Heavy Metals (Pb, As, Hg)

Blaine (Jess) Benson, Pharm.D.

Director, NMPDIC Associate Professor, UNM College of Pharmacy

Jebenson@salud.unm.edu

Program Objectives
1. Know available forms of lead, arsenic and mercury. 2. Describe the manifestations of poisoning from lead, arsenic and mercury. 3. Assess the severity of poisoning from lead, mercury and arsenic based on signs, symptoms and laboratory information. 4. Develop a treatment plan for lead, arsenic and mercury poisoned patients.

Example Case

A 3-year-old boy presents to the emergency department via ambulance after having a 20minute seizure at home. According to the mother, there had been a gradual change in the childs disposition over a two day period before the seizure. He had an upper respiratory infection. He was less active, had vomited several times and had developed twitching and abnormal eye movements.

Example Case continued

He had no access to medications or household products. The mother commented that she did find paint chips in his mouth three weeks earlier. The child was developmentally delayed in terms of speech and social skills. Prior to the seizure he spoke only single words, was not toilet trained and could not dress himself. He appeared postical, with flaccid muscle tone and minimal response to painful stimulation. The patients vital signs were: HR 110, BP 130/80, RR 10 shallow, T 98.6 F, Pulse oximetry 85% on room air

Initial Laboratory Results

Cerebral spinal fluid analysis: clear, colorless; 3 WBCs/mm3, 0 RBCs, glucose 108 mg/dL, protein 96 mg/dL WBC: 11,300/mm3 Hemoglobin: 6.6 g/dL (normal: 11.8 0.5) Mean corpuscular volume 50 m (normal: 87 7) Platelet count: 473,000/mm3 Peripheral blood smear: RBC basophilic stippling Electrolytes: Na 139, K 4.3, Cl 105, HCO3 22, BUN 15, S.Cr 0.3, Glucose 170

An Overview Of Chelation

Chelator forms a stable complex with the metal and redistributes the metal away from the target organ. The stability of the complex depends on the metal. The most useful chelators have a low order of toxicity, do not redistribute to other organs (ie brain) and are eliminated quickly without breakdown.

Dimercaprol (BAL)

Activity

Diffuses into brain and RBC's Enhances fecal and urinary elimination PB: 75 mg/m2 (4-5 mg/kg) IM q 4 hours for 5 days Hg, As: 3 mg/kg IM every 4-6 hours for 2 days then every 12 hours for 7-10 days

Dose

Dimercaprol (BAL) continued

Side Effects

Local pain at injection site Transient dose-related hypertension and tachycardia Nephrotoxicity (keep urine alkaline) Liver failure Glucose 6 phosphate dehydrogenase deficiency Peanut allergy During iron supplementation

Contraindications

Edetate Calcium Disodium (CaNa2EDTA)

Activity

Chelates extracellular lead only Excretion enhanced via compartment equilibration Pb Encephalopathy: 1500 mg/m2/d (30 mg/kg/d) in two or three doses IV for 5 days Symptomatic Pb poisoning, Pb 50-100 g/dL: 1000-1500 mg/m2/d for 3-5 days.

Dose

Edetate Calcium Disodium (CaNa2EDTA) continued

Side Effects

Proximal tubular damage Zinc and iron depletion Anuria

Contraindications

Succimer (DMSA)

Agents

Dimercaptosuccinic acid (DMSA) More effective than BAL Can be used to chelate Hg, As, and Pb Wider therapeutic index than BAL Does not re-distribute Pb to brain May produce transient elevation of serum alanine transaminase

Efficacy

Safety

Succimer (continued)

Dose

10 mg/kg (or 350 mg/m2) PO every 8 hours for 5 days then 10 mg/kg every 12 hours for 2 weeks Nausea, vomiting, flatus, diarrhea Mild elevations of aminotransferases Allergy to the drug

