unit 7.1: heavy metals

Lead

* Storage batteries, ammunition, metal alloys, solder, glass, plastics, pigments, and ceramics
* No useful purpose in the human body

respiratory and gastrointestinal tract

**Lead:** *Pharmacokinetics*

Absorbed slowly but consistently via ___

industrial exposure

**Lead:** *Pharmacokinetics*

Respiratory tract

non-industrial exposure

**Lead:** *Pharmacokinetics*

Intestinal tract

50%

**Lead:** *Pharmacokinetics*

in children

10-15%

**Lead:** *Pharmacokinetics*

in adults

**Low dietary calcium, iron deficiency and ingestion** on an empty stomach

**Lead:** *Pharmacokinetics*

increases absorption

99% to 1%

**Lead:** *Pharmacokinetics*

RBCs to free plasma ratio

* bone marrow, brain, kidney, liver, muscle and gonads; then bones
* placenta - may affect fetus

**Lead:** *Pharmacokinetics*

Distribution

1-2 months

**Lead:** *Pharmacokinetics*

half life

years to decades

**Lead:** *Pharmacokinetics*

half life in bones

in the urine

**Lead:** *Pharmacokinetics*

70%

elevate blood lead concentrations

**Lead:** *Pharmacokinetics*

In patients with **high bone lead burdens**, slow release from the skeleton may ___ for years after exposure ceases

**pathologic high bone turnover states**

* hyperthyroidism
* prolonged immobilization

**Lead:** *Pharmacokinetics*

may result in **frank lead intoxication**

* Inhibition of enzymatic function
* Interference with action of essential cations (calcium, zinc, iron)
* Oxidative stress generation
* Gene expression changes
* Cell signaling alteration
* Disruption of membrane integrity

**Lead:** *Pharmacodynamics*

Mechanisms of Action

**developing central nervous system** of the fetus and young __child__

**Lead:** *Pharmacodynamics -* __*Nervous System*__

most sensitive target organ for lead’s toxic effect

normocytic or microcytic and hypochromic

**Lead:** *Pharmacodynamics -* __*Blood*__

Lead can induce an **anemia** that may be ___

heme synthesis

**Lead:** *Pharmacodynamics -* __*Blood*__

Lead interferes with ___ by **blocking the incorporation of iron into protoporphyrin IX** and by **inhibiting the function of enzymes** in the heme synthesis pathway, including __aminolevulinic acid dehydratase and ferrochelatase__

increasing erythrocyte membrane fragility and decreasing red cell survival time

**Lead:** *Pharmacodynamics -* __*Blood*__

Lead also contributes to anemia by ___

**Basophilic stippling** on the peripheral blood smear

**Lead:** *Pharmacodynamics -* __*Blood*__

suggestive—albeit insensitive and nonspecific—diagnostic clue to the presence of lead intoxication

* thought to be a consequence of lead inhibition of the enzyme **3′,5′-pyrimidine nucleotidase**

renal interstitial fibrosis and nephrosclerosis

**Lead:** *Pharmacodynamics -* __*Kidneys*__

**Chronic** high-dose lead exposure

**“saturnine gout” -** recurrent bouts of gouty arthritis

**Lead:** *Pharmacodynamics -* __*Kidneys*__

Lead may alter **uric acid excretion** by the kidney, resulting in ___

transient azotemia, possibly as a consequence of intrarenal vasoconstriction

**Lead:** *Pharmacodynamics -* __*Kidneys*__

**Acute** high-dose lead exposure

stillbirth or spontaneous abortion

**Lead:** *Pharmacodynamics -* __*Reproductive Organs*__

High-dose lead exposure

diminished or aberrant sperm production

**Lead:** *Pharmacodynamics -* __*Reproductive Organs*__

In **males**, blood lead concentrations __higher than 40 mcg/dL__

loss of appetite, constipation, diarrhea

**Lead:** *Pharmacodynamics -* __*Gastrointestinal Tract*__

Moderate lead poisoning

**“lead colic” -** intermittent bouts of severe colicky abdominal pain

**Lead:** *Pharmacodynamics -* __*Gastrointestinal Tract*__

high dosage

**spasmodic contraction** of the smooth muscles of the intestinal wall

* mediated by **alteration in synaptic transmission** at the smooth muscle-neuromuscular junction

