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1 - SOD > Lead Poisoning and Thalassemia > Flashcards

Lead Poisoning and Thalassemia Flashcards

1
Q

What is the retention time of lead in tissues?

  • blood and soft tissues
  • hair and nails
  • bone
A

blood and soft tissue

  • rapidly cleared
  • retention time is days

hair and nails

  • loner retention time than blood and soft tissues
  • can be used to prove presence of lead

bone

  • major repository source (storage of lead) = is similar to calcium so can replace it in bones
  • major deposition site for chronic poisoning
  • lead my eventually leach out of the bones
  • retention time is years
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2
Q

What are the symptoms of acute lead poisoning?

A

haematological and gastrointestinal symptoms
- colic

disorders of the central nervous system

  • cramps
  • paralysis
  • loss of coordination
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3
Q

What are symptoms of chronic lead poisoning?

A

porphyrin - intermediate for synthesis of haemoglobin

raised levels of ALAD in the urine

  • 5-aminolevulinic acid dehydrogenase = is a zinc dependent enzyme, requires zinc to be catalytically active and be stable
  • inhibits ALAD which catalyses an essential step in porphyrin and haem biosynthesis

raised levels of protoporphyrins (porphyrin precursors) in the urine
- inhibits ferrochelatase = an enzyme which incorporates iron into the porphyrin ring

joint and muscle pain
kidney damage
sterility and miscarriages may occur - reproductive
restlessness, poor concentration = behavioural

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4
Q

What drugs are currently used to treat lead poisoning?

A

EDTA administered as CaNa2EDTA

DMSA - water soluble derivative of BAL (dithiol)

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5
Q

What are the advantages and disadvantages of EDTA as lead poisoning treatment?

A

administered CaNa2EDTA as to prevent calcium depletion and tetany.
hydrophilic - only mobilises extracellular metals but intracellular (tissue bound) metal may eventually be mobilised = prolonged treatment

advantages

  • has 6 binding sites = O and N donor groups
  • forms 5 membered chelate rings = forms strong complexes
  • undergo little to no metabolic changes in vivo
  • rapidly excreted

disadvantages

  • lack of specificity (non-specific chelator) = chelates a range of metal ions = can cause depletion of essential trace metals (Zn, Fe, Cu)
  • poorly absorbed from GIT so cannot be administered orally
  • nausea, kidney damage, diarrhoea
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6
Q

What are the advantages and disadvantages of DMSA as lead poisoning treatment?

A

removes soft metals

advantages

  • water soluble = less toxic
  • oral administration

disadvantages

  • water soluble = hydrophilic, only mobilises extracellular metals (blood plasma)
  • GI discomfort, skin reactions, raised liver enzymes = mild an temporary side effects
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7
Q

What is the synergistic therapy for lead poisoning?

A

a combination of BAL and EDTA

  • most effective method of reducing the body’s lead levels
  • withdrawal of chelator therapy should be done gradually = stop rebound of lead level due to leaching off bones

side effects of BAL are a serious disadvantage

  • susceptible to oxidation
  • rise in bp, vomiting, sweating, salivation, nausea, headache, conjunctivitis
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8
Q

What is thalessemia?

A

generic name for a group of blood disorders

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9
Q

What is the cause of thalessemia?

A

haemoglobin is made up of two proteins

  • alpha globin
  • beta globin

it is caused by mutation in the gene that is responsible for the production of these proteins
- mutations affecting m-RNA production or processing.

as result the

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10
Q

What are the types of thalessemia?

A

deficiency
alpha thalessemia
- patient does not have enough alpha globin (protein)

beta thalessemia

  • patient does not have enough beta globin (protein)
  • thalessemia minor
  • thalessemia intermediate
  • thalessemia major = Cooley’s Anemia
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11
Q

What is thalessemia major?

A

caused by a complete lack of beta globin (protein)
- arises as a result of mutations affecting m-RNA production or processing.

patients with this inherited condition develop life threatening anaemia within the first few months of life

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12
Q

What is the treatment for thalessemia major?

A

regular blood transfusions
- one unit of blood per month = 250 mg of iron

thalessmics increase dietary iron absorption to compensate for ineffective erythropoeisis (production of RBCs)

chelation therapy
- to remove the excess iron that builds up in the body as a result of the blood transfusions

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13
Q

What is the effect of excess iron levels?

A

iron status may exceed the storage capacity of ferritin (iron storage protein)
- results in free iron forming free radicals

free radicals may
- attack hepatocytes (liver cells) causing death = damaged hepatocytes are replaced by fibroblast cells leading to liver fibrosis and cirrhosis (liver scarring)

  • attack cardiac cells = patients die from heart failure
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14
Q

What are the drugs available for treatment of excess iron in the body?

A

desferrioxamine
deferiprone
deferasirox

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15
Q

How does desferrioxamine work as a chelating agents?

A

hexadentate - has 6 binding sites, forms a 1:1 comlex with iron
removes 30-70 mg of iron per week
half life of 20-30 minutes = patient requires a lot

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16
Q

What are the advantages and disadvantages of desferrioxamine?

A

advantages

  • lead to negative iron balance
  • few side effects
  • promotes urinary excretion = turns urine pink

disadvantages

  • high molecular weight = is not orally active
  • given by infusion via portable pump
  • poor patient compliance
  • expensive - not practical or affordable
  • some patients are intolerant

side effects
- relatively non-toxic but at high doses can be detrimental to hearing and vision

17
Q

What are the advantages and disadvantages of desferiprone?

A

advantages

  • orally active
  • less expensive than desferrioxamine
  • better patient compliance than desferrioxamine
  • more effective at mobilising intracellular iron
  • promotes urinary excretion of iron

disadvantages

  • less facial iron excretion
  • less selective for iron than desferrioxamine
  • large dosage required = must take three doses a day = bind in 1:3

side effects

  • joint pain
  • agranulocytosis
  • neutropenia
  • mild reduction in WBC count
18
Q

How does desferrioxamine work as a chelating agents?

A

bidentate - has 2 binding sites = bond in 1:3 complex with iron (iron co-ordination number is 6)

half life of 3-4 hours

19
Q

What are the advantages and disadvantages of desfirasirox?

A

advantages

  • specific for iron = chelates both intracellular and extracellular excess iron in the blood, liver and heart
  • more effective at removing intracellular iron than desferrioxamine

disadvantages
- expensive
- side effect = GI disturbances, skin rash, kidney damage,
GI bleeding and detrimental effects on hearing and vision

20
Q

How does desfirasirox work as a chelating agents?

A

half of 8-16 hours
- long half life so lower dose has the sae efficacy of a desferrioxamine

tridentate triazole - forms a 1:2 complex with iron

21
Q

List the drugs for iron chelating in order of cost

A

desferiprone - least expensive
desferasirox
desferrioxamine - most expensive

22
Q

What is the synergistic therapy for chelating excess iron?

A

desferrioxamine with desferiprone or desferasirox

  • desferiprone or desferasirox will promote mobilisation of intracellular iron
  • desferrioxamine enhances urinary and faecal excretion
23
Q

What is the ideal treatment for iron chelation therapy?

A

desferrioxamine is not ideal
- not orally active, given by infusion, most expensive, intolerance, side effects

desferiprone

  • orally active (higher patient compliance, no intolerance)
  • longterm effectiveness and toxicity is unknown

desferasirox

  • orally active
  • longterm effectiveness and toxicity is unknown
  • expensive

bone marrow transplant is the only known prospect for a cure

1 - SOD (27 decks)

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