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D&T 4, Exam 3 (Liver) > Valentovic - Heavy Metals > Flashcards

Valentovic - Heavy Metals Flashcards

1
Q

Name 5 Heavy Metals that come in to play in the medical field.

A

Pb, Hg, As, Cd and Cu

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2
Q

It’s not that you are exposed to metals, its the accumulation of these metals in your body that result in symptoms and conditions.

  • t1/2 > 10 yr (so over 40 years to get rid of)
  • Metals are not metabolized
  • Metals are water-soluble and don’t accumulate in fat
  • Metals bind to target proteins, enzymes via ____, _____, _____ functional groups

What are used for detoxification: _______________?

A

S, O, N functional groups

Chelators

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3
Q

An ideal Chelating Agent….

  • should bind the heavy metal complex and is _____ (less/more) toxic than the individual metal
  • enhances excretion of metal faster

-must work at what pH level?

-not readily metabolized (biotransformed so it holds on to the metal)

-hydrophilic, distribution similar to the heavy metals

-_________ (greater/less) affinity for metals than calcium or iron in body

A

less toxic complex

physiological pH = 7.4

greater

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4
Q

Name the chelator.

-metal displaces Ca++ in center of molecule

  • administration by IV and IM injection
  • ->IM: used for lead encephalopathy tx over 5+ days

-used for Lead and Cadmium

  • metal-chelator complex excreted in urine
  • ***CONTRAINDICATED** in renal disease
A

Calcium Disodium EDTA

*DON’T GET CONFUSED WITH DISODIUM EDTA, used for hypercalcemia (has no Calcium so seeks it out in the body)

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5
Q

Name the Chelator.

  • administered ORALLY
  • Sulfhydryl groups bind to metal
  • Excreted in Urine

-Lead Toxicity

-Low compliance d/t nausea and bad taste (rotten egg)

A

Succimer (Meso-2,3-dimercaptosuccininc acid, DMSA)

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6
Q

Name the Chelator.

  • SH groups bind to metal
  • Lead, Arsenic & *INORGANIC Mercury
  • Administered IM (in peanut oil)

*DON’T USE IN PATIENT ALLERGIC TO PEANUT

-Complex excreted in urine and bile
(If urine acidified, complex will dissociate)

A

Dimercaprol (2,3-Dimercaptopropanol, British Anti Lewisite (BAL))

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7
Q

What Chelator MUST BE AVOIDED in patients with allergies to peanuts?

A

Dimercaprol (BAL)

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8
Q

What type of drug administration?

  • When asymptomatic or light symptoms?
  • With more severe toxicities?
A

Asymptomatic: Oral

Severe: IM

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9
Q

What Chelator is contraindicated in Liver DIsease?

A

Dimercaprol (BAL) bc the metal-BAL complex is excreted in urine and bile.

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10
Q

Name the Chelator.

  • administered orally
  • sulfhydryl containing agent
  • Metal-Chelator complex excreted in Urine

-Lead, Arsenic and Copper

*Drug of Choice in Wilson’s Disease

A

Penicillamine

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11
Q

Drug of Choice in Wilson’s Disease? ******

A

Penicillamine d/t accumulation of Copper

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12
Q

What is the major serious adverse effect of Penicillamine?

What is it contradindicated for?

A

Agranulocytosis

Renal Disease

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13
Q

Name the Heavy Metal.

  • exposure by ingestion or inhalation
  • in water, soil, paint chips (old houses), home brew distilled in radiators, pottery made outside the US

Kids absorb >5x higher than adults.

-distributes 1st to Liver, Kidney, RBC then redistributes to the bone replacing Calcium in the brain and bone, where it stays and cannot be chelated! (t1/2 > 10 years)

A

Lead Toxicity

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14
Q

**** REMEMBER, for LEAD you take a WHOLE BLOOD SAMPLE, not a Plasma sample bc >95% of the lead is bound to Hb in the RBC ******

A
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15
Q

Lead distributes 1st to _______, _______, _______ then redistributes to the bone replacing __________ in the brain and bone forming tertiary lead phosphate, where it stays and cannot be chelated! (t1/2 > 10 years)

A

Liver, Kidney, RBC

Calcium

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16
Q

When do you have to use a chelating agent with Lead toxicity?

