Download Anti-anemia drug

AGENTS USED IN ANEMIA
Agents Used in Anemia
• Anemia ---a deficiency in erythrocytes or hemoglobin.
• Normal value
• Adult male
• Adult famale
RBC(104/μL)
12~16
11~15
Hb(g/dL)
400~550
350~500
Types of anemia
• Iron-deficiency anemia
• megaloblastic anemia
• aplastic anemia
• hemolytic anemia
Agents used in anemias
• Iron
• Vitamin B12
• Folic acid
Iron
• Iron deficiency
• most common nutritional cause of anemia
• result from inadequate iron intake, malabsorption, blood loss, or an
increased requirement, as with pregnancy
The Body Content of Iron
MG/KG OF BODY
WEIGHT
Male
Female
Essential iron
Hemoglobin
Myoglobin and enzymes
31
6
28
5
Storage iron
Total
13
50
4
37
Daily Iron Intake and Absorption
SUBJECT
IRON
REQUIRE
MENT,
mg/kg
Infant
67
Child
22
Adolescent (male)
21
Adolescent
(female)
20
Adult (male)
13
Adult (female)
21
Mid-to-late
pregnancy
80
Iron Cycle
• 5 - 10% of ingested iron is
absorbed
• Once ingested the acid in the
stomach:
• 1. Aids in ionization of
iron
• 2. Splits chelated food
iron from chelator
• 3. Maintains iron in
soluble form
• 4. Allows iron to remain
in the absorbable form
Fe3+
Mechanism of Iron Absorption
Iron Preparations
• Oral Iron
• Ferrous Sulfate (Feosol) – 300 mg tid
• Side Effects are extremely mild:
• Nausea, upper abdominal pain, constipation or diarrhea.
• Cheapest form of Iron and one of the most widely used
• Parenteral
• Iron Dextran (Imferon) – IM or IV
• Indicated for patients who cannot tolerate or absorb oral
iron or where oral iron is insufficient to treat the condition
ie. Malabsorption syndrome, prolonged salicylate therapy,
dialysis patients
Pharmacokinetics:
Absorption: Fe2+
Increase: Vitamin C, amino acid, gastric acid
Decrease:
phosphorus, calcium，Tannic acid, Antacids, H2-receptor blockers,
Proton pump inhibitors, Tetracyclines
• Transfer: transferrin
• Utilization:
transferrin-R on proliferating erythroid cells.
• Storage:
ferritin(Fe3+) in intestinal mucosal cells and in macrophages in the liver,
spleen, and bone.
Pharmacological actions:
• Iron is part of hemoglobin, the oxygen-carrying component of the blood.
Iron-deficient people tire easily because their bodies are starved for
oxygen.
• Iron is also part of myoglobin. Myoglobin helps muscle cells store
oxygen.
Therapeutic uses of Iron
• Iron Deficient Anemia
• Hookworn infestation
• Pregnancy
• Malabsorption Syndrome
• Premature Babies
• GI Bleeding due to:
• Blood loss
• Ulcers
• Aspirin
• Excess consumption of coffee
Oral iron therapy adverse effects
• Nausea
• Epigastric discomfort
• Abdominal cramps
• Constipation
• Diarrhea
Clinical toxicity
• Acute iron toxicity
•
•
•
•
Necrotizing gastroenteritis
Vomiting, abdominal pain, bloody diarrhea
Followed by shock, lethargy, dyspnea
Severe metabolic acidosis, coma, death
• Chronic iron toxicity (hemochromatosis)
• Deposit of iron in the heart, liver, pancreas
• Can lead to organ failure and death
Toxicity of Iron Overdose
• 5000 deaths/year in the US, usually in children
• 20% of children presenting with iron toxicity will die
• 1 to 2 grams are sufficient to cause death
• At high doses, Iron is absorbed through passive
diffusion with no regulation
Treatment of Iron Overdose
• Toxic levels
•
ALD – 200-300mgkg, plasma iron > 300ug/dl
• Bicarbonate for acidosis
• Fluids for blood loss
• Ipecac or lavage
• Chelation with Deferoxamine
Folate deficiency
• Nutritional
• Malabsorption
• Drug related – impaired absorption (eg. Anticonvulsants) folate
antagonists (eg. methotrexate)
• Increased Folate Requirements
Folic Acid
• Folic acid (pteroylglutamic acid) is composed of a
heterocycle (pteridine), p-aminobenzoic acid, and
glutamic acid.
