Specific Toxins Part I. Acids Examples –Toilet bowl cleaner –Rust remover –Phenol (carbolic...

Specific Toxins

Part I

Acids

• Examples– Toilet bowl cleaner– Rust remover– Phenol (carbolic acid)– Hydrochloric acid

• Severe burning of stomach

• Absorption, systemic acidemia

Acids

• Loss of airway = most immediate threat

• Secure airway against edema

• IV with LR, NS for volume loss

• Emesis, gastric lavage contraindicated

• Dilution with water, milk NOT recommended

Alkalis

• Examples– Drain cleaner– Washing soda– Ammonia– Lye (sodium hydroxide)– Bleach (sodium hypochlorite)

• Severe burning of esophagus, stricture formation

Alkalis

• Loss of airway = most immediate threat

• Secure airway against edema

• IV with LR, NS for volume loss

• Emesis, gastric lavage contraindicated

• Dilution with water, milk NOT recommended

Hydrocarbons

• Examples– Kerosene– Gasoline– Lighter fluid– Turpentine– Furniture polish

Hydrocarbons

• Signs/Symptoms– Choking, coughing, gagging– Vomiting, diarrhea, severe abdominal pain– Chemical pneumonitis, pulmonary edema

If the patient is coughing, aspiration has occurred

Hydrocarbons

• Signs/Symptoms– Euphoria, confusion/anxiety, seizures– Increased myocardial irritability, arrhythmias

(adrenergic agents may cause V-fib)

– Liver damage, hypoglycemia

Hydrocarbons

• Management– 100% oxygen with good humidification– IV tko– Monitor ECG– Drug therapy

• D50W for hypoglycemia

• Diazepam for seizures• Antiarrhythmics

Hydrocarbons

• Inducing emesis controversial– Should NOT be induced with low viscosity

hydrocarbons

Hydrocarbons

• If ingestion has occurred recently, emesis probably should be induced with:– Halogenated hydrocarbons (carbon tetrachloride)– Aromatic hydrocarbons (toluene, xylene, benzene)– >1cc/kg gasoline, kerosene, naptha– Petroleum products with toxic additives (lead

tetraethyl, pesticides)

Hydrocarbons

Seek advice of medical control and poison control center

Methanol

methyl alcohol

wood alcohol

wood naphtha

Methanol

• Sources– Industry– Household solvents– Paint remover– Fuel, gasoline additives– Canned heat– Windshield washer antifreeze

Methanol

• Toxic dose– Fatal oral: 30-240ml– Minimum: 100 mg/kg– Example

• Windshield washer fluid 10% Methanol• 10 kg child needs only 10 cc to be toxic

Methanol

• Mechanism of toxicity– Methanol slowly metabolized to formaldehyde– Formaldheyde rapidly metabolized to formic

acid• Acidosis• Ocular toxicity

Methanol Metabolism

OC

OH

H+_

HOC

OH

Formic Acid

CH

OH

Formaldehyde

HOHH

HC

Methanol

Alcohol dehydrogenase

Aldehyde dehydrogenase

Methanol

• Overdose Presentation– Inebriation– Gastritis– Osmolar gap

(osmolar gap as little as 10mOsm/L is consistent with methanol poisoning)

Methanol

• Overdose Presentation– Latent period of up to 30 hours – Severe anion gap metabolic acidosis– Visual disturbances, blindness

(“standing in a snowstorm”)– Seizures– Coma– DEATH

Methanol

• Management– High concentration oxygen– IV tko– ECG monitor– if < 30 minutes lavage or induce emesis

(if not done then it is probably useless)

Methanol

• Management– Sodium Bicarbonate– Folic acid

• 50mg IV every 4 hours

• Helps convert formic acid to CO2, H2O

– Give specific antidote

Methanol

• The specific antidote for methanol toxicity

10% EtOH solution in D5W

7.5 ml/kg loading dose and 1.5 ml/kg/hr maintenance

100 proof (50%) EtOH

1.5 ml/kg loading dose and 0.3 ml/kg/hr maintenance

Ethanol Metabolism

H

H

H

C HO

H

H

C

CH

OH

H

H

C

HOC

OH

H

H

C

Krebs Cycle

Ethanol

Acetic Acid

Acetaldehyde

Alcohol dehydrogenase

Aldehyde dehydrogenase

Methanol

Alcohol dehydrogenase

Ethanol Methanol

Acetic Acid

CO2 + H2O + Energy

Urine

Methanol

• Specific antidote– Fomepizole (4-methylpyrazole)– Inhibits alcohol dehydrogenase– Produces same end result as ethanol

without causing intoxication

Ethylene Glycol

• Antifreeze (95% ethylene glycol)

• Tastes sweet

• Kids, animals like taste/drink large quantities

Ethylene Glycol

• Mechanism of toxicity– Metabolized via alcohol dehydrogenase to

glycoaldehyde then to glycolic , glyoxylic, and oxalic acids

– Acids lead to anion gap metabolic acidosis– Oxalate binds with calcium

• Forms crystals causing tissue injury• Produces hypocalcemia

Ethylene Glycol

• Toxic dose– Approximate lethal oral dose: 1.5ml/kg– Example

• 10 kg child needs 15ml for lethal dose

Ethylene Glycol

• Overdose Presentation (first 3-4 hours)– Patient may appear intoxicated– Gastritis, vomiting– Increase in osmolar gap– No initial acidosis