A

When it first distributes to the Liver, Kidney and RBC.

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17
Q

What kind of poisoning?

Blood: microcytic anemia, basophilic stipling and hemolysis (Acute)

GI: colic (chronic)

Nerve: muscle weakness, memory loss, palsy - perpetual loss of muscle stregnth (chronic/irreversible)

MOST SERIOUS CONDITION: ENCEPHALOPATHY (convulsions, cerebral edema, death**)

A

Lead Poisoning

18
Q

What toxicity has the MOST SERIOUS CONDITION OF ENCEPHALOPATHY?

-convulsions, cerebral edema, death

A

Lead Poisoning - essentially takes over the role of Calcium in the brain.

19
Q

Target Tissues for ___________ (what heavy metal)

  • *Neurological:**
  • peripheral, axon degeneration
  • Brain, interferes with Ca++ dependent reactions
  • *Hematologic**
  • Most sensitive indicator of toxicity**
  • *-inhibits Heme synthesis**
  • basophilic stipling d/t ppt of RNA
  • Anemia d/t dec RBC life span and dec Heme synthesis
A

Lead

20
Q

What is the most sensitive indicator of Lead Toxicity?

*earliest sign of toxicity, not the earliest target

A

Lead levels in whole blood (inhibits heme synthesis)

21
Q

********Lead inhibits 2 Sulfhydryl-dependent enzymes in the Heme Pathway?

A

*******delta-aminolevulinate dehydratase (cytosolic)

*******ferrochelatase (mitochondrial) gets in bc looks like Calcium

22
Q

Lead Toxicity causes increased urinary levels of _______________ and _______________ due to inhibitition of enzymes in the Heme pathway.

A

Delta-Aminolevulinate Acid and Coporphryin III

23
Q

Chelation Therapy for Lead Toxicity?

Low Levels, Asymptomatic: ____________ and ____________

Aggressive Therapy: ________________ and ____________

A

Low Levels: Succimer (oral) and Penicillamine (Oral), not FDA approved

Aggressive Therapy: Calcium Disodium EDTA (IV) and Dimercaprol (IM)

24
Q

What Heavy Metal?

  • exists in 3 Chemical Forms (Elemental, Inorganic, Organomercurial)
  • Cellular Mechanism: binds to sulfhydryl groups and inactivates proteins and enzymes
A

Mercury

25
Q

Fact: Mercury exists in 3 Chemical Forms

(1) ELEMENTAL (Hg0) toxic through inhalation
(2) INORGANIC (Hg+2) toxic by oral or inhalation
(3) ORGANOMERCURIAL (C-Hg) most toxic, any route

A
26
Q

What Chemical form of Mercury?

  • inhalation (respiratory & neurological damage)
  • Oral, not toxic bc not absorbed
  • uncharged (Hg0) crossing BBB
  • converted from valence of 0 –> +2 by catalase in RBCs (it becomes trapped and accumulates in brain)

Symptoms: tremor, irritability, erethism (irritability, depressio, delirium d/t Hg vapor excess)

A

Elemental Mercury (Hg0)

27
Q

What Chemical Form of Mercury?

  • oral exposure
  • binds to SH-proteins in mouth and esophagus causing a gray color
  • GI, vomiting, hematochezia (bloody diarrhea)
  • Renal toxicity (proximal tubules and chronic tubular and glomerular damage)
  • Photophobia and Acrodynia (reddening of face & chest) occurs with chronic exposure
A

Inorganic Mercury

28
Q

What Chemical Form of Mercury?

*Most toxic form (Carbon-Hg Bond -> neutral molecules can cross BBB rapidly)

-Methyl Mercury or DiMethyl Mercury

**2 Drops of Dimethyl Mercury (dermal) –> LETHAL!

Targets: nervous system (rapidly crosses BBB)

Symptoms: muscle tremor, visual field constriction, ataxia

A

Organomercurials

29
Q

What disease?

  • toxic substance found in humans was methylmercury
  • permanent weakness, visual field constrction, ataxia/balance issues & numbness
  • release occured for 30 yrs
  • inorganic mercury released into environment taken up by algae & converted to methylmercury

-methylmercury then entered food chain as algae eaten by fish

A

Minamata Disease (Environmental disaster)

30
Q

Treatment of Mercury Toxicity

Hg measured for inorganic and elemental Mercury

Elemental and Inorganic mercury use _________ (low) & __________ (severe).

