Agents Used in Anemias

ANGGELIA.P, MD

PHARMACOLOGY AND THERAPEUTIC DEPT.

FACULTY OF MEDICINE
UNIVERSITY OF JAMBI, INDONESIA

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 1

INTRODUCTION
 Hematopoietic requires a constant supply of three essential nutrients iron,
vitamin B12, and folic acid as well as the presence of hematopoietic growth
factors (erytrropoetin, Myeloid growth factor..etc)
 Erythropoiesis (A)….stem cells through several cell division Hemoglobin
synthesized.
 Erythropoiesis is stimulated by the hormone erythropoietin (a glycoprotein),
 Need Vit B12 and Folic acid for cell multiplication (DNA synthesized)
 Need iron for Hb synthesized
 Anemia reduction in red blood cell count, hemoglobin content, or both. Oxygen
(O2) transport capacity is decreased.

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 2

INTRODUCTION
 Usually presents with pallor, fatigue, dizziness, exertional dyspnea, other sign and
symptom related tissue hypoxia.
 In order to properly treat the anemia, you must determine the cause.
 Cause of anemia:
1.Diminished production and or replacement of red blood cells.
2.Excessive breakdown and loss of red blood cells

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 3

DIMINISHED PRODUCTION AND OR REPLACEMENT OF RED BLOOD
CELLS.

Microcytic anemia – deficiency of Fe

 RBC’s appear pale and smaller, and we see more reticulocytes in
circulation.
 Can be caused by the chronic use of aspirin, which irritates the
stomach GI blood loss.

Normocytic anemia – deficiency of Erythropoietin

 Caused by compromised renal function.

Macrocytic Anemia- deficiency of folic acid and B12

 Diminished cell division and release of larger cells in circulation.

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 4

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 5
EXCESSIVE BREAKDOWN AND LOSS OF RED BLOOD CELLS

 Bleeding: can be due to an ulcer or in females blood loss

due to their menstrual cycle
 Use of drugs that irritate the GI tract (aspirin)
 Hemolysis (Hemolytic Anemia) can be caused by:
 Autoimmune disease
 Mechanical (heart valves, microvascular disease)
 Toxins (e.g., snake venom)

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 6

CYANOCOBALAMIN (VIT.B12)
 Consists of a porphyrin-like ring with a central cobalt atom
attached to a nucleotide.
 Deoxyadenosylcobalamin and methylcobalamin ….active forms
 Liver, meat, fish and milk product…rich sources of Vit B12
 Produced by bacteria in colon but absorp in distal ileum need
intrinsic factor that produced in stomach

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 7

PHARMACOKINETICS VIT B12

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 8

PHARMACOKINETICS VIT B12
 Daily need 2 mcg
 Vit B12 liver storage 3000-5000mcg….5 years to have anemia
megaloblast since daily intake has been stopped.
 Nutritional deficiency ec.lack of dietary intake is rare except strict
vegetarian for many years
 Often disturb in absorption: lack of intrinsic factor (gastritis
atrofi, gastrectomy), resection of ileum or distrub in ileum
function.

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 9

PHARMACODYNAMIC VIT B12 AND FOLIC ACID

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 10

CLINICAL PHARMACOLOGY
 Deficiency: megaloblastic anemia, neurologis deficit (parestesi,
weakness….spasticity, ataxia)
 Correction of Vit B12 def can prevent progression of neurologic deficit.
 Preparation available:
 Oral (cyanocobalamin): 100, 500, 1000, 5000 mcg tablets, 100, 250, 500 mcg
lozenges
 Nasal (Nascobal): 5000 mcg/mL (500 mcg/spray)
 Parenteral (cyanocobalamin): 100, 1000 mcg/mL for IM or SC injection
 Parenteral (hydroxocobalamin): 1000 mcg/mL for IM injection only
Dose: 100-1000 mcg daily for 1-2 weeks and maintenance by 100-1000 mcg a
month (IM)
Orally 1000 mcg/daily

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 11

FOLIC ACID (FA)
 Chemistry…heterocyclic, p-aminobenzoic acid and glutamic acid
 Daily needed 50 mcg, rich source food from leafy vegetables ,
yeast, and liver.
 Heat labile
 FA deficiency: anemia megaloblastic, congenital malformation
and vascular diseases

