Download DRUGS USED TO TREAT DISEASES OF THE BLOOD

DRUGS USED TO TREAT
DISEASES OF THE BLOOD
Presented by
Dr. Sasan Zaeri
ParmD, PhD
March, 2016
Agents Used in Anemias; Hematopoietic Growth
Factors
• Hematopoiesis:
– the production from undifferentiated stem cells of
circulating erythrocytes, platelets, and leukocytes
• Essential factors:
– Iron, vitamin B12, folic acid and hematopoietic
growth factors
• Inadequate supply results in:
– Anemia, thrombocytopenia and neutropenia
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AGENTS USED IN ANEMIAS:
IRON
• Iron deficiency
– the most common cause of chronic anemia
– leads to pallor, fatigue, dizziness, exertional
dyspnea, etc.
– small erythrocytes with insufficient hemoglobin
are formed >>> microcytic hypochromic anemia
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Pharmacokinetics
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Pharmacokinetics
• Iron sources to support hematopoiesis:
– catalysis of the hemoglobin in senescent or
damaged erythrocytes
– dietary iron from a wide variety of foods
• iron requirements can exceed normal dietary
supplies in
– growing children and pregnant women (increased
iron requirements)
– menstruating women (increased losses of iron)
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Pharmacokinetics
• ABSORPTION
– 0.5-1 mg/d iron from food by a normal individual
– 1-2 mg/d in normal menstruating women
– 3-4 mg/d in pregnant women
• The iron in meat (heme iron) can be efficiently
absorbed
• Nonheme iron in foods must be reduced to
ferrous iron (Fe2+) before it can be absorbed
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Pharmacokinetics
• TRANSPORT
– Iron is transported in the plasma bound to
transferrin
– The transferrin-iron complex enters maturing
erythroid cells by receptor-mediated endocytosis
– iron deficiency anemia is associated with an
increased concentration of serum transferrin
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Pharmacokinetics
• STORAGE
– primarily as ferritin in intestinal mucosal cells,
macrophages in the liver, spleen, and bone and in
parenchymal liver cells
– the serum ferritin level can be used to estimate total
body iron stores
– Apoferritin (precursor of ferritin) levels is regulated by
the levels of free iron
• ↓ free iron → ↓ apoferritin → ↑ iron binding to transferrin
• ↑ free iron → ↑ apoferritin → protection of organs from
the iron toxic effects
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Pharmacokinetics
• ELIMINATION
– no mechanism for excretion of iron:
• regulation of iron balance must be achieved by
changing intestinal absorption and storage of iron, in
response to the body's needs
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Clinical Pharmacology
• The only clinical indication:
– treatment or prevention of iron deficiency anemia
• Patients with increased iron requirements:
– infants, especially premature infants
– children during rapid growth periods
– pregnant and lactating women
– patients with chronic kidney disease
• Loss of erythrocytes at a relatively high rate during
hemodialysis
• Erythrocyte production at a high rate as a result of
treatment with erythropoietin
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Clinical Pharmacology
• The most common cause of iron deficiency in
adults: blood loss
– Menstruating women lose about 30 mg of iron
with each menstrual period
• many premenopausal women have low iron stores or
even iron deficiency
– In men and postmenopausal women, the most
common site of blood loss is the gastrointestinal
tract
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Clinical Pharmacology
• TREATMENT
– with oral or parenteral iron preparations
• Oral iron corrects the anemia just as rapidly and completely
as parenteral iron in most cases if iron absorption from the
gastrointestinal tract is normal
• for patients with advanced chronic kidney disease who are
undergoing hemodialysis and treatment with
erythropoietin, parenteral iron administration is preferred
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Clinical Pharmacology
• Oral iron therapy
– Only ferrous salts should be used
• Ferrous sulfate, ferrous gluconate and ferrous fumarate
– Different iron salts provide different amounts of
elemental iron
• Ferrous fumarate> Ferrous sulfate>ferrous gluconate
– 200-400 mg/d of elemental iron corrects iron
deficiency most rapidly
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Clinical Pharmacology
• Oral iron therapy
– lower daily doses can be given:
• slower but still complete correction of iron deficiency
– Treatment should be continued for 3-6 months
after correction of the cause of the iron loss
• This corrects the anemia and replenishes iron stores
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Clinical Pharmacology
• Oral iron therapy
• Common adverse effects:
– nausea, epigastric discomfort, abdominal cramps,
constipation, and diarrhea
• Adverse effects can often be overcome by
– lowering the daily dose of iron
– taking the tablets immediately after or with meals
– Changing from one iron salt to another
• Patients taking oral iron develop black stools
– This may obscure the diagnosis of continued
gastrointestinal blood loss
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Clinical Pharmacology
• Parenteral iron therapy
• Parenteral therapy should be reserved for
