pharmacology perspective on thalassemia which includes the description of the condition and its treatment.

1. THALASSEMIA
GROUP 4 MEMBERS:
Shoneza Kingston – 08/0509/3621
Radha Ramkissoon – 09/0509/0297
Endra Rampersaud – 08/0509/3761
Fizal Ali – 09/0509/1101
Ameenah Khan – 09/0509/1391
Kezia Boyal – 08/0509/0624

2. THALASSEMIA
• Thalassemia is an inherited blood disorder in which
the body produces an abnormal form of hemoglobin
which results in excessive destruction of red blood
cells and further leads to anemia.
• TYPES OF THALASSEMIA:
ALPHA THALASSEMIA BETA THALASSEMIA

3. Alpha Thalassemia
Alpha thalassemia is the result of
changes in the genes for the alpha
globin component of hemoglobin.

4. ETIOLOGY
Mutation in the DNA of cells that
produce hemoglobin
Inheritance

5. Pathophysiology
Alpha thalassemia results when there is disturbance in
production of α-globin from any or all four of the α-
globin genes.
 Genes are responsible for regulating the synthesis and
structure of different globins which are divided into 2
clusters.
 The α-globin genes are encoded on chromosome 16
and the γ, δ, and β-globin genes are encoded on
chromosome 11
 A normal person carries a linked pair of alpha globin
genes, 2 each from maternal and paternal
chromosome.

6. Pathophysiology
Therefore, alpha thalassemia occurs when
there is a disturbance in production of α-globin
from any or all four of the α-globin genes.
When functional point mutations, frame shift
mutations, nonsense mutations, and chain
termination mutations occur within or around
the coding sequences of the alpha-globin gene
cluster hemoglobin is impaired.
When that occurs, protein synthesis may be
inhibited.

7. Pathophysiology
 Normal production of alpha chains is absent which results in
excess production of gamma- globin chains in the fetus and
newborn or beta- globin chains in children and adults.
 The β-globin chains are capable of forming soluble tetramers
(beta-4, or HbH)
 This form of hemoglobin is still unstable and precipitates
within the cell, forming insoluble inclusions called Heinz
bodies
 These Heinz bodies damage the red blood cells.
 This further results in damage to erythrocyte precursors and
ineffective erythropoiesis in the bone marrow, hypochromia
and microcytosis of circulating red blood cells

9. Mutated Thalassemia
Alpha (0) thalassemia – More than 20 mutations
have been found.
Those that result in the functional depletion of both
pair of α -globin genes
Individuals with this disorder are not able to
produce any functional α -globin and thus are
unable to make any functional hemoglobin A, F, or
A2.
This leads to the development of hydrops fetalis or
hemoglobin Bart (excess buildup of fluid before
birth)

10. Mutated Thalassemia
 Alpha (+) thalassemia –More than 15 different
genetic mutations that result in decreased production
of α -globin usually due to the functional deletion of
1 of the 4 alpha globin genes.
 Further classification of Alpha (+) thalassemia:
A- Thalassemia (-α/α α)
 Characterized by inheritance of 3 normal α-genes.
 Patients clinically known as silent carriers of alpha
thalassemia.
 Also known as alpha thalassemia minima, alpha
thalassemia-2 trait, and heterozygosity for alpha (+)
thalassemia minor

11. Clinical Presentation
 Shortage of red blood cells- Anemia
 Pale skin
 Weakness
 Fatigue
 Enlarged liver and spleen- hepatosplenomegaly

12. Clinical Presentation
Heart defects
 Abnormalities of the urinary system or genitalia
 Hb Bart syndrome can cause complications in pregnancy such
as
• High blood pressure
• Premature delivery
• Abnormal bleeding
• Jaundice

13. Treatment of Alpha Thalassemia
• Treatment for thalassemia often involves regular blood
transfusions and folate supplements.
• If you receive blood transfusions, you should not take iron
supplements. Doing so can cause a high amount of iron to
build up in the body, which can be harmful.
• Persons who receive significant numbers of blood transfusions
need a treatment called chelation therapy to remove excess
iron from the body.
• Bone marrow transplant may help treat the disease in some
patients, especially children.

14. Surgical Treatment
– Perform splenectomy if transfusion requirements
are increasing.
– Surgical or orthodontic correction may be
necessary to correct skeletal deformities of the
skull and maxilla caused by erythroid hyperplasia.

