Chapter 57 - Heavy Metal Intoxication & Chelators

OUTLINE ● 70% excreted in the urine

I Toxicology of Heavy Metals ● 30% in sweat, hair and nails
A. Lead
B. Arsenic PHARMACODYNAMICS OF LEAD INTOXICATION
C. Mercury
II Pharmacology of Chelators ● Mechanism of action of Lead
a. Dimercaprol ○ Enzymatic function inhibition
b. Succimer ○ Interference with actions of essential
c. Edetate Calcium Disodium cations
d. Unithiol ○ Oxidative stress generation
e. Penicillamine ○ Changes in gene expression
f. Deferoxamine ○ Alteration of cell signaling
g. Defirasirox ○ Membrane integrity disruption
h. Deferiprone A. Nervous System
i. Prusian Blue ● CNS of newborn is the main target of Lead
intoxication
Heavy Metals ● Adults are less sensitive but may cause
memory loss and other neurological
● Generally defined as metals with relatively high density, ailments if exposed in a long period of time
atomic weights, or atomic numbers. B. Blood
● Some heavy metals are essential nutrients (e.g. Iron and ● May cause normocytic, microcytic or
zinc) and some are harmless but can be toxic in larger hypochromic anemia as lead interferes with
amounts or in certain forms (e.g. Silver) heme by
● Some heavy metals are highly poisonous such as Lead, ○ blocking the incorporation of iron
Arsenic and Mercury. into protoporphyrin IX and
○ by inhibiting the function of
Lead Intoxication enzymes in the heme synthesis
pathway
● Lead is the oldest occupational and environmental C. Kidneys
disease in the world. ● May lead to renal interstitial fibrosis and
● Mostly found in storage batteries, metal alloys, solder, nephrosclerosis
glass plastics, pigments and ceramics D. Reproductive System
● It has no useful purpose in the human body. ● May lead to preterm delivery and
spontaneous abortion in women and
PHARMACOKINETICS OF LEAD INTOXICATION dominished sperm production in men.
E. Gastrointestinal Tract
● Slowly but constantly absorbed via the respiratory ● At high dosage, lead colic may occur
tract and gastrointestinal tract. F. Cardiovascular System
○ GI Tract as major route for non-industrial ● May increase systolic and diastolic bp.
exposure
○ Respiratory tract for industrial exposure Major Forms of Lead Intoxication
● 50% is absorbed in children
● 10-15% of adults ● Inorganic Lead Poisoning
● Low dietary calcium, iron deficiency, and ingestion ○ Acute
on an empty stomach increase absorption ■ Intense exposure of short duration
● poor absorption in the skin. ○ Chronic
● When absorbed, 99& is bound to RBC while 1% is ■ Repeat low-level exposure over a
free in plasma prolonged period of time
● Distributed to bone marrow, brain, kidney, liver, ○
muscle, and gonads then bones.
● it crosses the placenta
 Chapter 57 - Heavy Metal Intoxication & Chelators
● Organolead Poisoning ● Groundwater may contain high amounts of arsenic
○ Very Rare due to the worldwide phase out ● Historically, used as a pharmaceutical agent but is
of tetraethyl and tetramethyl lead as in limited use now.
antiknock additives in gasoline.
PHARMACOKINETICS
ORGANIC vs. INORGANIC LEAD POISONING
● Well absorbed in the respiratory tract and
gastrointestinal tract.
Inorganic Lead Organic Lead
● Percutaneous absorption is limited
Poisoning Poisoning ● Metabolized by the liver via methylation
reactions
Major Gastrointestinal tract, Skin, ● Major excreted in the urine and in sweat
Route Respiratory tract Gastrointestinal and feces (minor)
tract, Respiratory
tract PHARMACODYNAMICS

Distribu Soft tissues; Soft tissues ● Mechanism of action

tion redistributed to especially liver ○ Enzymatic function inhibition
skeleton (>90% of and CNS ○ Oxidative stress generation
adult body burden) ○ Changes in gene expression
○ Alteration of cell signaling
Major CNS deficits; Encephalopathy
ARSENIC INTOXICATION
Clinical peripheral neuropathy;
Finding anemia; nephropathy;
s hypertension; Arsenic
reproductive toxicity.
Major Route Gastrointestinal tract,
Mechani Inhibits enzymes; Hepatic Respiratory tract
sm of interferes with dealkylation ->
Action essential cations; Trialkyl Distribution Predominantly soft tissue
alters membrane Metabolites -> (highest in liver and kidney).
structures dissociation to Tightly bound to skin, hair and
Lead nails

