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Historical Development of Toxicology

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Title: Historical Development of Toxicology


1
Historical Development of Toxicology
  • It is one of the oldest practical sciences which
    began with early cave dwellers who recognized
    poisonous plants and animals and used their
    extracts for hunting or in warfare. 
  • By 1500 BC, hemlock, opium, arrow poisons, and
    certain metals were used to poison enemies or for
    executions (Notable poisoning victims include
    Socrates, Cleopatra, and Claudius)
  • .

  • The Death of Socrates, 1787 Jacques-Louis David

2
  • By the time certain concepts fundamental to
    toxicology began to take shape especially by the
    studies of Paracelsus (1500AD) and Orfila (1800
    AD).
  • Paracelsus (1493 -1541)
  • His famous words were
  • "All substances are poisons there is none which
    is not a poison.  The right dose differentiates a
    poison and a remedy."
  • 1-He determined that specific chemicals were
    actually responsible for the toxicity of a plant
    or animal poison. 
  • 2-He also documented that the body's response to
    those chemicals depended on the dose received
  • Orfila (founder of toxicology -19th century)
  • Spanish physician who first correlated between
    the chemical and biological properties of
    poisons.
  • The 20th century is marked by an advanced level
    of understanding of toxicology.  DNA (the
    molecule of life) and various biochemicals that
    maintain body functions were discovered. Now our
    level of knowledge of toxic effects on organs and
    cells is being revealed at the molecular level. 

3
Scope of Toxicology
  • Toxicology is multidisciplinary as it entails
  • 1-Mechanistic Toxicology
  • Example
  • Biochemical toxicology
  • Behavioral toxicology
  • Carcinogenesis
  • Teratogenesis
  • Mutagenesis
  • 2-Applied Toxicology
  • Clinical Toxicology It deals with emergency
    cases such as overdoses, poisonings, attempted
    suicides by
  • Emergency care for patients.
  • Management of sign and symptom
  • Identification and quantification of the
    drug ,poisons, chemicalsetc
  • .

4
  • Forensic Toxicology
  • Economic Toxicology
  • Environmental Toxicology
  • 3-Analytical Toxicology
  • 4-Regulatory Toxicology
  • Risk assessment
  • It deals with analysis of toxicological
    data for the determination of Safe level of
    drugs for humans , safe level of heavy metals in
    water , safe levels pesticides...etc.
  • Legal aspect
  • Concerned with formulation of laws which are
    intended to minimize the effect of toxic
    chemicals on humans health the environment.

5
Toxicity
  • Def. The degree to which a substance can harm
    humans or animal
  • Different xenobiotics cause many types of
    toxicity by a variety of mechanisms. So, we have
    to take an idea about
  • -Different types of toxic agents
  • -Different type of toxicity
  • -Different mechanisms of toxic response
  • Toxic Agents
  • Toxic agent is anything that can produce an
    adverse biological effect.
  • -The most common terms used to describe a toxic
    agent are toxicant, toxin, poison.

6
Toxic Agents

7
  • Toxic Agents are classified
  • 1-According to their nature
  • 1-Chemicals as alcohols, phenols heavy metals
  • 2-Physical as radiation.
  • 2-Bilogical Snake scorpion venoms.
  • 2-According to their effect
  • i-Systemic toxicant
  • is one that affects the entire body or many
    organs rather than a specific site.
  • E.g. potassium cyanide is a systemic toxicant in
    that it affects virtually every cell and organ in
    the body by interfering with the cell's ability
    to utilize oxygen.
  • ii-Target organs toxicant
  • affect only specific tissues or organs while not
    producing damage to the body as a whole.
  • Examples
  • -Arsenic paracetamol are hepatotoxic.
  • -Digitalis antimony are cardiotoxic.
  • -Mercury gentamycin are nepherotoxic
  • -Lead is also a specific organ toxin however,
    it has three target organs (central
    nervous system, kidney, and hematopoietic
    system).

8
Types of poisoning
  • 1-According to circumstances of poisoning
  • a-Accidental Toxicity (non-intentional
    poisoning)
  • which occur by mistakes and usually happen to
    children (below 5-years old)
  • E.g.With aspirin, iron preparations, pesticides,
    kerosene..etc.
  • b-Deliberate self Toxicity (Suicidal or criminal
    poisoning)
  • which occur when a person attempts to kill
    himself or another person.
  • E.g. with cyanide, barbiturates,salicylates
    etc
  • 2-According to incidence of poisoning
  • a-Homicidal Which occurs in or around home.
  • E.g. pesticides, potassium hydroxide,
    disinfectants.
  • b-Occupational This includes industrial and
    agricultural poisoning.
  • E.g. inhalation of pesticides.

9
Types of Toxicity
  • 1-Systemic Toxicity
  • Toxicity may occur at multiple sites. This is
    referred as systemic toxicity. The following are
    types of systemic toxicity
  • a-Acute Toxicity
  • It occurs almost immediately (hours/days) after
    an exposure to single dose or a series of doses
    received within a 24 hour period. Death is a
    major concern in cases of acute exposures.
    Examples are
  • -In 1989, 5,000 people died and 30,000 were
    permanently disabled due to exposure to methyl
    isocyanate from an industrial accident in
    Bhopal, India.
  • -Many people die each year from inhaling
    carbon monoxide from faulty heaters.
  • b-Subchronic Toxicity (reversible)
  • It results from repeated exposure for several
    weeks or months. This is a common human exposure
    pattern for some pharmaceuticals and
    environmental agents. Examples are
  • -Ingestion of coumadin tablets (blood
    thinners) for several weeks as a treatment for
    venous thrombosis can cause internal
    bleeding.
  • -Workplace exposure to lead over a period of
    several weeks can result in anemia.

