Toxicology

Toxicology is "the science of poisons".Def. : It is the study of the adverse effects of chemicals or physical agents (xenobiotic) on living organisms.

Xenobiotic = foreign substance taken into the body .It is derived from the Greek term xeno which means

"foreigner".

"  Xenobiotics may produce beneficial effects (such as a pharmaceuticals) or they may be toxic (such as lead).

Historical Development of Historical Development of ToxicologyToxicology

It is one of the oldest practical sciences which began with early cave dwellers who 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 recognized poisonous plants and animals and used their extracts for hunting

or in warfareor in warfare  .  .

By 1500 BCBy 1500 BC, hemlock, opium, arrow poisons, and certain metals were used to , hemlock, opium, arrow poisons, and certain metals were used to poison enemies or for executions (Notable poisoning victims include Socrates, poison enemies or for executions (Notable poisoning victims include Socrates, Cleopatra, and Claudius)Cleopatra, and Claudius) . .

The Death of Socrates, 1787 Jacques-Louis DavidThe Death of Socrates, 1787 Jacques-Louis David( ( Metropolitan Museum of Art, New YorkMetropolitan Museum of Art, New York))

By the time certain concepts fundamental to toxicology began to take By the time certain concepts fundamental to toxicology began to take shape especially by the studies of Paracelsus shape especially by the studies of Paracelsus (~1500AD)(~1500AD) and Orfila and Orfila (~1800 AD)(~1800 AD)..

ParacelsusParacelsus (1493 -1541)(1493 -1541)::His famous words wereHis famous words were: :

""All substances are poisons; there is none which is not a poison.  The right dose All substances are poisons; there is none which is not a poison.  The right dose differentiates a poison and a remedydifferentiates a poison and a remedy".".

11--He determined that specific chemicals were actually responsible for the toxicity of He determined that specific chemicals were actually responsible for the toxicity of a plant or animal poisona plant or animal poison . .

22--He also documented that the body's response to those chemicals depended on the dose He also documented that the body's response to those chemicals depended on the dose receivedreceived

Orfila Orfila (founder of toxicology -19th century)(founder of toxicology -19th century)Spanish physician who first correlated between the chemical and biological properties of Spanish physician who first correlated between the chemical and biological properties of poisonspoisons..

The 20th century is marked by an advanced level of understanding of The 20th century is marked by an advanced level of understanding of toxicology.  DNA toxicology.  DNA (the molecule of life)(the molecule of life) and various biochemicals and various biochemicals that maintain body functions were discovered. Now our level of that maintain body functions were discovered. Now our level of knowledge of toxic effects on organs and cells is being revealed at knowledge of toxic effects on organs and cells is being revealed at

the molecular levelthe molecular level . .

Scope of ToxicologyScope of ToxicologyToxicology is multidisciplinary as it entailsToxicology is multidisciplinary as it entails::

11--Mechanistic ToxicologyMechanistic Toxicology:: ExampleExample::

Biochemical toxicologyBiochemical toxicology: It deals with determination of mode of action of toxins at the : It deals with determination of mode of action of toxins at the molecular levelmolecular level..

Behavioral toxicologyBehavioral toxicology: deals with the effect of toxin on the animal and human : deals with the effect of toxin on the animal and human behavior (mainly on CNS & autonomic NS)behavior (mainly on CNS & autonomic NS)CarcinogenesisCarcinogenesis:: deals with the chemical and biochemical events that lead cancer deals with the chemical and biochemical events that lead cancer..

Teratogenesis:Teratogenesis: deals with the chemical and biochemical events that lead to deleterious deals with the chemical and biochemical events that lead to deleterious effect on developmental processeffect on developmental process..

MutagenesisMutagenesis: it is concerned with toxic effect on the genetic material and the : it is concerned with toxic effect on the genetic material and the inheritance of these defectsinheritance of these defects..

22--Applied ToxicologyApplied Toxicology: : Clinical ToxicologyClinical Toxicology: It deals with emergency cases such as overdoses, poisonings, : It deals with emergency cases such as overdoses, poisonings, attempted suicides byattempted suicides by::

* * Emergency care for patientsEmergency care for patients..* * Management of sign and symptomManagement of sign and symptom

* * Identification and quantification of the drug ,poisons, chemicals…etcIdentification and quantification of the drug ,poisons, chemicals…etc . .

Forensic ToxicologyForensic Toxicology: : It deals with medical-legal aspects of poisonings byIt deals with medical-legal aspects of poisonings by:: * * Identification and quantification of poisonsIdentification and quantification of poisons..

* * Establish relationship between tissue residual level and Establish relationship between tissue residual level and the cause of death the cause of death . .

Economic ToxicologyEconomic Toxicology: It is concerned with development of drugs additives , : It is concerned with development of drugs additives ,

food additives and pesticides food additives and pesticides..

Environmental ToxicologyEnvironmental Toxicology: It is concerned with effects of different compounds : It is concerned with effects of different compounds on air, water and wildlife on air, water and wildlife

33--Analytical ToxicologyAnalytical Toxicology::It is concerned with quantitative & qualitative analysis of toxicant in body fluids, It is concerned with quantitative & qualitative analysis of toxicant in body fluids, secretion and /or tissuessecretion and /or tissues..

44--Regulatory ToxicologyRegulatory Toxicology:: Risk assessmentRisk assessment : :

It deals with analysis of toxicological data for the determination of: Safe level of 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 drugs for humans , safe level of heavy metals in water , safe levels pesticides...etc..

Legal aspectLegal aspect:: Concerned with formulation of laws which are intended to minimize the effect of Concerned with formulation of laws which are intended to minimize the effect of

toxic chemicals on humans health & the environment toxic chemicals on humans health & the environment..

ToxicityToxicityDef.:Def.: The degree to which a substance can The degree to which a substance can

harm humans or animalharm humans or animal Different xenobiotics cause many types of toxicity Different xenobiotics cause many types of toxicity by a variety of mechanisms. So, we have to take by a variety of mechanisms. So, we have to take an idea aboutan idea about : :

--Different types of toxic agentsDifferent types of toxic agents

--Different type of toxicityDifferent type of toxicity

--Different mechanisms of toxic responseDifferent mechanisms of toxic response

Toxic AgentsToxic AgentsTToxic agent: oxic agent: is anything that can is anything that can produce an adverse biological effectproduce an adverse biological effect . .

--The most common terms used to The most common terms used to describe a toxic agent are toxicant, describe a toxic agent are toxicant, toxin, poisontoxin, poison..

Toxic Agents are classifiedToxic Agents are classified: :

11--According to their natureAccording to their nature::11--ChemicalsChemicals: : as alcohols, phenols & heavy metalsas alcohols, phenols & heavy metals

22--Physical : as radiationPhysical : as radiation..22--Bilogical : Snake & scorpion venomsBilogical : Snake & scorpion venoms..

22--According to their effectAccording to their effect : :i-Systemic toxicanti-Systemic toxicant::

is one that affects the entire body or many organs rather than a specific siteis 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 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 oxygenand organ in the body by interfering with the cell's ability to utilize oxygen..ii-Target organs toxicantii-Target organs toxicant::

affect only specific tissues or organs while not producing damage to the body as a affect only specific tissues or organs while not producing damage to the body as a wholewhole . .ExamplesExamples::

--Arsenic& paracetamol are hepatotoxicArsenic& paracetamol are hepatotoxic..--Digitalis& antimony are cardiotoxicDigitalis& antimony are cardiotoxic..

--Mercury & gentamycin are nepherotoxicMercury & gentamycin are nepherotoxic- - Lead is also a specific organ toxin; however, it has three target organs Lead is also a specific organ toxin; however, it has three target organs (central (central

nervous system, kidney, and hematopoietic system) nervous system, kidney, and hematopoietic system)..

