Lecture 15 / 16: Toxicology Flashcards
What are the 5 main classes of Toxins?
- Insectisides
- Alcohols
- Metals
- Gases
- Dust and Others
Name an insectiside
Oganophosphate insecticide/nerve agents
Name some toxic alcohols
Methanol
Ethylene glycol
Toxic Metals
Lead
Arsenic
Methylmercury
Toxic Gases
Carbon Monoxide
Cyanide
Toxic Dust and Others
PCBs and Dioxin
Name 4 non-specific antidotes
- Activated Charcoal
- Liqui-Char
- Polyethylene glycol - PEG350
- GlycoLax, Miralax
Name 3 specific antidotes
Fomepizole
Hydroxocobalamin
Pralidoxime
Name 2 Metal Chelators
EDTA, Succimer
Define LD50. What does it measure?
lethal dose 50” dosage of a chemical that is needed to produce death in 50% of treated animals
Measure of acute toxicity, carcinogenic and teratogenic effects not accounted for
LC50
lethal concentration 50” same as LD50 but applies to exposure to gasses (inhalation or dermal
exposure).
NOAEL
“No Observed Adverse Effect Level” highest dose that does not produce a statistically significant toxic effect, subchronic (90 days) animals studies
RfD
Reference dose” - estimate of the daily exposure to an agent that is assumed to have no adverse health impact on the human population.
Name 5 Common Toxic Syndromes
- Anticholinergic Syndromes (atropine)
- Sympathomimetic Syndromes (Cocaine)
- Opiates (Heroin)
- Non-Opiates (alcohol)
- Cholinergic Syndromes (Insectisides)
Name some signs of Anticholinergic Syndromes (6)
Troubled Little Delinquents Enjoy Using Atropine
* Tachycardia
* Little change in BP
* Dry flushed hot skin
* Elevated temp.
* urinary retention
* agitated delirium
Common causes of anticholinergic syndrome (6)
- atropine
- scopolamine
- antihistamines
- anti-Parkinsons
- anti-psychotics
- plants
Treatment for anticholinergic syndrome
Physostigmine
Signs of Sympathomimetic Syndromes
Methamphetamines Probably Dont Help Students Take Diagnostic Tests
- Mydriasis
- Paranoia
- Diaphoresis
- Hypertension
- Seizures
- Tachycardia
- Delirium
- Temperature - elevated
Common Causes of Sympathomimetic Syndrome
- Cocaine
- Amphetamine
- OTC decongestants (ephedrine)
- Caffeine
- Theophylline
Sympathomimetic Syndrome Treatments
- Benzodiazepines for seizures
- Lidocaine for tachycardia and Ventricular Fibrillation
Signs and symptoms of opiate poisoning (7)
Hypotension, bradycardia, coma, respiratory depression, miosis, hyporeflexia, CNS depression
Common causes of opiate poisoning
Narcotics
Treatment of opiate poisoning
Symptomatic treatment and specific
antidotes as appropriate (naloxone; Narcan)
Common causes of non-opiate related poisoning
Barbiturates, benzodiazepines,
other sedatives, ethanol
Signs of non-opiate related poisoning
Hypotension, bradycardia, coma, respiratory depression, miosis, hyporeflexia, CNS depression
Treatment of non-opiate poisoning
Symptomatic treatment
specific antidotes as appropriate (flumazenil - benzo antagonist), IV saline
Identify signs of Cholinergic syndromes
Concert Conductors Make Music (1st 4)
1. Confusion
2. CNS depression
3. Muscle Twitching-weakness / paralysis
4. Miosis
5. Salivation
6. Lacrimation
7. Urination
8. Defecation
SLUD (last 4)
Common causes of cholinergic syndromes (5)
Organophosphate, carbamate insecticides, physostigmine, edrophonium, mushrooms
What are some treatments for Cholinergic syndrome?
atropine
Pralidoxime (2-PAM) for organophosphates only
Principles of Non-Specific Treatment: How do you determine nature of the poison?
toxic syndrome, history,
lab tests, poison control center
Activated Charcoal
Non-specific Treatment
non-specific chelator, limits drug absorption, not as efficacious if drug is rapidly absorbed
Gastric Lavage
Non-specific Treatment
recent ingestion of caustic liquids: not as useful for removal of pills or pill fragments
Syrup of Ipecac
Used only in rare occasions
Exposure < 30 min, ingestion of massive drug dose (100-150 aspirin tablets)
Whole bowel irrigation - when to use
Non specific treatment
Non-absorbable polyethylene glycol (PEG-350)
Used with large ingestion of drugs poorly absorbed by activated charcoal (Fe, Li)
Name some organophosphates and some key facts.
