HEAVY METALS

AND
HEAVY METAL
ANTAGONISTS
Presentation by
Md. Azharuddin
Registration no. 07111R0025
B.Pharmacy, Final year
Shadan college of Pharmacy
 INTRODUCTION
 ‘Metals’ originally included only gold, silver, copper,
iron, lead, and tin.
 Many other elements since added to the list with some of
these characteristics
 Dense, malleable, lustrous
 Conduct heat and electricity, cat ions
 IUPAC defined heavy metal poisoning as– “meaningless
term, change it to Toxic Elements!
 Heavy metals such as arsenic, bismuth, cadmium, iron,
lead, mercury etc., are of toxicological important as they
are associated with a number of poisonous effects.
 Metals act as ligands to many compounds of the body.
 LEAD POISONING
 Lead is the most common metal involved in metal
poisoning.
 It is widely used in industries.
 Lead occupies 1st position in list of poisoning metals as it
has capacity to effect haemotopoietic system &
neurobehavioral activity even in lower concentrations such
as 0.01mg/1ml & 0.25mg/1ml

SOURCES

1. Environmental exposure
2. Domestic exposure
3. Occupational exposure
MECHANISM OF TOXICITY
 TOXICOKINETICS
 ABSORPTION: Mainly from respiratory and GI tract.

 ACCUMILATION: ↑ Vit D and Phosphate conc. leads to deposition of

Pb into bones, where as low conc. leads to mobilization of Pb.

 DISTRIBUTION: Extensively distributed in bone, teeth, liver, lung,

kidney, brain and spleen.

 HALF LIFE:
• Blood-25days
• Soft tissues-40days

 EXCRETION: Slow process and takes few weeks to years. It is excreted

both in urine(65%) and bile(35%).
 SYMPTOMS OF TOXICITY
Lead poisoning can be either acute or chronic form.

1. Acute lead poisoning: In this condition rapid release of Pb from blood stream
to bone occurs.

Symptoms:

 Metallic taste
 GI irritation
 Dark stools
 Anaemia, haemoglobinuria.
 Uraemia
 SYMPTOMS OF TOXICITY
2. Chronic lead poisoning: It is mostly seen in children and
people working in paint, printing and petroleum industries.

Symptoms: Chronic lead poisoning shows effects on

following systems:
 Skeletomuscular manifestations:
• Lead palsy
• Atrophy
• Contractures
 SYMPTOMS OF TOXICITY
 CNS manifestations:
• Foetus & young children are more susceptible

Pb conc. Toxic effect

5 mcg/d Impaired neurocognitive

function

> 30 mcg/d Effects on behavioral and

neurocognitive processes

> 100mcg/d Lead encephalopathy

Conc. for months to years Neuropathy

exceeding 100mcg/d
 SYMPTOMS OF TOXICITY
Hematopoietic manifestations: lead inhibits
heme synthesis by acting on ALA- dehydratase
& ferro chelatase enzymes and leads to
anaemia.
MOA: succinyl coA + glycine
↓S- Aminolevullinate
S- Aminolevullinate
Pb ↓ S-ALA DEHYDRATASE
Porphobiliniogen

↓Uroporphyrinogen complex
Protoporphyrin
Pb↓FERROCHELATASE
 SYMPTOMS OF TOXICITY
 Renal manifestations:
• Renal interstitial fibrosis
• Nephrosceloris
• Saturnine gout

 GIT manifestations:
• Loss of appetite
• Constipation
• Diarrhoea
• Gingival lead lines

 CVS manifestations:
• Rise in systolic and diastolic B.P.
 DIAGNOSIS
 HEAMOTOPOITIC TESTS
• Complete blood count
• Peripheral smear
• FEP( free erythrocyte protoporphyrin)
• Atomic absorption spectroscopy(AAS)
• X-ray flourescence spectroscopy

 URINARY TESTS

 RADIOLOGICAL EXAMINATION
 TREATMENT
 FOR ACUTE POISONING
• Gastric lavage
• Laxatives
• Chelating agents
• Anti- spasmodics
• Diazepam
 FOR CHRONIC POISONING:
• Chelating agents ( CaNa2 EDTA and dimercaptosuccinic
acid).
• Diazepam
• Mannitol
• Thiamine
 ARSENIC POISONING
Sources:
1.Groundwater
2. Arsenic containing mineral ores
3. Industrial processes
Semiconductor manufacturing (gallium arsenide)
Fossil fuels
Wood treated with arsenic preservatives
Metallurgy
Smelting (copper, zinc, lead) and refining of metals and ores
Glass manufacturing
4. Commercial products
Wood preservatives
Pesticides
Herbicides
Fungicides
5. Food
Seafood and fish
6.Others
Antiparasitic drugs
Folk remedies
 ARSENIC POISONING
 A well known poison used throughout history (reportedly a
favorite of Nero)
 Naturally occurring arsenic contamination of drinking
water is a worldwide problem.
 Arsenic is well absorbed by the respiratory & GI tracts.