Metabol Renal (major); feces Urine and feces Major Clinical Cardiovascular: shock,
ism and and breast milk (major); Sweat Findings arrhythmias;CNS:
Eliminat (minor) (minor) Encephalopathy, Peripheral
ion NeuropathyOthers:
Gastroenteritis, Pancytopenias,
Cancer
Doc: wrong. Walay effect ang bullet na wala naremove sa
Mechanism of Enzymatic function inhibition,
body.
Action Oxidative stress generation,
TREATMENT Changes in gene expression,
and Alteration of cell signaling
● Immediate termination of exposure, supportive care,
and rational use of chelation therapy Metabolism and Methylation; Excreted via Urine
● Intravenous edetate calcium disodium Elimination (major), Sweat and feces
(CaNa2EDTA) at a dosage of 30-50mg/kg/d by (minor)
continuous infusion for up to 5 days
● Oral succimer (DMSA) after 5 days
● Retained lead objects require gastrointestinal
decontamination RAINDROP PATTERN

ARSENIC INTOXICATION ● Hyperpigmentation and hyperkeratosis involving

hands and feet
● Semiconductors, wood preservatives, nonferrous ● Usually due to chronic inorganic arsenic poisoning
alloys, glass and turf herbicide, known as
monosodium methane arsonate (MSMA)
 Chapter 57 - Heavy Metal Intoxication & Chelators

Major Cns: tremor, Acute Renal CNS effects;

TREATMENT Clinical behavioral Tubular birth defects
Forms (erethism); Necrosis;
● Immediate termination of exposure, supportive care, gingiva-stomatit Gastroenteriti
and chelation therapy. is, peripheral s; CNS
● Gut decontamination if appropriate
neuropathy; effects (rare)
● Acute Poisoning: Chelation with Unithiol 3-5mg/kg
acrodynia;
every 4-6 hours or dimercaprol every 4-6 hours.
pnuemonitis
MERCURY INTOXICATION
Mecha Inhibits Inhibits Inhibits
●Quicksilver or liquid metal nism of enzymes; alters enzymes; enzymes;
●Mined predominantly in cinnabar ores. Action membranes alters alter
●Electrolytic production of chlorine and caustic soda, membranes microtubules,
electrical equipment, thermometer, instruments, neuronal
fluorescent lamps, dental amalgams and artisanal structures
gold production
● Thimerosal, an organomercurial preservative, are
Metab Urine (major), Urine Deacylation.
now removed from almost all vaccines.
olism feces (minor) Fecal
● Environmental release of mercury from burning of
fossil fuels contributes to bioaccumulation in fishes and (alkyl,major);
Elimina Urine (after
MINAMATA DISEASE tion deacylation,
minor)
● Happened In minamata japan in 1950 where an
industrial company dumped mercury
(methylmercury) in sea poisoning aquatic and land
animals which later then poisoned locals who eat TREATMENT
local fish food.
● In commemoration, in 2013, minamata convention ● Immediate removal from source, supportive care
on mercury is established which results to the and chelation therapy
worldwide phase out of mercury in numerous ● Acute: Unithiol, Dimercaprol or Succimer
products such as thermometers, batteries and ● Dimecaprol should never be used for elemental or
measuring instruments. organic mercury intoxication

PHARMACOKINETICS PHARMACOLOGY OF CHELATORS

● Absorption varies depending on the chemical form ● Drugs used to prevent or reverse the toxic effects of
● Absorbed from the lungs, Gastrointestinal tracts, heavy metals on an enzyme or other cellular target
and percutaneous route. or to accelerate the elimination of metals from the
● Distributed well into tissues (most concentrated in body.
kidneys) ● The metal-metabolizing effects of a therapeutic
● Excreted via Urine and feces chelating agent may also redistribute some of the
metal to vital organs.
MERCURY INTOXICATION ● May also enhance the excretion of essential cations
● The longer the half-life of metal in a particular organ,
the less effective it can be removed by chelation.
Elemental Inorganic Organic
Mercury Mercury DIMERCAPROL