– patients unable to tolerate or absorb oral iron
– patients with extensive chronic blood loss who
cannot be maintained with oral iron alone:
• advanced chronic renal disease including hemodialysis
and treatment with erythropoietin
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Clinical Pharmacology
Parenteral iron therapy
• Iron-dextran
– deep IM injection or IV infusion
– the IV route is used most commonly
– Adverse effects of IV route:
• headache, light-headedness, fever, arthralgias, nausea
and vomiting, back pain, flushing, urticaria,
bronchospasm, and, rarely, anaphylaxis and death
– a small test dose should always be given before
full IM or IV doses are given
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Clinical Pharmacology
Parenteral iron therapy
• Alternative preparations to iron-dextran: Ironsucrose and iron-gluconate
– Can be given only by IM route
– Less likely than iron dextran to cause
hypersensitivity reactions
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Clinical Toxicity
• ACUTE IRON TOXICITY
– Seen almost exclusively in young children who accidentally
ingest iron tablets
• Even 10 tablets can be lethal in young children
• Adult patients should be instructed to store tablets out of the
reach of children
– Manifestations:
•
•
•
•
•
•
necrotizing gastroenteritis
Vomiting
abdominal pain
bloody diarrhea
Severe metabolic acidosis
Coma and death
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Clinical Toxicity
• ACUTE IRON TOXICITY
– Urgent treatment is necessary
– Whole bowel irrigation should be performed
– Deferoxamine, a potent iron-chelating compound, can
be given systemically to bind iron that has already
been absorbed and to promote its excretion in urine
and feces
– Activated charcoal does not bind iron and thus is
ineffective
– Appropriate supportive therapy for gastrointestinal
bleeding, metabolic acidosis, and shock must also be
provided
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Clinical Toxicity
• CHRONIC IRON TOXICITY
– Also known as iron overload or hemochromatosis
– excess iron is deposited in the heart, liver, pancreas,
and other organs
– It can lead to organ failure and death
– occurs in
• patients with inherited hemochromatosis (a disorder
characterized by excessive iron absorption)
• patients who receive many red cell transfusions over a long
period of time (e.g. patients with thalassemia major)
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Clinical Toxicity
• CHRONIC IRON TOXICITY
– In the absence of anemia is treated by intermittent
phlebotomy
– parenteral deferoxamine is much less efficient
• deferoxamine can be the only option for iron overload in
patients with thalassemia major
– deferasirox (oral iron chelator) has been approved for
treatment of iron overload
• Deferasirox appears to be as effective as deferoxamine at
reducing liver iron concentrations and is much more
convenient
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AGENTS USED IN ANEMIAS:
Vitamin B12
• Vitamin B12 serves as a cofactor for several essential
biochemical reactions in humans
• Deficiency of vitamin B12 leads to
– anemia
– gastrointestinal symptoms
– neurologic abnormalities
• Most common cause of B12 deficiency:
– inadequate absorption of dietary vitamin B12 especially in
older adults
• Active forms of the vitamin in humans:
– Deoxyadenosylcobalamin
– Methylcobalamin
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VITAMIN B12
• Inactive forms of the vitamin:
– Cyanocobalamin (available for therapeutic use)
– Hydroxocobalamin (available for therapeutic use)
– Other cobalamins found in food sources
• The chief dietary source of vitamin B12 :
– Meat, liver, eggs and dairy products
• Vitamin B12 is sometimes called extrinsic
factor to differentiate it from intrinsic factor
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Pharmacokinetics
• Vitamin B12 is avidly stored in the liver
– with an average total storage pool of 3000-5000 mcg (Lasting for 5
years)
• Vitamin B12 is absorbed only after it complexes with intrinsic factor
secreted by the parietal cells of the gastric mucosa
– intrinsic factor-vitamin B12 complex is subsequently absorbed in the
distal ileum
• Vitamin B12 deficiency results from malabsorption of vitamin B12
due to
– lack of intrinsic factor
– loss or malfunction of the specific absorptive mechanism in the distal
ileum
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Pharmacodynamics
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Pharmacodynamics
• Methylcobalamin converts N5methyltetrahydrofolate to tetrahydrofolate
• N5-methyltetrahydrofolate: major dietary and
storage folate
– Tetrahydrofolate: precursor of folate cofactors
• ↓ Vitamin B12 → ↓ Tetrahydrofolate → ↓folate
cofactors → ↓dTMP and purines and DNA in rapidly
dividing cells
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Pharmacodynamics
• Methylfolate trap:
– The accumulation of folate as N5methyltetrahydrofolate and the associated depletion
of tetrahydrofolate cofactors in vitamin B12 deficiency
• Folic acid can be reduced to dihydrofolate and
tetrahydrofolate by the enzyme dihydrofolate
reductase
– this explains why the megaloblastic anemia of vitamin
B12 deficiency can be partially corrected by ingestion
of relatively large amounts of folic acid
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Pharmacodynamics
• Administration of folic acid in the setting of
