MODULE 4│PHARM CHEM 5

TOXICOLOGY
TOXICOLOGY sola dosis facit venenum – “the dose makes the poison”

• Branch of Pharmacology that deals with the study of poison, - a.k.a. deleterious/ toxic
mechanism of toxicity and its treatment., Side effects
Adverse 1. Hypersensitivity
Effects 2. Idiosyncrasy
I. INTRODUCTION TO TOXICOLOGY Effects
3. Tolerance/
- related to therapy Desensitization
Forensic Toxicology Clinical Toxicology 4. Teratogenicity
– medicolegal Mechanistic – diseases cause by
US FDA Pregnancy Risk Classification
aspects of poisoning Toxicology toxicants
(mechansim of Category Animal studies Human studies
action) A Safe Safe
B Safe None
Risk NOT SAFE Safe
Assessment C NOT SAFE None
Regulatory None None
Descriptive
Toxicology D NOT SAFE: benefits outweigh risk
Toxicology
(decides if a X Contraindicated in pregnancy = Teratogenic
(toxicity effects
substance
testing)
possess a risk
Teratogens Presentation
Thalidomide Amelia/ Phocomelia
Warfarin Hypoplastic nose
Tetracycline Tooth discoloration
Environmental Toxicology – Lithium Ebstein’s anomaly
harmful effects of chemicals to ACE inhibitors Renal dysgenesis
the environment/ organisms Methimazole Aplasia cutis
Carbamazepine, Valproic acid Neural tube defects (spina bifida)
Diethylstilbestrol (DES) Clear cell adenocarcinoma of the
RISK ASSESSMENT vagina/ cervix
Phenytoin Fetal hydantoin syndrome
• estimate of potential effects of poison to human health and Ethanol Fetal alcohol syndrome
environmental significance of various types of chemical • Facial anomalies
exposure • Growth retardation
• Hazard – ability of a chemical agent to cause injury in a • Neuro-developmental
defects
given situation or setting
• Risk – expected frequency of the occurrence of an
undesirable effect arising from exposure to a chemical or Effects of Poison
Immediate vs. Delayed
physical agents
Immediate Delayed
• Seen after single • Seen after a lapse of time
POISON administration

• deleterious effects Reversible vs. Irreversible

• physical injuries Reversible Irreversible
• death • Reversed by administration of • Permanent damage
• Toxin – natural source the antidote • Carcinogenic and teratogenic
• Toxicants – man made/ artificial source effects

COMMON MAJOR PATHOPHYSIOLOGIC MECHANISMS Local vs. Remote vs. Systemic

CNS stimulation Causes nerve excitability → Seizures → Brain Local Remote Systemic
damage • Same route of • Different route of • Causes
CNS depression Loss of airway protective reflexes and respiratory administration administration widespread
drive → Respiratory depression and site of and site of derangement
Parasympathomimetic Diarrhea action action
effect Urination Example: Example: Example:
Miosis, Muscle fasciculations Phenol, caustic, Paraquat ingestion → Metabolic acidosis
(DUMBELS) Bronchoconstriction, Bradycardia corrosives → skin pulmonary fibrosis due to MUDPHILES
Emesis burn
Lacrimation
Salivation, Sweating MUDPHILES
Sympathomimetic Mydriasis Methanol
effects Agitation Uremia
Tachycardia Diabetic ketoacidosis
(MATHS) Hypertension Paraldehyde
Seizure, Sweating Isoniazid, Iron
Cardiovascular Heart: Cardiac Arrhythmias Lactic acidosis
effects Vasculature: Ethylene glycol
• Vasodilation → hypotension Salicylates
• Vasoconstriction → hypertension
Respiratory effects Aspiration → Bronchospasm Route of administration:
Cellular hypoxia Interference with O2 transport and utilization
Musculoskeletal Muscle breakdown and myoglobinuria → Renal
effects failure, lactic acidosis, hyperkalemia Ingestion
• Accidental and suicidal poisoning
Inhalational
• Occupational exposure
Dermal
• Occupational exposure
Parenteral
• Greatest effect and most rapid response
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Frequency D. Degree of Disability

