Mechanism of toxicity of heavy metals
Bind to sulfhydryl groups in various organ systems and enzymatic processes throughout the body
If the mechanism of heavy metal toxicity is all the same, why do different metals have different effects?
Affinity for organ system toxicity is a result of the characteristics of the heavy metal and its distribution sites
Heavy metal acute exposure of cardiovascular system can result in __
Tachycardia
dysrhythmias
cardiomyopathy
Heavy metal acute exposure of CNS can result in __
altered mental status
peripheral neuropathy
Heavy metal acute exposure of gastrointestinal system can result in __
N&V
diarrhea
Heavy metal acute exposure of renal system can result in __
proteinuria
aminoaciduria
acute tubular necrosis
What is the difference between acute and chronic metal exposure?
Chronic exposure has:
- more subtle findings.
- increased effects at organ sites that may be less accessible acutely
- CNS and PNS more apparent than GI effects
- hematologic abnormalities
- renal insufficiency
- skin, skeleton and connective tissue abnormalities
- neoplasm
Dimercaprol
Aka anti-lewisite
aka BAL
Chelates
- arsenic
- lead
- inorganic mercury
Dimercaprol (BAL) - adverse effects
- Peanut allergy (BAL is always mixed with peanut oil)
- Dose dependent
- nausea and vomiting
- increases in BP and HR
- pain at injection site (IM injection)
- Dissociation of BAL-metal chelate in acidic urine
- need urinary alkalinization during or before BAL therapy to prevent metal-induced renal toxicity
What is needed before adminstration of dimercaprol?
There is dissociation of BAL-metal chelate in acidic urine
Need urinary alkalinization during or before BAL therapy to prevent metal-induced renal toxicity
Succimer
2,3-dimercaptosuccinic acid
Chelation for:
- cadmium
- lead
- mercury
CaNa2EDTA
Edetate calcium disodium
Primarily used in lead poisoning
What is a caution that must be taken when using CaNa2EDTA?
Don’t accidentally confuse with Na2EDTA which can cause severe hypocalcemia
EDTA likes to chelate cations. Need to give the calcium*ized version so that it doesn’t bind up all your calcium
CaNa2EDTA - adverse effects
Renal toxicity (of proximal, distal tubules and glomeruli)
Malaise, fever, increases in ALT and AST
Prussian blue
Chelates:
- thallium
- cesium
Prussian blue - side effects
There is none. It is well tolerated and it is not absorbed after oral dosing
Iron toxicity - mechanism
- Direct corrosive effect to the GI mucosa –> hematemesis, melena, periportal necrosis of the liver and intentional ulceration and edema
- Uncoupler of oxidative phosphorylation –> metabolic acidosis (via shunting to anaerobic metabolism and production of lactic acid)
- hypotension (vomitting, negative inotropic effect & vasodilator)
How can iron cause hypotension?
Via 3 mechanisms
- vomitting –> volume depletion (remember it is direct toxin to Gi mucosa)
- direct negative inotropic effect –> decreased force of muscular contractions
- vasodilation –> hypotension
How do you diagnose iron toxicity? (Laboratory or clinical) why?
Iron toxicity is a CLINICAL diagnosis.
Laboratory findings are usually not useful. Iron needs to be > 500 mg/dl (norm 60 - 170) for you to have a clear diagnosis of iron toxicity. Anything under that value is useless.
Deferoxamine
Chelates iron (free iron and iron transported between transferrin and ferritin)
Does NOT chelate iron in transferrin, Hb, cytochromes or ferritin
Deferoxamine - adverse effects
rate-related hypotension
anaphylactoid reactions
acute lung injury (mechanism unknown) – occurs after 24 hours of dosing
Lead poisoning - what would you use to chelate?
What would you be concerned about with each drug?
dimercaprol – peanut allergy, need to alkalinize urine, dose dependent effects
succimer – well tolerated with some N&V
EDTA – renal toxicity
Arsenic poisoning - what would you use to chelate?
What would you be concerned about with each drug?
dimercaprol – peanut allergy, need to alkalinize urine, dose dependent effects
Mercury poisoning - what would you use to chelate?
What would you be concerned about with each drug?
same as arsenic
- dimercaprol – peanut allergy, need to alkalinize urine, dose dependent effects
- succimer – well tolerated with some N&V
