TOXICOLOGY

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I. INTRODUCTION III. POISONS

 Toxicology – study of poison, its mechanism of action, and its I. EFFECTS OF POISIONS
management; study of adverse effects/events of  According To Extent/Location
physical/chemical agents in humans, other organism and o Local – ex. Phenol
environment o Remote – ex. Paraquat  pulmonary fibrosis
 Poisons: (1) Mechanism of Toxicity; (2) Functional Effects; (3) o Systemic – ex. Metabolic Acidosis
Probability of Occurrence  According To Duration
 Risk Assessment – estimate potential effect on human health o Acute – ↑dose in short period of time
and environmental significance of various types of chemical o Chronic – ↓dose in longer period of time
exposure
 Areas of Toxicology II. FACTORS THAT INFLUENCE EFFECTS OF POISON
o Mechanistic – mechanism of toxicity  Route
o Descriptive – direct toxicity testing o Oral – most common/important; ↑A = lipid; ↓GER = delay
o Regulatory – decision making process using information absorption (ex. anticholinergic)
from: mechanistic and descriptive (asses safety) o Dermal – lipid soluble = ↑damage; ↑absorption – (ex.
 Specialized Areas of Toxicology phenol)
o Clinical Toxicology – study of adverse effects in humans o Inhalation – gases/particle < 0.5µm; systemic or local effects
caused by incidental/accidental overdose o Intravenous
o Environmental Toxicology – impact of pollutants to non- o Intramuscular
human organism o Rectal
o Forensic Toxicology – medicolegal  Concentration – ↑concentration = ↑toxicity
 Patient Related Factor
II. TOXICOKINETICS o Age
 Pediatric
I. ABSORPTION
 Child Inutero
 Parameters: Bioavailability (F) – rate and extent of absorption;
o 1-2 weeks – conception/implantation; abortion
extent/fraction of drug that enters systemic circulation
o 3-8 weeks – embryogenesis period; morphologic
 Affected by:
change (ex. ACE I)
o Physical Properties – lipid soluble = ↑extent; water soluble
o > 8 weeks – minor physiologic changes
= ↑rate
 Examples:
o Gastric Emptying Rate - ↓GER = ↓absorption
o Tetracycline – teeth discoloration and bone
o Health of GI Tract
problems
o First Pass Effect – hepatic metabolic
o ACE Inhibitors – renal dysgenesis
o Diethylstibestrol – uterine/cervical cancer to
II. DISTRIBUTION
daughter
 Parameters: Volume of Distribution (Vd)
𝑑𝑜𝑠𝑒 o Thalidomide – phocomelia  limb deformities
𝑉𝑑 =
𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
 Affected by: Protein Binding – ↓BP = ↓VD

III. METABOLISM AND EXCRETION

 Parameter: Clearance – rate by which a known volume of
plasma is cleared by drug
 Affected by: Liver and Kidney Function

