INTENTIONAL POISONINGS Flashcards
NERVE AGENTS
What are they?
- Extremely potent organophosphates, inhibit cholinesterase
- Clear, odorless, colorless and tasteless
- Aerosol doses LD50 10-400mg-minute/m3 (Tabun and Sarin)
- Dermal doses LD50 10-1700 mg (VX and Sarin)
- GA, GB, GD – volatile
- VX oily liquid
NERVE AGENTS
Pathophysiology
- Toxidromes – cholinergic (SLUDGE – muscarinic; days of the week, nicotinic)
- Rapid effects – (i) vapors within seconds to minutes, (ii) liquids – slightly
delayed due to absorption - Vapor exposure – most common issues eyes (miosis, pain, dim vision, loss of
acuity); headache, nausea, cough - Dermal exposure sweating, fasciculations, vomiting, diarrhea, weakness,
seizures, loss of consciousness - Long-term effects mostly psychological sequelae
- Lethal acute toxicity – death primarily caused by asphyxiation or cardiac arrest
Secondary exposures (Tokyo and Matsumoto) – evaporation from patients’
clothing - Liquid agents can permeate clothing and are hazard for health care personnel
NERVE AGENTS
Treatments
- Decontamination – should be done first, limit secondary exposures
- Atropine – is the standard anticholinergic antidote for muscarinic effects
- Adult – 2-6mg to start, repeated dosing until resolution of muscarinic toxicity
- Children begin 0.05mg/kg
- 2-PAM (pyridine-2-aldoxime) – Oximes are nucleophilic that reactivate cholinesterase
by removing dialkylphosphoryl moiety, time dependent (soman ~2-6 min, sarin3-5h,
tabun 14h, VX 48h) (~600mg) - Antiepileptics – severe toxicity induces convulsions (ie., 5-10mg diazepam)
- Pyridostigmine (pretreatment) – carbamate acetylcholinesterase inhibitor – good for
expected samon exposure
Dioxins
Viktor Yurshchenko (Dioxin, 2004)
* President of Ukraine 2005-2010
* Poisoned during election campaign
Dioxins
* Family of isomers – dibenzo-p-dioxin (major environmental pollutants)
* E.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) most potent
* Highly lipophilic, wide variation in dose-response, t½ (7-11 yrs)
* Binds to aryl hydrocarbon receptor (AHR) – inappropriate activation
* Class 1 carcinogen and endocrine disruptors
* Impact on reproductive function
* Immunological suppressive effects
* Carcinogenic effects
Chloracne
- Starts with excessive oily skin, leading to whiteheads, blackheads,
cysts, skin thicken, flake, peel, scar, change in coloration - Systemic toxicity
- MOA remains unknown – involves alterations of cellularity
RICIN
Toxicity
Est’d LD50 - Injection (~1-10ug/kg)
- Inhalation (~1-10ug/kg)
- Ingestion (~10mg/kg)
- Water soluble
- Easily made from waste ‘mash’ of castor oil production
- Composed of two proteins linked by disulfide bond
- B Chain facilities binding and entry into cell and localising
to the ER
- A Chain inhibits protein synthesis by inactivating
ribosomes - remove an adenine residue from rRNA
- rRNA is unable to bind to protein elongation factors
Clinical Symptoms
- Respiratory distress (inhaled with few hrs)
- Severe vomiting (ingestion)
- Gastroenteritis, hemorrhage and inflammation
- Multiple organ failure
- Death within 48-72h
- No treatments
CYANIDE
“Jonestown” remote settlement in Georgetown, Guyana (November 18, 1978)
* Peoples Temple Agricultural Project, San Francisco-based cult – Jim Jones
* 918 people died, plus five other murders
* Murder-suicide, drank the ‘kool-aid’ potassium cyanide
Tylenol Poisoning Chicago (September 29, 1982)
* Drug tampering in Chicago, laced with potassium cyanide
* 7 people died
