Toxicology Part 2

Question 1

Moving on to occupational and environmental toxic chemical toxicity. The first are air pollutants like carbon monoxide. What is carbon monoxide MOA?

Answer 1

Toxicity is a consequence of Cellular Hypoxia and Ischemia

• -CO binds tightly to the hemoglobin iron and this reduces the transport of O2 on blood.
• -Values over 60% HbCO are fatal
• –When CO binds at one or more of the 4 heme sites, hemoglobin shifts to the relaxed conformation, causing the remaining heme sites to bind oxygen with high affinity. Shifting the curve to the left (inability of the affected hemoglobin to release O2 to the tissues)
• –CO2 direct effects by binding to the reduced iron (Fe2+) of cytochromes

Question 2

What is the treatment for CO toxicity?

Answer 2

Administered Oxygen in the highest possible concentration

• -elimination half life of CO is about 320 minutes; this can be shortened to about 80 minutes with 100% O2
• -in severe cases hyperbaric oxygen can be used

Question 3

Next toxicity set of drugs are the solvents. The first is Ethanol, what is the treatment?

Answer 3

Maintenance of vital signs and prevention of aspiration after vomiting

• -IV dextrose
• -Thiamine administration is used to protect against Wernicke-Korsaoff Syndrome

Question 4

Second solvent toxicity is Methanol. what are some features?

Answer 4

Metabolized to formaldehyde and formic acid

• -toxicity is due to formic acid and causes severe acidosis, retinal damage and blindness
• -visual changes, GI distress, SOB, LOC and coma

Question 5

What is the treatment for methanol toxicity?

Answer 5

Fomepizole or Ethanol (IV)
–alcohol dehydrogenase has higher affinity for ethanol than for methanol and this reduces the metabolism of methanol to its toxic metabolites.
–fomepizole is an inhibitor of alcohol dehydrogenase
Treat the metabolic acidosis with sodium bicarb (IV)

Question 6

The third solvent toxicity is Ethylene Glycol, what are some features?

Answer 6

Antifreeze (sweet tasting)

• -metabolized to toxic aldehydes and oxalate
• -leads to severe acidosis and renal damage (urinary calcium oxalate crystals)

Question 7

What is the treatment for Ethylene Glycol?

Answer 7

Fomepizole or Ethanol

Tx metabolic acidosis with IV sodium bicarb

Question 8

Next up are the Pesticides. First up are the insecticides, which are cholinesterase inhibitors. What are some features?

Answer 8

Both organophosphate and Carbamate Cholinesterase inhibitors
–intentional ingestion via suicide or at work

Question 9

First insecticide are organophosphate inhibitors. What re some features of this toxicity?

Answer 9

Phosphorylate Acetylcholinesterase
–organophosphate-bound acetylcholinesterase can lose an alkoxy group in a process called ageing
Signs:
–abdominal cramps, diarrhea, excessive salivation, sweating, urinary frequency, and increased bronchial secretions. CNS involvement usually follows rapidly.
–stimulation of nicotinic receptors causes generalized ganglionic activation which can lead to HTN and either tachycardia or bradycardia. Muscle twitching and fasciculations may progress to weakness
–most common cause of death is resp paralysis

Question 10

What is the treatment for organophosphate inhibitor toxicity?

Answer 10

Atropine: control muscarinic excess

• -if given before ageing has occurred, pralidoxime is able to split the phosphate-enzyme bond and can be used as cholinesterase regenerator.
• -convulsions can be alleviated with diazepam or sodium thiopental.

Question 11

The second insecticide is carbamate insecticides. What are some features?

Answer 11

Inhibit acetylcholinesterase by carbamoylation of the active site
–the clinical effects due to carbamates are of shorter duration than those observed with oraganophosphorous compounds
Tx: atropine (pralidoxime should be given empirically)

Question 12

The next pesticide is rodenticides. The only one in this category is Warfarin. What are some features?

Answer 12

Toxicity depends on repeated ingestion
Tx:
–Vitamin K1 (phytonadione): restores production of clotting factors, however, will not restore clotting factors for 6 or more hours so patients with active hemorrhage may require fresh frozen plasma or fresh whole blood

Question 13

Moving on to Fumigants. The only one to speak about is Cyanide poisoning. Victims die within minutes of exposure. What are some features?