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  Geriatric - ↓liver/kidney function; ↓muscle mass; ↑fat  Counterindicated – absence of bowel sounds;
deposition evidence of intestinal obstruction; pre-existing
 Tolerance/Tachyphylaxis – increase dose to get same electrolytes imbalance; renal dysfunction; GI bleeding
effect; (ex. Nitrates; Morphine)  Whole Bowel Irrigation – administer with PEG with
 Idiosyncracy & Pharmacogenetics electrolytes until completely cleansed
o G6PD Deficiency – triggers: antimalarial, sulfadrugs,  Endgoal – effluent is same color of infusate
analgesics (ASA), acetanilide, antibiotics (Nalidixic  Indication – substances are poorly absorbed (ex. Li, Fe,
Acid), INH, nitrofurantoin Pb); slow release of preparations; late presentation
RBC = HEMOLYTIC ANEMIA (takes 2-4 hours)
 Forced Diuresis/pH Manipulation – kidneys  filtration,
GLUTATHIONE
OA
GLUTATHIONE
reabsorption, secretion;
(reduced form) (oxidized form)  Examples: salicyliates + NaHCO3 (alkalizer);
G6PD
amphetamine + Vit. C or NH4Cl (acidifier)
o Pseudocholinesterase Deficiency – ex. o Inhalation – remove from hazardous environment; (+) 100%
succinylcholine  malignant hyperthermia humidified O2; assisted ventilation; bronchodilators
o NAT2 Polymorphism – ex. Isoniazid  fast o Dermal Exposures – remove exposed clothes; rinse with
acetylators: Asians; slow acetylators: Caucasians copious H2O in 30 minutes
o Ocular Exposures – irrigate with saline solution for 15
III. MANAGEMENT OF POISONED PATIENT minutes with eyelids retracted
 Primary Survey – (ABCDE) o Extracorporeal Methods
o Airway  Hemodialysis – passing of blood through a semi-
o Breathing permeable membrane with counter current dialysate
o Circulation flow, allowing passage of solute
o Disability  Dialyzable Toxins:
o Exposure – remove clothing for better evaluation o Low Vd – (< 1L/kg)
 Secondary Survey – history (SATS – substance, amount, time, o Protein Binding < 50%
symptoms)and physical examination o Low MW – < 600 daltons
 Management – diagnostics and therapeutics  Supportive Measure – (A,E,I,O,U)
 Decontamination o Acid-Base disturbances that are unresponsive
o Ingestion o Electrolyte disturbances that are unresponsive
 Lavage – passage of tube via mouth or nose down to o Intensive Care disturbances that are unresponsive
stomach followed by sequential administration of warm o Overhydration
saline solution and removal of small volume of liquids o Uremia
 Dilution/Neutralization – counterindicated in alkali and  Hemoperfusion – blood passes through an adsorbent
acids (charcoal)
 Emesis – Syrup of Ipecac – toxin does not cause rapid  Indications – highly protein bound; high Vd; lipid
onset coma/convulsion  aspiration soluble
 Counterindicated:  Peritoneal Dialysis – least invasive; 10-15% as effective
o Children < 6 years old – underdeveloped airway than hemodialysis
protection mechanism
o Agents which may cause comatose – alcohol; short IV. COMMON MAJOR PATHOPYSIOLOGIC
acting barbiturates; non-barbiturates hypnotics; TCA
o Agents causes rapid onset convulsions – beta MECHANISM
blockers; calcium channel blockers; chloroquine; I. INTERFERE WITH O2 UTILIZATION
camphor; codein; TCA; mefenamic acid; Respiration  O2 transport  cellular respiration
organophosphate; strychnine; phencyclidine Energy Production: Glycolysis  Kreb’s Cycle  Electron
(angel’s dust) Transport Chain (ETC)  O2, ATP, CO2
 Activated Charcoal – adsorbs toxin  Carbon Monoxide – product of incomplete combustion;
 Gastrointestinal Dialysis – repeated dose of charcoal; presentation: pallor; headache; vertigo; cherry red skin (post
creates concentration gradient between intestinal mortem)
lumen and plasma CO + Hgb  methemoglobin (↑affinity to O2) = hypoxia
 Cathartics – saline cathartics

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 Hydrogen Sulfide – rotten egg odor; hot springs; highly toxic, weakness + fasciculations, adrenal medulla = increase
colorless gass; irritation of mucous membrane, respiratory epinephrine activity, tachycardia, cramping, hypertension
depression; treated by: amyl nitrite (inhalation) and NaNO 2 o Treatment
(IV), methemoglobin + sulfide ion  sulfmethoglobin,  Atropine – anticholinergic
hypertonic O2  Pralidoxime – early poisoning (24-36 hours); reverse bond
blocks cytochrome  blocks O2 utilization between acetylcholinesterase and organophosphate by
 Cyanide – found in prunus spp. (wild blackberry; bitteralmond; forming an oxime phosphate bond to release ACh E; done
apricot), cassava, lima beans, silver jewelry cleaner before aging into a covalent bond
Inhibits cytochrome oxidase = ↓O2 utilization
o Clinical Effects: CNS disturbances; death from seizure and IV. AFFECT VASCULATURE AND HEART
central respiratory depression  hypotension or cardiac arrhythmia; (ex. nitroglycerin)
o Treatment: ↑cGMP  relax smooth muscle  vasodilation
 12
V. AFFECTS LUNGS EITHER SYSTEMICALLY OR LOCALLY
 Paraquat – systemically
 Aspiration – locally

VI. LOCAL DAMAGE

 Phenol – aka carbolic acid; denatures protein; presentation:
burning sensation, tingling, numbness, leaves a burn mark;
treatment: castor oil or PEG