**Lead:** *Pharmacodynamics -* __*Gastrointestinal Tract*__

lead colic mechanism

**“gingival lead lines” -** sulfur ions released by microbial action may produce dark deposits of lead sulfide at the gingival margin

**Lead:** *Pharmacodynamics -* __*Gastrointestinal Tract*__

In heavily exposed individuals with **poor dental hygiene**

Inorganic

**Lead:** *Major Forms of Lead Intoxication*

lead oxides and salts

Organic

**Lead:** *Major Forms of Lead Intoxication*

tetraethyl lead

GI, Respiratory

**Lead:** *Major Forms of Lead Intoxication -* __*Major Routes*__

Inorganic

**Skin**, GI, Respiratory

**Lead:** *Major Forms of Lead Intoxication -* __*Major Routes*__

Organic

Soft tissues; **redistributed to skeleton**

**Lead:** *Major Forms of Lead Intoxication -* __*Distribution*__

Inorganic

Soft tissues **(esp liver and CNS)**

**Lead:** *Major Forms of Lead Intoxication -* __*Distribution*__

Organic

* CNS deficits
* peripheral neuropathy
* anemia
* nephropathy
* hypertension
* reproductive toxicity

**Lead:** *Major Forms of Lead Intoxication -* __*Clinical Findings*__

Inorganic

Encephalopathy

**Lead:** *Major Forms of Lead Intoxication -* __*Clinical Findings*__

Organic

* Inhibits enzymes
* interferes with essential cations
* alters membrane structures

**Lead:** *Major Forms of Lead Intoxication -* __*MOA*__

Inorganic

Hepatic dealkylation (fast) → Trialkyl metabolites (slow) → dissociation to lead

**Lead:** *Major Forms of Lead Intoxication -* __*MOA*__

Organic

* **Renal** (major)
* **feces and breast milk** (minor)

**Lead:** *Major Forms of Lead Intoxication -* __*Metabolism & Elimination*__

Inorganic

* **Urine and feces** (major)
* **Sweat** (minor)

**Lead:** *Major Forms of Lead Intoxication -* __*Metabolism & Elimination*__

Organic

immediate termination of exposure, supportive care, and the judicious use of chelation therapy

**Lead:** *Treatment -* __*Inorganic*__

Lead encephalopathy

**Lead:** *Treatment -* __*Inorganic*__

medical emergency that requires intensive supportive care

corticosteroids and mannitol or hypertonic saline

**Lead:** *Treatment -* __*Inorganic*__

**Cerebral edema** may improve with ___

Radiopacities on **abdominal radiographs**

**Lead:** *Treatment -* __*Inorganic*__

suggest the presence of retained lead objects requiring gastrointestinal decontamination

5 days

**Lead:** *Treatment -* __*Inorganic*__

Intravenous **edetate calcium disodium (CaNa₂EDTA)** is administered at a dosage of **1000–1500 mg/m2/d** (approximately 30–50 mg/kg/d) by **continuous infusion** for up to ___

Oral Succimer (DMSA)

**Lead:** *Treatment -* __*Inorganic*__

after 5 days

gastrointestinal decontamination

**Lead:** *Treatment*

Retained lead objects

decontaminating the skin

**Lead:** *Treatment -* __*Organic*__

Empiric chelation

**Lead:** *Treatment -* __*Organic*__

if **high blood lead concentrations** are present

anticonvulsants

**Lead:** *Treatment -* __*Organic*__

Treatment of seizures

Arsenic

* Semiconductors, wood preservatives, nonferrous alloys, glass and turf herbicide monosodium methane arsonate (MSMA)
* Groundwater
* used as a pharmaceutical agent but now limited in use