Side Effects

Contraindications

Occupational Exposures
Battery makers Brass worker Bronzers Cable makers/splicers Chemical operators Foundrymen Glass makers/polishers Gunshot/gun barrel makers Jewelers
Lead burners/smelters Metal grinders /burners/refiners Painters Pigment makers Pipe cutters Pottery workers Printers (linotype/electotype) Stained glass makers Welders

Adapted from Medical Toxicology by Ellenhorn and Barceloux (1988)

Non-Occupational Exposures
Battery burning Bullet retention Ceramic making Eating from unfired pottery Cooking in leaden pots Home distilled wine/wiskey Folk medicines (azarcon, greta) Home abortifacients Target shooting Ingestion of leadcontaining herbal medicines Use of leadcontaining cosmetics Soldering

Adapted from Medical Toxicology by Ellenhorn and Barceloux (1988)

Absorption

GI Tract

Adults: 10% - 15% Children : 40% - 50% Increased with Fe, Ca, Zn deficiency 50% - 70% if < 1 m Inorganic lead is non-absorbable

Lungs

Skin

Distribution
Diet + Air

Bone

Blood

Soft Tissue

Urine

Elimination

Kidney is responsible for 65% of leads elimination

Process is dependent on glomerular filtration rate and renal plasma flow Biliary excretion is responsible for 35% of leads elimination Integumentary: nails, sweat, hair Alimentary : salivary, biliary, gastric,and pancreatic

Integumentary & alimentary losses

Key Mechanisms

High affinity for electron-donor ligands Substitutes as calcium interfering with calcium dependent processes.

Mitochondrial metabolic pathways Second messenger systems that regulate energy production (calmodulin, protein kinase C, Na/K ATPase)

Mutagenic

Clinical Effects
Organ Bone Marrow RBC Kidneys Vascular Heart CNS Reproductive Skeletal Endocrine Gastrointestinal Effect Derangement of heme synthesis Increased fragility and decreased survival Falconi-like syndrome, chronic nephritis, gout Hypertension Myocarditis, fibrosis Encephalopathy, peripheral neuropathy, cognitive impairment Infertility Impaired bone growth, shortened stature Reduced thyroid and adrenopituitary function Abdominal pain, constipation, colic

Key Manifestations of Lead Intoxication (ABDCE)

Anorexia/apathy/anemia Behavioral disturbances Clumsiness Developmental skill deterioration Emesis-spordic vomiting/colic

Lead Encephalopathy (PAINT)

Persistent and forceful vomiting Ataxia Intermittent stupor with lucid intervals Neurologically intractable convulsion Tired/lethargic

RBC Pathophysiology
Succinyl-CoA + Glycine aminolevulinic acid
Delta ALA Dehydratase

Excreted in urine

Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX

Ferrochelatase

Excreted in urine

Coproporphyrinogen Decarboxylase

Accumulates in RBC (uorescent)

Heme

Routine Monitoring

CBC Urinalysis Renal function tests Radiographic evaluation

Lead Lines

Pb-Specific Laboratory Tests

Blood Lead Erythrocyte Protoporphyrin Urinary Delta-aminolevulinic Acid Levels

Blood Lead Levels

g/dl
10-15 15-20 < 25 30 40 70 80-100

Effects
Decits in neurobehavioral development; ALA-D inhibition; Reduced gestational age & wt at birth EP elevation; Impaired vitamin D metabolism Lower IQ, slower reaction time Slowed nerve conduction velocity Reduced hemoglobin; elevated CP & ALA-U Peripheral neuropathies; Frank anemia Encephalopathy; Colic; Kidney effects

Pediatric Treatment Plans

Symptomatic

Acute Encephalopathy Symptoms, Blood PB >70 Blood Pb >70 g/dl Blood Pb 45-69 g/dl Blood Pb 20-44 g/dl

BAL + CaNa2EDTA BAL + CaNa2EDTA BAL + CaNa2EDTA DMSA or CaNa2EDTA Abatement, nutritional supplementation and further assessment

