Heavy metal and Heavy metal antagonists

Heavy metals of concern areLeadMercuryArsenicCadmium

Exert there toxic effects by combining with one or more reactivegroups (Ligands) essential for normal physiological functions.

Heavy metals may react in the body with-Ligands containing Oxygen- -OH, -COO- Ligand containing Sulfur- -SHLigand containing Nitrogen- -NH2

Heavy metal antagonists (Chelating agents) are designed specifically to compete with these groups for the metals and prevent or reverse toxic effects and enhance the excretion of metals.

Chelate- complex formed b/w a metal and a compound that contains two or more potential ligands.

The stability of chelate varies with the metal and the ligand atoms.e.g- lead and mercury have greater affinities for sulfur and nitrogen than for oxygen.

Factors affecting effectiveness of chelating agents for treatment of poisoning by heavy metal

Relative affinity of the chelator for the heavy metal as compared to essential body metals.

The distribution of the chelator in the body as compared with the distribution of the metal.

The ability of the chelator to mobilize the metal from the body once chelated

Ideal Properties of a chelating agents It should have high solubility in waterShould have resistance to biotransformationAbility to reach sites of metal storageCapacity to form nontoxic comlexes with toxic metalsAbility to retain chelating activity at the pH of body fluidReadily excretion of the chelate

Note- a low affinity for calcium also is desirable because calcium in plasma is readily available for chelation and a drug might produce hypocalcemia despite high affinity for heavymetal.

LEAD

Primary source- leaded paints and drinking water environmental & industrial exposure

Absorption, distribution and excretion

Absorption – g.i.t & the respiratory system

g.i.t absorption varies with age-Adults absorb upto 10% of ingested leadChildren absorb upto 40% of ingested lead

Iron deficiency also enhance intestinal absorption of lead.

DistributionOnce lead is absorbed , about 99% of that in the blood streambinds to hemoglobin in erythrocytes.

initial distribution – in the soft tissues particularly tubular epithelium of kidney and in the liver

In time- redistributed and deposited in bone, teeth & hair.

Excretion- urinary excretionBecause most of the lead is in the erythrocytes, very little isFiltered lead is also excreted in milk & sweat.Placental transfer of lead is also known.

Average daily intake- 0.2mg approx.

ACUTE LEAD POISONINGInfrequent and occurs from ingestion of acid soluble lead compounds or inhalation of lead vapours.

Local action in mouth- astringency thrist metallic tasteNauseaAbdominal painVomiting (vomitus may be milky-lead chloride)Stool may be black from lead sulfide

Acute hemolytic crisis sometimes occurs & cause severe anemia & hemoglobinuria.

The kidneys are damaged & urinary changes are evident death mayOccur in 1-2 days.

CHRONIC LEAD POISONINGSigns and symptoms may be divided into six categories1. Gastrointestinal -

AnorexiaMuscle discomfortheadacheConstipation usually is an early sign

2. Neuromuscular – muscle weakness easy fatigue occur long before actual paralysis3. CNS- lead encephalopathyMost serious menifestation specially in children than in adultsEarly signs- vertigo, insomnia, restlessness, headache, irritabilityAs encephalopathy develops--patient may first become excited & confused-delirium with repetitive tonic-clonic convulsions & coma follows.-vomiting a common sign-visual disturbances

4. Hematological effectsAnemia due to two factors:•Decreased life span of the erythrocytes•Inhibition of heme synthesis

5. Renal effectsA reversible renal tubular disorderAn irreversible interstitial nephropathy

6. Other effects-ashen color of the face -appearance of premature aging-poor muscle tone-a black,grayish or blue-black lead line along the gingival margin

Succinyl CoA + Glycine δ-aminolevulinate synthase

δ-aminolevulinate (δ-ALA) δ-aminolevulinate dehydratase

Porphobilinogen

Uroporphobilinogen

Coproporphyrinogen

Protoporphyrin ferrochelatase +Fe2+

Heme

Diagnosis of lead poisoning-Children – lead in blood > 10µg/dl are at risk of Developmental disabilities

-Adults- concentration >30µg/dl functional injury or Symptoms

-Decrease in δ-aminolevulinate dehydratase activity

-Increase in urinary excretion of δ-ALA & increase in Erythrocyte protoporphyrin

Patients with lead concentration 30-75µg/dl have all theAbove laboratory abnormality

TREATMENT-Initial t/t of acute lead intoxication involves supportive measures-Prevention of further exposure-Seizures are treated with diazepam-Fluid & electrolyte balance must be maintained

Chelation therapy is indicated in symptomatic patients or patientsWith blood lead concentration > 50-60µg/dl.

Four chelators are employed1.Edetate calcium disodium (CaNa2EDTA)2.Dimercaprol3.D-penicillamine4. Succimer (2,3-dimercaptosuccinic acid)

Organic mercury-e.g. methyl mercury-Most difficult forms of mercury to mobilize from the body-Dimercaprol contraindicated because it increase brain concentrations of methylmercury.-penicillamine in dose of 2 g per day is used.-during 1-3 days concentration of mercury in bloodincreases before it decreases.This is due to mobilization of metal from tissues to blood at a rate more rapid than that for excretion of mercury into urine and feces.