Types of poisoningTypes of poisoningToxicity can be classified according to different variables as followToxicity can be classified according to different variables as follow::

11--According to circumstances of poisoningAccording to circumstances of poisoning::a-Accidental Toxicity (non-intentional poisoning)a-Accidental Toxicity (non-intentional poisoning)::

which occur by mistakes and usually happen to children (below 5-years old)which occur by mistakes and usually happen to children (below 5-years old)E.g.:With aspirin, iron preparations, pesticides, kerosene…..etcE.g.:With aspirin, iron preparations, pesticides, kerosene…..etc..b-Deliberate self Toxicity (Suicidal or criminal poisoning)b-Deliberate self Toxicity (Suicidal or criminal poisoning)::

which occur when a person attempts to kill himself or another personwhich occur when a person attempts to kill himself or another person . .E.g.: with cyanide, barbiturates,salicylates…………………etcE.g.: with cyanide, barbiturates,salicylates…………………etc

22--According to incidence of poisoningAccording to incidence of poisoning::a-Homicidal:a-Homicidal: Which occurs in or around homeWhich occurs in or around home..

E.g.: pesticides, potassium hydroxide, disinfectantsE.g.: pesticides, potassium hydroxide, disinfectants.…….……b-Occupationalb-Occupational: This includes industrial and agricultural poisoning: This includes industrial and agricultural poisoning..E.g.: inhalation of pesticidesE.g.: inhalation of pesticides..

Types of ToxicityTypes of Toxicity11--Systemic ToxicitySystemic Toxicity: :

Toxicity may occur at multiple sites. Toxicity may occur at multiple sites. This is referred as systemic toxicity. This is referred as systemic toxicity. The following are types of systemic The following are types of systemic toxicitytoxicity : :

--Acute ToxicityAcute Toxicity --Subchronic ToxicitySubchronic Toxicity

--Chronic ToxicityChronic Toxicity --CarcinogenicityCarcinogenicity

--Developmental ToxicityDevelopmental Toxicity --Genetic ToxicityGenetic Toxicity

a-Acute Toxicitya-Acute Toxicity::It occurs almost immediately (hours/days) after an exposure to single dose or a series of doses received within a 24 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 arehour 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 In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate

from an industrial accident in Bhopal, Indiafrom an industrial accident in Bhopal, India . .- - Many people die each year from inhaling carbon monoxide from faulty heatersMany people die each year from inhaling carbon monoxide from faulty heaters . .

b-Subchronic Toxicityb-Subchronic Toxicity::It results from repeated exposure for several weeks or months. This is a common human exposure pattern for It results from repeated exposure for several weeks or months. This is a common human exposure pattern for

some pharmaceuticals and environmental agents. Examples aresome pharmaceuticals and environmental agents. Examples are : :- - Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis

can cause internal bleedingcan cause internal bleeding . .- - Workplace exposure to lead over a period of several weeks can result in anemiaWorkplace exposure to lead over a period of several weeks can result in anemia . .

c-Chronic Toxicityc-Chronic Toxicity::It isa cumulative damage to specific organ systems and takes many months or years to become a recognizable It isa cumulative damage to specific organ systems and takes many months or years to become a recognizable clinical disease. This damage is so severe that the organ can no longer function normally and a variety of clinical disease. This damage is so severe that the organ can no longer function normally and a variety of

chronic toxic effects may result. Examples arechronic toxic effects may result. Examples are : :- - Cirrhosis in alcoholics who have ingested ethanol for several yearsCirrhosis in alcoholics who have ingested ethanol for several years

- - Chronic bronchitis in long-term cigarette smokersChronic bronchitis in long-term cigarette smokers - - Pulmonary fibrosis in Pulmonary fibrosis in coalcoal miners (black lung disease) miners (black lung disease)

d-Carcinogenicityd-Carcinogenicity::Carcinogenicity is a complex multistage process of abnormal cell growth and differentiation which can lead to Carcinogenicity is a complex multistage process of abnormal cell growth and differentiation which can lead to cancercancer . .

e-Developmental Toxicitye-Developmental Toxicity::Developmental Toxicity result from toxicant exposure to either parent before conception or to the mother and her Developmental Toxicity result from toxicant exposure to either parent before conception or to the mother and her developing embryo-fetusdeveloping embryo-fetus . .

f-Genetic Toxicityf-Genetic Toxicity::Genetic Toxicity results from damage to DNA and altered genetic expression. This process is known as 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 mutagenmutagenesis. The genetic change is referred to as a mutation and the agent causing the change as a mutagen . .

22--Organ Specific ToxicityOrgan Specific Toxicity: : Blood and Cardiovascular ToxicityBlood and Cardiovascular ToxicityHypoxia due to carbon monoxide binding of hemoglobin preventing transport of oxygenHypoxia due to carbon monoxide binding of hemoglobin preventing transport of oxygen

HepatotoxicityHepatotoxicityCCl4……..metabolized by HME…….CCl3 (causes lipid peroxidation in liver & lead to liver CCl4……..metabolized by HME…….CCl3 (causes lipid peroxidation in liver & lead to liver necrosis.)necrosis.)

NephrotoxicityNephrotoxicityMercury & gentamycin are nepherotoxicMercury & gentamycin are nepherotoxic..

NeurotoxicityNeurotoxicityOrganophosphorus compounds (insecticides)………damage to sensory fibersOrganophosphorus compounds (insecticides)………damage to sensory fibers..

Respiratory ToxicityRespiratory ToxicityAluminum…..emphysema……inflated lung …….fibrosis(aluminosis)Aluminum…..emphysema……inflated lung …….fibrosis(aluminosis)..

Dermal ToxicityDermal Toxicitydermal irritation due to skin exposure to gasolinedermal irritation due to skin exposure to gasoline dermal corrosion due to skin exposure to sodium hydroxidedermal corrosion due to skin exposure to sodium hydroxide skin cancer due to ingestion of arsenic or skin exposure to UV lightskin cancer due to ingestion of arsenic or skin exposure to UV light

Eye ToxicityEye Toxicityacids and strong alkalis may cause severe corneal corrosionacids and strong alkalis may cause severe corneal corrosion corticosteroids may cause cataractscorticosteroids may cause cataracts methanol (wood alcohol) may damage the optic nerve leading to blindnessmethanol (wood alcohol) may damage the optic nerve leading to blindness

Mechanism of Cellular Mechanism of Cellular InjuryInjury

Toxinemitted

Transported, dispersed,

and possibly altered

Ingested

Contactshuman

Reachesan organ

Metabolizedand/orstored

Physiologicalchain ofevents

Mechanism of Cellular Mechanism of Cellular InjuryInjury

Toxicity can result from adverse cellular, biochemical, or macromolecular Toxicity can result from adverse cellular, biochemical, or macromolecular changes.  Examples arechanges.  Examples are::

11--Alteration of a cell membrane permeabilityAlteration of a cell membrane permeability::Toxic agents could change cell membrane permeability through interaction with Toxic agents could change cell membrane permeability through interaction with

its component asits component as ; ;a-SH-containing proteinsa-SH-containing proteins::

Heavy metals as As or Hg react with them……… change in protein structure Heavy metals as As or Hg react with them……… change in protein structure ……… change membrane permeability……… change membrane permeability..

b-Lipidsb-Lipids--Free radicals attack fatty acids in the lipid layer of biological membrane causing 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 lipid peroxidation , these peroxides are toxic to the cell and alter membrane permeabilitypermeability..

E.g.: CCl4……..metabolized by HME……CCl3 (Trichloromethyl radical causes E.g.: CCl4……..metabolized by HME……CCl3 (Trichloromethyl radical causes lipid peroxidation and finally lead to liver necrosis.)lipid peroxidation and finally lead to liver necrosis.)