* Recall, est’d ~ 31 million bottles in circulation at the time
(found 3 bottles)
* Led to the development of tamper-resistant packaging,
such as induction seals and quality control measures
CYANIDE
Sources
- Cyanide is a chemical group that consists 1C and 3N
- Plants sources (ie., cassava roots, apricot pits, peach pits,
almonds) - Nitroprusside (hypertension therapy)
- Industrial usage (acetonitrile products, paper, textiles, plastics),
cigarette smoke - Common salts (NaCN, KCN) can react with water to form
hydrogen gas (HCN) colorless
CYANIDE
Pharmacology
- Exposed by air, water, food
- Cyanide gas is the most dangerous
- Gas is less dense than air so it will rise/disperse quickly
- Lethal oral dose ~200mg
- Lethal airborne ~270ppm
- Readily crosses membranes low MW (24Da) and nonionized
- CN is metabolized to thiocyanate (rhodanese, βmercaptopyruvate–CN sulfurtransferase)
- Limited by endogenous stores of sulfur
CYANIDE
Pathophysiology
- Cyanide inhibits multiple enzymes, succinic acid
dehydrogenase, superoxide dismutase, carbonic anhydrase and
cytochrome oxidase (cyt a3) - Induces cellular hypoxia, metabolic acidosis
- Very rapid onset of effects (seconds-minutes)
- Heart and CNS are impacted due to metabolic needs
- Survivors can develop delayed neurologic sequelae
CYANIDE
Treatment
Antidotes
- Supportive care – ventilate, give 100% oxygen, vasopressors
for hypotension, sodium bicarbonate
Antidotes - Hydroxocobalamin – metalloprotein with a central cobalt atom
that complexes CN forming cyanocobalamin (preferred) - Cyanide Antidote Kit – amyl nitrite, sodium nitrite and sodium
thiosulfate - Note: CN has a higher affinity for methemoglobin than
cytochrome a3 (amyl nitrite generates methemoglobin)
ANTHRAX…
Anthrax
* Bacillus anthracis, gram-positive spore forming bacillus found in soil
worldwide
* Inhalation causes mediastinitis, spores taken into lymphatic system
can germinate
* Produce 3 toxins: protective antigen (PA), edema factor (EF) and
lethal factor (LF)
* Develop fever, malaise, cough, chest discomfort (2-3days)
* Progress to severe respiratory distress, dyspnea, diaphoresis, stridor,
cyanosis
Treatment
* Antibiotics (ciprofloxacin, doxycycline)
* Raxibacumab (monoclonal antibody) blocks binding of anthrax PA
* Vaccine – avirulent non-encapsulated strain that produces PA
ARSENIC
Poisonings
- Arsenic poisonings have been around for 1000’s of years
- Hard to detect until the discovery of the Marsh test (1836)
- Metalloid existing in multiple forms: elemental, gaseous (arsine), organic and
inorganic, (As3+ and As5+) - Arsenic trioxide (As2O3) was a favoured poison, odourless, easily incorporated into
food and drink
ARSENIC
Toxicology
- As3+ - numerous effects but a primary effect inhibits pyruvate dehydrogenase (PDH)
▫ Impact on citric acid cycle (decrease ATP, OXPHOS) leads to ROS
▫ Decrease gluconeogenesis
▫ Effects cardiac repolarization - As5+ - readily reduced to As3+ and pentavalent arsenic resembles phosphate (ie.,
gets incorporated wherever phosphate would be), uncouple OXPHOS - Hepatic metabolism – methylated forms (monomethylarsine and dimethylarsine)
- ‘Disappears’ into the bodies pool of phosphate
- T½ - inorganic forms 4 to 6 hr, and 20-30h methylated forms
ARSENIC
Acute Toxicity
- GI symptoms – nausea, vomiting, abdominal pain, diarrhea 10minseveral hours
- Resembles cholera - diarrhea “rice water”
- Death from acute poisoning mostly due cardiovascular collapse
and hypovolemic shock - Arsenic trioxide (70-180mg lethal)
