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Flashcards in Toxicology Deck (69):
1

Routes of entry

oral, inhalation, parenteral (IV), dermal

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Most frequent pediatric emergency

poisoning

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Acute exposure

A single exposure or multiple exposures over a 24 hr period

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Subacute exposure

Multiple exposures over a 24 hr - 3 mo. period

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Chronic exposure

Multiple exposures over a 3 mo. or longer period

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Zero order rate constant

Ke = (Ao - A)/t

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Many toxic agents exhibit clearance saturation

Alcohol quickly saturates to zero order clearance. Salicylate at levels above 1 gram exhibits zero order clearance. That's only 3 asprin

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Heavy Metal

Long lasting in environment, not metabolized, may persist in the body for long periods of time. combine with essential amino acid residues on enzymes

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Acute inorganic lead poisoning

Severe GI distress, CNS abnormalities, difficult diagnosis - can mimic appendicitis, peptic ulcer, pancreatitis, etc.

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Diagnostic tests for Pb

Blood and urine analysis for Pb, also can check urine for delta-ALA and coproporphyrin III because the heme pathway is inhibited by lead

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Treatment for Pb poisoning

Prevent further exposure, support - seizures, cerebral edema. Initiate chelation therapy - dimercaprol, edtate Ca disodium, D-penicillamine

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Pb Pharmacokinetics

Distribution to soft tissues (kidney and liver), redistribution to bones, teeth and hair. Half-life of Pb in blood: 1-2 mo. Bone: 20 years. Excretion in urine and feces

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Chronic inorganic Pb poisoning

weakness, anorexia, nervousness, tremor, weight loss, headache, GI distress. Wrist drop extensor weakness without sensory loss.

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Organic Pb poisoning

Acute CNS, rapid progression to hallucinations, insomnia, headache and irritability. Usually caused by tetraethyl or tetramethyl Pb in gasoline

15

Mercury poisoning

Element poorly absorbed by GI, but better with inhalation, organic forms more readily absorbed, retained in kidney and brain

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Acute mercury intoxication

Inhalation leads to chest pain, shortness of breath, nausea/vomiting, kidney damage, gingivitis, muscle tremor, psychopathology.

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Biochemical effects of mercury

React with sulfhydryls as a corrosive, proteins precipitate. Methylmercury readily accumulates in cells

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Treatment of mercury poisoning

Remove exposure, chelation therapy may use oral penicillamine and monitor removal

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Arsenic

As3+ sulfhydryl reagent inhibiting SH-sensitive enzymes like the pyruvate dehydrogenase system. As5+ uncouples mitochondrial oxidative phosphorylation

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Cadmium

Long half-life, no treatment

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Heavy metal antagonists

Chlelating agents - 2 or more electronegative groups, coordinate covalent bonds with cationic metal atoms. Shares electrons - Think N, S, and O.

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Effectiveness of Heavy metal antagonist depends on

Affinity for heavy metal compared to essential body metals. Chelator distribution. Ability to mobilize metal. Water solubility. Resistance to metabolism. Readily excreted with little-to-no dissociation from heavy metal. Chelator-metal complex should be less toxic than free metal. Oral administration. Low inherent toxicity.

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Dimercaperol

2 SH groups, 1 OH group. Lots of side effects. Not to be used with cadmium - enhances accumulation

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EDTA

Binds lead, hexavalent binding via Oxygen group with iron

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Penicillamine

Binds Mercury. S and Amine group

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Carbon Monoxide

Affect brain and heart. Symptoms - headache, weakness, nausea/vomiting, unconsciousness, death

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CO treatment

Remove exposure, re-institute respiration with pure O2 in severe cases

28

Cyanide

Fatal dose - 50-200 mg depending on route of administration and compound used. Symptoms: giddiness, headache, palpitations, N>V ataxia, convulsions, coma, and death

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Cyanide treatment

CN binds Fe3+ in cytochrome oxidase. Administer sodium nitrite or amyl nitrite which reacts with Hemoglobin, iron in F(III) state which CN then binds instead of cytochrome

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Methanol

Alcohol dehydrogenase converts methanol to formaldehyde. Aldehyde dehydrogenase converts formaldehyde to formic acid. Symptoms are similar to ethanol with increased vision symptoms

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Treatment of methanol

Treat the acidosis. Paradoxically, give ethanol to saturate the alcohol dehydrogenase

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Ethylene glycol

Antifreeze. Patient appears drunk due to neurological involvement, tachycardia, mild hypertension, heart failure, pulmonary edema, renal failure, acute tubular necrosis. Causes formic acidosis and oxalic acidosis. Oxolate stones - renal damage

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Ethylene glycol treatment

Gastric levage, sodium bicarbonate for acidosis, ethanol slows metabolism, hemodialysis for kidney