15. Medications
• FOLIC ACID- ORAL
• FOLIC ACID - INJECTION
• DEFEROXAMINE - INJECTION

16. FOLIC ACID - ORAL
• BRAND NAME(S): FA-8
• USES
– Folic acid is the man-made
form of folate which is a B6-
vitamin naturally found in
some foods.
– It is needed to form healthy
cells, especially red blood
cells.
– Active forms of folic acid are:
L-methylfolate and
levomefolate
– Folic acid supplements are
used to treat or prevent low
folate levels.

17. Dosage
• Taken orally with or without food once daily.
• However, recommended dose for deficiency
states is 250-1000 mcg (micrograms) per day

18. SIDE EFFECTS
– Folic acid usually has very few side effects
– Possible side effects include:
• Serious allergic reaction, including: rash,
itching/swelling (especially of the
face/tongue/throat), dizziness, trouble
breathing

19. • Folic acid is safe to take during pregnancy when used
as directed. It is included in prenatal vitamin
products.
• Certain spinal cord birth defects may be prevented by
taking adequate amounts of folic acid during
pregnancy.

20. DRUG INTERACTIONS
– Fosphenytoin (Cerebyx)
Taking folic acid along with fosphenytoin (Cerebyx) might
decrease the effectiveness of the drug for preventing seizures
since folic acid increase the breakdown of the drug.
– Methotrexate (MTX, Rheumatrex)
Folic acid decrease the effectiveness of methotrexate.
- Phenobarbital (Luminal).
Taking folic acid can decrease how well phenobarbital (Luminal) works
for preventing seizures.

21. DRUG INTERACTIONS
– Primidone (Mysoline).
Folic acid can decrease the effectiveness of primidone
for preventing seizures.
– Pyrimethamine (Daraprim).
It is used to treat parasite infections. Folic acid might
decrease the effectiveness of pyrimethamine
(Daraprim)

22. FOLIC ACID - INJECTION
• BRAND NAME(S): Folvite
• USES: Folic acid is used to treat or prevent
– certain anemias caused by poor diet,
– pregnancy,
– alcoholism,
– Liver disease,
– certain stomach/intestinal problems,
– kidney dialysis, or
– relieve symptoms such as unusual tiredness and diarrhea

23. • ADMINISTRATION: This medication is given by
IM, IV OR SC usually once a day.
• DOSAGE:- 1-5 mg/day

24. DRUG INTERACTIONS
• Chloramphenicol-cause depletion of folic acid.
• Folic acid does not correct folate deficiency due to
dihydrofolate reductase inhibitor such as methotrexate.
Methotrexate, trimethoprim, and pyrimethamine prevent the
reduction of folic acid to tetrahydrofolate.
• Sulphasalazine depresses folic acid absorption.
• Folic acid is incompatible with oxidising and reducing agents
and ions with heavy metals.
• Folic acid may affect certain laboratory tests for vitamin B12
deficiency, resulting in false test results. Untreated vitamin
B12 deficiency may result in serious nerve problems (e.g.,
peripheral neuropathy with numbness/tingling symptoms).

25. DEFEROXAMINE - INJECTION
• BRAND NAME(S): Desferal
• Deferoxamine is an iron-binding agent
that belongs to a class of drugs known as
heavy metal antagonists. It works by
helping the kidneys and gallbladder get rid
of the extra iron.
Mechanism of Action
• Deferoxamine works in treating iron
toxicity by binding trivalent (ferric) iron
(for which it has a strong affinity),
forming ferrioxamine, a stable complex
which is eliminated via the kidneys.

26. Uses
• This medication is used along with other treatments (such as
syrup of ipecac) to treat sudden iron poisoning.
• It is most effective when given as soon as possible after the
iron was eaten.
• This medication can also be used to help get rid of iron in
patients with high iron levels due to many blood transfusions.
• This medication is not recommended for use in children less
than 3 years old
• This drug may also be used to treat high levels of aluminum in
dialysis patients and people with aluminum poisoning.

27. ADMINISTRATION & DOSAGE
• This medication is administered via IM, IV or SC.
• Intramuscular Administration: A dose of 1000 mg should be
administered initially. This may be followed by 500 mg every
4 hours for two doses. Depending upon the clinical response,
subsequent doses of 500 mg may be administered every 4-12
hours. The total amount administered should not exceed 6000
mg in 24 hours.