Potential Arsenic Exposures:

• Intentional poisoning
• Volcanic eruptions
• Coal
• Arsenic containing wood preservatives (pressure treated lumber)
• Smelting
• Pesticides/herbicides
• Drinking water (usually results in low level exposure)
• Gallium arsenide used in computer & semiconductor production
• Arsine gas- industrial exposure
• Organic arsenic in seafood
 MECHANISM OF TOXICITY
 Trivalent forms:
 bind to sulfhydryl groups leading to inhibition of enzymatic
systems.
 inhibit the Krebs cycle and oxidative phosporylation. These
lead to inhibition of ATP production.
 Pentavalent forms:
 can replace the stable phosphate ester bond in ATP and
produce an arsenic ester stable bond which is not a high
energy bond.
 Endothelial damage, loss of capillary integrity,
capillary leakage, volume loss, shock
 TOXICOKINETICS
 T1/2 of inorganic arsenic in the blood is 10 hrs and of
organic arsenic is around 30 hours.
 2-4 weeks after the exposure ceases, most of the remaining
arsenic in the body is found in keratin-rich tissues (nails,
hair, skin).
 Inorganic arsenic is converted to organic arsenic
(biomethylation to monomethyl arsonic- MMA or DMA)
in the liver. This may represent a process of detoxification.
 Renally excreted (30-50% of inorganic arsenic is excreted
in about 3 days). Both forms are excreted depend on the
acuteness of the exposure and dose.
 The toxic effects of arsenic are mainly seen due to trivalent
form, which shows its toxic action within a dose range of
200-300mg.
 SYMPTOMS OF TOXICITY
Bodily system affected Symptoms or signs
Systemic Thirst
Hypovolemia, Hypotension
Gastrointestinal Garlic or metallic taste, Burning mucosa
Nausea and vomiting,Diarrhoea
Abdominal pain
Hematopoietic system Hemolysis
Hematuria
Pulmonary Cough, Dyspnoea
(inhalational exposures) chest Pain, Pulmonary edema
Liver Jaundice, Fatty degeneration
Central necrosis
Kidneys Proteinuria, Hematuria
Acute renal failure
CNS Convulsions, encephalopathy, tremors
 SYMPTOMS OF TOXICITY
 SKIN MANIFESTATIONS:
• Hair loss
• Melanosis
• Bowen's disease
• Hyperkeratosis

Bowen's disease
 TREATMENT
 SUPPORTIVE THERAPY:
• Gastric lavage
• Drug treatment: dopamine (2.5mg/min/kg), adrenaline.

 CHELATION:
The specific antidote is dimercaprol (BAL).
Dosage:
• Initially 5mg/kg i.m every 4 hrs for 1 day.
• Then 2-3mg/kg every 8 hrs for 2 days.
• From 3rd day 2-3 mg/kg every 24 hrs.
 HAEMODIALYSIS
 MERCURY POISONING
 Compounds of Mercury are commonly used as antiseptics & preservatives.
 Occurs in three forms (elemental, inorganic salts, and organic compounds)
sources
• Mercury contaminated fish are a major concern throughout the world.
Organic mercury (mostly methyl-mercury) bio-accumulates and magnifies
in food chains; big fish have higher levels than small fish.
• Food treated with mercurial fungicides
• Dental amalgams
• Amalgam manufacturers
• Thimerosal (vaccine preservative)
• Mercury thermometers
• Dyes
• Accidental inhalation
• industrial discharges
 MECHANISM OF TOXICITY
 Hg bound to mitochondrial proteins- Induces K+
uptake into mitochondria resulting in loss of
membrane potential.
 At higher concentrations, electron transport system
was also inhibited.
 Mercury readily forms covalent bonds with sulfur,
When the sulfur is in the form of sulfhydryl groups,
divalent mercury replaces the hydrogen atom to form.
Even in low concentrations, mercurials are capable of
inactivating sulfhydryl groups of enzymes and thus
interfering with cellular metabolism and function.
 TOXICOKINETICS
 Absorption:
• Inhaled Hg→ by mucosal membrane of alveoli
• Hg salts → through skin

 Metabolism:
• converted to Hg ions

“Recent studies suggest

that mercury may have
no threshold below
which some adverse effects
do not occur.”
 SYMPTOMS OF TOXICITY
 Acute Hg poisoning:
On inhalation On ingestion

Dyspnoea Abdominal pain

Fever, cough Vomiting, diarrhoea

Blurred vision Haematemesis

GI disturbances Grayish coloring of GI mucosa

Metallic taste Pink colour in urine

pulmonary oedema Renal failure

Convulsions coma
 SYMPTOMS OF TOXICITY
 Chronic toxicity:
On inhalation On ingestion

Tremors Tremors

Ataxia Colitis

Erythema Dementia

Mercura lentis Acrodynia (pink disease)