Acute Eyes Verbal Motor

• Single administration (+4) Spontaneous (+5) Orientated (+6) Obey commands
• Time: < 24 hours (+3) To sound (+4) Confused (+5) Localizing
(+2) To pressure (+3) Words (+4) Normal flexion
• Acute exposure by inhalation: 4 hours (+1) None (+2) Sounds (+3) Abnormal flexion
Subacute (+1) None (+2) Extension
• Repeated exposure (+1) None
• Time: < 1 month Differential Diagnoses for altered Mental Status:

Sub-chronic 1. Head trauma or other causes of intracranial bleeding

• Repeated exposure 2. Abnormal levels of blood glucose, sodium, or other
• Time: 1-3 months electrolytes
3. Hypoxia
Chronic 4. Hypothyroidism
• Repeated exposure 5. Liver or renal failure
• Time: > 3 months 6. Environmental hyperthermia or hypothermia
7. Serious infections such as encephalitis and meningitis
II. GENERAL MANAGEMENT OF A POISONED PATIENT
Causes Agent Initial Dose
Primary Survey (ABCDE) Hypoglycemia Dextrose
• Adult 50% dextrose, 50mL (25g) IV
• Child 25% dextrose, 2mL/kg IV
History and PE Alcohol intoxication Thiamine 100 mg, in the IV solution or IM
Opioid intoxication Naloxone 0.2-0.4 mg IV or IM
Decontamination *if no response within 1-2 minutes,
give 2 mg IV
Antidotal Therapy Benzodiazepine Flumazenil 0.2 mg IV over 30 seconds
*Pediatric dose Is not established;
starts at 0.01 mg/kg
Toxin Elimination *if no response, give 0.3 mg
**if still no response, give 0.5 mg and
repeat every 30 seconds
PRIMARY SURVEY
E. Exposure/ Environment
Airway
HISTORY AND PHYSICAL EXAMINATION
Breathing
• A.k.a. SECONDARY SURVEY (“AMPLE”)
Circulation

Degree of Disability Allergy

Exposure/ Environment Medication
Past Medical History/ Pregnancy
A. Airway
Last meal
Airway Management
• Optimize airway position Events related to the injury
• Place the neck and head in “sniffing” position
• Apply the jaw-thrust maneuver DECONTAMINATION
• Place the patient in a head-down, left sided position
• CAUTION: Do not perform neck manipulation if neck A. Surface Decontamination:
injury is suspected
• Remove any obstruction or secretions 1. Dermal
• Use of artificial oropharyngeal or nasopharyngeal airway • Remove contaminated clothing
devices • Wash with copious amount of running (tap) water for 30
minutes
B. Breathing Topical Agents for Chemical Exposure to the Skin
Hydrofluoric acid Calcium soaks
Breathing Problems
Oxalic acid Calcium soaks
Ventilatory Failure Paralysis of Ventilatory Muscles: Phenol Mineral oil, Isopropyl alcohol
• Flaccid paralysis: Neuromuscular blockers, White Phosphorus Copper sulfate 1%
Botulinum toxin
• Spastic paralysis: Tetanospasmin,
Strychnine, Saxitoxin, Tetrodotoxin 2. Inhalational
CNS Depression: Alcohols, Sedative-hypnotics, • Remove the patient from the toxic environment → O2
Opioids, Antidepressant, Antipsychotics supplementation
Hypoxia Inert gases: CO2, Methane, Propane, Nitrogen
Cellular hypoxia: CO, Cyanide, 3. Ocular
Methemoglobinemia, H2S, Sulfahemoglobinemia • Wash with BSS/ NSS for 15 minutes of consume 2L
Pneumonia: Aspiration of gastric contents with lids retracted
Bronchospasm Beta-blocker, Hydrocarbon aspiration,
organophosphates and carbamates
B. Gastric Decontamination
C. Circulation
1. Activated Charcoal
• Highly adsorbent powdered material made from a
Circulation Management
distillation of wood pulp
• Check blood pressure and pulse rate and rhythm
• Dose: 10:1 (charcoal to toxin)
• Begin continuous ECG monitoring
• Contraindications:
• Secure venous access
• Unconscious patients
• Draw blood for routine studies
• Begin IV infusion