--This is why antioxidants should be used frequently by humans where it act as a 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. Cprotective measure against many diseases(e.g.) Vit. E & Vit. C..

c-Na-K ATPase pumpc-Na-K ATPase pump::Many toxicants can inhibit these pumps which are essential for transport of major Many toxicants can inhibit these pumps which are essential for transport of major amino acids and calcium across the cell membraneamino acids and calcium across the cell membrane..E.g.: Hg, Cu, Pb , As and alcoholE.g.: Hg, Cu, Pb , As and alcohol. .

22--Chang in enzyme activityChang in enzyme activity::a-Inhibitiona-Inhibition::

E.g.1: Carbamate esters (insecticides) reversibly inhibits anticholineserase leading E.g.1: Carbamate esters (insecticides) reversibly inhibits anticholineserase leading to increase in A.Ch. Level Toxicity (SLUD are the to increase in A.Ch. Level Toxicity (SLUD are the

most characteristic symptoms of toxicity)most characteristic symptoms of toxicity) . .E.g.2: Cyanide………inhibits cytochrome oxidase enzyme……no aerobic E.g.2: Cyanide………inhibits cytochrome oxidase enzyme……no aerobic respiration……….cell deathrespiration……….cell death..b-Activationb-Activation::

E.g.: Barbiturates induce hepatic microsomal enzymes increase the conversion E.g.: Barbiturates induce hepatic microsomal enzymes increase the conversion of some non carcinogenic agents (in cigarette smoke) into carcinogenic onesof some non carcinogenic agents (in cigarette smoke) into carcinogenic ones..

33--Interferance with co-enzymesInterferance with co-enzymes::E.g.: CN- binds to essential metals as Fe3+ needed for the activity of cyochrome E.g.: CN- binds to essential metals as Fe3+ needed for the activity of cyochrome oxidaseoxidase..

44--Modification of carriersModification of carriers::E.g.1: CO binds with hemoglobin instead of O2 (affinity to Hb to CO is 210 times E.g.1: CO binds with hemoglobin instead of O2 (affinity to Hb to CO is 210 times that for O2)……… carboxyhemoglobin…….hypoxia……deaththat for O2)……… carboxyhemoglobin…….hypoxia……death..

E.g.2: Nitrates ,aspirin and sulfonamides oxidize Fe2+ in Hb into Fe3E.g.2: Nitrates ,aspirin and sulfonamides oxidize Fe2+ in Hb into Fe3 + + Hb …………………MeHb (methemoglobin) which can not carry oxygenHb …………………MeHb (methemoglobin) which can not carry oxygen

NADPH-dependentNADPH-dependent Hypoxia Hypoxia

MeHb reductase & Vit. CMeHb reductase & Vit. C

55--Formation of reactive metabolitesFormation of reactive metabolites::E.g.: Benzo(α)pyrene metabolized by HME epoxide-7,8- dihydrodibenzo(α) E.g.: Benzo(α)pyrene metabolized by HME epoxide-7,8- dihydrodibenzo(α)

pyrene pyrene Non-carcinogenic CarcinogenicNon-carcinogenic Carcinogenic

In cigarette smokeIn cigarette smoke

66--Reactions causing depletion of GSHReactions causing depletion of GSH::Glutathione (GSH) is an antioxidant which protects the cell from the harmful effect of 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 oxidants. Reduction of GSH level into 20-30% causes impairment of cell defense

mechanismmechanism. . E.g.: N-acetyl-P-benzoquinone imine (NABQI) ,a toxic metabolite of paracetamol it is 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 conjugated with GSH depletion of reduced form of GSH leading to NABQI (Strong electrophilic agent) attack liver tissues causing liver necrosis(Strong electrophilic agent) attack liver tissues causing liver necrosis..

--We can increase the level of GSH or overcome its depletion by; methionin (a precursor We can increase the level of GSH or overcome its depletion by; methionin (a precursor of GSH) & N-acetylcysteine (contains –SH)of GSH) & N-acetylcysteine (contains –SH)..

77 - -Action on nucleic acidsAction on nucleic acids::E.g.: SO2 (air pollutant) + H2O HSO3(causing damage to DNA & mutation)E.g.: SO2 (air pollutant) + H2O HSO3(causing damage to DNA & mutation)..E.g.: Benzidine Metabolism by HME N-hydroxybenzidineE.g.: Benzidine Metabolism by HME N-hydroxybenzidine..

Non-carcinogenic Mutagenic & CarcinogenicNon-carcinogenic Mutagenic & Carcinogenic In cigarette smokeIn cigarette smoke

88 - -Disruption of protein synthesisDisruption of protein synthesis::SomeSome toxicants either increase or decrease protein synthesis leading to cellulartoxicants either increase or decrease protein synthesis leading to cellular injuryinjury..

99--Lysosomal changesLysosomal changes::a-Toxicants which causes labialization of lysosomal enzymesa-Toxicants which causes labialization of lysosomal enzymes::

E.g.: Hg , Cu , silica , nicotine , bee venom , hypervitaminosis A , monosodium ureate E.g.: Hg , Cu , silica , nicotine , bee venom , hypervitaminosis A , monosodium ureate crystals deposited in gout increase lysosomal membrane permeability release crystals deposited in gout increase lysosomal membrane permeability release of hydrolases cell deathof hydrolases cell death..b-Toxicants which causes stabilization of lysosomal enzymesb-Toxicants which causes stabilization of lysosomal enzymes::

E.g.: Corticosteroids causes indirect toxicity by decreasing the response of the body E.g.: Corticosteroids causes indirect toxicity by decreasing the response of the body defense mechanismdefense mechanism. .

Factors Influencing Factors Influencing ToxicityToxicity

There are many factors which can enhance, increase or decrease toxicity. These There are many factors which can enhance, increase or decrease toxicity. These factors are divided intofactors are divided into: :

I-Factors related to the hostI-Factors related to the host:: A-The speciesA-The species..

--Rats cannot vomit and expel toxicants before they cause severe irritation, whereas Rats cannot vomit and expel toxicants before they cause severe irritation, whereas humans and dogs are capable of vomitinghumans and dogs are capable of vomiting . .

Selective toxicity: refers to species differences in toxicity response between two species Selective toxicity: refers to species differences in toxicity response between two species simultaneously exposedsimultaneously exposed

--an insecticide is lethal to insects but relatively nontoxic to mammalsan insecticide is lethal to insects but relatively nontoxic to mammals???…???… malthionmalthion

Oxidation by ME HydrolysisOxidation by ME Hydrolysis))rapid in insects & slow in mammalsrapid in insects & slow in mammals) () (slow in insects & rapid in mammalsslow in insects & rapid in mammals((

Malaoxone Inactive substanceMalaoxone Inactive substance

))Lethal to insectsLethal to insects ( (

B-SexB-Sex:: --Male rats are 10 times more sensitive than females to liver damage from DDT &CClMale rats are 10 times more sensitive than females to liver damage from DDT &CCl 44 ?… ?…

C-AgeC-Age::- - Some chemicals are more toxic to infants or the elderly than to adultsSome chemicals are more toxic to infants or the elderly than to adults . .

ExampleExample : :11-(-(Bounded bilirubin with p.p.+Sulfonamides replacement from P.P. binding sitesBounded bilirubin with p.p.+Sulfonamides replacement from P.P. binding sites..

conjugated with glucoronyl transferaseconjugated with glucoronyl transferase

Free bilirubin excreted in adultsFree bilirubin excreted in adults) ) Low activity of GT + Immature B.B.B in neonatesLow activity of GT + Immature B.B.B in neonates((

Kernikterus (in newborn)Kernikterus (in newborn)

22-(-(Nitates(in well water) due to stomach pH is high in newborn Nitrite (oxidant)Nitates(in well water) due to stomach pH is high in newborn Nitrite (oxidant)

OxidationOxidation Hb MetHbHb MetHb

MetHb reductaseMetHb reductase

) ) v.weak in newbornsv.weak in newborns ( (HypoxiaHypoxia

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

D-GeneticsD-Genetics::

I-PharmacogenticesI-Pharmacogentices (Idiosyncratic reaction ):(Idiosyncratic reaction ): An odd response to a given normal dose of a An odd response to a given normal dose of a drug on hereditary basisdrug on hereditary basis..