10
  • c-Chronic Toxicity (irreversible)
  • It is a cumulative damage to specific organ or
    system and it takes many months or years to
    become a recognizable clinical disease. This
    damage is so severe that the organ can no longer
    function normally (irreversible) and a variety of
    chronic toxic effects may result. Examples are
  • -Cirrhosis in alcoholics who have ingested
    ethanol for several years
  • -Chronic bronchitis in long-term cigarette
    smokers
  • -Pulmonary fibrosis in coal miners (black
    lung disease)
  • d-Carcinogenicity
  • Carcinogenicity is a complex multistage process
    of abnormal cell growth and differentiation which
    can lead to cancer.
  • e-Developmental Toxicity
  • Developmental Toxicity result from toxicant
    exposure to either parent before conception or to
    the mother and her developing embryo-fetus.
  • f-Genetic Toxicity
  • Genetic Toxicity results from damage to DNA and
    altered genetic expression. This process is known
    as mutagenesis. The genetic change is referred to
    as a mutation and the agent causing the change as
    a mutagen.

11
  • 2-Organ Specific Toxicity
  • Blood and Cardiovascular Toxicity
  • Hypoxia due to carbon monoxide binding of
    hemoglobin preventing transport of oxygen
  • Hepatotoxicity
  • CCl4..metabolized by HME.CCl3 (causes lipid
    peroxidation in liver lead to liver necrosis.)
  • Nephrotoxicity
  • Mercury gentamycin are nepherotoxic.
  • Neurotoxicity
  • Organophosphorus compounds (insecticides)damage
    to sensory fibers.
  • Respiratory Toxicity
  • Aluminum..emphysemainflated lung
    .fibrosis(aluminosis).
  • Dermal Toxicity
  • dermal irritation due to skin exposure to
    gasoline
  • dermal corrosion due to skin exposure to sodium
    hydroxide

12
Mechanism of Cellular Injury
13
Mechanism of Cellular Injury
  • Toxicity can result from adverse cellular,
    biochemical, or macromolecular changes.  Examples
    are
  • 1-Alteration of a cell membrane permeability
  • Toxic agents could change cell membrane
    permeability through interaction with its
    component as
  • a-SH-containing proteins
  • Heavy metals as As or Hg react with them
    change in protein structure
    change membrane permeability.
  • b-Lipids
  • -Free radicals attack fatty acids in the lipid
    layer of biological membrane causing lipid
    peroxidation , these peroxides are toxic to the
    cell and alter membrane permeability.
  • E.g. CCl4..metabolized by HMECCl3
    (Trichloromethyl radical causes lipid
    peroxidation and finally lead to liver necrosis.)
  • -This is why antioxidants should be used
    frequently by humans where it act as a protective
    measure against many diseases(e.g.) Vit. E Vit.
    C.
  • c-Na-K ATPase pump
  • Many toxicants can inhibit these pumps which are
    essential for transport of major amino acids and
    calcium across the cell membrane.
  • E.g. Hg, Cu, Pb , As and alcohol .

14
  • 2-Chang in enzyme activity
  • a-Inhibition
  • E.g.1 Carbamate esters (insecticides) reversibly
    inhibits anticholineserase leading to increase in
    A.Ch. Level
    Toxicity (SLUD are the most
    characteristic symptoms of toxicity).
  • E.g.2 Cyanide inhibits cytochrome
    oxidase enzyme no aerobic respiration
    and finally cell death.
  • b-Activation
  • E.g. Barbiturates induce hepatic microsomal
    enzymes increase the conversion of some non
    carcinogenic agents (in cigarette smoke) into
    carcinogenic ones.
  • 3-Interferance with co-enzymes
  • E.g. CN- binds to essential metals as Fe3
    needed for the activity of cyochrome oxidase.
  • 4-Modification of carriers
  • E.g.1 CO binds with hemoglobin instead of O2
    (affinity to Hb to CO is 210 times that for
    O2) carboxyhemoglobin.hypoxiadeath.
  • E.g.2 Nitrates ,aspirin and sulfonamides oxidize
    Fe2 in Hb into Fe3
  • Hb
    MeHb
    (methemoglobin) which can not

    carry oxygen

  • NADPH-dependent


  • Hypoxia
  • MeHb
    reductase Vit. C

15
  • 5-Formation of reactive metabolites
  • E.g. Benzo(a)pyrene metabolized by HME
    epoxide-7,8- dihydrodibenzo(a)

    pyrene
  • Non-carcinogenic
    Carcinogenic
  • In cigarette smoke
  • 6-Reactions causing depletion of GSH
  • Glutathione (GSH) is an antioxidant which
    protects the cell from the harmful effect of
    oxidants. Reduction of GSH level into 20-30
    causes impairment of cell defense mechanism .
  • E.g. N-acetyl-P-benzoquinone imine (NABQI) ,a
    toxic metabolite of paracetamol it is
    conjugated with GSH depletion of reduced
    form of GSH leading to NABQI (Strong
    electrophilic agent) attack liver tissues causing
    liver necrosis.
  • -We can increase the level of GSH or overcome its
    depletion by methionin (a precursor of GSH)
    N-acetylcysteine (contains SH).
  • 7- Action on nucleic acids
  • E.g. SO2 (air pollutant) H2O
    HSO3(causing damage to DNA mutation).
  • E.g. Benzidine Metabolism by HME
    N-hydroxybenzidine.
  • Non-carcinogenic
    Mutagenic Carcinogenic
  • In cigarette smoke
  • 8- Disruption of protein synthesis
  • Some toxicants either increase or decrease
    protein synthesis leading to cellular injury.

16
  • 9-Lysosomal changes
  • a-Toxicants which causes labialization of
    lysosomal enzymes
  • E.g. Hg , Cu , silica , nicotine , bee venom ,
    hypervitaminosis A , monosodium ureate crystals
    deposited in gout increase lysosomal membrane
    permeability release of hydrolases cell
    death.
  • b-Toxicants which causes stabilization of
    lysosomal enzymes
  • E.g. Corticosteroids causes indirect toxicity by
    decreasing the response of the body defense
    mechanism .