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 • Poorly adsorbed substances: alkali, cyanide,
alcohols, fluoride, heavy metals, iron, lithium, TOXIN ELIMINATION
mineral acids potassium
A. Forced Diuresis
2. Emesis
• Use of syrup ipecac Review:
• Use when other measures are not available (especially Drug Environment Predominant Ideal for
for agents not adsorbed by activated charcoal) Weak acid Basic/ alkaline Ionized
Excretion
• Contraindication Weak base Acidic Ionized
• Unconscious patients, ingestion of CNS depressants,
patients < 6 months old Drug Environment Predominant What to give?
• Ingestion of corrosive agents Weak acid Basic/ alkaline Ionized Sodium bicarbonate
• Ingestion of aliphatic HC Weak base Acidic Ionized Ammonium chloride
3. Gastric lavage
• Used for massive ingestion B. Extracorporeal Methods
• Contraindications
• Unconscious patients 1. Hemodialysis
• Ingestion of corrosive substances
• Ingestion of SR and enteric-coated tablets

4. Cathartics
• Enhances gastrointestinal transit
• Contraindications:
• Ileus/ intestinal obstruction
• Renal insufficiency (Na/ Mg – containing cathartics)

5. Whole Bowel irrigation Diffusion

↑ Toxin/ Waste
• Use of a bowel-cleansing solution: non-absorbable (↑ solute conc.)
polyethylene glycol in a balanced electrolyte solution
• Generally used for substances poorly absorbed by
activated charcoal
• Indications:
• Iron/ lithium tablets
• SR/ enteric-coated tablets Hypotonic
• Foreign bodies, drug-filled packets, condoms (↓ solute conc.)
• Contraindications:
• Ileus/ intestinal obstruction Diffusion – movement of solute
• Unconscious patients particles from an area of higher solute
concentration to a lower solute
concentration
Oral binding Agents

Drug/ Toxin Binding Agent/s Indications for Hemodialysis:

Calcium Cellulose sodium phosphate • Acidosis (severe)
Chlorinated hydrocarbons, Digitoxin Cholestyramine
• Electrolyte imbalance (refractory hyperkalemia)
Heavy metals Egg white, milk
• Intoxication (salicylates, lithium, methanol, ethylene
Iron Sodium bicarbonate
Lithium, Potassium sodium polystyrene sulfonate
glycol)
(Kayexalate®) • Overload (volume)
Paraquat Fuller’s earth, Bentonite • Uremia (bleeding, altered mental status)
Thallium Prussian blue
Dialyzable Toxins
ANTIDOTAL THERAPY • Water soluble
• Volume of distribution <1L/kg
Physiologic Antidote Pharmacologic Antidote • Protein binding < 50%
• Binds to the same site/ • Binds to a different site/ • MW < 500 Da
receptor with the poison receptor from the poison
• Ex. Opioids: Naloxone • Ex. Anaphylaxis: Epinephrine 2. Hemoperfusion

Chemical Antidote Mechanical Antidote Non-Dialyzable Toxins

• Alters the chemical nature of • Removes the poison • Lipid soluble
the poison making it more physically from the • Volume of distribution >1L/kg
water soluble circulation/ GIT
• Ex. CN: Sodium thiosulfate • Ex. Gastric lavage
• Protein binding ≥ 50%
• MW ≥ 500 Da
Universal antidote
Activated charcoal Magnesium oxide Tannic acid

Poison Antidote
Paracetamol N-Acetylcysteine
Organophosphate, Carbamates Atropine, Pralidoxime
Anticholinergics Physostigmine
CCBs, Fluoride Calcium
Iron Deferoxamine
Digoxin Digoxin antibodies (Digibind®)
Theophylline, Caffeine Esmolol
Methanol, Ethylene glycol Ethanol; Fomepizole
Benzodiazepines Flumazenil
β-blockers glucagon
Cyanide Hydroxocobalamin
Opioids Naloxone
Carbon monoxide Oxygen 3. Peritoneal Dialysis
• Only 10-15% as effective as hemodialysis

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 III. INDUSTRIAL AND HOUSEHOLD TOXICANTS Methanol
• Colorless liquid, volatile at room temperature
Solvents • Common component of gasoline, antifreeze, perfume, wood
alcohol, paint solvents, household cleaners
Cyanide
Hydrogen sulfide
Acids/ Alkali
Phenol
Food Additives

