Lecture 16: Medical Toxicology III, Radation, Animal Venoms, and Environmental Toxicology

Ionizing Radiation

-exposure to high energy particles

-alpha, beta, gamma, X-rays, Cosmic radiation

Ionizing Radiation

radiation with enough energy to cause ionization in the medium through which it passes.

Oxidative Stress

imbalance between free radicals and antioxidants in the body

Free Radicals

oxygen-containing molecules with an uneven number of electrons that allows them to easily react with other molecules via oxidation, resulting in large chain chemical reactions

Ionizing Radiation

-damages DNA, RNA, lipids, proteins, and organelles

-Direct Damage

-Indirect damage through free radical formation and oxidative stress

Gray (Gy)

-unit of absorbed radiation dose

-= 1 joule/kilogram

Sievert (Sv)

-Unit of effective dose of ionizing radiation

-based on Strength of radiation

Acute Radiation Syndrome

• Direct whole body exposure to high dose for short duration

• GI - n/v

• Hematologic - aplasc anemia → pancytopenia → anemia, infecon, bleeding;

• Neurological - dizziness, HA, decreased consciousness

Acute Radiation Syndrome

Prodrome:

• n/v, HA, fatigue, fever, skin reddening

• Usually w/in 24 hrs., may last several months

-Decontaminate

-Blood transfusions

-Antibiotics prn

-Bone Marrow Transfusion

treatment for Acute Radiation Syndrome

Chronic Radiation Syndrome

• Exposure over months/years

• Low rate, natural repair competes with damage

• Usually, no overt symptoms

• Symptoms proportional to cumulative exposure

• Skin problems

• Recurrent GI or neurological problems

• Increased cancer

• Maximize distance from source

• Minimize time exposed

• Shielding

• Gas mask, good hygiene

• Potassium iodide (KI)

• Fractionation of dose (radiotherapy)

Describe Radiation Toxicity Prevention

Potassium iodide (KI)

-should be given asap after post-exposure of radiation

-protects thyroid

-blocks abs of radioactive iodine

• Decontaminate ASAP

• Supportive care

• Free radical scavengers - Vitamin E or N-Acetyl-Cysteine

• KI

• Prussian Blue

• DTPA

Radiation Toxicity Managment

DTPA

Chelates radioactive plutonium, americium, curium

Prussian Blue

Chelates radioactive cesium, thallium

Methanol

-Sources: solvents, denatured alcohol and windshield washer fluid, misguided attempt of substituting ethanol

-Route: oral

Methanol

•Formic acid and formaldehyde lead

to metabolic acidosis, coma and blindness

Methanol

-Initial: CNS depression and resp. distress

-Delayed: metabolic acidosis, hyperventilation, altered mental status, blurred vision that can lead to possible blindness (6-30 hours)

-Supportive

-Inhibit Alcohol Dehydrogase (Fomepizole and Ethanol)

-Sodium bicarbonate (IV) for metabolic acidosis

-Hemodialysis for severe toxicity

Treatment for Methanol Toxicity

Fomepizole

-prevent the formation of toxic metabolites in the case of methanol poisoning

-IV

- MOA: Competitive inhibitor of alcohol dehydrogenase

- Preferred if available

Ethanol

-prevent the formation of toxic metabolites in the case of methanol poisoning

-IV

- MOA: Competitive substrate for alcohol dehydrogenase

- May intensify CNS depression, difficult to safely dose and maintain adequate blood levels

Ethylene glycol

-Sources: antifreeze, solvents, accidental intoxication bc it tastes sweet

-Route: oral

Ethylene glycol

Mechanism of Toxicity:

• Toxic metabolites

o Hippuric, oxalic, and glycolic acids cause metabolic acidosis and coma

o Oxalic acid and glycolic acid lead to renal failure

Ethylene Glycol

-Initial: transient excitation followed by CNS depression

-Delayed: metabolic acidosis, renal failure, oxalate crystals in the urine

-Supportive

-Inhibit Alcohol Dehydrogase (Fomepizole and Ethanol)

-Sodium bicarbonate (IV) for metabolic acidosis

-Hemodialysis for severe toxicity

treatment for Ethylene Glycol poisoning

Crotalidae Venom

Toxin in Pit Vipers (rattlesnakes, copperheads, and cottonmouths)

Crotalidae Venom

What venom:

• Local: Severe pain, bruising and swelling

• Systemic: N&V, muscle fasciculations, paralysis and coagulopathy

• Keep calm and seek medical care

• Antivenom is 99% effective if administered with 2 hours

• Do NOT apply a tourniquet

• Antidote: Antivenin (Crotalidae) polyvalent immune Fab (CroFab)

Treatment for Crotalidae Venom (pit vipers)

Pterois Venom

what toxin is in Lionfish

Pterois Venom

What venom:

• Extreme pain, N&V, fever, dizziness, headache, numbness, tingling and sweating

Cnidarian Venom

Toxin of Venomous cnidarian (jellyfish)

Cnidarian Venom

What venom:

• Erythema, burning pain, hypersensitivity and inflammation

• Rinse area with sea water or vinegar

• Soak in hot water or use ice packs

• Use hydrocortisone or diphenhydramine for itching

Treatment for Cnidarian Venom (jellyfish)

Latrotoxin

toxin in a black widow

Latrotoxin

causes pore formation in presynaptic nerve terminals increasing intracellular Ca2+ and neurotransmitter release

Latrotoxin

What Venom:

-Muscle pain, muscle spasms, sweating, tachycardia, and abdominal pains

• Supportive care (anti-inflammatory, analgesics and antispasmodics)

• Antidote: Black widow antivenin

Treatment for Latrotoxin (Black widow)

Loxosceles Toxin

What venom is in a Brown Recluse?