Arsine

**Arsenic:**

an arsenous hydride (AsH3) gas with potent hemolytic effects

Fowler’s solution

**Arsenic:**

contains **1% potassium arsenite**, was widely used as a medicine for many conditions from the eighteenth century through the mid-twentieth century

**lewisite** (dichloro-\[2-chlorovinyl\]arsine)

**Arsenic:**

developed in the early 20th century as **chemical warfare agents**

Arsenic trioxide

**Arsenic:**

reintroduced into the United States Pharmacopeia in 2000 as an **orphan drug for the treatment of relapsed acute promyelocytic leukemia** and is finding expanded use in experimental cancer treatment protocol

Melarsoprol

**Arsenic:**

used in the treatment of advanced **African trypanosomiasis**

respiratory and GI tract

**Arsenic:** *Pharmacokinetics*

Well-absorbed via ___

Percutaneous absorption

**Arsenic:** *Pharmacokinetics*

**limited** but may be clinically significant after heavy exposure to concentrated arsenic reagents

methylation reactions

**Arsenic:** *Pharmacokinetics*

Metabolized by the liver via ___

prolonged

**Arsenic:** *Pharmacokinetics*

After massive ingestions, the **elimination half-life** is ___

**Arsenic binds to sulfhydryl groups** present in keratinized tissue, and following cessation of exposure, hair, nails, and skin

**Arsenic:** *Pharmacokinetics*

may contain elevated levels after urine values have returned to normal

Urine (major), sweat and feces

**Arsenic:** *Pharmacokinetics*

Excreted in the ___

Inhibition of enzymatic function

**Arsenic:** *Pharmacodynamics -* __*MOA*__

may result from **sulfhydryl group binding** by trivalent arsenic or by substitution for phosphate

* Oxidative stress generation
* Gene expression changes
* Cell signaling alteration

**Arsenic:** *Pharmacodynamics -* __*MOA*__

Inorganic arsenic or its metabolites

two to ten times more acutely toxic

**Arsenic:** *Pharmacodynamics*

**inorganic trivalent arsenic** (As3+, arsenite) is generally ___ than **inorganic pentavalent arsenic** (As5+, arsenate)

t**rivalent form of the methylated metabolites** (eg, monomethylarsonous acid \[MMAIII\])

**Arsenic:** *Pharmacodynamics*

more toxic than the inorganic parent compounds

Arsenic methylation requires *S*-adenosylmethionine

**Arsenic:** *Pharmacodynamics*

* a **universal methyl donor** in the body
* arsenic-associated perturbations in one-carbon metabolism
* may underlie some **arsenic-induced epigenetic effects** such as altered gene expression

Arsine gas

**Arsenic:** *Pharmacodynamics*

* oxidized in vivo and exerts a **potent hemolytic effect** associated with **alteration of ion flux** across the erythrocyte membrane
* disrupts cellular respiration

arsenobetaine

**Arsenic:** *Pharmacodynamics*

Marine organisms

arsenosugars

**Arsenic:** *Pharmacodynamics*

partially metabolized to dimethylarsinic acid

**Thioarsenite** compouns

**Arsenic:** *Pharmacodynamics*

occur as **minor metabolites** of inorganic arsenic

GI, Respiratory

**Arsenic***: Arsenic Intoxication*

Major Routes

* Predominantly soft tissues (highest in liver and kidney)
* Tightly bound to skin, hair and nails

**Arsenic***: Arsenic Intoxication*

Distribution

* **Cardiovascular**: shock, arrythmias
* **CNS**: Encephalopathy, Peripheral Neuropathy
* **Others**: Gastroenteritis, Pancytopenias, Cancer

**Arsenic***: Arsenic Intoxication*

Clinical Findings

* Methylation
* Excreted via **Urine** (major)
* **Sweat and Feces** (minor)