28. ADMINISTRATION & DOSAGE
• Subcutaneous Administration: A daily dose
of 1000-2000 mg/day should be administered
over 8-24 hours, utilizing a small portable
pump capable of providing continuous mini-
infusion. The duration of infusion must be
individualized. In some patients, as much iron
will be excreted after a short infusion of 8-12
hours as with the same dose given over 24
hours.

29. ADMINISTRATION & DOSAGE
• Intravenous Administration
• THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE
OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW
INFUSION BECAUSE DEFEROXAMINE CAN CAUSE HEART
PROBLEMS.
• THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR
FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV
DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO
EXCEED 125 MG/HR.
• This may be followed by 500 mg over 4 hours for two doses. Depending
upon the clinical response, subsequent doses of 500 mg may be
administered over 4-12 hours. The total amount administered should not
exceed 6000 mg in 24 hours.
• As soon as the clinical condition of the patient permits, intravenous
administration should be discontinued and the drug should be administered
intramuscularly.

30. SIDE EFFECTS
– fast heartbeats;
– blue lips, skin, or fingernails;
– severe, watery, bloody diarrhea with cramping;
– cough, wheezing, gasping, or other breathing problems;
– stuffy nose, fever, redness or swelling around your nose and eyes,
scabbing inside your nose;
– stomach or back pain, coughing up blood;
– easy bruising or bleeding, unusual weakness;
– urinating less than usual or not at all;
– vision or hearing problems; or
– leg cramps, bone problems, or growth changes (in a child using this
medication).

31. SIDE EFFECTS
• Less serious side effects:
– numbness or burning pain anywhere in the body;
– warmth, redness, or tingly feeling under the skin;
– mild itching or skin rash;
– mild diarrhea, nausea, or upset stomach;
– dizziness;
– reddish colored urine; or
– pain, burning, swelling, redness, irritation, or a hard lump
where the medicine was injected.

32. PRECAUTIONS
• Before using this medication, confirm with a health
professional if you have kidney problems, rheumatoid
arthritis, diabetes, or any fungal infection.
• If you are using this medication for aluminum
poisoning, consult a doctor if you experience
symptoms such as seizures, decreased calcium levels
in the blood, hyperparathyroidism.
• This drug may make you dizzy or cause blurred vision.
Do not drive, use machinery, or do any activity that
requires alertness or clear vision until you are sure you
can perform such activities safely.

33. PRECAUTIONS
• Limit intake alcoholic beverages.
• Children (especially those younger than 3 years of
age) may be more sensitive to the side effects of this
drug, especially the effects on bone growth.
• Older adults may be more sensitive to the side effects
of this drug, especially vision/hearing problems.
• During pregnancy, this medication should be used
only when clearly needed

34. DRUG INTERACTIONS
• Vitamin C: Patients with iron overload usually become vitamin C deficient,
probably because iron oxidizes the vitamin. Vitamin C increases availability of
iron for chelation. As an addidtive to iron chelation therapy, vitamin C in doses up
to 200 mg for adults may be given in divided doses, starting after an initial month
of regular treatment with Desferal. In general, 50 mg daily suffices for children
under 10 years old and 100 mg daily for older children.
• Prochlorperazine: Concurrent treatment with Desferal (deferoxamine) and
prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of
consciousness.
• Gallium-67: Imaging results may be distorted because of the rapid urinary
excretion of Desferal (deferoxamine) bound gallium-67. Discontinuation of
Desferal (deferoxamine) 48 hours prior to scintigraphy is advisable.

35. BETA THALASSEMIA
Beta thalassemia is a genetic blood disorder that
reduces the production of hemoglobin.

36. Beta Thalassemia
• Specifically, it is characterized by a
genetic deficiency in the synthesis
of beta- globin chains.
• Beta-globin is a component
(subunit) of hemoglobin.

37. Types
Thalassemia Major
(Cooley's anemia)
Thalassemia Minor
-severe form of beta
thalassemia - presence of one normal
gene and one with a
- presence of two mutation
abnormal genes that
cause either a severe - causes mild to
decrease or complete moderate mild
lack of beta globin anemia.
production.

38. Etiology
• Beta thalassemia is caused by a
deficiency of Beta globin inherited in
an autosomal recessive pattern, which
means both copies of the
HBB(Hemoglobin beta) gene in each
cell have mutations.
• The parents of an individual with an
autosomal recessive condition each
carry one copy of the mutated gene, but
they typically do not show signs and
symptoms of the condition.