SOLVENTS

• Alcohols • Treatment:
• Aldehydes • Ethanol
• Hydrocarbons • Fomepizole
• ↑ lipophilic, ↑ capacity to cause CNS disturbance
• Aldehydes are generally irritating Aldehydes
• Amides are sensitizers and may cause allergic reactions
• Hydrocarbons may be cytotoxic or mutagenic Formaldehyde
• Colorless liquid with pungent odor
Alcohols • Embalming fluid, used in cosmetics, deodorants, detergents,
• Examples: dyes
• Ethylene glycol
• Methanol Presentation
• General Mechanism of Toxicity (MOT): CNS depression Local effects: mucosal irritation → oral, pharyngeal, conjunctival
Metabolic acidosis

Hydrocarbons

Hydrocarbon and Petroleum Distillates

MOT: aspiration
Minimal viscosity, High votality
Methane Butane

Low viscosity, Intermediate volatility

Gasoline Turpentine

Low viscosity, Low volatility

Ethylene glycol Kerosene Petroleum spirits
• Antifreeze preparation in car radiators, coolants, deicers
• Common in industrial solvents, detergents, corrosives, High viscosity, Minimal volatility
lacquer and paints Mineral oil Lubricating oil
• Clear, odorless liquid Presentation:
• Burning sensation, cough
• Pneumonitis, atelectasis
• Benzene: blood dyscrasias (acute myeloblastic leukemia,
hairy cell leukemia)
• Chlorofluorocarbon, butane: potentiate epinephrine effects
→ arrhythmia

• Treatment:
• Mineral oil: to increase viscosity and ↓ risk of aspiration
• O2 support
• β2-agonists

CYANIDE

• Sources:
• Prunus sp. (almond, cherry, apple), cassava, lima
beans → cyanogenic glycosides
Presentation • Silver jewelry cleaner (SJC)
1st stage 30 mins to 12 hrs CNS depression • MOT: inhibits cytochrome oxidase
2nd stage 12-48 hrs Metabolic acidosis • Presentation:
Cardiopulmonary symptoms • CNS and CVS disturbances
• Arrhythmia • Respiratory depression
• Tachypnea → compensatory • Treatment:
respiratory alkalosis
• Cyanide Kit
3rd stage 24-72 hrs Acute renal failure: Oliguria/ anuria ↑
BUN/ Creatinine • Amyl nitrite (inhalational) + NaNO2 (IV) →
methemoglobinemia + CN →
• Treatment: cyanomethemoglobinemia + NaS2O3 → SCN
• Ethanol: competitive inhibition (relatively nontoxic, more polar)
• Fomepizole: 94-methylprazole): alcohol dehydrogenase • Hydroxocobalamin → Cyanocobalamine
inhibitor
• Vitamin B1 and B6

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 HYDROGEN SULFIDE Dimercaptosuccinic acid (DMSA)
• Water-soluble and more tolerable preparation of BAL
• Highly toxic, colorless gas with rotten egg odor • May be administered orally
• MOT: inhibits cytochrome oxidase
• Presentation: Deferoxamine
• Irritation of mucous membranes • Desferal®
• Respiratory depression • DOC for Fe Poisoning
• Treatment: • MOA: Binds Fe3+ (transferrin iron) → Ferrioxamine → rapidly
• Remove patient from toxic environment excreted in urine
• Amyl nitrate + NaNO2 → methemoglobinemia + S2- → • Fe2+ in hemoglobin and cytochrome oxidase not affected
Sulfamethemoglobin
• Hyperbaric O2 (100% O2) D-Penicillamine
• Cuprimine®
ACIDS AND ALKALI • DOC for Cu toxicity
• May also be used in Fe, Hg, Pb, Zn, As poisoning
• Acids: corrosive → coagulation necrosis → forms protective
eschar → less penetrating CaNa2 EDTA
• Alkali: caustic → liquefactive necrosis → more penetrating • Bind divalent and trivalent heavy metals → displaces Ca2+
• Treatment: → more polar, easily excretable
• Wash with amount of running (tap) water 30 minutes • Used in Cd, Co, Cu, U, Zn poisoning
• For acid ingestion: give egg whites
ARSENIC
PHENOL
• Lewisite metal
• Carbolic acid • Salvarsan, Compound 606, Arsphenamine
• Component of industrial paint removers
• Once widely used as antiseptic (Joseph Lister) Presentation
• MOT: protein denaturation Acute
• Presentation: • Garlic odor breath
• Tingling sensation/ numbness (local aesthetic effect) • Diarrhea, dehydration
• CNS: delirium, seizure, coma
• White discoloration of the skin → corrosive burns
Chronic
• Treatment: Dilute • Mee’s lines: white line cross the nails o fingers/ toes
• Wash with amount of running (tap) water 30 minutes • Milky/ rosy complexion
• For acid ingestion: give egg whites • Keratosis
• Hair loss
FOOD ADDITIVES • Abnormal weight gain