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 12

PHARMACOKINETIC FOLIC ACID
 Polyglutamine FA in food hydrolyzed to monoglutamin
FA…absorbed in proximal jejunum
 5-20 mg folate are storaged in liver
 Destroyed by catabolism process
 Excreted in urine and stool

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 13

CLINICAL PHARMACOLOGY FA
 Deficiency often caused by lack dietary intake
 Alcohol dependen and liver diseases….poor diet and dimished
liver storage
 Pregnant women and anemia hemolytic…increased daily
required
 Antimetabolite drug…destroy folate metabolism
 1 mg folic acid oraly daily
 Need FA supplementation to prevent FA deficiency…. alcohol
dependence, hemolytic anemia, liver disease, or certain skin
diseases, and patients on renal dialysis.

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 14

IRON
 Iron deficiency is the most common cause of chronic anemia.
 Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin
chains forms hemoglobin.
 Tissue hypoxia (pallor, fatigue, dizziness, exertional dyspnea)……,cardiovascular
adaptations to chronic anemia (tachycardia, increased cardiac output,
vasodilation).
 Free inorganic iron is extremely toxic, but iron is required for essential proteins
such as hemoglobin.
 Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of
the hemoglobin in senescent or damaged erythrocytes….small dietary required
 Special population: growing children, pregnant women, menstruating women

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 15

IRON CYCLE

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 16

IRON ABSORPTION

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 17

IRON PHARMACOKINETICS

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 18

IRON PHARMACOKINETICS
Absorption
 Fe2+ salt and heme Fe….duodenum and proximal jejunum
 The iron in meat protein can be efficiently absorbed than in vegetables or grains (tighly bound
in organic compound)
 Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active
transport of ferrous iron and absorption of iron complexed with heme .
Transport
 Bound to transferin, binds two molecules of ferrous iron.
 The transferrin-iron complex enters maturing erythroid cells by a specific receptor
mechanism…release iron….transferin back to plasma.
 Iron store depletion and iron deficiency anemia are associated with an increased
concentration of serum transferrin.

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 19

IRON PHARMACOKINETICS
Storage
 In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as
ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells .
 When free iron levels are high, more apoferritin is produced to sequester more iron and
protect organs from the toxic effects of excess free iron.
Excretion
 There is no mechanism for excretion of iron.
 Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace
amounts are excreted in bile, urine, and sweat.
 These losses account for no more than 1 mg of iron per day

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 20

THERAPEUTIC USES OF IRON
 Iron Deficient Anemia
 Pregnancy
 Premature Babies
 Blood loss
 Hookworn infestation
 Malabsorption Syndrome
 GI Bleeding due to:
 Ulcers
 Aspirin
 Excess consumption of coffee

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 21

IRON PREPARATION
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
 Alternative preparation Iron sucrose complex or iron gluconate
complex_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

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 22

CLINICAL PHARMACOLOGY
 Treatment with oral iron should be continued for 3–6 months after correction of
the cause of the iron loss
 Common adverse effects of oral iron therapy include nausea, epigastric
discomfort, abdominal cramps, constipation, and diarrhea
 Parenteral therapy should be reserved for patients with documented iron
deficiency who are unable to tolerate or absorb oral iron and for patients with
extensive chronic blood loss who cannot be maintained with oral iron alone.
 Iron toxicity: 1 to 2 grams are sufficient to cause death

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 23

 TREATMENT OF IRON OVERDOSE

Toxic levels
 ALD – 200-300mgkg, plasma iron > 300ug/dl
ABC’s supportive care
Bicarbonate for acidosis
Fluids for blood loss
Ipecac or lavage
Chelation with Deferoxamine

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 24

PAPER 1
Pharmacology of Iron chelating agent
1. Deferoxamine
2. Deferiprone
3. deferasirox

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 25

ERITROPOETIN PATHWAY

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 26

SITE OF ACTION EPO

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 27

THERAPEUTIC USES OF EPO
 Anemia of end stage renal disease
 To treat AIDS anemia caused by AZT’s suppression of bone
marrow
 Anemia related to cancer chemotherapy
 Others
 To increase RBC levels for autologous blood donation
 Anemia associated with rheumatoid arthritis

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 28

PAPER II

Biological ActioN AND PHARMACOLOGY of Other

Hematopoietic Growth Factors

ANGGELIA P, MD; PHARMACOLOGY AND THERAPY DEPT 29

TERIMAKASIH

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