11 ( (Succinylcholine apnea in individuals deficient in pseudo cholinesteraseSuccinylcholine apnea in individuals deficient in pseudo cholinesterase?.… ?.… 22 ( (Individuals deficient in glucose-6-phosphate dehydrogenase suffer from hemolytic Individuals deficient in glucose-6-phosphate dehydrogenase suffer from hemolytic

anemia upon using sulfa drugs , aspirin or naphthalene (oxidants)anemia upon using sulfa drugs , aspirin or naphthalene (oxidants)

glucose-6-phosphate + NADP 2 GSH (glucose-6-phosphate + NADP 2 GSH (protect RBCs from hemolysis by oxidants)protect RBCs from hemolysis by oxidants)

G6PD GSH reductaseG6PD GSH reductase

66--phosphogluconic acid + NADPH GSSGphosphogluconic acid + NADPH GSSG

In case of G6PD deficiency NADPH GSH Oxidants attack RBCs hemolysisIn case of G6PD deficiency NADPH GSH Oxidants attack RBCs hemolysis

II-Toxicogentices:II-Toxicogentices: An odd response to a given toxicant on hereditary basis An odd response to a given toxicant on hereditary basis * *smoking causes emphysema in certain individuals deficient in smoking causes emphysema in certain individuals deficient in αα1- 1- antitrypsinantitrypsin..

III-Hypersensitivity (aIII-Hypersensitivity (allergic reactions)llergic reactions)::e.g. Some people suffer from an anaphylactic reaction when given penicilline.g. Some people suffer from an anaphylactic reaction when given penicillin..

Allergic reactionsAllergic reactions = an immune response that occurs after prior sensitization = an immune response that occurs after prior sensitization

--These reactions range from mild, itchy ,severe skin rash to anaphylaxisThese reactions range from mild, itchy ,severe skin rash to anaphylaxis--Intensity is determined by degree of sensitization and not by the doseIntensity is determined by degree of sensitization and not by the dose..

Penicillin as an examplePenicillin as an example : :We can get sensitization from molds in the air or from antibiotics given to We can get sensitization from molds in the air or from antibiotics given to animals we eat, we don’t necessarily have to be given a dose of animals we eat, we don’t necessarily have to be given a dose of Penicillin to become sensitized to itPenicillin to become sensitized to it..

Penicillin is not antigenic by itself because it is too small. To become Penicillin is not antigenic by itself because it is too small. To become capable of eliciting an allergic reaction, it must first be metabolized capable of eliciting an allergic reaction, it must first be metabolized and then one of its metabolites attaches to endogenous protein to form and then one of its metabolites attaches to endogenous protein to form a happen-protein complex. Now, antibodies can be made to this a happen-protein complex. Now, antibodies can be made to this complex and an allergic reaction occurcomplex and an allergic reaction occur..

E-Dietary factorsE-Dietary factors11 ( (Calcium and proteins :increase GIT absorption of PbCalcium and proteins :increase GIT absorption of Pb

22((Low protein in diet:P.P. level decrease free drug toxicityLow protein in diet:P.P. level decrease free drug toxicity. . 33((Food containing tyramine as old cheese ,salted dried fish ,banana & Food containing tyramine as old cheese ,salted dried fish ,banana &

wines increase MAOIs toxicitywines increase MAOIs toxicity..

F-Health factorsF-Health factors::

11((Acidosis: insulin activity decrease leading to hyperglycemiaAcidosis: insulin activity decrease leading to hyperglycemia

22((Asthma: patient is more liable to the effect of air pollutants as SO2Asthma: patient is more liable to the effect of air pollutants as SO2..

33((Kidney & liver diseases: toxicity of many drugs increaseKidney & liver diseases: toxicity of many drugs increase..

End of factors related to HostEnd of factors related to Host

II-Factors releated to the poisonII-Factors releated to the poison::

a-a-DoseDose It is the amount of a substance administered at one timeIt is the amount of a substance administered at one time . .

However, the number of doses, frequency, and total time of the exposure are also However, the number of doses, frequency, and total time of the exposure are also very importantvery important . . ExampleExample : :

b-Routes of exposureb-Routes of exposure --Ingested chemicals, Ingested chemicals, when absorbedwhen absorbed from the intestine, distribute first to the liver from the intestine, distribute first to the liver

and may be immediately detoxifiedand may be immediately detoxified. .

--Inhaled toxicants immediately enter the general blood circulation and can Inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liverdistribute throughout the body prior to being detoxified by the liver . .

Intravenous › Inhalation › Interapertoneal › Intramuscular › Subcutaneous › Intravenous › Inhalation › Interapertoneal › Intramuscular › Subcutaneous › Oral › InteradermalOral › Interadermal

c-c-Chemical structureChemical structure--Silica (amorphous) Silica (amorphous) after it is heatedafter it is heated silica (crystalline) silica (crystalline)

has little effect on health serious lung damagehas little effect on health serious lung damage . .

--Cr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancerCr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancer.. d-Composition and formulation: d-Composition and formulation: ( mainly › absorption)( mainly › absorption)

--ConcentrationConcentration. . --Lipid solubilityLipid solubility..

--Chemicals in liquid form are more toxic than those in solid formChemicals in liquid form are more toxic than those in solid form--Coloring agents as tartazin yellow cause allergyColoring agents as tartazin yellow cause allergy..

--Micronization increase toxicityMicronization increase toxicity..--Vehicles as alcohols increase CNS depressant action of hypnoticsVehicles as alcohols increase CNS depressant action of hypnotics..

--Impurities; some herbicide as 2,4,5-trichlorophenoxy acetic acid may contain the toxic impurity Impurities; some herbicide as 2,4,5-trichlorophenoxy acetic acid may contain the toxic impurity DIOXIN which is mutagenic ,teratogenic and carcinogenicDIOXIN which is mutagenic ,teratogenic and carcinogenic..

--pH of the preparation (high acidity or alkalinity) cause local sever effectpH of the preparation (high acidity or alkalinity) cause local sever effect..--Low stability of the compound + bad storage condition increase toxicity as food contaminants Low stability of the compound + bad storage condition increase toxicity as food contaminants

aflatoxin ( it is a product of certain molds)aflatoxin ( it is a product of certain molds)

e-The innate chemical activitye-The innate chemical activity: : Some toxicants can quickly damage cells causingSome toxicants can quickly damage cells causing immediate immediate cell death.  Others cell death.  Others slowly interfereslowly interfere only only with a cell's functionwith a cell's function..

- - Hydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia andHydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia and rapid rapid death death --Nicotine binds to cholinergic receptors in the central nervous system (CNS) altering nerve Nicotine binds to cholinergic receptors in the central nervous system (CNS) altering nerve

conduction and inducing conduction and inducing gradual gradual onset of paralysisonset of paralysis

III-Toxicokinetic factorsIII-Toxicokinetic factors::i-Factors affecting absorptioni-Factors affecting absorption::

* * GITGIT: : Gastric contentGastric content::

--Empty stomach has higher emptying rate ToxicityEmpty stomach has higher emptying rate Toxicity..--Carbonated beverages increase G.E. ToxicityCarbonated beverages increase G.E. Toxicity..

--A full stomach with proteins & fats ToxicityA full stomach with proteins & fats Toxicity..Secretion Secretion : : Pepsin & HCl digest peptide poisonsPepsin & HCl digest peptide poisons. .