what do they inhibit / reversible / irreversible
methyl parathion, VX nerve agent and
carbamates
Acetylcholine Esterase Inhibitors
irreversible—organophosphates (2-PAM can “reverse”)
reversible—-carbamates
Organophosphate Signs and Symptoms
headache, nausea, dizziness
cholinergic complaints —-SLUD
Organophosphate Mechanism
extremely toxic—respiratory failure due to diaphragm muscle paralysis, central depression of respiratory centers in CNS and bronchoconstriction
Organophosphate Treatment
Treatment: ◼ atropine for both carbamates and organophosphates
◼ Pralidoxime (2-PAM) for organophospate
VX nerve agent
Cholinergic
Colorless, odorless fast-acting chemical weapon
Sources of Methanol Poisoning
◼ windshield washer solvent for cars
◼ mixed solvents (paint removers)
◼ hand sanitizer during COVID pandemic
Methanol poisoning signs and symptoms
CNS depression like ethanol
Methanol Metabolic Mechanism of toxicity
metabolized to formaldehyde by alcohol dehydrogenase and formate by (aldehyde dehdydrogenase) – blindness, metabolic acidosis
Methanol Treatment
◼Metabolic acidosis with Na bicarbonate IV
◼Folic acid B vit. complex, converts formate to CO2 and H2O
ADH inhibitors
◼Fomepizole (Antizol®)
◼Ethanol
Sources of ethylene glycol poisoning
found in auto antifreeze (95%)–other industrial solvents
Ethylene glycol signs and symptoms
◼ CNS depression like ethanol
◼ metabolized —eventually to oxalic acid
◼** hypocalcemic tetany and oxalicaciduria –crystals **
Ethylene Glycol Treatment
◼Hypocalcemia treat with Ca2+ IV
◼Pyridoxine, folate, thiamine – cofactors for eth. glyc. metabolism
ADH inhibitors
◼ Fomepizole (Antizol ®)
◼ Ethanol
Sources of Lead Poisoning
consuming contaminated food prepared with lead cooking utensils, lead-soldered food cans
ingestion of lead paint chips and inhalation of lead dust are major lead sources.
10-20% of exposure due to contaminated drinking water (lead pipes)
Toys made in other countries have lead contaminated paint
Lead in gasoline
Occupational exposure
Signs and Symptoms of Lead poisoning: Blood / PNS / CNS
Blood - hypochromic microcytic anemia
PNS - weak wrist and ankle extensor muscles
CNS - lead encephalopathy w/ delirium, hallucinations and convulsions - can be fatal
Signs and Symptoms of Lead poisoning: GI / Kidney / Reproductive
GI- more common in long term exposures; colic loss of appetite
Kidney - increased uric acid (gout)
Reproductive - stillbirths in women; altered sperm
Lead poisoning mechanism. What does it inhibit?
Unknown, possible molecular mimicry occurs and Pb replaces Ca, Zn, Mg normally found in enzymes, proteins, bone mineral, etc…
Inhibits hemoglobin synthesis - resulting in a build up of hemoglobin precursors in red blood cells
Lead poisoning treatment
1st line drug, 2nd, cerebral edema
Find lead source and remove patient
For severe cases (≥ 45 µg/dl in children, ≥ 50 µg/dl in adults), metal chelators are given (succimer is first line drug)
EDTA is second line drug
Dexamethasome is given for cerebral edema
Lead: Children v. Adults
absorption, blood brain barrier, IQ
- Children absorb 40% of ingested lead, adults 10%
- Pb deteriorates blood brain barrier, more so in children who may not have fully formed BBB
- Childhood Pb exposure is associated with lower IQ, ADHD, aggressive behavior and juvenile delinquency
Arsenic: Which forms are the most toxic and least toxic
several forms exist with varying degree of toxicity
elemental forms are the most toxic (e.g. trivalent or pentavalent).
Organic arsenicals are considered least toxic and occur naturally in seafood.
Sources of Arsenic Poisoning
◼ contaminant of coal, metal ores, rural/municipal water
supplies in US but especially in Bangladesh
◼ industrial workers in semiconductor industry at risk
Signs and Symptoms of Acute Arsenic Poisoning:
GI
Odor
Vessels
What happens if patient survives
◼ violent nausea, laryngitis, bronchitis, hemorrhagic gastroenteritis (rice water diarrhea)
◼ garlic odor on breath
◼ capillary damage–dehydration, shock, death
◼ if patient survives– sensory neuropathy follows
Chronic Arsenic Intoxication: Signs and Symptoms
dermal, cutaneous, bone marrow, liver, cancer
Chronic intoxication:—more common and insidious
◼ can be few symptoms until irreversible injury
◼ dermal manifestations —hyperkeratosis, exfoliative dermatitis, vesicular lesions on feet, peripheral neuropathy
◼ cutaneous vasodilation —”Milk and Roses” complexion
◼bone marrow depression, fatty liver degeneration—death
◼Increased risk of cancers
Arsenic Mechanims - what group does it bind to?