Answer 13

High affinity for iron ferric state
–when absorbed it binds to the Fe3+ in the heme of cytochrome a,a3 in mitochondria and prevents oxygen from reacting with cytochrome a,a3 and therefore cellular respiration is inhibited resulting in lactic acidosis

Question 14

What is the first treatment for cyanide?

Answer 14

Cyanide Antidote Kit

• -toxicity results from binding to the ferric acid of cytochrome oxidase, therefore tx is aimed at prevention or reversal of binding by providing a large pool of ferric iron to compete for cyanide.
• -kit contains: amyl nitrate pearls, sodium nitrate, and sodium thiosulfate
• -Amyl nitrate is administered via inhalation with sodium nitrate IV and nitrates oxidize hemoglobin to methemoglobin, which competes with cytochrome oxidase for the cyanide ion and the reaction favors methemoglobin bc of mass action. Cyanmethemoglobin is formed and cytochrome oxidase is restored.

Question 15

What is the major physiological mechanism for removing cyanide from the body?

Answer 15

Via enzymatic conversion, by the mitochondrial enzyme rhodanese to thiocyanate and to accelerate detoxification sodium thiosulfate is administered IV

• thiosulfate is a sulfur donor that promotes conversion of cyanide to thiocyanate by rhodanese
• -thiocyanate formed is readily excreted in the urine

Question 16

Once cyanide has been detoxified, methemoglobin can be returned to its ferrous form by administration of what?

Answer 16

Methylene Blue
–acts as a cofactor for the enzyme NAPH-methemoglobin reductase
NOTE: oxygen alone, even at hyperbaric pressures, has only a slight protective effect in cyanide poisoning

Question 17

The other treatment for cyanide poisoning is cyanokit, what are some features?

Answer 17

New cyanide antidote

• –active ingredient hydroxocobalamin is a precursor of vitamin B12
• -hydroxocobalamin reacts with cyanide yielding cyanocobalamin which is excreted in the urine

Question 18

Next toxicity are heavy metals, what are some general features, before we go into each heavy metal?

Answer 18

Inactive enzymes and disrupt membranes

• -exert toxic effects by combining with one or more reactive groups essential for normal physiological function
• -therapy of heavy metal intoxication is usually chelation of the metal with a chelating agent. Chelators are organic compounds with two or more electronegative groups that can form complexes with heavy metals and thereby prevent or reverse the binding of metallic cations to body ligands.

Question 19

The first heavy metal to discuss is Lead. Lead may damage the hematopoietic tissues, liver, nervous system, kidneys, GI tract and reproductive system. Lets first discuss acute lead poisoning

Answer 19

Industrial exposure and in children who have ingested a large quantity of chips or flakes from surfaces covered with lead containing paint
–primary signs: acute abdominal colic and CNS changes
(in kids the latter may take the form of acute encephalopathy)
Mortality is high in lead encephalopathy and prompt chelation therapy is mandatory

Question 20

Now lets discuss chronic lead poisoning. What are some features?

Answer 20

Much more common
–signs: peripheral neuropathy (Wrist drop), anorexia, anemia, tremor, weight loss, and GI symptoms
Heme Effects:
–anemia can be either normocytic, microcytic or hypochromic.
–delta-ALA and ferrochelatase are inactivated by lead. Thus there is decreased production of heme. Anemia results from lack of hemoglobin and energy production decreases because of lack of cytochromes for the electron transport chain

Question 21

Finally what is organic lead poisoning?

Answer 21

Due to tetraethyl lead or tetramethyl lead

• -form of lead is readily absorbed through skin and lungs
• -signs: CNS (hallucinations, headache and irritability)

Question 22

What is the treatment of lead poisoning?