17
Factors Influencing Toxicity
  • There are many factors which can enhance,
    increase or decrease toxicity. These factors are
    divided into
  • I-Factors related to the host
  • A-The species.
  • -Rats cannot vomit and expel toxicants before
    they cause severe irritation, whereas humans and
    dogs are capable of vomiting.
  • Selective toxicity refers to species
    differences in toxicity response between two
    species simultaneously exposed
  • -an insecticide is lethal to insects but
    relatively nontoxic to mammals???

  • malthion
  • Oxidation by ME

    Hydrolysis
  • (rapid in insects slow in mammals)
    (slow in insects rapid in mammals)
  • Malaoxone

    Inactive substance
  • (Lethal to insects)

18
  • B-Sex
  • .Men traditionally weigh more than women.
    Therefore, doses of a chemical in a male would be
    expected to produce lower blood and tissue levels
    than the same in females, simply because of the
    male's larger blood volume and greater tissue
    mass which dilute the chemical.
  • For substances that are injected
    intramuscularly, lower blood levels can be
    expected with those drugs in individuals (usually
    men) with a greater muscle mass.
  • Also, drugs with a high lipid coefficient that
    normally partition into fat may produce different
    toxicological responses in different sexes, based
    on the individual's ratio of body fat/total
    weight.
  • C-Age
  • -Some chemicals are more toxic to infants or the
    elderly than to adults.
  • Example
  • 1)-Bounded bilirubin with p.p.Sulfonamides
    replacement from P.P. binding sites.
  • conjugated
    with glucoronyl transferase
  • Free bilirubin

    excreted in adults
  • (Low activity of
    GT Immature B.B.B in neonates)

  • Kernikterus (in newborn)
  • 2)-Nitates(in well , s water) due to stomach
    pH is high in newborn Nitrite
    (oxidant)



  • Oxidation

  • Hb

    MetHb

19
  • 3)-Chloramphenicol conjugation by GT is low in
    neonates accumulation of it ,and it
    oxidizes Hb into MetHb Grey baby
    syndrome (hypoxia, cyanosis , collapse and
    death).

  • D-Genetics
  • I-Pharmacogentices (Idiosyncratic reaction ) An
    odd response to a given normal dose of a drug on
    hereditary basis.
  • 1) Succinylcholine apnea in individuals deficient
    in pseudo cholinesterase .?
  • 2) Individuals deficient in glucose-6-phosphate
    dehydrogenase suffer from hemolytic anemia upon
    using sulfa drugs , aspirin or naphthalene
    (oxidants)
  • glucose-6-phosphate NADP
    2 GSH (protect RBCs from hemolysis by
    oxidants)


  • G6PD
    GSH reductase


  • 6-phosphogluconic acid NADPH
    GSSG
  • In case of G6PD deficiency NADPH
    GSH Oxidants attack RBCs hemolysis
  • II-Toxicogentices An odd response to a given
    toxicant on hereditary basis
  • smoking causes emphysema in certain
    individuals deficient in a1- antitrypsin.
  • III-Hypersensitivity (allergic reactions)

20
Pharmacogentices (Idiosyncratic reaction)
21
  • Allergic reactions an immune response that
    occurs after prior sensitization
  • -These reactions range from mild, itchy ,severe
    skin rash to anaphylaxis
  • -Intensity is determined by degree of
    sensitization and not by the dose.
  • Penicillin as an example
  • We can get sensitization from molds in the air or
    from antibiotics given to animals we eat, we
    dont necessarily have to be given a dose of
    Penicillin to become sensitized to it.
  • Penicillin is not antigenic by itself because it
    is too small. To become capable of eliciting an
    allergic reaction, it must first be metabolized
    and then one of its metabolites attaches to
    endogenous protein to form a happen-protein
    complex. Now, antibodies can be made to this
    complex and an allergic reaction occur.
  • E-Dietary factors
  • 1) Calcium and proteins increase GIT absorption
    of Pb
  • 2)Low protein in diet P.P. level decrease
    free drug toxicity .
  • 3)Food containing tyramine as old cheese ,salted
    dried fish ,banana, Beer, Canned figs, Chicken
    liver ,Chocolate, Sherry wines increase MAOIs
    (e.g., pargyline, phenelzine) toxicity which is
    severe symptoms of hypertensive crisis and even
    death may occur.
  • 4) Calcium in milk, which may bind to
    tetracycline, and thus reduce its absorption.
  • 5) Foods rich in pyridoxine may significantly
    lower the pharmacological action of levodopa

22
  • F-Health factors
  • 1)Acidosis insulin activity decrease leading to
    hyperglycemia
  • 2)Asthma patient is more liable to the effect of
    air pollutants as SO2.
  • 3)Kidney liver diseases toxicity of many drugs
    increase.
  • End of factors
    related to Host

23
  • II-Factors releated to the poison
  • a-Dose
  • It is the amount of a substance administered at
    one time.
  • However, the number of doses, frequency, and
    total time of the exposure are also very
    important .
  • Example
  • b-Routes of exposure
  • -Ingested chemicals, when absorbed from the
    intestine, distribute first to the liver and may
    be immediately detoxified .
  • -Inhaled toxicants immediately enter the general
    blood circulation and can distribute throughout
    the body prior to being detoxified by the liver.
  • Intravenous Inhalation Interapertoneal
    Intramuscular Subcutaneous Oral
    Interadermal