Tartrazine (FD&C 5) Monosodium Glutamate • Treatment: BAL if severe + Penicillamine

MOA: Anaphylaxis vs. Anaphylactoid (bot IgE-mediated)
Presentation: Presentation: Chinese Restaurant LEAD
• Hives Syndrome
• Difficulty of breathing • Difficulty of breathing • Component of leaded paints, newsprint, automobile exhaust,
• Shock • Facial flushing
earthenware
• Tachycardia
Treatment: Epinephrine, Antihistamines
• Half-life (t ½):
• Bones: 32 years
IV. HEAVY METALS AND CHELATING AGENTS • Kidney: 7 years
• MOT: inhibits enzymes in heme synthesis
• ALA dehydrogenase: important for lab diagnosis
Arsenic Lead • Ferrochelatase

Presentation
Acute ingestion:
Heavy • Milky vomitous
Cadmium Mercury
metals • Black stools
• Encephalopathy
Chronic cumulative exposure:
• Lead palsy (wrist and foot drop): weakening of extensor muscles
Iron Copper • Anemia
• Burton line: black-blue line on gums
• Developmental delay in children

• Common MOT: bind to –SH group of enzymes → • Treatment:

inactivation
• BAL
• Treated with the use of Chelators/ Chelating agents
• CaNa2 EDTA
• Forms water-soluble complexes with heavy metals → • DMSA
easily excreted
• BAL
CADMIUM
DMSA
• Deferoxamine
• Component of solders, anti-dandruff shampoos, stink bombs,
• Penicillamine
batteries
• CaNa2 EDTA • MOT: binds to bone (compete with Ca) → distortion of bone
structures
Dimercaprol
• British Anti-Lewisite (BAL) Presentation
• 1st agent used clinically • Itai-itai disease: due to Cd contaminated rice
• Most toxic, lipophilic • Back pain, joint pain
• Indications: • Fractures, Osteomalacia
• Treatment as As, Hg, Au poisoning • Waddling gait: weakness of pelvic muscles
• Adjunct CaNa2 EDTA for severe Pediatric Pb poisoning • Renal failure
• Contraindications: Cd, Se, Te, Fe poisoning
• Side effects: Hypertension, Pain on injection site • Treatment: CaNa2 EDTA