• Folic acid is required for the synthesis of amino
acids, purines, and DNA.
• Megaloblastic anemia of folate deficiency is
microscopically indistinguishable from B12
deficiency.
• Folate deficiency does not cause neuropathy.
The structure and numbering of atoms of folic acid .
•Folic acid
• Process in body
FA → FH2 → FH4 → 5-CH3-FH4
• Machinism: One carbon unit carrier
• Reduction of folic acid →
↓dTMP →↓ DNA→megaloblastic anemia
↓amino acid biosynthesis
Folate metabolism. Folate is essential for the de novo synthesis of
purines, deoxythymidylate monophosphate (dTMP), and
methionine, serving as an intermediate carrier of1-carbon
fragments used in the biosynthesis of these compounds. Its active
form is tetrahydrofolate (THF). THF acquires the 1-carbon fragment
principally from serine, which is converted to glycine in the course
of the reaction. For purine synthesis, the 1-carbon fragment is first
oxidized to the level of formic acid, then transferred to substrate.
For methionine synthesis, a cobalamin-requiring reaction, the 1carbon fragment is first reduced to the level of a methyl group,
then transferred to
homocysteine. In these reactions the cofactor is released as THF,
which can immediately participate in another 1-carbon transfer
cycle. During the production of dTMP from dUMP, however, the 1carbon fragment is reduced from formaldehyde to a methyl group
in the course of the transfer reaction. The hydrogen atoms used for
this reduction come from the cofactor, which is therefore released,
not as THF, but as dihydrofolate (DHF). To participate further in the
1-carbon transfer cycle, the DHF has to be re-reduced to THF, a
reaction catalyzed by dihydrofolate reductase.
Enzymatic reactions that use folate
Pharmacokinetics
•Only 5-20 mg of folates are stored in the
liver.
•Folates elimination is high, so serum levels
fall within a few days when intake is
diminished.
•Megaloblastic anemia can develop within
1-6 months after the intake of folic acid
stops.
Folic acid: Clinical pharmacology
• Deficiency
• result in megaloblastic anemia
• Often caused by inadequate dietary intake
• Pregnant woman has increased folate requirement
• A dose of 1 mg is sufficient
Clinical Pharmacology
• Folic acid deficiency is seen in:
• Alcohol dependence and liver disease (poor diet and diminished hepatic storage)
• Pregnancy and hemolytic anemia (increased folate requirement)
• Malabsorption syndromes
• Renal dialysis (dialysis removes folates)
• Some drug ingestion: methotrexate, trimethoprim and pyrimethamine (inhibit
dihydrofolate reductase)
Therapeutic Uses of Folic Acid
• 1. Megaloblastic Anemia due to inadequate dietary
intake of folic acid
• Can be due to chronic alcoholism, pregnancy, infancy, impaired
utilization: uremia, cancer or hepatic disease.
• 2. To alleviate anemia that is associated with
dihydrofolate reductase inhibitors.
• i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine
(Antimalarial)
• Administration of citrovorum factor (methylated folic acid)
alleviates the anemia.
Therapeutic Uses of Folic Acid (cont)
• 3. Ingestion of drugs that interfere with intestinal
absorption and storage of folic acid.
• Mechanism- inhibition of the conjugases that break off folic acid
from its food chelators.
• Ex. – phenytoin, progestin/estrogens (oral contraceptives)
• 4. Malabsorption – Sprue, Celiac disease, partial
gastrectomy.
• 5. Rheumatoid arthritis – increased folic acid demand or
utilization.
B12 Deficiency
• A B12 deficiency will cause peripheral neuropathy
and a macrocytic anemia, a pernicious anemia.
• Folic Acid administration can correct the macrocytic
anemia but will fail to correct the peripheral
neuropathy.
• To treat the neuropathy, Vit B12 must be utilized.
Vitamin B12
Vitamin B12
• Vitamin B12 deficiency causes:
• Megaloblastic anemia, thrombocytopenia and/or leukopenia
• GI and neurologic abnormalities.
• Deficiency of B12 in older adults due to inadequate
absorption is a common and easily treated disorder.
• Deoxyadenosylcobalamin and methylcobalamin are the
active forms of the B12 in humans.
• Cyanocobalamin and hydroxocobalamin (available for
therapeutic use) are converted to the active forms.
Vitamin B12
•The dietary source of vitamin B12 is meat
(especially liver), egg, and dairy
products.