24
  • c-Chemical structure
  • -Silica (amorphous) after it is
    heated silica (crystalline)
  • has little effect on health
    serious lung damage.
  • -Cr3 is relatively nontoxic whereas Cr6 causes
    skin or nasal corrosion and lung cancer.
  • d-Composition and formulation ( mainly
    absorption)
  • -Concentration .
  • -Lipid solubility.
  • -Chemicals in liquid form are more toxic than
    those in solid form
  • -Coloring agents as tartazin yellow cause
    allergy.
  • -Micronization increase toxicity.
  • -Vehicles as alcohols increase CNS depressant
    action of hypnotics.
  • -Impurities some herbicide as 2,4,5-trichlorophen
    oxy acetic acid may contain the toxic impurity
    DIOXIN which is mutagenic ,teratogenic and
    carcinogenic.
  • -pH of the preparation (high acidity or
    alkalinity) cause local sever effect.
  • -Low stability of the compound bad storage
    condition increase toxicity as food contaminants
    aflatoxin ( it is a product of certain molds)
  • -The particle size Only particles having a small
    diameter (1 mm or less) will effectively reach
    the alveoli and be available for pulmonary
    absorption. Larger particles may be deposited on
    the walls of the throat and trachea to produce
    irritation.

25
  • e-The innate chemical activity
  • Some toxicants can quickly damage cells causing
    immediate cell death.  Others slowly interfere
    only with a cell's function.
  • -Hydrogen cyanide binds to cytochrome oxidase
    resulting in cellular hypoxia and rapid death
  • -Nicotine binds to cholinergic receptors in the
    central nervous system (CNS) altering nerve
    conduction and inducing gradual onset of
    paralysis
  • F-Temperature
  • -Toxic response as environmental temperature is
    lowered ( but the duration of the overall
    response may be prolonged)
  • The reasons for these are
  • a. Decreased rate of absorption occurring in the
    colder environment
  • b. Lowered rate of metabolic degradatio
  • On the other hand, atropine-like compounds may
    produce significantly greater toxicity in a warm
    environment than in a colder one. Because
    anticholinergic agents inhibit sweating, the body
    temperature becomes elevated because the absence
    of perspiration prevents cooling of the body so
    the toxic effects are from hyperthermia.
  • End of factors
    related to Toxicant

26
  • III-Toxicokinetic factors
  • i-Factors affecting absorption
  • GIT
  • Gastric content
  • -Empty stomach has higher emptying rate
    Toxicity.
  • -Carbonated beverages increase G.E.
    Toxicity.
  • -A full stomach with proteins fats
    Toxicity.
  • Secretion Pepsin HCl digest peptide poisons
    .
  • GIT flora migration of intestinal flora into the
    stomach in newborns due to their high gastric pH
    ,this flora can convert nitrates into nitrite,
    oxidizing Hb into metHb Hypoxia.
  • Skin (Thickness Keratin layer protect
    the skin )
  • -Newborn (thin delicate skin).
  • -Lipophilicity of insecticides.
    Toxicity
  • -Cutting , abrasions dryness of skin
  • Pulmonary
  • -Conc. Of toxicants in air.
  • -Solubility of the toxin in blood tissues.
  • -Respiration rate.

27
  • ii-Factors affecting metabolism
    (biotransformation)
  • There are two types of metabolism detoxification
    and bioactivation. Detoxification is the process
    by which a xenobiotic is converted to a less
    toxic form. Bioactivation is the process by which
    a xenobiotic may be converted to more reactive or
    toxic forms.

28
  • iii-Factors affecting distribution
  • Main mechanisms opposing distribution of the
    toxicants are
  • a-Plasma proteins
  • -Bilirubin in neonates???.
  • -High affinity for binding to P.P. may cause
    toxicity due to drug interaction as sulfonamide
    displace tolbutamide from P.P. binding site
    causing hypoglycemia.
  • b-Storage
  • -DDT is stored in fat tissues and upon short term
    diet ,mobilization of fats occur leading to
    release of DDT and toxicity.
  • -Fluoride bind to calcium in bones flurosis.
  • -Pb is stored in bones (non toxic to it) ,
    osteoporosis mobilize Pb leading to toxicity.
  • c-Special barriers (B.B.B.)
  • -Mainly depends on lipid solubility

29
  • iv-Factors affecting excretion
  • -The kidney is the primary excretory organ,
    followed by the gastrointestinal tract, and the
    lungs (for gases). Xenobiotics may also be
    excreted in sweat, tears, and milk.
  • -Impaired cardiac , kidney or liver function
    causes slower elimination of toxicants and
    increases their toxic potential.
  • End of
    Toxicokintics factors
  • And
    Factors related to poison

30
  • IV-Chemical Interactions
  • Humans are normally exposed to several chemicals
    at one time rather than to an individual
    chemical.
  • Examples are-Hospital patients on the average
    receive 6 drugs daily-Home influenza treatment
    consists of aspirin, antihistamines, and cough
    syrup taken simultaneously-Drinking water may
    contain small amounts of pesticides, heavy
    metals, solvents, and other organic chemical-Air
    often contains mixtures of hundreds of chemicals
    such as automobile exhaust and cigarette
    smoke-Gasoline vapor at service stations is a
    mixture of 40-50 chemicals
  • -There are four basic types of interactions.

31
  • Additivity-A tranquilizer and alcohol, often
    cause depression equal to the sum of that caused
    by each drug.-Chlorinated insecticides and
    halogenated solvents (which are often used
    together in insecticide formulations) can produce
    liver toxicity with the interaction being
    additive.
  • P.S. this same combination of chemicals
    produces a different type of interaction on CNS.
    Chlorinated insecticides stimulate CNS whereas
    halogenated solvents cause its depression . So,
    the effect of simultaneous exposure on CNS is an
    antagonistic interaction.
  •  
  • PotentiationIt occurs when a chemical that does
    not have a specific toxic effect makes another
    chemical more toxic.
  • Example-Warfarin (a widely used anticoagulant
    in cardiac disease) is bound to plasma albumin so
    that only 2 of the warfarin is active (FREE).
    Drugs which compete for binding sites on albumin
    increase the level of free warfarin to 4
    causing fatal hemorrhage.