Ethylene Glycol

• Overdose Presentation (after 4-12 hours)– Anion gap acidosis– Hyperventilation– Seizures, coma– Cardiac conduction disturbances, arrhythmias– Renal failure– Pulmonary, cerebral edema

Ethylene Glycol

• Management– Lavage if within 2 hours– Sodium bicarbonate– Fomepizole or ethanol– Folic acid, pyridoxine, thiamine

(enhance metabolism of glyoxylic acid to nontoxic metabolites)

Cyanide

But first…• A little review of

biochemistry and biophysics

Staying alive requires energy...

• The natural tendency of the universe is for things to become more disorderly.

• This trend toward disorder is called entropy.

• Complex systems (including us) don’t tend to last long, unless…

• They have a constant supply of energy to combat entropy.

Organisms capture and store the energy they need in the form of...

• The “currency” cells use to pay off the energy debt built up fighting entropy.

• Formed by capturing energy released as the cell breaks down large molecules through glycolysis and the Krebs Cycle.

Adenosine Triphosphate (ATP)

Glycolysis• In cytoplasm• Does not require oxygen• Breaks glucose molecule into

two pyruvic acid molecules• Net gain of 2 ATP• If oxygen absent, pyruvate

converted to lactate• If oxygen present, pyruvate

changed to acetate (acetyl-CoA) and sent to Krebs Cycle

The Krebs Cycle• In mitochondria• Requires oxygen• Strips H+ and electrons

off of acetate, leaving CO2

• Sends the H+ and electrons to the electron transport chain

Electron Transport/Oxidative Phosphorylation

• In mitochondria• Electrons pass down a

series of carriers--losing energy as they go

• It’s like a series of waterfalls• Energy is released and

stored as ATP

• Electrons and H+ bind to O2, making H2O

• 36 ATP produces per glucose molecule

Oxidative Phosphorylation

NAD NADH2

2H

FAD FADH2

Ox. Cyt. b Red. Cyt. b

Ox. Cyt. c Red. Cyt. c

Ox. Cyt. a Red. Cyt. a

Red. Cyt. a3Ox. Cyt. a3

1/2O2

2H+

H2O

ADP + Pi

ADP + Pi

ADP + Pi

ATP

ATP

ATP

Putting It All Together• Cells have to have energy to stay alive.• Cells get energy by breaking down glucose in two phases: glycolysis

and the Krebs Cycle.• Glycolysis yields 2 ATP and pyruvate.• Pyruvate is changed to acetate (acetyl-CoA) and sent to the Krebs

Cycle.• The Krebs Cycle strips hydrogen and electrons off acetate and feeds

them into the electron transport chain.• Movement of electrons down the transport chain releases energy which

is trapped as ATP.

• At the end of the chain, the electrons combine with hydrogen and

oxygen to form water.

Cyanide

• Chemical, plastic industries

• Metallurgy, jewelry making

• Blast furnace gases

• Fumigants, pesticides

• Present in various plants– apples, pears, apricots, peaches, bitter

almonds

Cyanide

• Acrylonitrile is metabolized to cyanide

• Nitroprusside (Nipride) if given too long is metabolized to cyanide

• Acetonitrile in some fingernail glues has caused pediatric deaths

Cyanide is so common that all mammals have an enzyme called rhodonase that detoxifies cyanide by

converting it to thiocyanate

Cyanide

• Mechanism of Toxicity– Chemical asphyxiant– Inhibits functioning of cytochrome a3– Stops electron transport, oxidative

phosphorylation– Blocks aerobic utilization of oxygen

Cytochrome A3

Fe2+Fe3+ 2H+

2e-

2e-

1/2 O2

H2O

Cytochrome a

Cyanide Toxicity

Fe2+Fe3+ 2H+

2e-

2e-

1/2 O2

H2O

Cytochrome a

CN-

Cyanide

• Clinical Presentation– Variable onset speed with different forms– Headache, nausea, dyspnea, confusion– Rapid, weak pulse– Bright-red venous blood– Syncope, seizures, coma– Agonal respirations, bradycardia,

cardiovascular collapse

Cyanide

• Management– Treat all cases as potentially lethal– Support oxygenation, ventilation– ECG– IV tko– Cyanide Antidote Kit

Cyanide Antidote Kit

• Amyl nitrite, Sodium nitrite– Oxidize iron in hemoglobin from Fe2+ to Fe3+

(methemoglobinemia)– Methemoglobin binds cyanide, removing it

from cells

• Sodium thiosulfate– Provides rhodonase with sulfide anion– Speeds conversion of cyanide to thiocyanate