Asymptomatic

Adult Treatment Plan

Symptomatic

Acute Encephalopathy Abdominal Syndromes Painless peripheral neurophathy Blood Pb >100 g/dl Blood Pb 70-100 g/dl Blood Pb <70 g/dl

BAL + CaNa2EDTA BAL + CaNa2EDTA DMSA BAL + CaNa2EDTA DMSA Remove from exposure

Asymptomatic

Monitoring Therapy

Maintain generous urine flow Monitor blood lead daily Daily urinary protein & serum creatinine Measure blood lead in 10 - 12 days after chelation

Types of Mercury

Elemental (metallic)

Hg0 Example: liquid metallic mercury Hg+2X Example: mercuric chloride (HgCl2), mercuric bichloride; calomel or mercurous chloride (Hg2Cl2) Short chain: methyl mercury, ethyl mercury Long chain: phenyl mercury, methoxyethyl mercury

Inorganic mercury salts

Organic mercury

Occupational Sources of Mercury

Non-Occupational Sources of Mercury

Mechanism

Covalently binds to sulfur replacing hydrogen Reacts with phosphoryl, carboxyl, and amide groups found in enzymes, membranes, structural proteins and transport mechanisms => interrupts cell function and metabolism. Most vulnerable tissues are CNS, kidneys and lungs

Features of Elemental Hg Poisoning

Acute

Inhalation is the most common route Cough, fever, chills, dysnpnea, metallic taste, headaches Tremor, oral cavity lesions, rash, salivation, headaches, diaphoresis, erethism Peripheral neuropathy

Chronic

Features of Inorganic Mercury Poisoning

Acute

Nausea, vomiting, abdominal pain, hematemesis, shock and cardiovascular collapse Renal failure Tremor, stomatitis, gingivitis, sensorymotor deficits, peripheral vision loss, and erethism

Chronic

Features of Organic Mercury Poisoning

Short chain

Tremor, ataxia, dysarthria, parethesias of hands, feet, and mouth, tunnel vision, hearing impairment, spasticity Congenital abnormalities (microcephaly, blindness, mental retardation, symmetric motor defects, microagnathia) Similar to chronic inorganic mercury

Long chain

Acrodynia (Pink Disease)

Idiosyncratic hypersensitivity Pink swollen hands and feet, desquamation, evanescent rashes, burning and pain of extremities Primarily affected young children treated with calomel teething powder.

Laboratory Assessment

Mercury levels

Inorganic/elemental

Whole blood: nl 10-20 g/L; toxic: >35 g/L Urine (24 hr): nl <20 g/L; toxic: >100 g/L Whole blood: toxic: >20 g/L

Organic

CBC, electrolytes, renal function tests, urinalysis

Mercury Treatment

Preventing absorption

Ingestions of Elemental Hg

GI decontamination usually not required Lavage within 2 hours Consider adding milk or egg white (sulhydryl groups) WBI (when confirmed by Xray)

Ingestions of inorganic or organic

Mercury Treatment (2)

Antidote: Chelation (in order of preferance)

DMSA 2. BAL for inorganic or elemental 3. D-penicillamine for inorganic and elemental Endpoints: Improvement of symptoms Inorganic/elemental: 24 hr urine levels of <20 g/L (1 week after chelation) Organic: whole blood level < 20 g/L
1.

Sources of Arsenic

Types of Arsenic

Trivalent: Arsenite (+3)

More toxic than pentavalent Interferes with conversion of pyruvate to acetyl coenzyme A Interferes with alpha-ketoglutarate dehydrogenase Substitutes for inorganic phosphate during production of ATP Uncouples oxidative-phosphorolation by forming adenosine di-phosphate arsenate complexes

Pentavalent: Arsenate (+5)

Krebs Citric Acid Cycle

Clinical Presentation

Acute

Dysphagia, metallic taste, nausea, vomiting, abdominal pain, rice-like diarrhea, cardiovascular collapse, peripheral neuropathy, renal insufficiency Peripheral neuropathy, headache, and dermal manifestations. Lung cancer and skin cancer