VII. DELAYED EFFECTS ON LIVER AND KIDNEY – (ex.

acetaminophen; heavy metals)
 Hydroxycobalamin (B12) – binds with CN 
cyanocobalamin
 Methylene Blue – high dose to produce methemoglobin V. SPECIFIC TOXICANTS
 Nitrites/Nitrates I. INDUSTRIAL + HOUSHOLD TOXICANTS
o Inorganic Nitrates – preservatives: KNO3  Salt Peter;  Solvents – ex. alcohol, glycol, aldehydes, hydrocarbons;
NaNO3  Chile Salt ↑lipophilic = ↑chances CNS disturbances; aldehydes –
o Organic Nitrates – ISDN, glyceryl trinitrate generally irritating; amides – sensitizers  allergic reaction;
o Inorganic Nitrites – NaNO3 halogenated HC – cytotoxic; mutagenicity
o Mechanism of Toxicity o Ethylene Glycol – anti-freeze preparation
 Methemoglobin Formation
 ↑ cGMP  desphosphorylate myosin light chain 
smooth muscle relaxation  vasodilation
o Clinical Effects: cyanosis; dizziness; headaches;
lightheadedness; nausea; diarrhea; vomiting
o Treatment: methylene blue ↓ doses 1-2mg/kg

II. DEPRESSION OR STIMULATE CNS CAUSING COMA OR

CONVULSION
 Depression – coma; (ex. alcohol; sedative; hypnotics)
 Stimulate – convulsions; (ex. cocaine; sympathomimetics)