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 MERCURY Presentation
• Rosy complexion
• Quicksilver • Headache, confusion
• MOT: Inhibits monoamine oxidase (MAO) • Tachycardia
Forms • Syncope, coma, death
If >40% of hemoglobin converted carboxyhemoglobin
Inorganic HgCl: calomel
HgCl2: corrosive, sublimate, bichloride of mercury
Organic Thimerosal: Merthiolate® Sulfur Dioxide
Methylmercury: bioaccumulate and bioamplification in fishes • Produce from combustion of sulfur containing fossil fuels
• MOT: SO2 form sulfurous acid → irritation of respiratory
Presentation membranes → bronchoconstriction
Acute inorganic:
• GI disturbances Nitrogen oxide
• Renal failure • Nitrogen dioxide
Chronic inorganic: Mad hatter’s disease • Irritating to respiratory mucous membranes particularly type
• Triad: gingivitis, tremors, neuropsychiatric changes 1 cells of the alveoli → impaired gas exchange
• Acrodynia: pink discoloration of hands and feet
• Sympathomimetic effects: MATHS
Organic: Minamata disease
Ozone
• Cerebral palsy, intellectual disability • Occurs around high voltage electrical equipment and in
• Blindness, deafness water or air purifiers
• Treatment: • MOT: formation of free radicals
• Acute inorganic: BAL, DMSA
• Chronic inorganic: BAL Treatment: (CO, SO2, NO, Ozone)
• For HgCl2: NA formaldehyde sulfoxylate • Remove patient from toxic environment
• Hyperbaric O2 (100% O2)
IRON
INSECTICIDES
• Usual cause of toxicity is ingestion of OTC preparation by
children • Organophosphates
• MOT: has corrosive effects in the GI bleeding • Carbamates
• Chlorinated hydrocarbons
Presentation • Pyrethroids
GI bleeding
• Coffee ground material on vomitous Organophosphates and Carbamates
• Hematemesis Organophosphates Carbamates
• Melena • Malathion • Physostigmine
• Hematochezia • Parathion • Neostigmine
MOT: inhibits acetylcholinesterase and other plasma cholinesterase
• Treatment: Deferoxamine (Desferal®) Presentation
Parasympathomimetic effects: DUMBELS
COPPER
Nicotinic stimulation: MATCH
Muscle weakness
• Toxicity usually occurs in Wilson’s disease Adrenal medulla hyperactivity
• MOT: binds to hepatic enzymes and serum proteins → free Tachycardia
radicals → hepatotoxicity and nephrotoxicity Cramps
Hypertension
Presentation
• Liver and Kidney failure Treatment:
• Kaiser-Fliescher rings: Copper deposits on corneal limbus Pralidoxime
• Regenerates acetylcholinesterase
• Treatment: Penicillamine (Cuprimine®) • Must be given within 36 hours of exposure

Carbamates
V. ENVIRONMETAL TOXICOLOGY • Displaces organophosphates thus preventing bond aging

Atropine
Air Pollutants
Insecticides Chlorinated Hydrocarbons and Pyrethroids
Chlorinated Hydrocarbons Pyrethroids
Rodenticides • DDT • More commonly used
(Dichlorodiphenyltrichloroethane) insecticide
Herbicides • Lindane • Thousand times more
• Chlordane toxic to insects than
Fungal/ Animal Toxins humans
MOT: MOT: ↑ NA+ conductance and
AIR POLLUTANTS • Altered K / Na flux → CNS
+ +
↓ Cl conductance → CNS
-

hyperexcitability hyperexcitability
• Produces myocardial irritability
• Carbon monoxide Presentation Presentation:
• Sulfur dioxide • CNS excitation: tremors, • Dizziness, headache,
• Nitrogen oxides agitation, headache, fatigue
• Ozone disorientation, coma • Coma/ Seizures
• Airway irritation → Pulmonary edema • Respiratory depression after
• Chronic exposure → Gradual lung damage → Chronic seizures
pulmonary disease • Nausea and vomiting

Carbon monoxide RODENTICIDES

• Odorless, colorless gas produced from partial oxidation of
carbon containing compounds → when operating stoves • Coumarin Derivatives
internal combustion engine • Phosphorus
• MOT: Greater affinity to hemoglobin (200x) than oxygen → ↓
O2 utilization → hypoxia

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Coumarin Derivatives Other Animal Toxins:
• Examples: Tetrodotoxin
• Warfarin • Sources: amphibians, mollusks (snails, octopus), pufferfish
• Brodifacoum (Japan)
• Coumatetralyl • MOT: Na+ channel blocker
• MOT: inhibits Vitamin K epoxidase reductase • Presentation:
• Presentation: Bleeding • Perioral numbness
• Treatment: Vitamin K • Flaccid paralysis
• Treatment: Airway support (intubation)
Phosphorus
• Red: red amorphous powder, non-poisonous; used to Toxin Animal
produce matches and fireworks Bufotoxin Bullfrogs
• Violet: prepared from red phosphorus Clupeotoxin Oysters
• Black: resembles graphite in texture, produced from white Gemblid Mackerel
phosphorus Venerupin Sardines
• White: waxy, fat soluble, highly poisonous Saurine Tuna
Presentation
Acute: VI. CLINICAL TOXICOLOGY
• Luminous vomitus and stools, severe GI irritation Ergot Alkaloids
• Garlic odor breath
• Arrythmia, coma Nitrates
Chronic
• Phossy jaw (bony necrosis of the mandible) Paracetamol