34

Acetaminophen

Toxic dose - 25 g, CYP450 metabolism leads to reactive APAP which binds macromolecules in liver leading to hepatocyte death. (remember Acetaminophen is harmless when glucuronated or sulfonated)

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APAP treatment

And SH compounds to replenish hepatic GSH and acts as an alternate binding target for activated APAP. Example: N-acetylcystein and must be given as quickly as possible

36

Vitamin Poisoning

Major cause of poisoning in children under 5. Magadose is 10x RDA. toxicity from fat-soluble vitamins most commonly (A and D)

37

Chlorinated Hydrocarbon Insecticides

Fat soluble, low molecular weight. DDT, cyclodiens and hydrocarbone. Rapid repetitive neuronal firing - interferes with inactivation of sodium channels

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DDT

Hydrophobic builds up in adipose tissue, poor biodegradability, persistent, crosses BBB and placenta.

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Treatment of acute DDT poisoning

Supportive only. Note: survival of acute phase, may still experience increased risk of cancer

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Symptoms of acute DDT poisoning

Nausea and vomiting, neurological hypersensitivity, respiratory failure and death.

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Organophosphorous Insecticides

Phosphate esters, phosphothiol groups, highly toxic, inhibit acetylcholine esterase by phosphorylating enzyme

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Symptoms of acute Organophosphate poisoning

autonomic and somatic effects

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Carbamate insecticides

Highly to moderately toxic, inactivates acetylcholine esterase reversibly. They do not persist in environment or bioaccumulate

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Herbicides

Do not accumulate in animals, only slowly metabolized but readily excreted in urine, mechanism of toxicity largely unknown

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Bipyridyl herbicides

Paraquat - primary sites of damage are lung, liver, kidney. Proliferation of lung fibroblast, redox cycling and oxidative stress

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Polycholorinated biphenyls

PCBs, environmental pollutants, very lipophilic, stable, poorly metabolized, bioaccumulates

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Drug interactions

Very important when margin of safety is small and when patient is taking multiple drugs. May be caused by multiple mechanisms - physical binding, metabolism inducement or inhibition, plasma protein displacemtne

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Interactions due to alcohol

Chronic use cause some CYP450 induction in liver, may increase of decrease drug effects, competitve substrate for some p450s. CNS interactions

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Interactions due to caffeine

Inducer and substrate for microsomal drug metabolizing enzymes. Risk with benzodiazepines, oral contraceptives, cimetidine, MAOI, phenothiazines, thephylline

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Interactions due to tobacco

Some drug metabolizing enzymes induced, decrease effects of acetaminophen, anti-depressants, benzodiazapine, cimetidine, oral contraceptives, estrogens, insulin, propranolol, theophylline

51

Toxicity and elderly patients

altered physiology, drug metabolism and polypharmacy. Changes in ADME, adjust dose monitor progress, individualize therapy, consider benefit to risk ratio.

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Bioactivation of xenobiotics to stable but toxic metabolites

Cyanide and Carbon Monoxide

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Biotransformation of xenobiotics to reactive, electrophilic metabolites

Acetaminophen, bromobenzene, benzo(a)pyrene, 2-acetylaminofluorene, N-dimethylnitrosamines, trichloroethylene

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Biotransformation of xenobiotics to free radicals

Carbon tetrachloride

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Formation of reduced oxygen metabolites

Paraquat, quinones

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Metabolic derangements associated with xenobiotic transformation

Galactosamines, ethionine, fructose, fluroacetate

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Dicloromethane

Carbon monoxide (from CYP450, then glutathione metabolism, then formaldehyde dehydrogenase)

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Acetonitrile

Cyanide (from CYP450, then rhodanese) unstable intermediate

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Hard nucleophiles

High electronegativity, low polarizability, difficult to oxidize. Ex. Amino groups, oxygen-containing functional groups in DNA and protein

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Soft nucleophiles

Low electronegaticity, high polarizability, easy to oxidize. Ex. Thiol group of GSH and cystein. Protein sulfhydryl group

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Hard Electrophiles

High positive charge, small size, lacks unshared electrons in valence shell, Ex. Alkyl carbonium ion

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Soft electrophiles

low positive charges, relatively larges size, unshared electrons in valence shell. Michael acceptors. Beta-unstaturated carbonyl compound

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Reactions of free radicals

Initiation, propagation (injury) and termination. Ex. Tetrachloride (CYP450) or reactive oxygen intermediates

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Paraquat

Herbicide - redox cycle, keeps releasing superoxide - lung fibrosis

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Menadione

Quinone (similar to vit. K) NADPH consumed to create semiquinone, releasing superoxide forming hydroquinone. Cycle starts again

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Galactosamine

UTP depletion

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Ethionine

ATP depletion from s-adenosylethionine

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Fructose

ATP depletion from fructose 1-P

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Fluroacetate

fluroacetyl-coA inhibits aconitase leading to cytotoxicity