•The ultimate source of B12 is microbial
synthesis; B12 is not synthesized by
animals or plants.
•Vitamin B12 is also called extrinsic factor.
Pharmacokinetics
• B12 is stored in the liver with a storage pool of 30005000 mcg.
• Daily requirements are 2 mcg, it would take 5 years
for megaloblastic anemia to develop.
• B12 is absorbed only in complex with intrinsic factor
(IF) secreted by the parietal cells of the stomach.
• The IF-B12 complex is absorbed in the distal ileum.
• It is transported in the blood by transcobalamin II.
The assimilation of cobalamin. On entering the
stomach, dietary cobalamin (Cbl) forms a complex
with R binding protein. As this protein is digested in
the small intestine, cobalamin is transferred to
intrinsic factor (IF). This complex passes through
the intestine until it reaches specific receptors on
the mucosa of the distal ileum. The internalized Cbl
is then transferred to transcobalamin II (TC II),
which circulates in the plasma until it binds to
receptors on cells throughout the body and is
internalized.
Relation to Folic Acid
•Methylfolate trap is the biochemical step
whereby B12 and folic acid are linked.
•That is why the anemia of B12 deficiency can
be partially corrected by folic acid.
•Folic acid will not prevent neuropathies of
B12 deficiency.
Enzymatic reactions that use folates. Section 1 shows the vitamin B-12
dependent reaction that allows most dietary folates to enter the
tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin
B 12deficiency. Section 2 shows the dTMP cycle. Section 3 shows the
pathway by which folic acid enters the tetrahydrofolate cofactor pool.
Double arrows indicate pathways with more than one intermediate step
Enzymatic reactions that use vitamin B .12
Mechanism for Peripheral
Neuropathy
• Cobalamin is a cofactor for the enzyme
Methylmalonyl-CoA mutase which converts
methylmalonyl-CoA to succinyl-CoA.
• Succinyl-CoA enters the Krebs cycles and goes into
nerves to make myelin.
• If no Vitamin B12, methylmalonyl-CoA goes on to
form abnormal fatty acids and causes subacute
degeneration of the nerves. Only B12 can correct
this problem.
Clinical Pharmacology
• The most common causes of vitamin B12 deficiency
are:
• Pernicious anemia
• Partial or total gastrectomy
• Abnormality in the distal ileum (malabsorption
syndromes, IBD, small bowel resection).
• Pernicious anemia results from defective secretion
of intrinsic factor.
• Patients have gastric atrophy and fail to secrete
intrinsic factor and hydrochloric acid.
Vitamin B12: clinical pharmacology
• Treat or prevent deficiency
• Megaloblastic anemia
• Neurologic syndrome
• Degeneration of myelin sheaths
• Disruption of axons in the dorsal and lateral horns of spinal cord and in peripheral
nerves
Clinical uses:
1. Megaloblastic anemia
2 .Pernicious anemia
3 .Nervous system diseases
4. Hepatopathy
Hematopoietic growth factors
Erythropoietin (EPO)
Granulocyte colony-stimulating
factor (G-CSF)
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)
Erythropoietin (EPO)
source: produced by the kidney in response to tissue hypoxia.
Pharmacological effects:
• stimulates erythroid proliferation and differentiation
• Stimulates maturation of red blood cell
• also induces release of reticulocytes from the bone marrow
Clinical uses:
• patients with chronic renal failure
• patients with aplastic anemia
• anemias associated with chronic inflammation, AIDS, and cancer
Adverse reaction:
• a rapid increase in hemoglobin
• hypertension and thrombotic complications.
Granulocyte colony-stimulating
factor (G-CSF)
Pharmacological effects:
• stimulates proliferation and differentiation of progenitors to
neutrophils
• Increase release of neutrophils from bone marrow
• activates the phagocytic activity of mature neutrophils and prolongs
their survival in the circulation.
Clinical uses: neutropenia
Granulocyte-macrophage colonyfactor (GM-CSF)
stimulating
Pharmacological effects:
• stimulates proliferation and differentiation of early
and late granulocytic progenitor cells as well as
erythroid and megakaryocyte progenitors
• stimulates the function of mature neutrophils
• Clinical uses: neutropenia
• Adverse reaction: fevers, malaise, arthralgias, myalgias,
peripheral edema and pleural or pericardial effusions,
allergic reactions
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-PHARMA STREET