• Treatment: CuSO4 lavage Salicylates

Isoniazid
HERBICIDES
Digoxin
• MOT: inhibition of superoxide dismutase
• Paraquat: Pulmonary fibrosis, Hemorrhage, Edema Drugs of Abuse
• Diquat: Burning pain (in the mouth, throat, chest, upper
abdomen), Pulmonary edema, Pancreatitis, Renal damage, ERGOT ALKALOIS
CNS effects
FUNGAL/ ANIMAL TOXINS • Source: Claviceps purpurea
• Related drugs:
• Aflatoxin • Ergotamine (acute migraine)
• Saxitoxin • Ergonovine, methysergide (post-partum bleeding,
• Amatoxin abortifacient)
• Latrotoxin
• Other Animal Toxins Presentation
Convulsive:
Aflatoxin • Painful seizures
• Source: Aspergillus flavus • Painful spasms
• Found in improperly dried peanuts and grains Gangrenous:
• Excessive vasoconstriction → poorly vascularized distal structures
Presentation (fingers, toes) → dry gangrene
Adults: ↑ tolerance → Asymptomatic
Children: acute hepatic necrosis → liver cirrhosis → liver cancer • Treatment: vasodilators (tolazoline, Na nitroprusside)

• Treatment: Supportive (IV fluids, electrolytes) NITRATES

Saxitoxin • Inorganic:
• Source: Dinoflagellates • KNO3 (saltpeter)
• Causes red tide poisoning, paralytic shellfish poisoning • NaNO3 (Chile saltpeter, salitre)
(PSP) • NaNO2 (used in cyanide poisoning)
• MOT: Na+ channel blocker (important for muscle • Organic:
depolarization → contraction) → flaccid paralysis • NTG
• Complication: respiratory depression → death • ISGN
• Treatment: airway support (intubation) • ISMN
• Glyceryl trinitrate
Amatoxin • MOT:
• Source: Amanita phalloides (destroying angel)
• MOT: inhibits RNA polymerase II in the liver →↓ protein
synthesis → hepatotoxicity
• Treatment:
• Supportive (IV fluids, electrolytes)
• Benzylpenicillin (Penicillin G): competitively inhibits
amatoxin in its liver receptors (theoretical)

Latrotoxin
• Source: Latrodectus mactans (black widow/ hourglass
spider)
• MOT: causes presynaptic release of acetylcholine
• Presentation:
• Parasympathomimetic effects: DUMBELS
• Conjunctivitis
• Restlessness
• Hypertension
• Treatment: Antivenom • Presentation
• Dizziness
• Lightheadedness

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 • Nausea and vomiting Presentation
• Monday sickness (loss f tolerance Confusion, hallucination
• Treatment: Xanthopsia (yellow/ green color blindness)
• For NaNO2: methylene blue → reverse Fatal arrhythmia (ventricular tachycardia) → d/t stimulation of automatic
methemoglobinemia cardiac cells 9SA nodes, AV node, bundle of His, ventricular muscle)

PARACETAMOL • Treatment:
• Digoxin Fab fragments (Digibind®)
NAPQ: N- • Lidocaine: DOC for digoxin-induced ventricular
acetylparabenzo- tachycardia
quinoneimine
Toxic dose: >4g/day DRUGS OF ABUSE
Presentation:
• Nausea and Opioids and Opiates
vomiting
• Abdominal pain
Opioids = semi-synthetic/ synthetic: heroin, fentanyl, tramadol,
• Jaundice
Treatment:
nalbuphine
• N-acetylcysteine
(NAC) → replenish Opiates = natural: morphine, codeine
GSH stores • Source: Papaver somniferum

Receptors Function Affinity

Mu (μ) Analgesia, sedation, inhibition of Endorphin >
respiration, slowed GI transit, enkephalin >
modulation of hormone and dynorphin
neurotransmitter release,
euphoria
Delta (δ) Analgesia modulation of hormone Enkephalin >
and neurotransmitter release, endorphin and
SALICYLATES development of tolerance dynorphin
Kappa (κ) Analgesia, psychotomimetic Dynorphin >>
• Examples: aspirin (Acetylsalicylic acid/ ASA), methyl salicylate effect, slowed GI transit Endorphin and
• MOT: accumulation of salicylic acid enkephalin