1) CaNa2EDTA- initiated at a dose of 30-50mg/kg per day divided in two doses,either by deep i.m injection or slow i.v infusion for 5 consecutive daysThe first dose of CaNa2EDTA should be delayed until 4 hrs after the first dose of dimercaprol.

An additional course may be given after an interruption of 2 days

Each course of therapy should not exceed a total dose of 500mg/kg

2) Dimercaprol- 4mg/kg i.m route every 4 hrs for 48 hrs, then every every 6hrs for 48 hrs finally every 6-12 hrs for additional 7 days.

3) D- Penicillamine- effective orally 250mg 4 times daily for 5 daysDuring chronic therapy with penicillamine, the dose should notExceed 40mg/kg per day.

4) SuccimerFirst orally active chelator available for children with safety & efficacy profile-10mg/kg every 8hrs for 5 days,then every 12hrs for additional 2 weeks.

MERCURY

Occupational and environmental exposure to mercury-Chloralkali- e.g. bleach- Electrical equipment-Paints-Thermometers-Dental-Laboratory

Salts of mercury exist in two states of oxidation- as monovalent mercurous salts or as divalent mercuric salts

Mechanism of action-

It readly forms covalent bond with sulfur, & it is this property that accounts for most of the biological properties of the metal.

Also combines with phosphoryl, carboxyl, amide and amine group.

TOXICITYElemental mercuryShort term exposure to vapour of elemental mercury may produce-Weakness-Chills-Metallic taste-Nausea,vomiting-Cough-Pulmonary toxicity may progress to an interstitial pneumonitis

Chronic exposure to mercury vapours produce serious form of toxicity dominated by neurological effects,the syndrome is Referred as asthenic vegetative syndrome.

Concentration in urine- normal 5µg/liter

TREATMENTInorganic mercury -maintenance of fluid & electrolyte balance-emesis can be induced if patient is awake & alert chelation therapyDimercaprol- 5mg/kg i.m initially,followed by 2.5mg/kg i.m every 12-24 hrs for 10 days. ORPenicillamine – 250mg orally every 6 hours

Inorganic salts of mercuryIonic mercury e.g mercuric chloride can produce severe acute toxicity.-Precipitation of mucus membrane proteins by mercuric salts results in ashen-grey appearance of the mucous of the mouse intestine pain vomiting

Diagnosis of mercury poisoning The upper limit of nontoxic concentration of mercury in blood is- 3-4 µg/dl >4 µg/dl suggests need of medical examination

ARSENIC-Found in soil, water and air as a common environmental Toxicant-Major source of occupational exposure to arsenic –containingCompounds is from manufacture of arsenical herbicides & pesticides.

Mechanism of actionArsenate (pentavalent) is a well known uncoupler of mitochondrial oxidative phosphorylation.

There is competitive substitution of arsenate for inorganic Phosphate in the formation of adenosine triphosphate

Subsequent formation of an unstable arsenate ester that is rapidly hydrolysed (Arsenolysis).

Toxicological effects of arsenicCVS- Acute & subacute doses induces mild vasodilation this leads to an edema, particularly facial. -hypotention -congestive heart failure -cardiac arrythmiasGIT- -mild abdominal cramping -diarrhoea -severe gastroentritis associated with shock.

TREATMENT

-Fluid replacement

Chelating therapyDimercaprol- 3-4mg/kg i.m every 4-12hrs

Penicillamine- in 4 divided doses to a maximum of 2 g per day

Dialysis may become necessary with severe arsenic-induced Nephropathy is there.

KidneysSevere renal damage

SkinHyperpigmentation in raindrop pattern

Nervous systemEncephalopathyNeurological lesions

Liver- necrosis

Carcinogenesis- skin tumors

CADMIUM

-occurs in nature in association with zinc & lead and extraction & processing of these metals thus often lead to experimental contamination with cadmium-It is absorbed from g.i.t & transported in blood,bound mainly to blood cells & albumin.

Acute Cadmium Poisoning-results from inhalation of cadmium dusts & fumes-ingestion of cadmium salts-early toxic effects are due to local irritation

-nausea-vomiting-salivation-abdominal cramps

Symptoms that appear in a few hours-irritation of respiratory tract with severe,early pneumonitis-chest pain-dizziness

Chronic cadmium poisoningKidney- proximal tubular injury proteinuriaLung- dyspnea

Bone- osteomalacia

Testis- testicular necrosis

Treatment of cadmium poisoning

-remove the patient from source-respiratory support

Chelation therapy

-CaNa2EDTA 75 mg/kg per day in 3-6 divided doses for 5 days after 2 days again 5 day course is repeated

Total dose per 5 day should not exceed 500 mg/kg.