Lead Poisoning and Thalassemia Flashcards
What is the retention time of lead in tissues?
- blood and soft tissues
- hair and nails
- bone
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
What are the symptoms of acute lead poisoning?
haematological and gastrointestinal symptoms
- colic
disorders of the central nervous system
- cramps
- paralysis
- loss of coordination
What are symptoms of chronic lead poisoning?
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
What drugs are currently used to treat lead poisoning?
EDTA administered as CaNa2EDTA
DMSA - water soluble derivative of BAL (dithiol)
What are the advantages and disadvantages of EDTA as lead poisoning treatment?
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
What are the advantages and disadvantages of DMSA as lead poisoning treatment?
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
What is the synergistic therapy for lead poisoning?
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
What is thalessemia?
generic name for a group of blood disorders
What is the cause of thalessemia?
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
What are the types of thalessemia?
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
What is thalessemia major?
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
What is the treatment for thalessemia major?
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
What is the effect of excess iron levels?
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
What are the drugs available for treatment of excess iron in the body?
desferrioxamine
deferiprone
deferasirox
How does desferrioxamine work as a chelating agents?
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
What are the advantages and disadvantages of desferrioxamine?
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
What are the advantages and disadvantages of desferiprone?
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
How does desferrioxamine work as a chelating agents?
bidentate - has 2 binding sites = bond in 1:3 complex with iron (iron co-ordination number is 6)
half life of 3-4 hours
What are the advantages and disadvantages of desfirasirox?
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
How does desfirasirox work as a chelating agents?
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
List the drugs for iron chelating in order of cost
desferiprone - least expensive
desferasirox
desferrioxamine - most expensive
What is the synergistic therapy for chelating excess iron?
desferrioxamine with desferiprone or desferasirox
- desferiprone or desferasirox will promote mobilisation of intracellular iron
- desferrioxamine enhances urinary and faecal excretion
What is the ideal treatment for iron chelation therapy?
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