Major Respiratory Gastrointesti Gastrointesti ● 2,3-Dimercaptopropanolol, BAL

Routes Tract nal tract, nal tract, ● MOA: Increases the rate of excretion of Arsenic and
Skin(minor) Skin, Lead.
Respiratory ● Initially made as antidote against warfare agent
known as lewisite thus making it known as british
tract(minor)
anti-lewisite or BAL
● Given Intramuscularly
Distrib Soft tissue (esp. Soft tissues Soft Tissues
● Excreted via Kidney
ution In kidneys and (esp.
CNS) kidneys)
 Chapter 57 - Heavy Metal Intoxication & Chelators

THERAPEUTIC USE

● Used as a single-agent therapy of acute poisoning THERAPEUTIC USE

by arsenic and inorganic mercury.
● As a conjunction therapy with EDTA for severe lead ● Indicated mainly for chelation of Lead
poisoning. ● Chelator of Zinc, Manganese, and certain heavy
● Prevents and reverses arsenic-induced inhibition of Radionucleotide poisoning
sulfhydryl-containing enzyme ● Chelates Extracellular metal ions much more
effectively compared to intracellular metal ions
TOXICITY
TOXICITY
● Redistribute Arsenic and Mercury to CNS
● Hypertension ● Nephrotoxicity
● Tachycardia
● Nausea UNITHIOL
● Vomiting
● Salivation ● (Dimercaptopropanesulfonic acid, dmps)
● Fever
● Pain at the injection site ● Water-soluble analog of Dimercaprol
● Thrombocytopenia ● Used in the initial treatment of acute
Inorganic Mercury and Arsenic Poisoning
● Increase Prothrombin time
● Increase urinary excretion or Lead, Arsenic
SUCCIMER and Mercury
● Excreted via Kidney
● dimercaptosuccinic acid, dmsa
● a water-soluble analog of Dimercaprol. TOXICITY
● MOA: Prevents and reverses metal-induced
inhibition of sulfhydryl-containing enzyme
● Dermatologic reaction
● Given Orally and Intravenously ● Isolated cases of SJS
● The elimination half-time of transformed succimer is ● Erythema multiforme
approximately 2-4 hours.
● PENICILLAMINE

THERAPEUTIC USE ● D-Dimethylcysteine

● White, Crystalline, Derivative of Penicillin
● Increases rate of excretion of Lead ● D-Penicillamine is less toxic than the
● Decreases mercury content in the Kidney L-isomer form
● Has a protective effect against Arsenic ● Used primarily to treat or prevent Copper
poisoning
● Used to treat Blood lead concentration of
>45mcg/dL in children.
● Used in Severe Rheumatoid Arthritis
● Given Orally
ADVERSE EFFECT
TOXICITY
● Gastrointestinal tract disturbance
● Rashes ● Hypersensitivity
● Increases Liver aminotransferase and mild to ● Nephrotoxicity with proteinuria
moderate neutropenia ● Pancytopenia
● Pridoxine insufficiency
Edetate Calcium Disodium
IRON CHELATING AGENTS
● Ethylenediaminetetraacetic Acid, EDTA
● Calcium disodium salt from EDTA DEFEROXAMINE
● Given in IV infusion
● Excreted via Urine ● Isolated from Streptomyces pilosus
● Contraindicated in anuric patients. ● It acts by binding free iron or aluminum in the
bloodstream and enhancing its elimination in the
urine.
 ● Mainly Used as a parenteral chelator of choice for
iron poisoning

Chapter 57 - Heavy Metal Intoxication & Chelators

● Combined with hemodialysis for aluminum

● poisoning.
● Given IM or IV
● Excreted via Urine

ADVERSE EFFECT

ADVERSE EFFECT ● CONSTIPATION

● Hypotension
● Flushing
● Abdominal Discomfort
● Rashes
● Pulmonary Complications

DEFERASIROX

● Tridentate Iron chelator

● Mainly used to treat Iron Overload due to blood
transfusion
● Given orally
● Excreted in Bile

ADVERSE EFFECT

● Mild to moderate GI tract disturbances

● Skin rashes
● Liver and liver impairment and failure

DEFERIPRONE

● Bidentate Iron Chelator

● Second-line oral chelator for iron overload due to
blood transfusion
● Given Orally
● Excreted via Urine

ADVERSE EFFECT

● Neutropenia
● Agranulocytosis

PRUSSIAN BLUE

● Indicated treatment of contamination with

radioactive Cesium and intoxication with thallium
salts
● Ion exchange and mechanical trapping or
absorption
● given Orally
● Minimal GI absorption
● Excreted via feces