Toxicology 2 (Arsenic, Mercury, Methemoglobin-producing Agents) Flashcards
What are the different forms of arsenic that can enter the body
- Inorganic arsenic salts
- trivalent Arsenites/As(OH)3 (most toxic)
- Pentavalent arsenates/O=As(OH)3
Most frequent source of arsenic intoxication
Manufactures of... Semiconductors Herbicides Insecticides Wood preservatives Groundwater may contain it
Major route of absorption
Respiratory and GI tract (mucosa)
Distribution of Arsenic
First of all liver and kidney Soft tissues Skin Hair nail
Metabolism and elimination of arsenic
methylation, mainly in the liver and the elimination via kidney
Pharmacodynamics of arsenic
Inhibits enzymes via sulfhydryl binding
Interferes with oxidative phosphorylation
Major clinical effects of arsenic (acute)
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
Arsenic major clinical effects (chronic)
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
Acute and chronic therapy of arsenic
Acute
-Gut decontamination, intensive supportive care, dimercaprol 3-5 mg/kg every 4-6 hours
Contraindicated: Succimer orally because gastroenteritis limits absorption
Chronic
-chelators?
Major clinical effects of arisine gas poisoning
Major clinical effects
- general initial symptoms (dyspnea, vomiting, abdominal pain)
- Intravascular hemolysis
- oligouric kidney failure (hemoglobinuria)
Therapy for arsine gas poisoning
Supportive care
-blood transfusion
-forced alkaline dieresis
Chelators
Mercury form entering the body
Elemental mercury
-inorganic Hg+ (less toxic) and Hg++ organic
Most frequent source of intoxication of Mercury
Manufacturers of electrical equipments, paint products, dental amalgam
Major route of mercury absorption
Respiratory tract (elemental) GI tract and skin (inorganic) GI and respiratory tract (organic skin=moderate)
Distribution of mercury
First of all kidney
Soft tissues
Elimination of Mercury
Via kidney
Pharmacodynamic of Mercury
Inhibits enzymes via sulfhydryl binding
Major clinical effects of Mercury (acute)
Acute
Elementary
-pulmonary edema
Inorganic (HgCl2)
-corrosive hemorrhagic gastroenteritis leading to hypovolemic shock
-acute tubular necrosis, oliguric kidney failure
Major clinical effects of Mercury (chronic)
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
Therapy for mercury poisoning
Acute -Supportive care -Thiol chelators Chronic -Chelators? -Dimercaprol redistributes Mercury to CNS
Methylmercury poisoning major clinical effects
Affects mainly the CNS
-paresthesia, ataxia, visual and hearing impairment
-tremor, spasticity
-coma, death
In case of prenatal exposure-mental retardation
Methemoglobin-producing agents classification
- ) Oxidating agents
- ) Nitrites
- ) Aromatic amino- and nitro-compounds
- ) Redox-dyes
Methemoglobin-producing agents MOA
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.
Which methemoglobin producing agents last the longest?
Aromatic amino- and nitro compounds last 8 hours while nitrites last 4-5 hours
Therapy for Methemoglobin producing agents
Therapy Redox dyes Balance at 8% Hb. Fe3+ -10 ml 1-2% methylene blue -10 ml 0.2% thionine -20 ml 4% tholuidin blue