GIT floraGIT flora:: migration of intestinal flora into the stomach in newborns due migration of intestinal flora into the stomach in newborns due to their high gastric pH ,this flora can convert nitrates into nitrite, to their high gastric pH ,this flora can convert nitrates into nitrite, oxidizing Hb into metHb Hypoxiaoxidizing Hb into metHb Hypoxia..

* * Skin Skin (Thickness & Keratin layer protect the skin )(Thickness & Keratin layer protect the skin )::--Newborn (thin delicate skin)Newborn (thin delicate skin)..

--Lipophilicity of insecticides. ToxicityLipophilicity of insecticides. Toxicity--Cutting , abrasions & dryness of skinCutting , abrasions & dryness of skin

* * PulmonaryPulmonary::--Conc. Of toxicants in airConc. Of toxicants in air..

--Solubility of the toxin in blood & tissuesSolubility of the toxin in blood & tissues..--Respiration rateRespiration rate..

--Exposure timeExposure time..

ii-Factors affecting metabolism (biotransformation)ii-Factors affecting metabolism (biotransformation)::There are two types of metabolism :detoxification and bioactivation. Detoxification is the 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 is converted to a less toxic form. Bioactivation is the

process by which a xenobiotic may be converted to more reactive or toxic formsprocess by which a xenobiotic may be converted to more reactive or toxic forms..

iii-Factors affecting distributioniii-Factors affecting distribution::Main mechanisms opposing distribution of the toxicants areMain mechanisms opposing distribution of the toxicants are : :a-Plasma proteinsa-Plasma proteins::

--Bilirubin in neonatesBilirubin in neonates.???.???--High affinity for binding to P.P. may cause toxicity due to High affinity for binding to P.P. may cause toxicity due to

drug interaction as sulfonamide displace tolbutamide from drug interaction as sulfonamide displace tolbutamide from P.P. binding site causing hypoglycemiaP.P. binding site causing hypoglycemia . .b-Storageb-Storage::

--DDT is stored in fat tissues and upon short term DDT is stored in fat tissues and upon short term diet ,mobilization of fats occur leading to release of DDT diet ,mobilization of fats occur leading to release of DDT and toxicityand toxicity..

--Fluoride bind to calcium in bones flurosisFluoride bind to calcium in bones flurosis..--Pb is stored in bones (non toxic to it) , osteoporosis mobilize Pb is stored in bones (non toxic to it) , osteoporosis mobilize

Pb leading to toxicityPb leading to toxicity..c-Special barriers (B.B.B.)c-Special barriers (B.B.B.)::

--Mainly depends on lipid solubilityMainly depends on lipid solubility

iv-Factors affecting excretioniv-Factors affecting excretion::--The kidney is the primary excretory organ, followed by the gastrointestinal tract, 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 and the lungs (for gases). Xenobiotics may also be excreted in sweat, tears, and milkmilk . .

---Impaired cardiac , kidney or liver function causes slower elimination of Impaired cardiac , kidney or liver function causes slower elimination of toxicants and increases their toxic potentialtoxicants and increases their toxic potential..

- - End of Toxicokintics factorsEnd of Toxicokintics factors

- And Factors related to poisonAnd Factors related to poison

IV-Chemical InteractionsIV-Chemical InteractionsHumans are normally exposed to several chemicals at Humans are normally exposed to several chemicals at one time rather than to an individual chemicalone time rather than to an individual chemical . .

Examples are:Examples are:-Hospital patients on the average receive 6 drugs daily-Hospital patients on the average receive 6 drugs daily-Home influenza treatment consists of aspirin, antihistamines, and cough syrup taken -Home influenza treatment consists of aspirin, antihistamines, and cough syrup taken simultaneouslysimultaneously-Drinking water may contain small amounts of pesticides, heavy metals, solvents, and other -Drinking water may contain small amounts of pesticides, heavy metals, solvents, and other organic chemicalorganic chemical-Air often contains mixtures of hundreds of chemicals such as automobile exhaust and -Air often contains mixtures of hundreds of chemicals such as automobile exhaust and cigarette smokecigarette smoke-Gasoline vapor at service stations is a mixture of 40-50 chemicals-Gasoline vapor at service stations is a mixture of 40-50 chemicals

--There are four basic types of interactionsThere are four basic types of interactions . .

AdditivityAdditivity-A tranquilizer and alcohol, often cause depression equal to the sum of that -A tranquilizer and alcohol, often cause depression equal to the sum of that caused by each drug.caused by each drug.-Chlorinated insecticides and halogenated solvents -Chlorinated insecticides and halogenated solvents (which are often used (which are often used together in insecticide formulations)together in insecticide formulations) can produce liver toxicity with the can produce liver toxicity with the interaction being additiveinteraction being additive..

P.S. : P.S. : this same combination of chemicals produces a different type of interaction on this same combination of chemicals produces a different type of interaction on CNS. Chlorinated insecticides stimulate CNS whereas halogenated solvents cause CNS. Chlorinated insecticides stimulate CNS whereas halogenated solvents cause its depression . So, the effect of simultaneous exposure on CNS is an antagonistic its depression . So, the effect of simultaneous exposure on CNS is an antagonistic interactioninteraction..

   

PotentiationPotentiationItIt occurs when a chemical that does not have a specific toxic effect makes occurs when a chemical that does not have a specific toxic effect makes

another chemical more toxicanother chemical more toxic . .

Example:Example:-Warfarin -Warfarin (a widely used anticoagulant in cardiac disease) (a widely used anticoagulant in cardiac disease) is bound to plasma is bound to plasma albumin so that only 2% of the warfarin is active (FREE). Drugs which 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% compete for binding sites on albumin increase the level of free warfarin to 4%

causing fatal hemorrhagecausing fatal hemorrhage . .

AntagonismAntagonismIt is often a desirable effect in toxicology and it is the basis for most antidotesIt is often a desirable effect in toxicology and it is the basis for most antidotes . .

Examples includeExamples include::

SynergismSynergism

--Exposure to both cigarette smoke and asbestos results in a significantly greater Exposure to both cigarette smoke and asbestos results in a significantly greater risk for lung cancerrisk for lung cancer-The hepatotoxicity of a combination of ethanol and carbon tetrachloride is -The hepatotoxicity of a combination of ethanol and carbon tetrachloride is much greater than the sum of the hepatotoxicity of eachmuch greater than the sum of the hepatotoxicity of each..

End of Factors affecting ToxicityEnd of Factors affecting Toxicity

How do we measure How do we measure toxicitytoxicity??Toxicity is measured in numerous ways. The classic measure isToxicity is measured in numerous ways. The classic measure is... ...

LDLD5050: Lethal Dose that kills 50% of the population: Lethal Dose that kills 50% of the population..

Dosage are measured in a mg toxin/kg body weightDosage are measured in a mg toxin/kg body weight..

WhileWhile::Drug action is measured byDrug action is measured by::

EDED5050: Effective Dose that produces the desired effect in 50% of the : Effective Dose that produces the desired effect in 50% of the populationpopulation..

Dose-Response Curves characterize the Dose-Response Curves characterize the response to different levels of a drug or toxinresponse to different levels of a drug or toxin..

Dose Response curveDose Response curve

The dose-response correlates exposures and the spectrum of induced effectsThe dose-response correlates exposures and the spectrum of induced effects . .--Generally, the higher the dose, the more severe the responseGenerally, the higher the dose, the more severe the response . .

--The dose-response relationship is based on data from experimental animal, human clinical, or cell The dose-response relationship is based on data from experimental animal, human clinical, or cell studiesstudies..

--The dose-response curve normally takes the form of a sigmoid curve. For most effects, small The dose-response curve normally takes the form of a sigmoid curve. For most effects, small doses are not toxicdoses are not toxic . .