Chronic

Laboratory Assessment

General Workup

CBC, renal function tests, liver function tests, urinary analysis, ECG Acute: abdominal x-ray Urinary arsenic (>50 g/L, >100 g/g creatinine, or >100 g/24 urine collection) Hair or nail analysis

Specific Tests

Arsenic Treatment

Supportive

Rehydration and replenishment of glucose and glycogen stores with dextrose and hyperalimentation Avoid class IA, IC, and III antidysrhythmics (increase QT interval) WBI Continuous nasogastric suctioning

Prevent Absorption

Arsenic Treatment (2)

Antidote

Acute: BAL Chronic: Succimer Endpoint: 24-hour urinary As <50 g/L Consider hemodialysis only if the patient is being chelated and has renal failure

Enhancing elimination

Case Discussion - Note

S: A 3-year-old boy presents to the emergency department via ambulance after having a 20minute seizure at home. According to the mother, there had been a gradual change in the childs disposition over a two day period before the seizure. He had an upper respiratory infection. He was less active, had vomited several times and had developed twitching and abnormal eye movements.

Subjective - Continued
He had no access to medications or household products. The mother commented that she did find paint chips in his mouth three weeks earlier. The child was developmentally delayed in terms of speech and social skills. Prior to the seizure he spoke only single words , was not toilet trained and could not dress himself. He appeared postical, with flaccid muscle tone and minimal response to painful stimulation.

Objective
O: The patients vital signs were: HR 110, BP 130/80, RR 10 shallow, T 98.6 F, Pulse oximetry 85% on room air Initial laboratory values were as follows: Cerebral spinal fluid analysis: clear, colorless; 3 WBCs/mm3, 0 RBCs, glucose 108 mg/dL,, protein 96 mg/dL

Objective-Continued
WBC: 11,300/mm3 Hemoglobin: 6.6 g/dL (normal: 11.8 0.5) Mean corpuscular volume 50 m (normal: 87 7) Platelet count: 473,000/mm3 Peripheral blood smear: RBC basophilic stippling Electrolytes: Na 139, K 4.3, Cl 105, HCO3 22, BUN 15, S.Cr 0.3, Glucose 170

Assessment
A: Seizure of unknown etiology that could be toxicologic in origin. Consider:
W= withdrawl I= isoniazid T= theophylline, tricyclics H= hypoglycemia, hypoxia L= lead, lithium, local anesthetics A= anticholinergics C= camphor, cholinergics, CO, CN O= organophosphates P= phencyclidine, phenothiazines, propoxyphene S= salicylates, strychnine, sympathomimetics

Assessment-Continued
The most likely agent is lead since 1) the patient has symptoms consistent with encephalopathy (nausea, vomiting, lethargy, convulsion), 2) there is a history of possible lead exposure 3) he has a microcytic anemia. The patient is at risk for permanent brain damage or death. Emergent chelation should be performed.

Plan
Supportive Care 1)Consider 40 mg IV furosemide, 1 gram/kg of mannitol, 250 mg acetazolamide QID, a short course of prednisone for treatment of cerebral edema. 2)Seizures: Diazepam , 0.2 mg/kg IV; If a longer-acting agent is required, change to Phenobarbital 15 mg/kg IV or midazolam 0.1 mg/kg (load) followed by 2 g/kg/min. Patient will also need to be mechanically ventilated.

Plan-Continued
Antidote 3)BAL: 75 mg/m2 (4-5 mg/kg) IM q 4 hours for 5 days 4)Four hours after 1st dose of BAL, begin Edetate Calcium Disodium, 1500 mg/m2/d (30 mg/kg/d) in three divided doses IV for 5 days Additional Labs To Order: Blood lead, urinalysis (glucosuria, proteinuria), radiologic evaluation (paint flecks in gastrointestinal tract, evidence lead in long bones)