32
  • Antagonism
  • It is often a desirable effect in toxicology and
    it is the basis for most antidotes.
  • Examples include
  • Synergism
  • -Exposure to both cigarette smoke and asbestos
    results in a significantly greater risk for lung
    cancer-The hepatotoxicity of a combination of
    ethanol and carbon tetrachloride is much greater
    than the sum of the hepatotoxicity of each.
  • End of Factors affecting Toxicity

33
  • Sources of information on safety
  • 1. Experimental studies
  • Experimental toxicology is a branch of
    toxicology, which deals with toxicity studies in
    experimental animals to evaluate the safety of a
    new chemical (drugs, food additives, pesticides
    and industrial chemicals).
  • 2. Controlled clinical studies
  • Drug is tested on small number (5060) of healthy
    volunteers in a controlled dose for specified
    time
  • 3. Epidemiological studies
  • Thalidomide its teratogenic activity was
    discovered in the 1960s.
  • Sulphonamide elixir (1930) its vehicle was
    ethylene glycol (metabolize to oxalic acid) that
    resulted in titanic convulsion

34
  • Toxicity studies
  • Goals of toxicity studies
  • Predict the toxicity of chemical in human
  • Give information about mechanism of toxicity
  • Give information about toxicity of dosage used
    in humans
  • Toxicity studies indicate the therapeutic index
    which gives information about safety.
  • We can perform different experimental protocols
    using different routes of administration. And
    from this we can determine the following doses
  • 1. No-effect dose it is the maximum dose that
    produces no observable toxic effect on the
    animals.
  • 2. Minimal toxic dose it is the dose that
    produces the least toxicity
  • 3. Median lethal dose (LD50 LC50) This is the
    dose that kills 50 of the animals.

35
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36
How do we measure toxicity?
  • Toxicity is measured in numerous ways. The
    classic measure is ...
  • LD50 Lethal Dose that kills 50 of the
    population.
  • Dosage are measured in a mg toxin/kg body weight.
  • While
  • Drug action is measured by
  • ED50 Effective Dose that produces the desired
    effect in 50 of the population.
  • Dose-Response Curves characterize the response to
    different levels of a drug or toxin.

37
  • Dose Response curveThe dose-response correlates
    exposures and the spectrum of induced effects.
  • -Generally, the higher the dose, the more severe
    the response.
  • -The dose-response relationship is based on data
    from experimental animal, human clinical, or cell
    studies.
  • -The dose-response curve normally takes the form
    of a sigmoid curve. For most effects, small doses
    are not toxic.

38
  • -Knowledge of the shape and slope of the
    dose-response curve is extremely important in
    predicting the toxicity of a substance at
    specific dose levels.
  • -Major differences among toxicants may exist not
    only in the point at which the threshold is
    reached but also in the percent of population
    responding per unit change in dose (i.e., the
    slope).
  • -As illustrated above, Toxicant A has a higher
    threshold but a steeper slope than Toxicant B.

39
  • -Dose-response curves are also used to derive
    dose estimates of chemical substances EDs TDs.
  • Toxic Doses (TDs) the doses that cause adverse
    toxic effects.
  • -The knowledge of the effective and toxic dose
    levels aides the toxicologist and clinician in
    determining the relative safety of
    pharmaceuticals.
  • -As shown above, two dose-response curves are
    presented for the same drug, one for
    effectiveness and the other for toxicity. In this
    case, a dose that is 50-75 effective does not
    cause toxicity whereas a 90 effective dose may
    result in a small amount of toxicity.

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  • The Therapeutic Index (TI) It is the ratio of
    the dose producing 50 toxicity to the dose
    needed to produce the 50 therapeutic response.
  • - For example, if the LD50 is 200 and the ED50 is
    20 mg, the TI would be 10 (200/20). A clinician
    would consider a drug safer if it had a TI of 10
    than if it had a TI of 3.

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  • NOAEL and LOAEL-No Observed Adversed Effect
    Level (NOAEL)
  • -Lowest Observed Adverse Effect Level (LOAEL)
  • -They are the actual data points from clinical or
    experimental animal studies.
  • -They do not necessarily imply toxic or harmful
    effects ,and may be used to describe beneficial
    effects of chemicals as well.

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GENERAL MANAGEMENT OF POISONED PATIENTS
43
General Information
  • Remember
  • All chemicals have potential to be poisons if
    given in a large enough dose
  • Poisoning occurs when exposure to a substance
    adversely affects function of any organ system

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Treatment
  • DECONTAMINATION! ALWAYS be sure that the patient
    has been decontaminated PRIOR to doing anything
    to them!
  • ABCs Always stabilize the patient like you
    would any other patient initially.
  • Draw labs, obtain your EKG, get x-rays if needed,
    begin fluids, and if needed.
  • Decrease absorption or Enhance elimination

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Management Steps
  • 1-Supportive
  • Maintain airway clean, and assure respiration.
  • Correct hypoxia, hypotension, dehydration, hypo-
    or hyperthermia, and acidosis
  • Control seizures
  • 2-Monitor
  • PR, BP, ECG, Oxygenation
  • 3-History Physical examination
  • 4-General Steps
  • ? Absorption
  • ? Elimination
  • 5-Specific antidotes

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I-Emergency stabilization
  • First priorities are ABCs
  • Vital sign including pulse ,oxygen and
    hypoglycemia must be corrected
  • Only in very rare incidences does administration
    of antidote precede stabilizing ABCs and vital
    signs
  • Unresponsive pts treated empirically with coma
    cocktail Oxygen, naloxone, glucose, and thiamine