--Threshold dose level :The point at which toxicity first appears ,and below which no effect occurThreshold dose level :The point at which toxicity first appears ,and below which no effect occur..---In the hypothetical curve above, no toxicity occurs at 10 mg whereas at 35 mg 100% of the In the hypothetical curve above, no toxicity occurs at 10 mg whereas at 35 mg 100% of the

individuals experience toxic effectsindividuals experience toxic effects..---A threshold for toxic effects occurs at the point where the body's ability to detoxify a A threshold for toxic effects occurs at the point where the body's ability to detoxify a

xenobiotic or repair toxic injury has been exceeded. For most organs there is a reserve xenobiotic or repair toxic injury has been exceeded. For most organs there is a reserve capacity so that loss of some organ function does not cause decreased performance. For capacity so that loss of some organ function does not cause decreased performance. For example, the development of cirrhosis in the liver may not result in a clinical effect until over example, the development of cirrhosis in the liver may not result in a clinical effect until over 50% of the liver has been replaced by fibrous tissue50% of the liver has been replaced by fibrous tissue..

--Knowledge of the shape and slope of the dose-response Knowledge of the shape and slope of the dose-response curve is extremely important in predicting the toxicity of a curve is extremely important in predicting the toxicity of a substance at specific dose levelssubstance at specific dose levels . .

--Major differences among toxicants may exist Major differences among toxicants may exist not onlynot only in the in the point at which the threshold is reached point at which the threshold is reached but alsobut also in the in the percent of population responding per unit change in dose percent of population responding per unit change in dose ((i.e., the slopei.e., the slope)) . .

--As illustrated above, Toxicant A has a higher threshold but a As illustrated above, Toxicant A has a higher threshold but a steeper slope than Toxicant Bsteeper slope than Toxicant B..

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Dose(ex. grams of carbon monoxide/ kg of body weight

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Dose-Response CurveDose-Response Curve

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--Dose-response curves are also used to derive dose estimates of chemical Dose-response curves are also used to derive dose estimates of chemical substances: EDs & TDssubstances: EDs & TDs..

Toxic Doses (TDs) : the doses that cause adverse toxic effectsToxic Doses (TDs) : the doses that cause adverse toxic effects . .

--The knowledge of the effective and toxic dose levels aides the toxicologist and The knowledge of the effective and toxic dose levels aides the toxicologist and clinician in determining clinician in determining the relative safetythe relative safety of pharmaceuticals of pharmaceuticals . .

--As shown above, two dose-response curves are presented for As shown above, two dose-response curves are presented for the samethe same drug, one drug, one for effectiveness and the other for toxicity. In this case, a dose that is 50-75% for effectiveness and the other for toxicity. In this case, a dose that is 50-75% effective effective does notdoes not cause toxicity whereas a 90% effective dose may result in a cause toxicity whereas a 90% effective dose may result in a small amount of toxicitysmall amount of toxicity..

  

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

The use of the ED50 and LD50 doses to derive the TI may be misleading to safety, The use of the ED50 and LD50 doses to derive the TI may be misleading to safety, depending on the slope of the dose-response curves for therapeutic and lethal depending on the slope of the dose-response curves for therapeutic and lethal effects. To overcome this deficiency, toxicologists often use another term to effects. To overcome this deficiency, toxicologists often use another term to

determine the safety of a drugdetermine the safety of a drug. .

The Margin of Safety (MOS)The Margin of Safety (MOS)..It is the ratio of the dose that is just within the lethal range (LD01) to the dose that is It is the ratio of the dose that is just within the lethal range (LD01) to the dose that is

99% effective (ED99). The MOS = LD01/ED9999% effective (ED99). The MOS = LD01/ED99 . .--A physician must take care when prescribing a drug with MOS less than 1A physician must take care when prescribing a drug with MOS less than 1..

      

NOAEL and LOAEL:NOAEL and LOAEL:--No Observed Adversed Effect Level (NOAEL)No Observed Adversed Effect Level (NOAEL)

--Lowest Observed Adverse Effect Level (LOAEL)Lowest Observed Adverse Effect Level (LOAEL)

--They are the They are the actual data pointsactual data points from clinical or experimental animal from clinical or experimental animal

studiesstudies . .--They do not necessarily imply toxic or harmful effects ,and may be They do not necessarily imply toxic or harmful effects ,and may be

used to describe beneficial effects of chemicals as wellused to describe beneficial effects of chemicals as well..

Emergency Management of Emergency Management of poisoningpoisoning

General approach for management of General approach for management of poisoned patientpoisoned patient::

11--Emergency stabilization: provide the patient with Emergency stabilization: provide the patient with good supportive care (maintain respiration & good supportive care (maintain respiration & circulation)circulation)..

22--Clinical evaluation: Identify the drug or poison as Clinical evaluation: Identify the drug or poison as quickly as possible it include case history , quickly as possible it include case history , physical exam and analytical procedures to physical exam and analytical procedures to analyze urine, blood, stomach contents (HPLC, analyze urine, blood, stomach contents (HPLC, mass spec. can be used)mass spec. can be used)

33 - -Reduce or prevent absorptionReduce or prevent absorption44 - -Enhance the elimination of the poisonEnhance the elimination of the poison..

55--AntidotAntidot66--Supportive therapy and observationSupportive therapy and observation

I-Emergency stabilizationI-Emergency stabilization

Emergency stabilizationEmergency stabilization::--ABCs, check gag reflexABCs, check gag reflex . .

--For patients with no obvious intoxication: obtain -IV For patients with no obvious intoxication: obtain -IV access, draw electrolytes, obtain rapid fingerstick access, draw electrolytes, obtain rapid fingerstick

glucose, and send urine toxicology screenglucose, and send urine toxicology screen  .  .--Consider ABG (if necessary to look for carbon Consider ABG (if necessary to look for carbon

monoxide, you must order this specifically)monoxide, you must order this specifically) . .--Give isotonic fluid if hypertensive, but with caution Give isotonic fluid if hypertensive, but with caution

(narcotics and naloxone can promote pulmonary (narcotics and naloxone can promote pulmonary edema)edema) . .

--If comatose with pinpoint pupils and decreased If comatose with pinpoint pupils and decreased respirations, give 1-2 mg naloxone IVrespirations, give 1-2 mg naloxone IV ???.… ???.…

  

A- Case history of poisoning:A- Case history of poisoning:An accurate history include:An accurate history include:i-Identification of the poison, amount and time of ingestion or length of contact (Empty bottles , If he was taken from i-Identification of the poison, amount and time of ingestion or length of contact (Empty bottles , If he was taken from garage….?,a factory…etc).garage….?,a factory…etc).ii-The patient's psychological profile: This is difficult because the poisoned individual may be unconscious, ii-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.unresponsive or confused. Information usually obtained from relatives or friends.

iii-Identify if the patient performed any self treatment or took any medicationiii-Identify if the patient performed any self treatment or took any medication??

B-Physical examinationB-Physical examination::Some poisons produce clinical characteristics which strongly suggest the type of the poisonSome poisons produce clinical characteristics which strongly suggest the type of the poison

11--Presence of characteristic odourPresence of characteristic odour;; phenol, alcohol, kerosene, bitter almond odour of cyanidephenol, alcohol, kerosene, bitter almond odour of cyanide

22--Skin manifestationSkin manifestation::a- Changes in the skin Colora- Changes in the skin Color

- -Red in carbon monoxide poisoningRed in carbon monoxide poisoning.. - -Flushed and dry in atropine poisoningFlushed and dry in atropine poisoning..

- -Flushed and sweaty in LSD and cocaineFlushed and sweaty in LSD and cocaine.. - -Cyanosed in cyanide, nitrites and carbon monoxideCyanosed in cyanide, nitrites and carbon monoxide..