III. AFFECT THE AUTONOMIC NERVOUS SYSTEM,

PARASYMPATHETIC (ACh), SYMPATHETIC (NE/E), ENTERIC  Clinical Presentation
NERVOUS SYSTEM  1st Stage – (30 minutes to 12 hours); CNS depression
 Organophosphate + Carbamates – insecticides;  coma  ethanol intoxication
organophosphate  malathion, parathion; carbamates   2nd Stage – (12 hours to 98 hours); cardiopulmonary
edrophonium, physostigmine symptoms; tachypnea; tachycardia
o Mechanism of Toxicity – inhibit acetyl cholinesterase;
irreversibly (OP); reversibly (carbamates); muscarinic –
increase cholinergic activity (DUMBBELS); nicotinic – muscle
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  Treatment: II. ACIDS + ALKALIS – household bleach; drain cleaners;
 Ethanol – competes with alcohol dehydrogenase disinfectant
 Thiamine/Pyridoxine – facilitate conversion to α-  Mechanism of Toxicity
hydroketoadipate glycine o Acids – coagulation necrosis – eschor (protective)  deeper
 Leucovorin – facilitate conversion of formate  CO2 layer (protects)
 Fomepizole – aka 4-methylpyrazole; alcohol o Bases – liquefactive necrosis  deeper penetration
dehydrogenase inhibitor  Treatment – supportive; surgery  perforation; avoid
 Methanol – colorless liquid volatile at room neutralization and dilution
temperature
methanol (non-toxic)  metabolites (formic acid) III. HEAVY METALS
toxic  Common MOT – binds sulfhydryl groups of enzymes causing
methanol –[o]-> formaldehyde –[o]-> formic acid inactivation; treated with chelators
o Formic Acid – inhibits cytochrome oxidase in optic
nerve blindness VI. CHELATOR PHARMACOLOGY
o Clinical Presentation  substances that has lone pair of e- (-NH, -SH, -OH)
 Metabolic Acidosis
 Deferoxamine – complexes with ferric ion  hexadentate
hyperventilation – compensation; pale +
complex ferrioaxime  urine; does not bind with Hgb,
clammy skin
cytochrome
confusion/lethargy – decrease; intracerebral
 Dimercaprol – British Anti-Lewisite (BAL); Lewisite – arsenic
pH
gas; first commercially available chelator; As, Au, Hg; adjunct
hypotension – H+ (negative inotrope);
with severe Pb poisoning (CaEDTA); forms stable dimercaptide
myocardial depression
(dimercaprol [2:1] metal); most toxic among all chelator;
arrhythmia – H+  K+ shifts outside cells
median lethal dose is 1 mmcl/kg; ↑systolic + diastolic BP by 50
 Blindness – treatment: ethanol – competes with
mmHg; pain in injection site
alcohol dehydrogenase
o Counter Indication – Cd, Se, Tc, Fe and organomercurial 
o Formaldehyde – colorless liquid with pungent odor;
increases tissue uptake
embalming liquid
 Dimercaptosuccinic Acid/Succimer/DMSA – water soluble
 Clinical Effects:
form of BAL; orally
 Local Effects – mucosal irritation; (oral, oropharyngeal,
 D-penicillamine – cuprimine; oral chelator, monothiol; DOC
conjunctiva)
for Cu toxicity (Wilson’s Disease); bind Fe, Hg, Pb, Zn, As
 Metabolic Acidosis
possibly other heavy metals
o Hydrocarbons and Petroleum Distillates
o Counter Indication – penicillin allergy
 Hydrocarbons – organic compounds H and C
 CaEDTA – binds both divalent and trivalent metals; forms H2O
 Distillates – mixture of aromatic and aliphatic HC
soluble complex  kidneys; used for Cd, Co, Cu, U, Zn
 Physical Properties
poisoning
 High Volatility, Minimal Viscosity – simple gases such
as methane and butane
 Intermediate Volatility, Low Viscosity – gasoline and VII. HEAVY METALS
turpentine  Arsenic – lewisite metal; Salvarsan, Arsphenamine
 Low Volatility, Low Viscosity – petroleum spirits, o Clinical Presentation – Mee’s Line – white lines in nails;
kerosene milky + rosy complexion; abnormal weight gain
 Minimal Volatility, High Viscosity – lubricating oil, o Treatment – BAL; BAL + penicillamine (severe)
mineral oil  Lead – leaded gasoline; paint; newspapers; earthenwave;
 Mode of Transmission – aspiration associated with automobile exhaust
increasing volatility but decreasing viscosity - ↑irritation o Kinetics – t½ (bones) = 32 years; t½ (kidneys) = 7 years
to the lungs o MOT: interferes with heme synthesis  cytochrome
 Clinical Presentation – burning sensation; choking; production  anemia
coughing; gagging; atelectasis and bronchopneumonia; o Clinical Presentation – peripheral neuropathy – wrist drop,
CNS manifestation foot drop; anemia; encephalopathy – ataxia, delirium, coma,
 Treatment – respiratory support; selective β2 agonist  ↓IQ
bronchospasm; mineral oil  ↑viscosity ↓aspiration o Treatment – CaEDTA; BAL; succimer; DMSA; DMPs
 Cadmium – causes Itai-Itai disease
o MOT – displaces Ca2+ in bones
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 o Clinical Presentation X. HERBICIDES
 Osteomalacia, Fracture, Renal Abnormalities – fanconi-
 bipyridyl herbicides; MOT: inhibition of superoxide mutase
like syndromes
 Paraquat – pulmonary fibrosis; hemorrhage; edema
 Fanconi Syndrome – proteinuria; aminoaciuria; glucosuria
 Diquat – burning pain in mouth; throat chest; upper
and ↓phosphate reabsorption
abdomens; pulmonary edema; pancreatitis; renal damage;
 Gait Disturbances
CNS effects
o Treatment – EDTA
 Mercury – quicksilver; Minamata Disease
o Types: XI. MEDICAL TOXICOLOGY
 Elemental Hg – thermometers; amalgam I. ANALGESICS
 Inorganic Hg – HgCl2 (corrosive sublimate); Hg2Cl2  Aspirin
(calomel) o Reye’s Syndrome – fatty liver + hepatic encephalopathy due
 Organic Hg – thimerosal (merthiolate) to ASA in children after viral infection
o Clinical Presentation – acrodynia/pink disease – pink palm o MOT – direct effect on CNS  respiratory alkalosis +
and soles; irritability; photophobia bicarbonaturia; severe cases: CNS respi center 
o Treatment – BAL – inorganic; penicillamine – low level Hg; respiratory acidosis; uncoupling of oxidative
Na formaldehyde sulfoxinate – most useful antidote phosphorylation  hyperthermia; inhibition of
 Iron – caused by ingestion of Fe tablets among children aminotransferase in Kreb’s cycle  metabolic acidosis;
o Clinical Presentation – GI hemorrhage salicylic acids  metabolic acidosis
o Treatment – Deferoxamine o Clinical Presentation
 Copper – probably binds to hepatic enzymes  free radicals  Mild – salicylism – tinnitus; hyperthermia;
 hepatic injury and renal tubular injuries hyperventilation
o Clinical Presentation  Severe – hallucinations; acid base balance disturbances
 Acute kidney/liver injury  kidney/liver failure  Fatal – respiratory depression
 Kaiser-Fleischer rings  copper deposits of limbs of o Treatment – activated charcoal; forced alkaline diuresis;
cornea gastric lavage; emesis; ice blanket (hyperthermia); NaHCO3
o Treatment – penicillamine solution (acidosis)
 Acetaminophen – paracetamol
VIII. INSECTICIDES – include OP + carbamates
 Chlorinated HC – lidocaine; chlordane; DDT; neurotoxin
o MOT – after Na+/K+ flux (myocardial irritation)  CNS
hyperexcitability
o Clinical Presentations – CNS excitations – tremors,
headaches, agitation, seizures, disorientation, coma;
respiratory depression; nausea + vomiting
 Pyrethoids – more commonly used in insecticides; 1000x more o MOT – hepatic injury
toxic to insect than man o Clinical Manifestation – non-specific; nausea, vomiting,
o MOT – ↑Na conductance +; ↓Cl conductance – abdominal pain; jaundice
o Clinical Effects – dizziness; headache; fatigue; o Treatment – N-acetylcysteine (Fluimucil®)
seizure/coma
II. ISONIAZID – inhibits pyridoxal phosphokinase; presentation –
IX. RODENTICIDES signs of liver failure, irritability, seizure; isoniazid metabolites 
 Coumarin Derivatives – MOT: inhibits vitamin K dependent toxic (hepatic)
clotting factors; Treatment: vitamin K (phytonadione)
 Phosphrous III. DRUGS OF ABUSE
o Yellow – waxy; fat-soluble; highly poisonous  Opioids and Opiates
o Red – granular; non-absorbed; non-poisonous o MOT – stimulation of opioid receptors
o Clinical Presentations – luminous vomitus or stool with o Clinical Presentation – pinpoint pupils; coma; respiratory
garlic odor; hypocalcemia; cardiac arrhythmia; coma; depression
cardiac arrest o Treatment – antidote: Naloxone – competitive opioid
o Treatment – CuSO4 lavage; BZD – for seizures antagonist

