures are Injections and eye route The consequences of a given dose are not determined by the dose response and route of exposure alone, but are strongly influenced by the following factors:  Dose amount: A quantitative measure of the dose.  Dose frequency: How often the exposure occurs (e.g., daily, weekly, biweekly or monthly ).  Dose duration: The length of the total period of dose exposure (e.g., 24 hours or one week ).  Individual characteristics: Natural traits such as age, sex, state of health and genetic background.  Route exposure : How the person is exposed. Bioavailability  Bioavailability when a medication is administered intravenously, its bioavailability is 100 % .  However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first - pass metabolism) . Distribution  Distribution -is defined as the apparent volume into which a substance is distributed.  Volume of distribution (Vd) is calculated from the dose taken and the resulting plasma concentration:  Vd = dose /plasma concentration Distribution.. Exercise E .g A 60Kg epileptic victim attempted suicide by ingesting Phenytoin tablets. Vd listed is 0.6 L/Kg. Peak blood concentration measured by the laboratory is 50mg/ L. What is the dose of the drug that was taken by the victim? Dose=plasma concentration x Vd =50mg/L x (0.6L/Kg x 60Kg) = 1800mg Biotransformation (metabolism)  Biotransformation is the biochemical transformation of a chemical  It is a process by which the body transforms a chemical and makes it more water soluble so the chemical can be eliminated more rapidly via the kidney into the urine  Biotransformation can produce metabolites that are pharmacologically active and toxic Phases of biotransformation  Phase I – the drug is converted into more polar compound e .g oxidation, reduction, & hydrolysis  Phase II (conjugation) – a drug or its metabolite is conjugated with an endogenous substance e .g glucuronide conjugate  Enzyme inhibition - by this the biotransformation of drugs is delayed & is a cause of increased toxicity  Enzyme induction - by this the biotransformation of drugs is accelerated & is a cause of therapeutic failure  First – pass effect – is the biotransformation of some chemicals by the liver during the initial pass from the portal circulation after oral administration .  Half life (t 1 ⁄ 2 ) – is the time required to reduce the blood concentration of the chemical to half . Excretion  Excretion is the final means of chemical elimination, either as metabolites or unchanged parent chemical .  Excretion through the lungs is the major route for gaseous substances ; and in the case of non -volatile water – soluble drugs, the kidneys are the most important routes of excretion .  Additional routes include sweat, saliva, tears, nasal secretions, milk, bile and feces Clearance  Elimination of chemicals from the body may be described by the term clearance (CL ).  It is a quantitative measure of the volume of blood cleared of drug per unit time, usually expressed in milliliter per minute.  Clearance is calculated as follows CL = 0.7 (VD)/ (t1/2) = ml/min Where the VD is expressed in milliliter per kilogram & the half -life is expressed in minutes or hours Toxicodynamics  Toxicodynamics is the mechanism of action of a toxic chemical to the body (what chemicals do to the body )  The targets for the toxicodynamic actions of toxic chemicals are - Enzymes - Membrane receptors - Intracellular receptors - Ion channel Toxicodynamics  Toxic effects generally result from adverse cellular, biochemical, or macromolecular changes which attained by - Damage to an enzyme system - Disruption of protein synthesis - DNA damage - Modification of an essential biochemical function Median lethal dose (LD50) – is the dose which is expected to kill 50% of the population in the particular group. Median effective dose (ED50) –is the dose that produces a desired response in 50% of the test population when pharmacological effects are plotted against dosage. Median toxic dose (TD50) – is the dose which is expected to bring toxic effect in 50% of the population in the particular group. Dose response relationships are: Common effects of chemicals to cause symptoms  Interfere with the transport or tissue utilization of oxygen (carbon monoxide, cyanide), resulting in hypoxia or a decrease in an essential substrate such as glucose  Depress or stimulate the CNS, producing coma (sedative - hypnotics) or convulsions (Sympathomimetics such as cocaine , amphetamines )  Affect the autonomic nervous system, producing cholinergic action (organophosphate insecticide )  Affect the lungs by aspiration (hydrocarbon )  Affect the heart and vasculature producing myocardial dysfunction , dysrrhythmias (antiarrhythmic agents) and hypertension or hypotension . Potential sources of toxicities  Therapeutic agents – drug toxicity can be due to over doses, unusual adverse effects, frequent administrations of therapeutic doses & drug interactions  Industrial chemicals - these chemicals may contribute to environmental pollution & they may be a direct hazard in the work place they are used  House -hold chemicals – The top household products ingested are cleaning agents, cosmetics & personal products & berries  Environmental contaminants - main sources of pollution to the environment are industrial processes, pesticides & smokes from factories & vehicles . Environmental pollutants may be released into the air, water, or dumped onto land  Natural toxicants - many plants & animals produce toxic substances for both defense & offensive purposes . Natural toxins may feature in poisoning via containing in food, by accidental ingestions of poisonous plants or animals & by stinging & biting Potential sources of toxicities  Food additives – have usually low biological activity  Many different additives are added to food to alter the flavor or colour , prevent spoilage or in some other way change the nature of the food stuff  There are also many potentially toxic substances which are regarded as contaminants  Traditional medicines (Botanicals) – the medical use of botanicals in their natural &unprocessed form undoubtedly noticed long time ago  The use of botanicals has increased dramatically  Unfortunately , misconceptions regarding safety &efficacy of the agents are common  In fact, these products can be adulterated, misbranded or contaminated  Furthermore , the doses for active botanical substances may be higher  Adverse effects have been documented for a variety of botanical medications Potential sources of toxicities  Drugs of abuse - Excessive or improper use of drugs or other substances for non -medical purposes, usually for altering consciousness but also for body building is known as abuse of drug .  There are a lot of drugs of abuse with high potential of dependence & tolerance (e .g alcohol, nicotine ... ) Environmental considerations  A . The degradability of the substance ; its mobility through air, water and soil ; whether or not bioaccumulation occurs ; and its transport and biomagnification through food chains . B. Bioaccumulation & Biomagnification  If the intake of a long -lasting contaminant by an organism exceeds the latter’s ability to metabolize or excrete the substance, the chemical accumulates within the tissues of the organism (e .g DDT) . This is called bioaccumulation  Although the concentration of a contaminant may be virtually undetectable in water, it may be magnified hundred or thousand time as the contaminant passes up the food chain . This is called biomagnification Poison prevention & control strategies  Keep all household poisons separate from food  Keep all products in their original containers  Always read all labels carefully before using the product  Never give or take any medication in the dark  Dispose all products in a safe and proper manner  Encourage periodic home hunts and dispose of old medicine  Teach children never to take medication unless given by an adult they know and trust  Buy only those drugs supplied in childproof packaging  Once a child has been poisoned, be on the alert for repeat episodes  Teach children not eat plants or berries  Store all drugs or potentially toxic substances out of sight and out of reach of children :use cabinet locks  References  Some information in the current lecture refer to the toxicology notes for undergraduate students by Dr . Biruh Alemu , Ato Misire Wolde ; Hawassa University .  Gilbert, S.G ., 2004 . A small dose of toxicology : The health effects of common chemicals .CRC Press