Presentation Presentation
Children: Reye syndrome → hepatitis → encephalitis Triad of: Pinpoint pupils, Coma, Respiratory depression
Adults:
• Treatment: Naloxone (opioid receptor antagonist)
Sedative hypnotics

• MOT: enhances the action of GABA by ↑ chloride channel

opening → hyperpolarization of the cell (harder to stimulate)
• Barbiturate: ↑ duration
• Benzodiazepine: ↑ frequency

Presentation
Slurred speech, altered mental status
Ataxia, drowsiness
Paradoxical hyperactivity (children) → d/t anxiolytic effect

• Treatment: Flumazenil (Romazicon®) for BZD toxicity

Hallucinogens
• LSD
• Treatment: supportive • PCP
• Activated charcoal, gastric lavage, emesis • Stimulants
• Alkalinize the urine (NaHCO3) • Marijuana
• Ice blanket (for hyperthermia)
Management
ISONIAZID • Most have no specific antidote → supportive treatment
• Hypertension: Labetalol, Na nitroprusside
• Isoniccotinylhydrazide (INH) • Seizure: Diazepam, Phenytoin, Barbiturates
• 1st line anti-TB medication • Hyperthermia: ice blanket
• MOA: (as inti-TB agents): inhibits mycolic acid synthesis
• MOT: inhibits pyridoxal phosphokinase → coverts pyridoxine a. LSD
to pyridoxal phosphate • Lysergic acid diethylamine, acid
• Presentation: • Ergot derivative (rye parasite)
• Peripheral neuropathy • MOT: targets 5-HT2a receptors → hallucination
• Hepatotoxicity • Presentation:
• Triad of: Seizure, Coma, Metabolic acidosis • Hypertension
• Treatment: Pyridoxine/ Vitamin B6 (1:1) • Tremors
• Vomiting
DIGOXIN • Profound mydriasis

• Source: Digitalis lanata/ Digitalis purpura b. PCP

• MOT: inhibits Na+-K+ ATpase • Phencyclidine, angel dust
• Factors Affecting Toxicity: • Most dangerous hallucinogenic agent
• Hypercalcemia • MOT: antagonist at the glutamate NMDA receptors
• Hypokalemia • Presentation:
• Chronic antibiotic use • Dissociative anesthesia (like ketamine)
• Concomitant quinidine administration • Psychotic reaction → impaired judgement → reckless
behavior
Module 4 – Toxicology Page 8 of 9 RJAV 2021
 • Marked hypertension
• Fatal seizures

c. Stimulants
• Cocaine, amphetamine, methamphetamine, ecstasy
(methylenedioxymethamphetamine/ MDMA)
• MOT: inhibits reuptake of adrenergic neurotransmitters,
could also directly stimulate adrenergic receptors
• Presentation:
• Hypertension
• Mydriasis
• Seizure
• Bruxism (teeth grinding)
• Delusional parasitosis
• Hyperthermia (most toxic)

d. Marijuana
• Source: Cannabis sativa (hemp)
• Weed, pot, grass, damo, Mary Jane, hash
• Active ingredient: tetrahydrocannabinol (THC)
• MOT: Activates cannabinoid receptors
• Improves concentration, memory
• Feeling of being “high”, uncontrollable laugh
• Alters depth and time perception
• Presentation:
• Rhinitis
• Conjunctivitis
• Musty sweet odor

ALCOHOL

• MOT: CNS depression

Presentation
“Head to toe” progression
Wernicke-Korsakoff syndrome: d/t Vitamin B1 deficiency → loss of
memory/ black out
Hypoglycemia: inhibition of hepatic gluconeogenesis

• Treatment: Treatment: Thiamine/ Vitamin B1 Glucose

Reference/ Source:
• Casarett & Doull’s Toxicology (The basic
science of poison)
• Review notes (Manor review center)
• PACOP

Module 4 – Toxicology Page 9 of 9 RJAV 2021