**Arsenic***: Arsenic Intoxication*

Metabolism and Elimination

Arsine gas poisoning

**Arsenic***: Arsenic Intoxication*

distinctive pattern of intoxication dominated by **profound hemolytic effects**

Oliguric renal failure

**Arsenic***: Arsenic Intoxication -* __*Gas poisoning*__

a consequence of **hemoglobin deposition in the renal tubules**, often appears within 1–3 days

Paul Ehrlich’s “**magic bullet”**

**Arsenic***: Arsenic Intoxication -* __*Gas poisoning*__

for **syphilis** (arsphenamine, Salvarsan) was an arsenical

**“Raindrop pattern”**

**Arsenic***:*

* Hyperpigmentation and hyperkeratosis involving hands and feet
* Usually due to chronic inorganic arsenic poisoning
* Dermatologic lesions associated with chronic ingestion of arsenic in **drinking water**

Chelation with **Unithiol** 3-5mg/kg every 4-6 hours or **Dimercaprol** every 4-6 hours

**Arsenic***: Treatment*

Acute Poisoning

Mercury

* **Quicksilver** or liquid metal
* Mined predominantly as HgS in **cinnabar ores**
* Electrolytic production of chlorine and caustic soda; electrical equipment, thermometer, instruments, fluorescent lamps; dental amalgams; artisanal gold production
* Environmental release from burning of fossil fuels contributes to **bioaccumulation in fishes**

Thimerosal

**Mercury:**

an **organomercurial preservative** that is metabolized in part to ethylmercury, has been removed from almost all the vaccines in which it was formerly present

depending on chemical form

**Mercury:** *Pharmacokinetics*

absorption

Elemental mercury

**Mercury:** *Pharmacokinetics*

volatile and can be absorbed from the lungs

intact gastrointestinal tract

**Mercury:** *Pharmacokinetics*

poorly absorbed

Inhaled mercury

**Mercury:** *Pharmacokinetics*

**primary source** of occupational exposure

kidneys

**Mercury:** *Pharmacokinetics*

Distributed well into **tissues** (most concentrated in ___)

**Alkylmercury** compounds

**Mercury:** *Pharmacokinetics*

appear to be well absorbed through the skin

acute contact with a few drops of **dimethylmercury**

**Mercury:** *Pharmacokinetics*

resulted in severe, delayed toxicity

urine and feces

**Mercury:** *Pharmacokinetics*

Inorganic mercury is excreted through ___

1–3 months

**Mercury:** *Pharmacokinetics*

After **inhalation of elemental mercury vapor**, urinary mercury levels decline with a half-life of ___

50 days

* undergoes biliary excretion and enterohepatic circulation

**Mercury:** *Pharmacokinetics*

Methylmercury blood and whole-body half-life

sulfhydryl groups in keratinized tissue, and as with lead and arsenic

**Mercury:** *Pharmacokinetics*

appear in the hair and nails

**Acute** inhalation of __elemental__ mercury

**Mercury:** *Major Forms of Mercury Intoxication*

may cause chemical pneumonitis and noncardiogenic pulmonary edema

**Acute** ingestion of inorganic mercury salts

**Mercury:** *Major Forms of Mercury Intoxication*

an result in a corrosive, potentially life-threatening **hemorrhagic gastroenteritis** followed within hours to days by acute tubular necrosis and oliguric renal failure

**Chronic** poisoning from inhalation of mercury vapor

**Mercury:** *Major Forms of Mercury Intoxication*

classic triad of tremor, neuropsychiatric disturbance, and gingivostomatitis.

Gingivostomatitis

**Mercury:** *Major Forms of Mercury Intoxication -* __*Chronic*__

accompanied by **loosening of the teeth**, may be reported after high-dose exposure

Acrodynia

**Mercury:** *Major Forms of Mercury Intoxication -* __*Chronic*__

* uncommon **idiosyncratic reaction** to subacute or chronic mercury exposure and occurs mainly in children
* painful erythema of the extremities

Respiratory tract

**Mercury:** *Major Forms of Mercury Intoxication -* __*Major Routes*__

Elemental Mercury