High affinity for –SH groups on proteins
Likely causes severe oxidative stress and disrupt protein function by binding to –SH containing amino acids
Arsenic Treatment
◼The metal chelator Dimercaprol (BAL) – British Antilewisite given IM
Source of Arsine Gas
Only occurs in miners; gas formed when acid touches arsenic metal
Signs and Symptoms of Arsine Gas
Low dose?
◼ produces rapid hemolysis and death
◼ low dose produces partially reversible kidney damage
Arsine Gas Poisoning Treatment
◼ NO Antidote—-supportive therapy only
Methylmercury toxicity
several forms of mercury exist with varying degrees of toxicity.
organic forms are more toxic, specifically methylmercury
Inorganic and elemental forms of mercury tend to be poorly absorbed.
Methylmercury is highly absorbed from GI tract and readily passes blood brain barrier
Sources of mercury poisoning
◼ Hgo (metallic/elemental mercury) metal in dental labs, old thermometers, gold mining
◼ HgCl2, Hg2Cl2 (inorganic salts) used as preservatives, insecticides
◼ HgNO3 in making felt hats (Mad Hatter’s Disease 1800’s)
◼ Methlymercury –** consumption of contaminated fish and
grain fungicide**; ethylmercury – thimerosal an antibacterial
antifungal agent in multi-dose vaccine vials
Organic Mercury Signs and Symptoms (6)
All irreversible:
- Loss of balance
- ataxia
- sensory defects
- loss of visual field
- deafness
- dysarthria
Organic mercury mechanism
Unknown, shown to increase intracellular calcium and bind to metallothionein
Mercury: Special Dietary Considerations
Consumption of predatory fish (swordfish, shark) should be limited to one serving per week
Women who are nursing or pregnant need to avoid eating predatory fish
Canned tuna is considered safe however the MeHg levels depend on many variables
Metal-Chelators: Effect, when is it used, is it effective in chronic cases?
Chelators bind metals → excreted from body
Only used in patients with severely elevated metal levels or toxicity
Chronic metal accumulation occurs over a life time, can accumulate significant amounts of metal stored in bone and other tissue.
Chelation therapy only reduces readily accessible pool of metal
After therapy, blood metal levels can rebound
Edetate Calcium (EDTA):
1. Type
2. Route and what for
3. Toxicity
- Metal Chelator
- Given IV or IM for severe lead poisoning
- Toxic to kidney at high dose
EDTA Side-Effects
Chills, fever, nausea, vomiting, allergies
Succimer:
1. Type
2. Effectiveness for lead
3. Side effects
4. Other possible metals
- First orally effective chelator
- More rapidly effective than EDTA for lead
- GI distress, rash, diarrhea, increase in serum transaminases
- Studies suggest it may also be useful for arsenic and mercury —Important chelator
Carbon Monoxide: Physical characteristics and sources
Colorless, odorless, tasteless, nonirritating, ubiquitous
Sources: any burning or combustion process will generate CO
CO poisoning signs and symptoms
organs with greatest O2 demand will show signs of exposure first
headache, dizziness and increased heart rate
CO poisoning mechanism
- out competes oxygen binding to hemoglobin, 220 greater affinity than oxygen
- when bound to one of the four oxygen binding sites on hemoglobin forms carboxyhemoglobin
- Carboxyhemoglobin reduces the ability of oxygen to dissociate from hemoglobin and be delivered to the deep tissues needing oxygen.
CO poisoning treatment
remove from CO, then hyperbaric O2
Chronic CO exposure
possible cardiovascular problems
Cyanide Gas sources
present in smoke (burning of plastics, wool), industrial exposure (plastics and metal plating), chemical warfare agent
Cyanide Gas Poisoning Signs and Symptoms
“bitter almond” breath, headache, nausea, tachypnea, apnea, loss of consciousness, seizures and coma
Cyanide Gas Poisoning: Mechanism
binds to cytochrome oxidase resulting in inhibition of electron transport chain and the ability of the cell to utilize oxygen in producing ATP
Cyanide treatment
2 ways to Treat:
* Cyanokit is first line with a 2- step method used as a backup
* Cyanide + Hydroxocobalamin (Cyanokit®) → cyanocobalamin
(vitamin B12)
* Older method 2 steps: can not be given with CO inhalation
1. Na nitrite → methemoglobin + cyanide → cyanomethemoglobin
2. cyanomethemoglobin + Na thiosulfate → thiocynate (urine)
PCB’s and Dioxin: Sources
Flame retardants, plasticizers, insulating material in electric transformers
Recent finding that farm raised Salmon had higher PCB content than wild Salmon
Environmentally stable, still present even though use curtailed in 1970s
PCB/s and Dioxin: Signs and Symptoms
dermal acne-like eruptions
called chloracne, nausea, headache, vomiting
Treatment for Dioxin poisoning
None
