Toxicology 2 (Arsenic, Mercury, Methemoglobin-producing Agents)

Question 1

What are the different forms of arsenic that can enter the body

Answer 1

• Inorganic arsenic salts
• trivalent Arsenites/As(OH)3 (most toxic)
• Pentavalent arsenates/O=As(OH)3

Question 2

Most frequent source of arsenic intoxication

Answer 2

Manufactures of...
Semiconductors
Herbicides
Insecticides
Wood preservatives
Groundwater may contain it

Question 3

Major route of absorption

Answer 3

Respiratory and GI tract (mucosa)

Question 4

Distribution of Arsenic

Answer 4

First of all liver and kidney
Soft tissues
Skin
Hair
nail

Question 5

Metabolism and elimination of arsenic

Answer 5

methylation, mainly in the liver and the elimination via kidney

Question 6

Pharmacodynamics of arsenic

Answer 6

Inhibits enzymes via sulfhydryl binding

Interferes with oxidative phosphorylation

Question 7

Major clinical effects of arsenic (acute)

Answer 7

GI symptoms
-capillary leak and GI fluid loss leading to bloody diarrhea, hematemesis, hypotension, shock
Cardiopulmonary toxicity, arrhythmia
CNS
-encephalopathy, delirium (first few days
-Neuropathy (weeks later)
- neuromuscular respiratory failure

Question 8

Arsenic major clinical effects (chronic)

Answer 8

General cachexia
Non-specific GI symptoms 
Skin changes (transverse white striae called Mees lines, raindrop hyperpigmentation, hyperkeratosis)
Neuropathy
Anemia
Portal hypertension
Peripheral vascular disease
Cancer years after exposure

Question 9

Acute and chronic therapy of arsenic

Answer 9

Acute
-Gut decontamination, intensive supportive care, dimercaprol 3-5 mg/kg every 4-6 hours
Contraindicated: Succimer orally because gastroenteritis limits absorption
Chronic
-chelators?

Question 10

Major clinical effects of arisine gas poisoning

Answer 10

Major clinical effects

• general initial symptoms (dyspnea, vomiting, abdominal pain)
• Intravascular hemolysis
• oligouric kidney failure (hemoglobinuria)

Question 11

Therapy for arsine gas poisoning

Answer 11

Supportive care
-blood transfusion
-forced alkaline dieresis
Chelators

Question 12

Mercury form entering the body

Answer 12

Elemental mercury

-inorganic Hg+ (less toxic) and Hg++ organic

Question 13

Most frequent source of intoxication of Mercury

Answer 13

Manufacturers of electrical equipments, paint products, dental amalgam

Question 14

Major route of mercury absorption

Answer 14

Respiratory tract (elemental)
GI tract and skin (inorganic)
GI and respiratory tract (organic skin=moderate)

Question 15

Distribution of mercury

Answer 15

First of all kidney

Soft tissues

Question 16

Elimination of Mercury

Answer 16

Via kidney

Question 17

Pharmacodynamic of Mercury

Answer 17

Inhibits enzymes via sulfhydryl binding

Question 18

Major clinical effects of Mercury (acute)

Answer 18

Acute
Elementary
-pulmonary edema
Inorganic (HgCl2)
-corrosive hemorrhagic gastroenteritis leading to hypovolemic shock
-acute tubular necrosis, oliguric kidney failure

Question 19

Major clinical effects of Mercury (chronic)

Answer 19

Chronic
Tremor- choreiform movements of limbs
Neuropsychiatric disturbances
-memory loss, fatigue, insomnia
-change in mood, depression, and anger
-May alternate (erethism)
-neuropathy, anemia, portal hypertension
Gingivostomatitis, loosening of teeth
Acrodynia (in children)- painful erythema of the extremities

Question 20

Therapy for mercury poisoning

Answer 20

Acute
-Supportive care
-Thiol chelators
Chronic
-Chelators?
-Dimercaprol redistributes Mercury to CNS

Question 21

Methylmercury poisoning major clinical effects

Answer 21

Affects mainly the CNS
-paresthesia, ataxia, visual and hearing impairment
-tremor, spasticity
-coma, death
In case of prenatal exposure-mental retardation

Question 22

Methemoglobin-producing agents classification

Answer 22

1. ) Oxidating agents
2. ) Nitrites
3. ) Aromatic amino- and nitro-compounds
4. ) Redox-dyes

Question 23

Methemoglobin-producing agents MOA

Answer 23

Methemoglobinemia is a condition caused by elevated levels of methemoglobin in the blood that contains the ferric [Fe3+] form of iron. The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric hemoglobin unit. This leads to an overall reduced ability of the red blood cell to release oxygen to tissues, with the associated oxygen–hemoglobin dissociation curve therefore shifted to the left. When methemoglobin concentration is elevated in red blood cells, tissue hypoxia may occur.
Normally, methemoglobin levels are <1%, as measured by the CO-oximetry test. Elevated levels of methemoglobin in the blood are caused when the mechanisms that defend against oxidative stress within the red blood cell are overwhelmed and the oxygen carrying ferrous ion (Fe2+) of the heme group of the hemoglobin molecule is oxidized to the ferric state (Fe3+). This converts hemoglobin to methemoglobin, resulting in a reduced ability to release oxygen to tissues and thereby hypoxia. This can give the blood a bluish or chocolate-brown color.

Spontaneously formed methemoglobin is normally reduced (regenerating normal hemoglobin) by protective enzyme systems, e.g., NADH methemoglobin reductase (cytochrome-b5 reductase) (major pathway), NADPH methemoglobin reductase (minor pathway) and to a lesser extent the ascorbic acid and glutathione enzyme systems. Disruptions with these enzyme systems lead to methemoglobinemia.

Hypoxia occurs due to the decreased oxygen-binding capacity of methemoglobin, as well as the increased oxygen-binding affinity of other subunits in the same hemoglobin molecule, which prevents them from releasing oxygen at normal tissue oxygen levels.

Question 24

Which methemoglobin producing agents last the longest?

Answer 24

Aromatic amino- and nitro compounds last 8 hours while nitrites last 4-5 hours

Question 25

Therapy for Methemoglobin producing agents

Answer 25

Therapy
Redox dyes
Balance at 8% Hb. Fe3+
-10 ml 1-2% methylene blue
-10 ml 0.2% thionine 
-20 ml 4% tholuidin blue