---Yellow “Jaundice” in acetaminophen, carbon tetrachlorideYellow “Jaundice” in acetaminophen, carbon tetrachloride

b- Needle markersb- Needle markers: Indicate addiction by intravenous route e.g. heroin and cocaine: Indicate addiction by intravenous route e.g. heroin and cocaine..

c- Alopeciac- Alopecia: in Thallium: in Thallium..

d-Burns & corrosion:d-Burns & corrosion: Acids & alkali Acids & alkali

33--Eye manifestationEye manifestation::a- Eye globea- Eye globe::

i- Lacrimation: In organic phosphorousi- Lacrimation: In organic phosphorous ii- Nystagmus: In barbituratesii- Nystagmus: In barbiturates..

b- Pupilsb- Pupils:: i- Dilated reactive pupils: In alcohol and cocainei- Dilated reactive pupils: In alcohol and cocaine..

ii- Dilated fixed pupils: In ii- Dilated fixed pupils: In atropineatropine..iii- Constricted pupils: In phenol and opiumiii- Constricted pupils: In phenol and opium..

44--Gastro-intestinal manifestationsGastro-intestinal manifestations::a- Moutha- Mouth::i- Salivation: In organophosphorous compoundsi- Salivation: In organophosphorous compounds..ii- Dry mouth: In atropine and other anticholinergic drugsii- Dry mouth: In atropine and other anticholinergic drugs..iii- Corrosion : With corrosivesiii- Corrosion : With corrosives..iv- Gum discoloration: Lead causes blue line. Cadmium causes yellow line. Mercury causes iv- Gum discoloration: Lead causes blue line. Cadmium causes yellow line. Mercury causes grey linegrey line..

b- Vomitingb- Vomiting::Most poisons except narcoticsMost poisons except narcotics..

c- Abdominalc- Abdominal:: i- Diarrhea in all heavy metals except leadi- Diarrhea in all heavy metals except lead..

ii- Constipation with opium and leadii- Constipation with opium and lead..

55--Cardio-vascular manifestationsCardio-vascular manifestations::a- Tachycardia: In alcohol, atropinea- Tachycardia: In alcohol, atropine..b- Bradycardia : In digitalis ,opium, cyanide & β blockersb- Bradycardia : In digitalis ,opium, cyanide & β blockers..

c- Rise in blood pressure: Lead,amphetamine, and tricyclic c- Rise in blood pressure: Lead,amphetamine, and tricyclic antidepressantantidepressant..d- Hypotension: In barbituratesd- Hypotension: In barbiturates . .

66--Respiratory manifestationsRespiratory manifestations::- - Acute respiratory failure in barbituratesAcute respiratory failure in barbiturates..

- - Pulmonary edema due to inhalation of petroleum and arsenic fumesPulmonary edema due to inhalation of petroleum and arsenic fumes . .

77--Central nervous system manifestationCentral nervous system manifestation::a- Coma: Barbiturates, Paraldehyde, and ethylene glycola- Coma: Barbiturates, Paraldehyde, and ethylene glycol..

b-Convulsions: Amphetamines, camphor, chlorinated hydrocarbons, b-Convulsions: Amphetamines, camphor, chlorinated hydrocarbons, lead, strychnine, cocaine, alcohol, anticholinergic, antihistaminiclead, strychnine, cocaine, alcohol, anticholinergic, antihistaminic..c-Hyperpyrexia: Salicylates, amphetamine and theophylinec-Hyperpyrexia: Salicylates, amphetamine and theophyline . .

d-Hypothermia: Clonidine and tricyclic antidepressantsd-Hypothermia: Clonidine and tricyclic antidepressants..e-Muscle fasciculations: With nicotine, strychnine and camphore-Muscle fasciculations: With nicotine, strychnine and camphor..

f-Tremors: Occurs with amphetamines, carbon monoxide, hallucinogenic f-Tremors: Occurs with amphetamines, carbon monoxide, hallucinogenic drugs, xanthines (theophylline) and tricyclic antidepressantsdrugs, xanthines (theophylline) and tricyclic antidepressants . .

C- Analytical toxicological laboratory screeningC- Analytical toxicological laboratory screening::These give the correct diagnosis and could be These give the correct diagnosis and could be done on biological fluids .This usually includedone on biological fluids .This usually include::

--CBCCBC--Serum electrolyte levelSerum electrolyte level..

--BUNBUN--Blood glucose, …… ,prothrombin timeBlood glucose, …… ,prothrombin time..

--Urine analysisUrine analysis..--X-ray on the chestX-ray on the chest..

--Spinal tap (meningitis (coma, fever)Spinal tap (meningitis (coma, fever)

Once emergency procedures have been Once emergency procedures have been performed and the poisoned patient is performed and the poisoned patient is stabilized, or at least is out of immediate stabilized, or at least is out of immediate danger, additional steps can be taken to danger, additional steps can be taken to remove the poison, prevent a delay remove the poison, prevent a delay absorption, enhance excretion, or administer absorption, enhance excretion, or administer a specific antidotea specific antidote..

III-Prevent absorption and removal of poisonIII-Prevent absorption and removal of poison

A general rule is that nothing should be administered orally to an unconscious patientA general rule is that nothing should be administered orally to an unconscious patient

A)- Topical decontaminationA)- Topical decontamination

11 - -Skin decontaminationSkin decontamination::Rapid decontamination is needed specially if the poison is a corrosive or is easily absorbed Rapid decontamination is needed specially if the poison is a corrosive or is easily absorbed from the skinfrom the skin..

- - Wash contaminated areas as well as exposed areas with warm water or saline , with 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 foldscareful washing of the skin, behind ears, under nails, and skin folds..Phenol:Phenol: Can apply olive oil Can apply olive oil. . Oxalic acidOxalic acid: Soak the affected area with solution of calcium gluconate: Soak the affected area with solution of calcium gluconate..OrganophosphorusOrganophosphorus: Soap water: Soap water

22--Eye decontaminationEye decontamination : : i- Irrigation of the eyes with large amounts of wateri- 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 ii- The eye is usually affected by a corrosive :apply anesthetic drops e.g. cocaine HCI (Xylocaine) (Xylocaine)After first aid treatment the patient should be referred to an ophthalmologist in order to After first aid treatment the patient should be referred to an ophthalmologist in order to asses and treat any inflammationasses and treat any inflammation..

33 - -DemulcentsDemulcentsMany plants and chemicals cause oral and gastric mucosa irritation but no serious toxicity. 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 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 intoxicationsserve as a source of readily available protein, have been given for corrosive intoxications..

B)-If the poison was ingested:B)-If the poison was ingested: 1- Dilution: 1- Dilution: By using water & milk immediately after poisoning.By using water & milk immediately after poisoning.- This reduce the gastric irritation induced by many ingested poisons.- This reduce the gastric irritation induced by many ingested poisons.2- Milk provides dilution and is also a demulcent.2- Milk provides dilution and is also a demulcent.

2- Delay gastric emptying:2- Delay gastric emptying:a)-Emesisa)-Emesis : induced by : induced by i-Syrup of Ipecac: orally administeredi-Syrup of Ipecac: orally administered ii- Apomorphine: given by s.c. injection (most rapid) ,but cause CNS depressionii- 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.iii- Liquid detergent 30-45 ml in 120-240 ml juice or water. Contraindications:Contraindications:1- Ingestion of a strong acids ,alkalis or hydrocarbon e.g. kerosene????????1- Ingestion of a strong acids ,alkalis or hydrocarbon e.g. kerosene????????2-Do not induce vomiting if the patient:2-Do not induce vomiting if the patient:• Is Unconscious or comatose, convulsant , has sever cardiovascular disease or, Is Unconscious or comatose, convulsant , has sever cardiovascular disease or,

emphysema or under 6 months of age??emphysema or under 6 months of age??

b)-Gastric lavage:b)-Gastric lavage: Gastric lavage is only effective when ingestion of the poison is discovered within 4 hours Gastric lavage is only effective when ingestion of the poison is discovered within 4 hours

except salicytates may be within 10 hours (it sticks to the mucous membrane).This except salicytates may be within 10 hours (it sticks to the mucous membrane).This procedure is often reserved for patients with impaired consciousness and uncooperative procedure is often reserved for patients with impaired consciousness and uncooperative or when ipecac failed to produce emesis.or when ipecac failed to produce emesis.