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  • Airway
  • If the victim loss airway protective reflexes
    ..Airway obstruction by flaccid tongue, or
    aspiration of gastric contents.Respiratory
    arrest
  • .Death
  • -If reflexes were lost or the victim is comatos
    ----do endotracheal intubation
  • Endotracheal intubations
  • Not easy--------requires expertise
  • 1-Nasotracheal intubations
  • -requires local anaesthetic(
    lidocaine) ----reduces pain
    -vasoconstrictor
    (phenylephrine) ----reduces bleeding
  • 2-Orotracheal intubations
  • -requires neuromuscular
    blocker e.g. suxamethonium
  • ( is contraindicated in
    children so pancuronium is recommended in
    children)

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  • BREATHING
  • Breathing difficulties major cause of morbidity
    and death.
  • Complications
  • 1. Ventilatory failure
  • 2. Hypoxia
  • 3. Bronchospasm
  • A-Ventilatory failure
  • CAUSES OF VENTILATORY FAILURE
  • a) Failure of respiratory muscles e.g,
    Neuromuscular blockers, Snake bite
  • b) Depression of respiratory center e.g. by
    barbiturates, alcohols, opioids
  • c) Severe pneumonia.
  • d) Pulmonary oedema

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  • HYPOXIA
  • CAUSES OF HYPOXIA
  • A.Insufficient oxygen in air (e.g. displacement
    of oxygen by inert gases).
  • B.Disruption of oxygen absorption by the lung
  • resulting from
  • 1- pneumonia The most common cause of pneumonia
    in overdosed patients is pulmonary aspiration of
    gastric contents.
  • Pneumonia may also be caused by intravenous
    injection of foreign material or bacteria,
    aspiration of petroleum distillates or inhalation
    of irritant gases.
  • 2-Pulmonary edema
  • -Cardiogenic pulmonary edema caused by Beta
    blockers, Cyclic antidepressants, Quinidine
  • -Non-cardiogenic pulmonary edema caused by
    aspiration of hydrocarbons (e.g. petroleum)
  • C- Cellular hypoxia
  • methemoglobinemia, by oxidizing agents which
    limit binding of oxygen to hemoglobin, and
    cyanide, which blocks oxygen utilization.

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  • Bronchospasm
  • Examples
  • 1.Direct irritant injury from inhaled gases or
    pulmonary aspiration of petroleum distillates or
    stomach contents.
  • 2.Pharmacologic effects of toxins, e.g.
    organophosphate or carbamate insecticides or
    beta-adrenergic blockers.
  • Treatment
  • 1. Assist breathing manually with a
    bag-valve-mask device
  • 2. Perform endotracheal intubation
  • 3.Use oxygen (usually 3035 to start).
  • -Administer 100 oxygen in carbon monoxide
    poisoning
  • 4.Give cyanide antidote kit for cyanide
    poisoning.
  • 5.Remove the patient from the source of exposure
    to any irritant gas.
  • 6.Administer bronchodilators in case of
    bronchospasm
  • a.
    salbutamol inhaler
  • b. If
    this is not effective, give aminophylline, IV.
  • For patients with bronchospasm and bronchorrhea
    caused by organophosphate or other
    anticholinesterase poisoning, give atropine.

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  • CIRCULATION
  • General assessment
  • Check blood pressure and pulse rate and rhythm.
  • Perform cardiopulmonary resuscitation (CPR) if
    there is no pulse
  • perform continuous (ECG) for monitoring of
    arrhythmias
  • 1-Examples of drugs and toxins causing
    bradycardia or AV block
  • Beta blockers, Cholinergic ,Digitalis glycosides
    and Organophosphates.
  • Treatment
  • 1.Administer supplemental oxygen.
  • 2.Rewarm hypothermic patients.
  • 3.Administer atropine or an emergency pacemaker.
  • 2-Examples of drugs and toxins causing
    hypotention
  • -Beta blockers , TCA ,Barbiturates ,Calcium
    antagonists ,Cyanide ,Opiates ,Organophosphates
    and carbamates
  • Hypotension usually responds readily to
    empirical therapy with intravenous fluids and low
    doses of presser drugs (eg, dopamine)

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  • 3-Examples of drugs and toxins causing
    tachycardia
  • Amphetamines ,Caffeine, Cocaine ,Agents causing
    cellular hypoxia Carbon monoxide ,Cyanide
    ,Oxidizing agents (methemoglobinemia) and
    Anticholinergic agents
  • Treatmente.g.For sympathomimetic-induced
    tachycardia, give propranolol, or esmolol,
  • For anticholinergic-induced tachycardia, give
    physostigmine, or neostigmine.
  • 4-Examples of drugs and toxins causing
    hypertention
  • Amphetamines ,Antihistamines ,Cocaine ,Atropine
    ,Epinephrine ,LSD (lysergic acid diethylamide)
    ,Ethanol and drug withdrawal (Marihuana )
    ,Nicotine , Monoamine oxidase inhibitors
    ,Organophosphates, and TCA.
  • Treatment
  • For hypertension with little or no tachycardia,
    use nifedipine or nitroprusside.
  • For hypertension with tachycardia, add to the
    above treatment propranolol, or esmolol , or
    labetalol.
  • Caution Do not use propranolol or esmolol alone
    to treat hypertensive crisis beta blockers may
    paradoxically worsen hypertension if it is caused
    primarily by alpha stimulation.

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History of poisoning
  • 1-History is key to the approach of the poisoned
    patient.
  • 2-Establish an exposure time , Estimate the dose.
  • 3-Determine other factors that may be present and
    affecting your treatment.
  • What type of exposure was this?
  • Environmental, industrial, accidental,
    homicidal, suicidal, or unknown? (Empty bottles ,
    if he was taken from garage.?,a factoryetc).
  • Establish the dose if known. Number of pills in
    the bottle, time ingested/exposed, or have they
    vomited since ingestion?
  • The patient's psychological profile This is
    difficult because the poisoned individual may be
    unconscious, unresponsive or confused.
    Information usually obtained from relatives or
    friends.
  • Identify if the patient performed any self
    treatment or took any medication?