vitamin B12 deficiency will not prevent
neurologic manifestations
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Clinical Pharmacology
• Vitamin B12 deficiency manifestations:
– megaloblastic anemia (most characteristic clinical
manifestation)
– The neurologic syndrome
• paresthesias, weakness ,ataxia, other central nervous
system dysfunctions
• Correction of vitamin B12 deficiency arrests the
progression of neurologic disease, but it may not fully
reverse neurologic symptoms that have been present
for several months
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Clinical Pharmacology
• Upon diagnosis of megaloblastic anemia:
– it must be determined whether vitamin B12 or folic
acid deficiency is the cause
• This can usually be accomplished by measuring serum
levels of the vitamins
• If vitamin B12 deficiency is the cause,
– The Schilling test, which measures absorption
and urinary excretion of radioactively labeled
vitamin B12, can be used to further define the
mechanism of vitamin B12 malabsorption
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Clinical Pharmacology
• The most common causes of vitamin B12 deficiency:
– partial or total gastrectomy
– conditions that affect the distal ileum
• Pernicious anemia results from defective secretion of
intrinsic factor by the gastric mucosal cells
– The Schilling test shows diminished absorption of
radioactively labeled vitamin B12
– absorption is corrected when intrinsic factor is
administered with radioactive B12
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Clinical Pharmacology
• conditions that distal ileum is damaged:
– inflammatory bowel disease
– Surgical resection of the ilium
• In the above situations, radioactively labeled
vitamin B12 is not absorbed in the Schilling
test, even when intrinsic factor is added
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Clinical Pharmacology
• Treatment of vitamin B12 deficiency
– Parenteral injections of vitamin B12 are required for
therapy
– Vitamin B12 for parenteral injection is available as
cyanocobalamin or hydroxocobalamin
• Hydroxocobalamin is preferred because it is more tightly
protein-bound
– Initial therapy: 100-1000 mcg of vitamin B12 IM daily
or every other day for 1-2 weeks to replenish body
stores
– Maintenance therapy: 100-1000 mcg IM once a
month for life
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AGENTS USED IN ANEMIAS:
FOLIC ACID
• Reduced forms of folic acid are required for
synthesis of amino acids, purines, and DNA
• The consequences of folate deficiency:
– Anemia
– congenital malformations in newborns
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Pharmacokinetics
• The richest sources of folic acid:
– yeast, liver, kidney and green vegetables
• Body stores of folates are relatively low and
daily requirements high
– folic acid deficiency and megaloblastic anemia
can develop within 1-6 months after the intake of
folic acid stops
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Clinical Pharmacology
• Folate deficiency results in a megaloblastic
anemia that is indistinguishable from the
anemia caused by vitamin B12 deficiency
– folate deficiency does not cause the characteristic
neurologic syndrome seen in vitamin B12
deficiency
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Clinical Pharmacology
• Causes of folic acid deficiency
– inadequate dietary intake of folates
– alcohol dependence
– liver diseases (diminished hepatic storage of
folates)
– Pregnancy
• maternal folic acid deficiency may cause fetal neural
tube defects e.g. spina bifida
– hemolytic anemia
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Clinical Pharmacology
• Causes of folic acid deficiency
– renal dialysis (folate loss during dialysis)
– Drugs
• Methotrexate, trimethoprim and pyrimethamine
– Leading to megaloblastic anemia
• Long-term therapy with phenytoin
– Rarely leading to megaloblastic anemia
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Clinical Pharmacology
• Treatment of folic acid deficiency:
– 1 mg/d folic acid orally
• reverses megaloblastic anemia
• restore normal serum folate levels
• replenishes body stores of folates
– Therapy should be continued until the underlying cause of
the deficiency is removed or corrected
• Folic acid supplementation to prevent folic acid
deficiency should be considered in high-risk patients:
– pregnant women, patients with alcohol dependence,
hemolytic anemia, liver disease, or certain skin diseases,
and patients on renal dialysis
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HEMATOPOIETIC GROWTH FACTORS
• Definition:
– glycoprotein hormones that regulate the proliferation
and differentiation of hematopoietic progenitor cells
in the bone marrow
• Including:
– erythropoietin (epoetin alfa)
– granulocyte colony-stimulating factor (G-CSF)
– granulocyte-macrophage colony-stimulating factor
(GM-CSF)
– interleukin-11 (IL-11)
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ERYTHROPOIETIN
• Two recombinant forms:
– Epoetin alfa
– Darbepoetin alfa
• a glycosylated form of erythropoietin
• having a twofold to threefold longer half-life than
epoetin alfa
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Pharmacodynamics
• Endogenous erythropoietin is primarily produced
in the kidney
• In response to tissue hypoxia, more
erythropoietin is produced
– This results in correction of the anemia, provided that
the bone marrow response is not impaired by
