Title 17. CLINICAL SYMPTOMS AND MANAGEMENT OF CHRONIC POISONING WITH THE FOLLOWING AGENTS - HEAVY METALS.pdf ✅

PHARMD GURU Page 1  Heavy metal poisoning is the accumulation of heavy metals, in toxic amounts, in the soft tissues of the body. Symptoms and physical findings associated with heavy metal poisoning vary according to the metal accumulated.  Many of the heavy metals, such as zinc. copper, chromium. iron and manganese, are essential to body function in very small amounts.  But, if these metals accumulate in the body in concentrations sufficient to cause poisoning, then serious damage may occur.  The heavy metals most commonly associated with poisoning of humans are lead, mercury, arsenic and cadmium.  Heavy metal poisoning may occur as a result of industrial exposure, air or water pollution, foods, medicines, improperly coated food containers, or the ingestion of lead-based paints. ARSENIC Ingestion of arsenic is relatively common in the setting of homicide and is occasionally used in deliberate self-poisoning. Arsine gas and CCA exposure are not uncommon industrial exposures. Most organs can be involved and the diagnosis may not be obvious. TOXICITY LEVELS:  Acute toxicity from trivalent arsenic (arsenite) compounds occurs at lower doses than from pentavalent arsenic (arsenate) compounds. Arsine gas is the most toxic form and the only one that causes significant haemolysis, however it does not generally lead to long term toxic effects (also see treatment).  200 to 300 mg for arsenic trioxide.  In general, the pentavalent form of arsenic (arsenate) is less toxic than the trivalent form (arsenite) because it is less water soluble. CLINICAL SYMPTOMS AND MANAGEMENT OF CHRONIC POISONING WITH THE FOLLOWING AGENTS: HEAVY METALS: ARSENIC, LEAD, MERCURY, IRON, COPPER
PHARMD GURU Page 2  The most toxic form is arsine gas (25 to 30 ppm can be lethal in 30 minutes). MECHANISM: 1. Arsenic binds to a range of sulphydryl containing proteins. These include enzymes involved in oxidative metabolism (leading to lactic acidosis, shock and multiorgan failure), haemoglobin synthesis (leading to a siderocytic anaemia) and methionine synthetase (leading to homocysteinaemia, and atherosclerosis). 2. Mechanisms behind many other features of arsenic poisoning are less well understood but presumably involve similar inhibition of metabolic pathways. Arsenic is also a clastogen and known human carcinogen. CLINICAL (TOXIC) SYMPTOMS:  ACUTE ARSENIC POISONING: The onset of symptoms is usually within a few hours. Local gastrointestinal effects include oropharyngeal burns, dysphagia, vomiting, abdominal pain, and bloody diarrhoea. Multiple organ failure with shock, ARDS, acute renal and hepatic failure, and encephalopathy may lead rapidly to death.  ARSINE GAS POISONING: The above symptoms may be seen but the major manifestation is severe haemolysis leading to haematuria. Abdominal pain, renal failure, and hyperkalaemia are common. Facial skin burning and dyspnoea may also result (perhaps partly from local effects of the gas exposure). Treatment is different from other arsenic poisonings utilizing exchange transfusion and dialysis. Symptom onset may be delayed up to 24 hours in some cases.  CHRONIC ARSENIC POISONING: Subacute or chronic exposures lead to a variety of insidious presentations with peripheral sensorimotor neuropathy, dementia, bone marrow depression resembling myelodysplasia, myocarditis, severe peripheral vascular disease ("Blackfoot disease") and lung and skin cancers. Skin changes including alopecia, pigmentation, nail changes and hyperkeratosis may lead to suspicion of arsenic as the underlying cause.
PHARMD GURU Page 3 INVESTIGATIONS/DIAGNOSIS:  Haematology: Full blood count and coagulation studies -The full blood count will detect early onset of haemolysis and late onset bone marrow depression.  Biochemistry: Hepatic and renal toxicity is common, as is a lactic acidosis.  ECG: Arrhythmias and QT prolongation may be seen.  Imaging: Abdominal x-ray may identify arsenic (from ingested arsenic salts) contained within the gastrointestinal tract.  Hair level: Although considered to be an important diagnostic criterion, it is actually virtually useless since it cannot discriminate between external deposition and toxic accumulation. If hair is sent for arsenic quantitation, pubic hair instead of scalp hair should be sent because of the possibility of scalp hair being contaminated with arsenic from the environment. MANAGEMENT:  Supportive measures: gastric lavage, intravenous fluids, cardiac monitoring, etc.  Chelation therapy: This can be done with BAL (British Anti Lewisite or dimercaprol), penicillamine, DMSA (Dimercapto succinic acid), or DMPS (Dimercapto propane sulfonic acid).  Antidotes: Antidotes for arsenic are chelating agents. Chelation therapy is not useful if the source of arsenic has not been removed. Succimer (where available) is the chelating agent of choice for patients without life-threatening arsenic poisoning, due to its relatively low toxicity. Where urgent parenteral therapy is required, British Anti- Lewisite (BAL) is usually preferred (although DMPS may be available in some places). Iron and zinc supplementation can be given between courses of chelation therapy but not during courses. D-Penicillamine is an oral chelating agent that binds to iron, lead, arsenic, antimony, zinc, mercury, and copper.  Haemodialysis or exchange transfusion.
PHARMD GURU Page 4 COPPER  Copper is a lustrous, ductile, malleable, odourless solid with a distinct golden-red or reddish-brown colour. It is an essential trace element, being the third most abundant trace element in the body, and is an important catalyst for haeme synthesis and iron absorption. Metallic copper itself probably has little or no toxicity, although reports in the literature are conflicting.  Copper salts produce toxicity. Soluble salts, such as copper sulfate are strong irritants to skin and mucous membranes. USES:  Copper has excellent electrical conductivity, corrosion resistance, malleability and ductility, which make it very useful as an industrial metal.  Money metal, another copper alloy, is copper alloyed with nickel.  Copper's contraceptive effects (as a spermatocide) are exploited for intrauterine devices. Its contraceptive effects permit the use of a smaller device, resulting in few side effects such as pain and bleeding. TOXICITY LEVEL: About 10 to 20 grams of copper sulfate MECHANISM:  Humans possess a combination of regulated import, sequestration, and enhanced export mechanisms to protect against metal-induced toxicity.  These mechanisms regulate metal status through metal-binding proteins at transcriptional, translational, and enzymatic levels.  The presence of a complex system of metal ion transporters and chaperones to regulate Cu homeostasis ensures Cu is provided to essential proteins without causing cellular damage.  Disruptions in the homeostasis of Cu is associated with tissue damage and a number of diseases. In addition to the direct interact with essential macromolecules and minerals,