Glomerulonephritis Renal dysfunction

 Fatal dose is 1-2gm, death occurs in 3-5 days

 TREATMENT
 Identify the source and end the exposure.
 In case of ingestion
• Administration of proteinaceous substances.
• Administration of suspension of medicinal charcoal.
• Administration of sodium formaldehyde.
 In case of injection
• Supportive measures to treat shock
• Antibiotics for secondary infections
 Chelating agents
• Dimercaprol: Recommended treatment includes dimercaprol 5 mg/kg
intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12
to 24 hours for 10 days.
• Penicillamine: (250 mg orally every 6 hours) may be used alone or
following treatment with dimercaprol.
• The orally effective chelator (succimer) appears to be an effective
chelator.
 IRON POISONING
 Iron is not an environmental poison, accidental
intoxication with ferrous salts used to treat iron
deficiency is a frequently encountered source of
poisoning in young children.
 It is an essential element and its deficiency can cause
anemia.
 The color of blood is due to the haemogobin an iron-
containing protein. As illustrated by hemoglobin, iron
often is bound to cofactors, e.g. in hemes.
 Iron toxicity can result from inborn errors and also
from overdosage of iron salts.
 MECHANISM OF TOXICITY
 The maximum dose for children is 40 mg per day & for adults
it is 45 mg per day.
 Iron toxicity occurs, when serum level exceeds the total
binding capacity (TIBC).

Iron in free form can cause

• Metabolic acidosis
• Damage to GI mucosa
• Liver failure
• Improper functioning of mitochondria
 SYMPTOMS OF TOXICITY
 Iron toxicity mainly occurs in children and the symptoms are classified in
four stages

Stages Onset of effect symptoms

Stage 1 Within 30 min to 6 hrs Vomiting ,diarrhoea

leucocytosis

Stage 2 6-24 hrs No symptoms

Stage 3 24-48 hrs Organ failure like GI

tract,CNS,CVS.
Coma and death.

Stage 4 After 1 week Corrosion of GI mucosa

 TREATMENT
 Gastric lavage
 Mg(OH)2 1% solution orally
 Electrolytes
 Vasopressor agents
 Diazepam
 Chelation: deferoxamine i.v or orally.
 Liver transplantation in hepatic failure
conditions.
 CADMIUM POISONING
 Cadmium has no constructive purpose in the
human body. Cadmium is extremely toxic
even in low concentrations, and will
accumulate in organisms and ecosystems.
 It is widely used in industries.
 the blood brain barrier is competent to
cadmium so the CNS effects seen with other
metals (Pb) are absent.
 Cd is not well absorbed from the GI tract
(~20%), it is stored primarily in the kidney,
liver and testis.
 SOURCES
 Cigarette smoke (the most concentrated source
for most individuals)
 Batteries
 Refined foods
 Water pipes
 Coffee & Tea
 Coal
 Shell fish
 Ceramics
 Dental materials
 Cereal grains
 root vegetables
 MECHANISM OF ACTION
 Cd competes with zinc for binding
sites and interferes with zinc’s
essential functions (enzyme co-
factor), it also can acts as a catalyst
in oxidation reactions producing free
radicals. Cd toxicity is exacerbated
when concomitant Zn deficiency
occurs.
 SYMPTOMS OF TOXICITY
 Acute: Acute exposure to Cd may cause a flu like
syndrome with fever, chills and myalgias (“The
Cadmium Blues”). More severe exposures can cause
upper airway inflammation, pneumonitis and
pulmonary edema.
 Chronic: Concentration in the kidneys can result in
renal hypertension and proteinuria and eventually
renal failure (often the cause of death from Cd
poisoning).
 Other symptoms like pigmentation of teeth &
anosmia can be seen.

 Treatment:
• Calcium gluconate i.v
 THALLIUM POISONING
 Thallium is available in the form of salts.
 It is used as insecticides and in dye, glass,
firework industries.
 Its poisoning may occur due to
administration of accidental overdosage.
 Toxic effects are seen after 1-12 days.
 It is absorbed by skin.
 SYMPTOMS OF TOXICITY

Acute Chronic
GI inflammation Alopecia

Abdominal pain Ataxia

Tachycardia B.P, cardiomyopathy

Hepatic & renal failure optic nerve atrophy

Bone marrow depression paralysis of cranial nerve

Dark pigmentation of skin and

scalp

hallucinations
 TREATMENT
 gastric lavage with prussian blue solution
(potasium ferrocyanide or potassium
hexacyanoferrate).
 Haemodialysis and haemoperfussion.
 Forced diuresis.
 Activated charcoal.
 GOLD POISONING
 Gold salts are used in the treatment of rheumatoid arthritis.
 Gold is rapidly absorbed from i.m route and distributed to kidneys, liver,
spleen and body tissues.

toxicity
 Soluble compounds such as gold chloride are toxic to the liver and kidneys.
Common cyanide salts of gold such as potassium gold cyanide, used in gold
electroplating, are toxic both by virtue of their cyanide and gold content.

Symptoms
 Dermatitis
 Nephropathy
 Bone marrow depression
 Liver damage
 TREATMENT

 Prednisolone: (10-20 mg daily).

 Dimercaprol
• 3mg/kg i.m at 4 hour interval for 2 days
• Then same dose at 8 hour interval for
next 10 days
 OTHER METALS
 Antimony
 Bismuth
 Zinc
 Silver
 Manganese etc.,
 ANTAGONISTS
 Used in the treatment of heavy metal poisoning.
 Chelating agents