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  • B-Physical examination
  • Physical exam should include all body systems.
  • Many clues may be obtained from the physical
    exam.
  • Some poisons produce clinical characteristics
    which strongly suggest the type of the poison
  • 1-Presence of characteristic odour
  • phenol, alcohol, kerosene, bitter almond odour
    of cyanide
  • 2-Skin manifestation
  • a- Changes in the skin Color
  • - Red in carbon monoxide poisoning.
  • - Pale and dry in atropine poisoning.
  • - Flushed and sweaty in LSD and cocaine.
  • - Cyanosed in cyanide, nitrites.
  • -Yellow Jaundice in acetaminophen, carbon
    tetrachloride
  • b- Needle markers Indicate addiction by
    intravenous route e.g. cocaine.
  • c- Alopecia in Thallium.
  • d-Burns corrosion Acids alkali
  • e-Fingernails may hold many lines in a variety of
    poisonings. Brittle fingernails in thalidomide
    ingestion. Lines/Grooves in sodium fluoride.
    Heavy metals may cause staining or other
    abnormalities of the nails.

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  • 3-Eye
    manifestation
  • a- Eye globe
  • i- Lacrimation In organic phosphorous
  • ii- Nystagmus In barbiturates.
  • b- Pupils
  • i- Dilated reactive pupils In alcohol and
    cocaine.
  • ii- Dilated fixed pupils In atropine.
  • iii- Constricted pupils In phenol and opium.
  • iv- Miosis clonidine, carbamates, opiates,
    organophosphates
  • v-Mydriasis anticholinergics or sympathomimetics
  • 4-Gastro-intestinal manifestations
  • a- Mouth
  • i- Salivation In organophosphorous compounds.
  • ii- Dry mouth In atropine and other
    anticholinergic drugs.
  • iii- Corrosion With corrosives.
  • iv- Gum discoloration Lead causes blue line.
    Cadmium causes yellow line. Mercury causes grey
    line.
  • b- Vomiting

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  • 5-Cardio-vascular manifestations
  • a- Tachycardia In alcohol, atropine.
  • b- Bradycardia In digitalis ,opium, cyanide ß
    blockers.
  • c- Rise in blood pressure Lead,amphetamine, and
    tricyclic antidepressant.
  • d- Hypotension In barbiturates.
  • 6-Respiratory manifestations
  • -Acute respiratory failure in barbiturates.
  • -Pulmonary edema due to inhalation of
    petroleum and arsenic fumes.
  • 7-Central nervous system manifestation
  • a- Coma Barbiturates, Paraldehyde, and
    ethylene glycol.
  • b-Convulsions Amphetamines, camphor, chlorinated
    hydrocarbons, lead, strychnine, cocaine, alcohol,
    anticholinergic, antihistaminic.
  • c-Hyperpyrexia Salicylates, amphetamine and
    theophyline.
  • d-Hypothermia Clonidine and tricyclic
    antidepressants.
  • e-Muscle fasciculations With nicotine,
    strychnine and camphor.
  • f-Tremors Occurs with amphetamines, carbon
    monoxide, hallucinogenic drugs, xanthines
    (theophylline) and tricyclic antidepressants.
  • 8. Skeletal muscle muscle paralysis is produced
    by lead, curare and flaxedil.

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  • C- Analytical toxicological laboratory screening
  • These give the correct diagnosis and could be
    done on biological fluids .This usually include
  • -CBC
  • -Serum electrolyte level.
  • -BUN
  • -Blood glucose, prothrombin time.
  • -Urine analysis.
  • -X-ray on the chest.
  • -Spinal tap (meningitis (coma, fever)
  • Once emergency procedures have been performed and
    the poisoned patient is stabilized, or at least
    is out of immediate danger, additional steps can
    be taken to remove the poison, prevent a delay
    absorption, enhance excretion, or administer a
    specific antidote.

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III-Prevent absorption and removal of poison
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A)-Topical decontamination
  • Prior to the assessment of the patient, you MUST
    be
  • sure the toxin is not toxic to you.
  • If the patient needs to be decontaminated, do
    this PRIOR
  • to your assessment. No need for 2 or more
    patients.
  • -Generally achieved by undressing patients and
    washing them thoroughly with copious amounts
    of water
  • -Should occur outside of ER (Pt should initially
    be in isolated area)
  • -All towels and clothing should be put into
    hazardous waste bags
  • 1- Skin decontamination
  • Rapid decontamination is needed specially if the
    poison is a corrosive or is easily absorbed from
    the skin.
  • -Wash contaminated areas as well as exposed areas
    with warm water or saline , with careful washing
    of the skin, behind ears, under nails, and skin
    folds.
  • 1-Phenol Can apply olive oil .
  • 2-Oxalic acid Soak the affected area with
    solution of calcium gluconate.
  • 3-Organophosphorus Soap water

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  • 2-Eye decontamination
  • i- Irrigation of the eyes with large
    amounts of water.
  • ii- The eye is usually affected by a
    corrosive apply anesthetic drops
    e.g. cocaine HCI (Xylocaine)
  • iii-After first aid treatment the patient
    should be referred to an
    ophthalmologist in order to asses and treat any
    inflammation.
  • 3- Demulcents
  • Many plants and chemicals cause oral and gastric
    mucosa irritation but no serious toxicity.
    Management for these acute ingestion may include
    ice cream or milk. Egg whites, which serve as a
    source of readily available protein, have been
    given for corrosive intoxications.

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B)-If the poison was ingested
  • Three general methods involve removing toxin from
    stomach via the mouth, binding it inside gut
    lumen, or mechanically flushing it through GIT.
    Each method has benefits and risks. However, we
    usually begin with dilution
  • 1- Dilution
  • - By using water milk immediately after
    poisoning.
  • - This reduce the gastric irritation induced by
    many ingested poisons.
  • - Milk provides dilution and is also a demulcent.

