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 characteristicsDense, malleable, lustrousConduct 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 TOXICITYLead 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

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

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 exceeding 100mcg/d

Neuropathy

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

HEME

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.

SYMPTOMS OF TOXICITY

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 ores3. Industrial processes

Semiconductor manufacturing (gallium arsenide)Fossil fuelsWood treated with arsenic preservativesMetallurgySmelting (copper, zinc, lead) and refining of metals and oresGlass manufacturing

4. Commercial products Wood preservatives Pesticides Herbicides Fungicides

5. FoodSeafood and fish

6.OthersAntiparasitic drugsFolk 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 TOXICITYBodily system affected

Symptoms or signs

Systemic ThirstHypovolemia, Hypotension

Gastrointestinal Garlic or metallic taste, Burning mucosaNausea and vomiting,DiarrhoeaAbdominal pain

Hematopoietic system

HemolysisHematuria

Pulmonary (inhalational exposures)

Cough, Dyspnoeachest Pain, Pulmonary edema

Liver Jaundice, Fatty degenerationCentral necrosis

Kidneys Proteinuria, HematuriaAcute 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.

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.”

TOXICOKINETICS

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:

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

On inhalation On ingestion

Tremors Tremors

Ataxia Colitis

Erythema Dementia

Mercura lentis Acrodynia (pink disease)

Glomerulonephritis Renal dysfunction

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 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.

CADMIUM POISONING

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

Abdominal pain

Tachycardia

Hepatic & renal failure

Bone marrow depression

Dark pigmentation of skin and scalp

hallucinations

Alopecia

Ataxia

B.P, cardiomyopathy

optic nerve atrophy

paralysis of cranial nerve

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

AntimonyBismuthZincSilverManganese etc.,

ANTAGONISTS Used in the treatment of heavy metal poisoning. Chelating agents