Solutions used :sodium bicarbonate, saline, tannic acid or water.Solutions used :sodium bicarbonate, saline, tannic acid or water. Contraindications:Contraindications:Strong acid and alkalis, in convulsion, in sever respiratory and cardiac insufficiency???Strong acid and alkalis, in convulsion, in sever respiratory and cardiac insufficiency???

33--AdsorbentsAdsorbents : activated charcoal, starch and flour : activated charcoal, starch and flour. . Activated charcoal: is administered orally to adsorb or bind toxins and allows Activated charcoal: is administered orally to adsorb or bind toxins and allows them to pass from the GIT without being absorbed into the systemic them to pass from the GIT without being absorbed into the systemic

circulationcirculation . . ContraindicationsContraindications::

11 - -Absence of the bowel soundsAbsence of the bowel sounds. . 22 - -Intestinal obstructionIntestinal obstruction . .

33 - -Many preparation add sorbitol to the mixture ,so repeated dose lead to Many preparation add sorbitol to the mixture ,so repeated dose lead to diarrhea, dehydration, hypernatraemia in children and elderlydiarrhea, dehydration, hypernatraemia in children and elderly..

44--DO NOT give with syrup of ipecac because it will bind the syrup of ipecacDO NOT give with syrup of ipecac because it will bind the syrup of ipecac..

44--Cathartic AgentsCathartic Agents::Such as Magnesium citrate, sodium sulfate , polyethylene glycol and sorbito1. Such as Magnesium citrate, sodium sulfate , polyethylene glycol and sorbito1. Careful monitoring of the fluid and electrolyte status is necessaryCareful monitoring of the fluid and electrolyte status is necessary..

ContraindicationsContraindications::--Catharsis should not be attempted when the poison is strongly corrosive, the Catharsis should not be attempted when the poison is strongly corrosive, the

patient has electrolyte disturbance or bowel sounds are absentpatient has electrolyte disturbance or bowel sounds are absent..--Magnesium containing cathartics-should not be used in cases of renal failure…… Magnesium containing cathartics-should not be used in cases of renal failure……

because of the possibility of causing CNS depression due to accumulation of because of the possibility of causing CNS depression due to accumulation of high concentration of magnesium in the serumhigh concentration of magnesium in the serum..

--Sodium containing cathartics are, likewise, best avoided by persons with Sodium containing cathartics are, likewise, best avoided by persons with congestive heart failurecongestive heart failure

--Oil cathartics e.g. castor oil may increase the absorption of fat-soluble poisons Oil cathartics e.g. castor oil may increase the absorption of fat-soluble poisons such as pesticidessuch as pesticides . .

IV-Enhancement of ExcretionIV-Enhancement of Excretion

11--Forced Diuresis:Forced Diuresis: its useful to enhance renal elimination of its useful to enhance renal elimination of poisons. Saline to expand fluid volume and furosemide may poisons. Saline to expand fluid volume and furosemide may be used to enhance diuresisbe used to enhance diuresis..

22--Acid Diuresis:Acid Diuresis: with ammonium chloride can enhance the with ammonium chloride can enhance the elimination of weak bases e.g. phencyclidine, elimination of weak bases e.g. phencyclidine, amphetamine, strychnine and quinidineamphetamine, strychnine and quinidine . .

33--Alkaline Diuresis:Alkaline Diuresis: with Sodium bicarbonate can remove with Sodium bicarbonate can remove weak acids (e.g. salicylates and Phenobarbital)weak acids (e.g. salicylates and Phenobarbital) . .

44--Dialysis and HemoperfusionDialysis and Hemoperfusion--As adjuncts for management of severely intoxicated patientsAs adjuncts for management of severely intoxicated patients..

--Dialysis and hemoperfusion should never replace more Dialysis and hemoperfusion should never replace more specific antidotesspecific antidotes..

--These procedures would be of little value in treating acute These procedures would be of little value in treating acute ingestions of cytotoxic poisons such as cyanide which ingestions of cytotoxic poisons such as cyanide which produce toxic effects very rapidlyproduce toxic effects very rapidly..

V- Specific AntidoteV- Specific Antidote

Chemical antidotesChemical antidotes:: In oxalic acid poisoning, absorption produces renal damage. Calcium salts react with oxalic 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 acid to yield a poorly soluble compound, calcium oxalate, which passes through the intestine without being absorbedintestine without being absorbed..Antidotes such as dimercaprol (BAL) and deferoxamine form chemical chelates with heavy Antidotes such as dimercaprol (BAL) and deferoxamine form chemical chelates with heavy metals. Chelated complexes are water soluble and readily excreted by the kidneymetals. Chelated complexes are water soluble and readily excreted by the kidney..

Receptor antidotesReceptor antidotes:: Compete with the poison for receptor sitesCompete with the poison for receptor sites..

--Naloxone reversal of morphine-induced respiratory depressionNaloxone reversal of morphine-induced respiratory depression--Cholinergic blockade by atropine (parathion poisoning)Cholinergic blockade by atropine (parathion poisoning)..

--For atropin or other anticholinergic poisons, physostigmine is a specific antidoteFor atropin or other anticholinergic poisons, physostigmine is a specific antidote..

Dispositional antagonismDispositional antagonism:: In acetaminophen overdose, a toxic metabolite is conjugated with glutathione(a sufhydrylIn acetaminophen overdose, a toxic metabolite is conjugated with glutathione(a sufhydryl

) )sH group donorsH group donor .( .(When glutathione reserves are depleted……..hepatotoxicityWhen glutathione reserves are depleted……..hepatotoxicity.. N-acetylcysteine is also a source of sulfhydryl groups which serve the same function as 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 endogenous glutathione. Acetaminophen and its toxic metabolite are therefore detoxified and the liver cells are not subjected to prolonged toxicityand the liver cells are not subjected to prolonged toxicity . .

Function (physiologic) antagonistFunction (physiologic) antagonist:: Epinephrine reverses the bronchoconstriction due to anaphylactic reaction following Epinephrine reverses the bronchoconstriction due to anaphylactic reaction following

administration of certain drugsadministration of certain drugs..

Poison Poison AntidoteAntidote

Acetaminophen N-Acetaminophen N-acetylcysteineacetylcysteine Lead,Arsenic, EDTA ,DimercaprolLead,Arsenic, EDTA ,Dimercaprol

Atropine Atropine PhysostigminePhysostigmineCyanide, nitroprusside Antidote kitCyanide, nitroprusside Antidote kitDigoxin Fab fragmentsDigoxin Fab fragmentsEthylene glycol, MeOH EthanolEthylene glycol, MeOH EthanolIron DeferoxamineIron Deferoxamine Opioids NaloxoneOpioids NaloxoneOrganophosphates Organophosphates Atropine,PralidoximeAtropine,Pralidoxime Warfarin Vitamin K1Warfarin Vitamin K1

VI-Supportive therapy & VI-Supportive therapy & ObservationObservation

- - I.V. fluidsI.V. fluids

--Frequent blood and urine pH Frequent blood and urine pH adjustmentadjustment..

--Intensive nursing careIntensive nursing care..

--Avoid unnecessary drugsAvoid unnecessary drugs..

--Treatment for hypo- or hyperthermiaTreatment for hypo- or hyperthermia..

--Management of hypotensionManagement of hypotension . .