40. Etiology-cont’d
• The HBB gene provides instructions for making a
protein called beta-globin.
• When there is a mutations in the HBB gene, it
prevents the production of any beta-globin.
• The absence of beta-globin is referred to as beta-
zero (B0) thalassemia.
• Other HBB gene mutations allow some beta-globin
to be produced but in reduced amounts. A reduced
amount of beta-globin is called beta-plus (B+)
thalassemia.

41. Etiology-cont’d
• A lack of beta-globin leads to a reduced amount of
functional hemoglobin. Without sufficient
hemoglobin, red blood cells do not develop
normally, causing a shortage of mature red blood
cells.
• The low number of mature red blood cells leads to
anemia and other associated health problems in
people with beta thalassemia.

42. Clinical Presentations
Thalassemia minor- characterized by mild anemia
Symptoms of beta thalassemia major appear in the first two years
of life.
• Fatigue and weakness
• Pale skin or jaundice (yellowing of the skin)
• Protruding abdomen with enlarged spleen and liver

43. Clinical Presentations
• Dark urine
• Abnormal facial bones and poor growth
• A poor appetite.
• Adolescents with the severe form of beta
thalassemia may experience delayed
puberty.

44. Pathophysiology
• In Beta thalassemia major, patients have severe anemia, ineffective
erythropoiesis, extramedullary hematopoiesis, and iron overload
resulting from transfusion and increased iron absorption.
• The skin may show pallor from anemia and jaundice from
hyperbilirubinemia.
• The skull and other bones may be deformed secondary to erythroid
hyperplasia with intramedullary expansion and cortical bone
thinning.
• Heart examination may reveal findings of cardiac failure and
arrhythmia, related to either severe anemia or iron overload.

45. Pathophysiology- Cont’d
• Abdominal examination may reveal changes in the liver,
gallbladder, and spleen.
• Patients who have received blood transfusions may have
hepatomegaly or chronic hepatitis due to iron overload.
• The gallbladder may contain bilirubin stones formed as a result
of the patient's lifelong hemolytic state.

46. Pathophysiology- Cont’d
• Splenomegaly typically is observed as part of the
extramedullary hematopoiesis or as a hypertrophic response
related to the extravascular hemolysis.
• In addition to cardiac dysfunction, hepatomegaly, and hepatitis,
iron overload can also cause endocrine dysfunction, especially
affecting the pancreas, testes, and thyroid.
• Transfusion-associated viral hepatitis resulting in cirrhosis or
portal hypertension also may be seen.

47. Surgical Treatment
• Splenectomy- decrease transfusion
requirements
• Cholecystectomy- Patients with thalassemia
minor may have bilirubin stones in their
gallbladder and, if symptomatic, may require
treatment. Perform a cholecystectomy using a
laparoscope or carry out the procedure at the
same time as the splenectomy.

48. Treatment
Treatment for beta thalassemia involves iron chelation.
1. Deferoxamine
2. Deferasirox
Deferoxamine is an intravenously administered chelation agent.
Desferal (deferoxamine) chelates iron by forming a stable complex
that prevents the iron from entering into further chemical
reactions. It readily chelates iron from ferritin and hemosiderin
but not readily from transferrin; it does not combine with the
iron from cytochromes and hemoglobin. It does not cause any
demonstrable increase in the excretion of electrolytes or trace
metals.

49. Adverse Effects
• Hypotension (with too rapid IV infusion)
• Pulmonary edema with over 24 hr IV infusion
• Anaphylaxis (rare)
• Renal failure
• Hepatic dysfunction
• Yersinia enterocolitica, Y. pseudotuberculosis, and fungal infections
Cautions
• In acute iron toxicity, give IV only to patients with cardiovascular collapse or in
shock
• Do NOT administer by rapid IV
• Increased serum creatinine (possibly dose related); acute renal failure and renal
tubular disorder reported
• NOT a substitute for standard measures generally used in iron toxicity (eg, induced
emesis, gastric lavage)
• Risk of potentially fatal infections

50. Drug Interactions
There are a number of drug interactions that should be monitored closely when
giving Deferoxamine e.g.:
• ascorbic acid
• calcium carbonate calcium carbonate
• ferric carboxymaltose
• ferric gluconate
• ferrous fumarate
• polysaccharide iron
• prochlorperazine
• sodium bicarbonate
• sodium bicarbonate
• aluminum hydroxide- deferoxamine decreases levels of aluminum hydroxide
by inhibition of GI absorption. Applies only to oral form of both agents.
• sodium citrate/citric acid- deferoxamine decreases levels of sodium
citrate/citric acid by inhibition of GI absorption. Applies only to oral form of
both agents.