Answer 22

Seizures: diazepam
Cerebral Edema: mannitol and dexamethasone
Chelation therapy with edetate calcium disodium, dimercaprol, succimer or unithiol
Tx of organic lead poisoning is symptomatic

Question 23

Next heavy metal is Arsenic which exists in the elemental form and in trivalent and pentavalent oxidation states. Arsine (AsH3) is a gas with potent hemolytic effects is used in industry. What is the MOA?

Answer 23

Trivalent arsenicals (including inorganic arsenite, react with sulfhydryl groups)
–PDH complex is sensitive to trivalent arsenicals because they interact with the SH groups of the coenzyme lipoic acid
Arsenate (pentavalent) is an uncoupler of mitochondrial oxidative phosphorylation (arsenolysis)
Trivalent is more toxic than pentavalent but in vivo interconversion is known to occur
Arsine gas is oxidized and exerts a potent hemolytic effects (depletion of erythrocyte glutathione)

Question 24

There are three clinical presentations of Arsenic poisoning. The first is acute inorganic arsenic poisoning, what are some features?

Answer 24

GI discomfort: vomiting, ricewater stools, capillary damage with dehydration and shock. A sweet or garlicky odor may be detected in breathe and stools
–tx with chelating therapy: Dimercaprol IM (first line) and Unithiol IV
Once patient is stable: parenteral chelation may be changed to oral chelation with either oral unitholor oral succimer.

Question 25

Next presentation for Arsenic poisoning is chronic inorganic arsenic poisoning, what are some features?

Answer 25

Skin changes, hair loss, bone marrow suppression, depression, anemia, chronic nausea and GI disturbances
Tx– Succimer

Question 26

Last presentation for Arsenic poisoning is arsine gas poisoning, what are some features?

Answer 26

Causes massive hemolysis and hemoglobin deposits in the renal tubules may cause renal failure
Tx:
–IV hydration and osmotic diuresis with mannitol to maintain urine output
–Sodium bicarb: to induce urinary alkalinization which may prevent heme pigment nephropathy by decreasing hemoglobin crystallization in renal tubules
–Initial tx with dimercaprol in patients who present within 24 hours of exposure
–After 24 hours, consider chelation with oral or parenteral unithiol or oral succimer

Question 27

Next heavy metal to discuss is Mercury. There are three major chemical forms: mercury vapor, salts of mercury and organic mercurials. Mercury interferes with SH groups in vivo, inhibiting enzymes and altering cell membranes. What are features of acute mercury poisoning?

Answer 27

Occurs through inhalation of elemental mercury
—chest pain, SOB, nausea and vomiting , kidney damage
Acute ingestion of inorganic mercury salts such as mercuric chloride can result in corrosive, potentially life threatening hemorrhagic GI followed by renal failure

Question 28

What are features of chronic mercury poisoning?

Answer 28

Can occur with inorganic or organic mercury

• -poisoning from inhalation of mercury vapor results in a class triad of tremor, neuropsychiatric disturbance and gingivostomatitis
• -acrodynia is an idiosyncratic reaction to subacute or chronic mercury exposure and occurs mainly in children (painful erythema of the extremities, and may be associated with HTN, diaphoresis, anorexia)

Question 29

Finally what are features of organic mercury intoxication?

Answer 29

Consumption of fish containing methylmercury

–affects mainly the CNS and results in paresthesias, ataxia and hearing impairment

Question 30

What is the treatment of acute and chronic exposure?

Answer 30

Acute exposure:
–oral or IV unithiol, IM dimercaprol or oral succimer
Chronic exposure:
–Unithiol and Succimer: will increase urinary mercury excretion following acute or chronic metallic mercury inhalation
–Despite its protective effects in acutely intoxicated animals, dimercaprol may redistribute mercury to the central nervous system, and it is not advocated for treatment of chronic poisoning

Question 31

The final heavy metal is iron and it is not an environmental poison, but accidental intoxication with ferrous salts used to treat iron deficiency anemias has made iron a frequently encountered source of poisoning in young children. What is acute iron toxicity?

Answer 31

Seen in young children who have ingested a number of iron tablets
–symptoms: vomiting, GI bleeding, lethargy, and gray cyanosis

Question 32

What is treatment for iron heavy metal toxicity?

Answer 32

Deferoxamine is the chelator of choice