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  • 2- Delay gastric emptying
  • a)-Emesis
  • induced by
  • i-Syrup of Ipecac orally administered
  • ii- Apomorphine given by s.c. injection
    (most rapid) ,but cause CNS depression
  • iii- Liquid detergent 30-45 ml in 120-240 ml
    juice or water.
  • Contraindications
  • 1- Ingestion of a strong acids ,alkalis or
    hydrocarbon e.g. kerosene????????
  • 2-Do not induce vomiting if the patient is
    Unconscious or comatose, convulsant , has sever
    cardiovascular disease or, emphysema or under 6
    months of age??
  • b)-Gastric lavage
  • Gastric lavage is only effective when
    ingestion of the poison is discovered within 1
    hours except salicytates may be within 4-6 hours
    (it sticks to the mucous membrane).This procedure
    is often reserved for patients with impaired
    consciousness and uncooperative or when ipecac
    failed to produce emesis.
  • Solutions used sodium bicarbonate, saline,
    tannic acid or water.
  • Indicated for
  • Heavy metals
  • Iron
  • Lithium
  • Sustained or delayed release formulations
  • Contraindications

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  • 3-Adsorbents
  • activated charcoal, starch and flour .
  • Activated charcoal is administered orally to
    adsorb or bind toxins and allows them to pass
    from the GIT without being absorbed into the
    systemic circulation.
  • Contraindications
  • 1- Absence of the bowel sounds .
  • 2- Intestinal obstruction.
  • 3- Many preparation add sorbitol to the mixture
    ,so repeated dose lead to diarrhea,
    dehydration, hypernatraemia in children and
    elderly.
  • 4-DO NOT give with syrup of ipecac because it
    will bind it .
  • 4-Cathartic Agents
  • Such as Magnesium citrate, sodium sulfate ,
    polyethylene glycol and sorbito1. Careful
    monitoring of the fluid and electrolyte status is
    necessary.
  • Contraindications
  • -Catharsis should not be attempted when the
    poison is strongly corrosive, the patient has
    electrolyte disturbance or bowel sounds are
    absent.
  • -Magnesium containing cathartics-should not be
    used in cases of renal failure because of the
    possibility of causing CNS depression due to
    accumulation of high concentration of magnesium
    in the serum.
  • -Sodium containing cathartics are, likewise, best
    avoided by persons with congestive heart failure
  • -Oil cathartics e.g. castor oil may increase the
    absorption of fat-soluble poisons such as
    pesticides.

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IV-Enhance Excretion
67
  • IV-Enhancement of Excretion
  • 1-Forced Diuresis its useful to enhance renal
    elimination of poisons. Saline to expand fluid
    volume and furosemide may be used to enhance
    diuresis.
  • 2-Acid Diuresis with ammonium chloride can
    enhance the elimination of weak bases e.g.
    phencyclidine, amphetamine, strychnine and
    quinidine.
  • 3-Alkaline Diuresis with Sodium bicarbonate can
    remove weak acids (e.g. salicylates and
    Phenobarbital).
  • 4-Dialysis and Hemoperfusion
  • -As adjuncts for management of severely
    intoxicated
  • patients.
  • -Dialysis and hemoperfusion should never replace
    more
  • specific antidotes.
  • -These procedures would be of little value in
    treating acute
  • ingestions of cytotoxic poisons such as cyanide
    which produce
  • toxic effects very rapidly.
  • Dialysis reserved for specific toxins
    salicylates, methanol,
  • ethylene glycol, lithium, theophylline, amanita
    (mushrooms)
  • Benefits removal of toxins already absorbed by
    gut

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V-Antidote
69

  • V- Specific Antidote
  • Chemical antidotes
  • In oxalic acid poisoning, absorption produces
    renal damage. Calcium salts react with oxalic
    acid to yield a poorly soluble compound, calcium
    oxalate, which passes through the intestine
    without being absorbed.
  • Antidotes such as dimercaprol (BAL) and
    deferoxamine form chemical chelates with heavy
    metals. Chelated complexes are water soluble and
    readily excreted by the kidney.
  • Receptor antidotes
  • Compete with the poison for receptor sites.
  • -Naloxone reversal of morphine-induced
    respiratory depression
  • -Cholinergic blockade by atropine (parathion
    poisoning).
  • -For atropin or other anticholinergic poisons,
    physostigmine is a specific antidote.
  • Dispositional antagonism
  • In acetaminophen overdose, a toxic metabolite is
    conjugated with glutathione(a sufhydryl
  • ( sH group donor). When glutathione reserves are
    depleted..hepatotoxicity.
  • N-acetylcysteine is also a source of sulfhydryl
    groups which serve the same function as
    endogenous glutathione. Acetaminophen and its
    toxic metabolite are therefore detoxified and the
    liver cells are not subjected to prolonged
    toxicity.
  • Function (physiologic) antagonist
  • Epinephrine reverses the bronchoconstriction due
    to anaphylactic reaction following administration
    of certain drugs.

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  • Poison Antidote
  • Acetaminophen N-acetylcysteine
  • Lead,Arsenic EDTA
    ,Dimercaprol
  • Atropine Physostigmine
  • Cyanide, nitroprusside Antidote kit
  • Digoxin Fab
    fragments
  • Ethylene glycol, MeOH Ethanol
  • Iron Deferoxamine
  • Opioids Naloxone
  • Organophosphates Atropine,Pralidoxime
  • Warfarin Vitamin K1

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  • VI-Supportive therapy Observation
  • -I.V. fluids
  • -Frequent blood and urine pH adjustment.
  • -Intensive nursing care.
  • -Avoid unnecessary drugs.
  • -Treatment for hypo- or hyperthermia.
  • -Management of hypotension.
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