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 Sedative Hypnotics – BZDs/Barbiturates
o Clinical Presentation – drowsiness; ataxia; somnolence;
confusion
o Treatment – BZD (Flumenzenil)
 Hallucinogen – no specific antidotes
o Lysergic Acid Diethylamide (LSD) – ergot derivative
 MOT – targets 5HT2a receptors  hallucination
 Clinical Presentation – HTN; tremors; vomiting; profound
mydriasis
o Amphetamine + Related Compounds
 Ecstasy – MDMA; cocaine
 MOT – stimulate adrenergic receptors  releases NE
 Clinical Presentation – bruxism (teeth grinding);
hyperthermia (most toxic); hypertension
 Treatment – Labetalol; Na Nitroprusside
o Phencylidine – angel dust; ketamine-like  dissociative
anesthesia
 Clinical Presentation – disorganized thought process;
nystagmus; hypertension
o Marijuana – hashish; hashoids; active: THC  delta-9-
tetrahydrocannabinoids; most commonly used illegal drugs
 MOT – stimulates cannabinoid receptors  CNS
 Clinical Presentation – tachycardia; rhinitis; increase
appetite; impaired short-term memory; impaired reaction
time; acute psychosis; bizarre behavior; motor
disturbances
o Alcohol
 MOT – CNS depressant – rostral to caudal progression;
GABA ergic; acid-base disturbances; respiratory acidosis =
decrease CNS respiratory center; metabolic alkalosis =
increase vomitus; metabolic lactic acidosis  lactic acid

 Clinical Presentation – metabolic acidosis; coma;

hyperthermia; hypoglycemia
 Treatment
o Vit B1 + glucose – Wernicke-Korsakoff Syndrome
o Severe – hemodialysis
o Dehydration – IV fluid; supportive

IV. AIR POLLUTANTS

 CO, NO, SO2 + O3; airway irritation; pulmonary edema
 Chronic – gradual
 Lung Damage – chronic cardiopulmonary disease

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