Loxosceles Toxin

What Venom:

-Dermonecrotic skin lesions, bites can lead to systemic effects (N&V, fever, anemia and thrombocytopenia)

• No established treatment

• Antihistamines can be given for itching

• Antibiotics to prevent infection

• Surgery

• Antidote: None currently available

treatment for Loxosceles Toxin (brown recluse)

Cyanide (CN-)

-Sources: Pesticides, burning polymers (hydrogen cyanide, HCN), tobacco smoke, drugs, cassava, certain seeds and nuts, suicide, homicide, and terrorism

-Route: Oral and inhalation

Cyanide (CN-)

-toxicity is the result of mitochondrial respiratory chain collapse caused by the high affinity of CN- for the cytochrome c oxidase

o Cellular hypoxia and lactic acidosis

-has a high affinity for methemoglobin forming cyanmethemoglobin

Cyanide (CN-)

Shortness of breath, agitation, tachycardia, seizures, coma and hypotension

• Supportive care and AC therapy (oral)

• Cyanide antidote kit: Amyl nitrite (inhalant), sodium nitrite (IV) and sodium thiosulfate (IV)

• Hydroxocobalamin (IV) is an alternative antidote

treatment for Cyanide poisoning

Amyl nitrite (inhalant), sodium nitrite (IV) and sodium thiosulfate (IV)

-Cyanide Antidote Kit

o High doses of nitrites convert hemoglobin to methemoglobin; which pulls the CN off cytochrome oxidase to form cyanmethemoglobin

o Administration of sodium thiosulfate converts the cyanmethemoglobin to thiocyanate ion (SCN-); a less toxic product that can be excreted

Hydroxocobalamin (IV)

-an alternative antidote for Cyanide

• MOA: Directly binds with CN- to form cyanocobalamin

• Limited availability

• Cost ( <$1000)

Carbon Monoxide (CO)

-Sources: byproduct of incomplete combustion; cars, exhaust, residential fire, accidental and suicide

-Route: inhalation

Carbon Monoxide (CO)

leading cause of poisoning in the US

Carbon Monoxide (CO)

• Binds to the oxygen-binding site on hemoglobin with a ~200-250 times greater affinity than oxygen forming carboxyhemoglobin

• Carboxyhemoglobin cannot carry oxygen and inhibits the transfer of oxygen from oxyhemoglobin

• Reduces the delivery of oxygen to the body

Casarett & Doull's Toxicology: The Basic Science of Poisons, Ninth Edition, 9th Edition, Chapter 22-24; Goldfrank's Toxicologic Emergencies,

Carbon Monoxide (CO)

• Progressive hypoxia, headache, loss of attention span, dizziness, nausea, vomiting, tachycardia, tachypnea, seizures, coma and respiratory failure

• Chronic exposure may contribute to atherosclerosis in smokers

• Removal from the source

• Maintain respiration

• Administer 100% O2

treatment for Carbon Monoxide (CO) poisoning

Acetaminophen

-Sources: OTC analgesics, prescription analgesic combinations

• Current recommendation is < 4g/24 hours

Acetaminophen

• Oxidation by CYP2E1 forms N-acetyl p-benzoquinoneimine

(NAPQI)

o Glutathione depletion

o Mitochondrial damage

• Chronic alcohol use will increase the toxicity by inducing CYP2E1

• Acute alcohol coingestion may act as a competitive substrate and decrease toxicity

Acetaminophen

• Nausea, vomiting and abdominal discomfort (1-12 hours)

• Right upper abdominal quadrant tenderness (1-2 days)

• Jaundice, scleral icterus and bleeding (3-10 days)

• Hepatic encephalopathy with severe poisoning (5-10 days)

• Elevated AST, ALT and serum bilirubin

N-acetylcysteine

treatment for Acetaminophen poisoning

Rumack-Matthew Nomogram

used to assess the risk posed by acetaminophen, but it is only valid for acute doses.

Salicylates

Exposure:

• Aspirin (Acetylsalicylic acid)

• OTC analgesics and antipyretics

• Accidental (children) or intentional (suicide) ingestion

Salicylates

Uncoupling of oxidative phosphorylation

Salicylates

• Contraindicated in children with viral infections:

o Reye's syndrome (an often fatal, fulminating hepatitis with cerebral edema)

• First-order kinetics at low doses

• Zero-order kinetics at higher doses

Salicylates

• Initial: Hyperventilation and respiratory alkalosis

• Followed by: Metabolic acidosis, hyperthermia, vomiting, dehydration, hypokalemia, seizures and coma

• Gastric lavage, AC therapy, and whole bowel irrigation if necessary and appropriate

• IV fluids for dehydration

• Moderate intoxication: Sodium bicarbonate (IV) to alkalinize the urine

• Severe intoxication (severe acidosis, coma): Hemodialysis

treatment for overdose of Salicylates