Metal Toxicity & Chelation Therapy Flashcards
How do heavy metals cause toxicity? What are the major signs of acute exposure? Chronic? How do chelators work? What is the ideal chelator?
MOA: Bind to sulfhydryl groups in various organ ystems and enzymatic processes. Acute: GI!! (almost always the initial presentation), CNS (altered mental status, peripheral neuropathy, “stocking & glove” –> lead), renal, cardiovascular (esp. aresenic –> prolonged QTc). Chronic: “multiple system organ failure w/o other cause – this is a diagnosis of exclusion.” Chelator + Metal = Chelate. Ideal chelator: Vd of the chelator is greater than that of the chelate, high water solubility, resistant to biotransformation, ability to reach site where metal is stored, forms nontoxic complexes, stable at physiological pH, chelate has greater stability than the endogenous chelator, low affinity for trace elements, readily excreted.
What is EDTA? MOA? Uses? If given w/ BAL, how must it be given? Side effects? How is this given? What is Na2EDTA – is that the same thing?
Edetate Calcium Disodium / CaNa2 ethylenediaminetetraacetic acid / CaNa2EDTA. Displacement of calcium by lead to form a lead chelate that is excreted in urine; it also promotes redistribution from soft tissue to bone to chelate formation; all in all it reverses the toxic effect of lead on hemoglobin synthesis; Used in lead poisoning, and CAN be used in severe lead poisoning and lead encephalopathy / BAL. To prevent redistribution to the brain, give with BAL prior to the CaNa2EDTA to prevent this from occurring (BAL has a wider Vd and can penetrate more tissues, and thus will chelate iron in the brain). Side effects: Renal toxicity!! (proximal tubules, distal tubules, glomeruli); ALT/AST increase, malaise, fever. Given IV; DO NOT CONFUSE WITH Na2EDTA (can lead to life-threatening hypocalcemia!!)
What is prussian blue? MOA? Uses? Side effects?
Ferric hexacyanoferrate = Prussian Blue. MOA: Stays in gut and not absorbed until it grabs metal; goes into gut and is excreted in feces. Uses: Thallium and radioactive cesium poisoning. Side effects: This is not absorbed with oral dosing so it is very well tolerated (essentially no side effects). Some concern that cyanide is liberated from Prussian Blue, however the amount released appears to be quantitatively minimal & not clinically significant.
What is deferoxamine (DFO)? Uses? Side effects?
MOA: Chelates free iron (Fe3+ ferric NOT Fe2+ ferrous) and iron transported between transferrin and ferritin and allows for renal excretion; Can mobilize and chelate intracellular iron in RE cells in the spleen, liver, BM. Use: Acute iron poisoning; chronic iron
overload; Side effects: Rate-related hypotension, anaphylactoid reactions, yersinia enterocolitis; acute lung
injury/ARDS — Can only treat for 24 hours before
acute lung injury manifests.
What are the two dithiol chelators? For each, give mxn, what metal toxicities they treat, and any side effects. For the first, how is it given? Who is allergic? When must this be started? For the second, how is it given? In other countries, how is it given?
British Anti-Lewisite (BAL) - Dimercaprol & 2,3-Dimercaptosuccinic Acid (Succimer). BAL: Forms stable chelate via electron pair donation and coordination with metal ion, allowing excretion in urine & feces; Used for arsenic, lead – incl. LEAD ENCEPHALOPATHY, inorganic mercury poisoning; Side effects - Renal toxicity (unless urine is alkalinized, due to dissociation – if urine is acidic, the BAL-metal chelate will destabilize and decrease renal excretion), pain at injection site (IM), nausea, vomiting; increases in BP/HR; Given IV or IM; allergic implications (peanut oil); need to start using ASAP!! Succimer: Coordinate bonding to sulfur (arsenic and mercury) or sulfur and oxygen (lead and cadmium); Used for arsenic, lead, mercury, cadmium poisoning to promote renal excretion – may not be effective in severely lead poisoning with encephalopathy; Side effects - Mild ALT/AST elevation, N/V/D/flatus (usually only 2 - 3 times upper limit normal and transient)…overall, well tolerated; Given orally in US; given IV in other countries with more severe adverse events secondary to IV administration.
Describe iron toxicity. Can we measure iron levels to diagnose toxicity?
Local toxicity: GI w/ hematemesis and volume depletion, high anion gap metabolic acidosis (this disrupts oxidative phosphorylation and is an uncoupler!), direct negative inotropic effect, vasodilator. Iron levels are not all that helpful in diagnosing toxicity – it is a clinical diagnosis based on acid-base balance and acute blood loss.