Difficult to measure methyl mercury, rapidly taken up in to brain

____________ (moderate success)
____________ CONTRAINDICATED increases brain levels!

A

Penicillamine (low)
Dimercaprol (severe)

Penicillamine
Dimercaprol (CONTRAINDICATED bc inc. lipophilicity and inc. brain levels)

31
Q

What Heavy Metal?

  • *Forms:**
  • inorganic (As+3, As+5)
  • Organoarsenical
  • Arsine gas (AsH3) can happen in semiconductor industry (computer chips)
  • *Mechanism of Toxicity**
  • As+3 binds to sulfhydryl groups
  • As+5 replaces Phosphorus in ATP production causing uncoupling of oxidative phosphorylation
  • *-AsH3** causes spontaneous, rapid hemolysis
A

Arsenic

32
Q

What toxicity?

Vascular: vasodilator, increases capillary permeability (leakiness), arrhythmia

GI: inc. blood flow, loss of albumin into Small Intestine coagulates giving gelatinous diarrhea termed “rice water diarrhea” bc losing protein

Skin: cancer and hyperkaratosis (thickening of palms and soles)

**Arsine Gas: hemolysis

Kidney: proximal tubular and glomerular

A

Arsenic toxicity

33
Q

Facts: Chronic Arsenic Toxicity

  • Muscle weakness
  • Hyperkeratosis
  • Arrhythmia
  • Enlarged liver
  • Garlic odor to breath & sweat (arsenic binds to sulfhydrl groups in mucosa)
  • Mee’s lines on fingernails (horizontal) - binds to proteins in fingernails
A
34
Q

Treatment for Arsenic Toxicity?

1.

2.

  1. Arsine Gas?
A
  1. Penicillamine
  2. Dimercaprol (bc Arsenic likes to bind sulfhydrl groups)
  3. Chelation Therapy ineffective –> Treat Symptoms
35
Q

Name the Heavy Metal.

-Ingestion (contaminated water, oysters)
*target is Kidney (damage to proximal tubules)

-Inhalation (industry)
*target: kidney and lung
*Kidney: proximal tubular necrosis
*Lung: pulmonary edema, irritation and chronic exposure causes emphysema

A

Cadmium

36
Q

Cadmium Toxicity

_______________ is an inducible zinc finger protein.

  • induced by Cadmium, Mercury & Arsenic exposure
  • endogenous chellating agent in the body
  • high cysteine content, metal-SH binding
A

Metallothionein

37
Q

Cadmium accumulates in Liver & Kidney bound to ____________.

This complex taken up by liver/kidney. Cadium can be cleaved giving high levels in the tissues. Part of the reason you get Renal Toxicity.

A

Metallothionein

38
Q

Treatment for Cadium.

Chelation Therapy: ___________

What is CONTRAINDICATED? _____________, increases renal toxicity

A

Calcium Disodium EDTA

Dimercaprol (BAL)

39
Q

What biomarker is utilized to monitor Cadmium toxicity?

  • occupational exposure
  • protein excretion increased following renal damage
  • excellent correlation of cadmium exposure and urinary excretion
A

urinary B2 microglobulin

40
Q

What Disease?

  • environmental accident
  • accidental ingestion of Cadmium in H2O and food
  • chronic exposure combined with low Ca+2 diet
  • caused renal damage, osteoporosis and bone pain
  • replacement of Ca+2 by Cd
A

Itai Itai Disease (‘ouch, ouch’ disease)

41
Q

Name the Disease.

-inappropriately high Copper Levels

  • defect in ATP7B protein -> problem in transporter protein
  • impacts biliary copper excretion in to the bile
  • diminished copper incorpation within the ceruloplasmin in the plasma
A

Wilson’s Disease

42
Q

What is the 1st line of therapy for Wilson’s Disease?

If not tolerated, what is the alternate choice chelator?

A

Chelator Therapy: Penicillamine - must monitor Agranulocytosis!

Trientine (oral)

D&T 4, Exam 3 (Liver) (19 decks)

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