CN-

Cyanide Antidote Kit

Fe3+ Fe2+ 2H+

2e-

2e-

1/2 O2

H2O

Cytochrome a Fe2+ Fe3+CN-NO2 -

SCN-

Cyanide Antidote Kit

• Amyl nitrite, sodium nitrite – Only be used in serious cyanide poisonings– Can induce life-threatening tissue hypoxia

secondary to methemoglobinemia

• Sodium thiosulfate – Can be used by itself– Is relatively benign

Salicylates

Salicylates

• Examples– Aspirin– Oil of wintergreen

• Uses– Analgesics– Antipyretics– Anti-inflammatories– Platelet function inhibitors

Salicylates

• Mechanism of Toxicity– Direct stimulation of respiratory center, causing

respiratory alkalosis– Irritation of gastrointestinal tract, causing decreased

motility, pylorospasm, nausea, vomiting, hemorrhagic gastritis

– Decreased prothrombin levels/platelet dysfunction, causing prolonged clotting times

– Uncoupling of oxidative phosphorylation

Aspirin Toxicity

NAD NADH2

2H

FAD FADH2

Ox. Cyt. b Red. Cyt. b

Ox. Cyt. c Red. Cyt. c

Ox. Cyt. a Red. Cyt. a

Red. Cyt. a3Ox. Cyt. a3

1/2O2

2H+

H2O

ADP + Pi

ADP + Pi

ADP + Pi

Heat

Heat

Heat

Results of Oxidative Phosphorylation Uncoupling

• ATP production decreases, resulting in CNS and cardiovascular failure.

• Cells attempt to compensate by increasing the rate they process glucose anaerobically through glycolysis.

• Lactic and pyruvic acids accumulate, leading to metabolic acidosis.

• Hypoglycemia results as liver sugar stores are depleted.• In absence of sugar cells begin to metabolize lipids, ketone

bodies are produced, acidosis worsens.• Energy normally trapped as ATP is wasted as heat, causing

a rise in body temperature.• The rise in body temperature accelerates metabolism,

increasing tissue oxygen demand and worsening acidosis.

Salicylates

– Vomiting– Lethargy– Hyperpnea– Respiratory alkalosis– Metabolic acidosis

– Coma– Seizures– Hypoglycemia– Hyperthermia– Pulmonary edema

Clinical Presentation: Acute Toxicity

Salicylates

• Clinical Presentation: Chronic Toxicity– Usually young children, confused elderly– Confusion, dehydration, metabolic acidosis– Higher morbidity, mortality than acute

overdose– Cerebral, pulmonary edema more common

Salicylates

• Acute Toxicity Management– Oxygen, monitor, IV– GI tract decontamination– Activated charcoal– Replace fluid losses, but do NOT overload– Control hyperthermia

Salicylates

• Acute Toxicity Management– Bicarbonate for metabolic acidosis– D50W for hypoglycemia– Diazepam for seizures

Acetaminophen

Acetamophen

• Examples– Tylenol– Tempra– Datril

• Uses– Analgesic– Antipyretic

Acetaminophen

• Mechanism of toxicity– N-acetyl p-benzoquinonimine, normal

product of acetaminophen metabolism, is hepatotoxic

– Normally is detoxified by glutathione in liver– In overdose, toxic metabolite exceeds

glutathione capacity, causes liver damage

Acetaminophen Metabolism

APAP APAP-glucuronide

APAP-sulfate

Urine Urine Urine

N-acetyl-p-benzo-quinonimine

Cysteine Congugates

UrineGlutathione

28- 52% 45-55%

2- 4%

2- 4%

2- 4%P-450 MFO

Acetaminophen Toxicity

APAP APAP-glucuronide

APAP-sulfate

Urine Urine Urine

Cysteine Congugates

Urine

Hepatocyte Protein

Congugates

Cell DeathGlutathione

N-acetyl-p-benzo-quinonimine

Acetaminophen• Minimum toxic dose

– Adult: 7 grams– Child: 140 mg/kg

• Onset of symptoms is slow, initially non-specific

Stage Time Symptoms

I 1/2 to 24h Anorexia, NV, malaise, diaphoresis

II 24 to 48h Abdominal pain, liver tenderness, increased liver enzymes, oliguria

III 72 to 96h Peak enzyme abnormality, Increased bilirubin and PT

IV 4d to 2wk Resolution or progressive hepatic failure

Acetaminophen

• Management– Induce emesis– Do NOT give activated charcoal– Give specific acetaminophen antidote

Acetaminophen

• The specific antidote for acetaminophen toxicity.

Mucomyst

• N-acetylcysteine Another sulfur-containing amino acid Substitutes for glutathione. Allows continued detoxification of NAPBQI. 140mg/kg initially followed by 70mg/kg every 4 hours

17 times. Tastes, smells like rotten eggs Mix with chilled fruit juice to decrease odor, taste

Can Mucomyst (NAC) Be Given If The Patient’s Gotten Activated

Charcoal?• AC and NAC are not given simultaneously• AC is given in the first 4 hours. NAC is given after 4 hours.• The effective dose of NAC is equal to the amount of APAP

ingested.• Patients receive a total dose of 1330 mg/kg, so most are

over-treated.• The reduction in NAC absorption caused by AC (8 to 39%)

applies only to the first dose.• So the potential total decrease in absorption is 4.5%• A patient would have to ingest 1275 mg/kg for this to

become a problem.