51. Dosing Forms & Strengths
Powder for injection
• 500mg/vial
• 2g/vial
Acute Iron Poisoning
• Initial 1 g IM (ALL patients not in shock) or slow IV infusion (ONLY
patients with cardiovascular collapse or shock), THEN;
• 500 mg IM/IV q4hr x2, THEN;
• Depending on clinical circumstance, may administer additional doses of
500 mg IM/IV q4-12hr PRN;
• IV infusion rate: initial 1 g at 15 mg/kg/hr, all subsequent doses no more
than 125 mg/hr;
• No more than 6 g/day (IM or IV), but in severe cases should continue
infusion up to 24 hours

52. Dosing Forms & Strengths
Chronic Iron Overload
• 500-1000 mg IM everyday, PLUS
• 2000 mg IV infusion at no more than 15 mg/kg/hr with (but
separately) each unit of blood transfused
• No more than 1 g/day (without transfusion); 6 g/day (with
transfusion)
• Alternatively, 1-2 g/day SC infusion over 8-24 hours

53. Deferasirox- Exjade
Mechanism of Action
• Exjade (deferasirox) is an orally active chelator that is
selective for iron (as Fe3+). It is a tridentate ligand that binds
iron with high affinity in a 2:1 ratio. Although deferasirox has
very low affinity for zinc and copper there are variable
decreases in the serum concentration of these trace metals after
the administration of deferasirox.

54. Adverse Effects
• Serum creatinine increase (dose related)
• Proteinuria
• Pyrexia
• Cough
• Influenza
• Rash
• Respiratory tract infection
• Bronchitis
• ALT increased
• Acute tonsillitis
• Rhinitis
• Anaphylaxis
• Angioedema
• Cytopenias, including agranulocytosis, neutropenia and thrombocytopenia;
leukocytoclastic vasculitis

55. Precautions
• Do not take with aluminum-containing antacids
• Concomitant cholestyramine -Coadministration with
a single dose of cholestyramine decreases deferasirox
AUC by 45%; avoid concomitant use. If
coadministration is necessary, consider increasing
initial deferasirox dose to 30 mg/kg and monitor
serum ferritin levels and clinical responses for further
dose modification.
• Risk of hepatic failure, some with fatal outcome;
most occurred with age >55 yr and with comorbid
conditions (eg, liver cirrhosis, multiorgan failure)

56. Drug Interactions
There are approximately thirteen (13) minor drug interactions. Two of these
are:
• Galantamine- deferasirox will decrease the level or effect of galantamine
by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
• Imipramine- deferasirox will decrease the level or effect of imipramine by
affecting hepatic/intestinal enzyme CYP3A4 metabolism.
In addition there are 217 interactions that should closely monitored. E.g.:
• Amlodipine
• Aspirin- Combination may increase GI bleeding, ulceration and irritation.
Use with caution.
• Atorvastatin
• Cyclosporine
• Vancomycin- Coadministration of deferasirox with potentially nephrotoxic
drugs, including vancomycin may increase the risk of this toxicity. Monitor
serum creatinine and/or creatinine clearance in patients.

57. Dosing Forms & Strengths
Tablets
• 125mg
• 250mg
• 500mg
Iron Overload Due to Blood Transfusion
• 20 mg/kg PO qd, titrate based on serum ferritin, not to exceed
30 mg/kg qd
• Coadministration with potent UGT1A1 inducers (eg, rifampin,
phenytoin,phenobarbital, ritonavir) or cholestyramine:
Consider increasing intial dose to 30 mg/kg; these drugs
decrease systemic exposure (AUC)

58. Administration
• Do not chew tablet; disperse table in water, apple juice, or orange juice
• <1 g in 3.5 oz liquid; >1 g in 7 oz liquid
• Take on empty stomach at least 30 minutes prior to food
Renal & Hepatic Impairment
• Renal impairment
• Reduce daily dose by 10mg/kg if serum creatinine increases by >33% (on 2
consectutive visits) above pretreatment levels
• Hepatic impairment
• Moderate (Child-Pugh B): Decrease initial dose by 50%
• Severe (Child-Pugh C): Avoid use

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61. THANK YOU!