• red cell nutritional deficiency (especially iron deficiency)
• primary bone marrow disorders
• bone marrow suppression from drugs or chronic diseases
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Pharmacodynamics
• An inverse relationship exists between the
hematocrit or hemoglobin level and the serum
erythropoietin level
– The most important exception to this inverse
relationship is in the anemia of chronic renal
failure:
• erythropoietin levels are usually low because the
kidneys cannot produce the growth factor
• These are the patients most likely to respond to
treatment with exogenous erythropoietin
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Clinical Pharmacology
• Erythropoietin has a significant positive impact
for patients with anemia of chronic renal failure
– improvements of hematocrit and hemoglobin level
– elimination of the need for transfusions
• 50-150 IU/kg erythropoietin IV or SC three times
a week maintains hematocrit of about 35%
• Failure to respond to erythropoietin is most
commonly due to concurrent iron deficiency
– this can be corrected by giving oral or parenteral iron
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Clinical Pharmacology
• Erythropoietin is used also for:
– anemia produced by zidovudine treatment in
patients with HIV infection
– anemia of prematurity
• Erythropoietin is one of the drugs banned by
the International Olympic Committee
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Clinical Pharmacology
• The most common adverse effects of
erythropoietin:
–
– hypertension and thrombotic complications due
to a rapid increase in hematocrit and hemoglobin
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MYELOID GROWTH FACTORS
• Filgrastim
– Recombinant form of G-CSF
• Sargramostim
– Recombinant form of GM-CSF
• Pegfilgrastim
– A polyethylene glycol (PEG)-formulated filgrastim
– has a much longer serum half-life than filgrastim
– can be injected once per myelosuppressive
chemotherapy cycle instead of daily for several days
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Pharmacodynamics
• G-CSF stimulates proliferation and differentiation
of progenitors already committed to the
neutrophil lineage
– It also activates the phagocytic activity of mature
neutrophils and prolongs their survival in the
circulation
• G-CSF also mobilizes hematopoietic stem cells, ie,
to increase their concentration in peripheral blood
– This biologic effect underlies a major advance in
transplantation:
• the use of peripheral blood stem cells (PBSCs) rather than
bone marrow stem cells for autologous and allogeneic
hematopoietic stem cell transplantation
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Pharmacodynamics
• GM-CSF has broader biologic actions than GCSF
– It is a multipotential hematopoietic growth factor
that stimulates proliferation and differentiation of
granulocytic, erythroid and megakaryocyte
progenitors
• GM-CSF mobilizes peripheral blood stem cells,
but it is significantly less efficacious than GCSF
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Clinical Pharmacology
• CANCER CHEMOTHERAPY-INDUCED
NEUTROPENIA
– G-CSF, GM-CSF and pegfilfrastim accelerate the
rate of neutrophil recovery after dose-intensive
myelosuppressive chemotherapy
• They reduce the risk of serious infections
– Pegfilgrastim can be administered less frequently
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Clinical Pharmacology
• autologous stem cell transplantation
– High-dose chemotherapy with autologous stem
cell support is increasingly used to treat patients
with tumors that are resistant to standard doses
of chemotherapeutic drugs
– The myelosuppression is then counteracted by
reinfusion of the patient's own hematopoietic
stem cells (which are collected prior to
chemotherapy)
– The administration of G-CSF or GM-CSF early after
autologous stem cell transplantation has been
shown to reduce the time to engraftment and to
recovery from neutropenia
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Clinical Pharmacology
• Mobilization of peripheral blood stem cells
(PBSCs)
– Stem cells collected from peripheral blood have
nearly replaced bone marrow
• G-CSF is the cytokine most commonly used for
PBSC mobilization
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Toxicity
• G-CSF is used more frequently than GM-CSF
because it is better tolerated
• G-CSF can cause bone pain, which clears when
the drug is discontinued
• GM-CSF can cause more severe side effects:
– fever, malaise, arthralgias, myalgias, peripheral
edema and pleural or pericardial effusions
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MEGAKARYOCYTE GROWTH FACTORS
• Oprelvekin
– the recombinant form of interleukin-11
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Pharmacodynamics
• Interleukin-11 acts synergistically with other
growth factors to
– stimulate the growth of primitive megakaryocytic
progenitors
– Increase the number of peripheral platelets and
neutrophils
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Clinical Pharmacology
• Interleukin-11 is the first growth factor to gain
FDA approval for treatment of
thrombocytopenia
– Patients with thrombocytopenia have a high risk
of hemorrhage
• It is approved for the secondary prevention of
thrombocytopenia in patients receiving
cytotoxic chemotherapy
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