Haematopoietic agents
& Erythropoeitin
Dr. Babatunde Alabi
Haematopoietic system
• Erythrocytes
• Leukocytes
• Thrombocytes
• Exogenous nutrients
• Endogenous nutrients
Types of anaemia
• Microcytic hypochromic anaemia
• Megaloblastic anaemia
• Pernicious anaemia
• Haemolytic anaemia
• Aplastic anaemia
• Sickle cell anaemia
• Sideroblastic anaemia
Iron deficiency anaemia
• Pallor
• Fatigue
• Dizziness
• Exertional dyspnoea
• Iron deficiency
• Dietary deficiency
Faulty absorption, transport and storage
Excessive blood loss
Worm infestation
• Max iron absorption: duodenum & jejunum
• Haem iron & non haem iron (Fe+++)
• Ascorbic acid, SH, Succinic acid facilitate conversion of Fe+++ to Fe++
form
ANEMIA?
Anemia can be defined as a reduction in the
hemoglobin, hematocrit or red cell number.
In physiologic terms an anemia is any disorder
in which the patient suffers from tissue hypoxia
due to decreased oxygen carrying capacity of
the blood
HEMATINICS
These are drugs used to treat anemia
Iron
Vitamin B12, Cyanocobalamin
Folic acid
Erythropoietin
IRON FACTS
• All body cells need iron. It is crucial for oxygen transport, energy
production, and cellular growth and proliferation.
• The human body contains an average of 3.5 g of iron
(males 4 g, females 3 g).
• The typical daily normal diet contains 10–20 mg of iron.
• Only about 10% of dietary iron is absorbed (1–2 mg/day).
IMPORTANCE OF IRON
Iron forms the nucleus of the iron-porphyrin heme ring,
This with globin chains forms hemoglobin.
Function of Haemoglobin:
Reversibly binds oxygen and provides the critical
Mechanism for oxygen delivery from the lungs to other
tissues.
In the absence of adequate iron, small erythrocytes
With Insufficient hemoglobin are formed, giving rise to
Microcytic hypochromic anemia
IRON ABSORPTION
• Iron is mainly absorbed in the duodenum and upper jejunum.
• A protein called divalent metal transporter 1 (DMT1) facilitates iron
transfer across intestinal epithelial cells.
• Normally, individuals absorb less than 10% of dietary iron, or 1–2 mg per
day balancing the daily loss from desquamation of epithelia.
• Most absorbed iron is used in bone marrow for erythropoiesis.
• Iron homeostasis is closely regulated via intestinal absorption.
• Once iron is absorbed, there is no physiologic mechanism for excretion of
excess iron from the body other than blood loss (i.e., pregnancy,
menstruation or other bleeding.)
IRON TRANSPORT
• Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin.
• Transferrin is a carrier protein that plays a role in regulating the transport of iron from the site of
absorption to virtually all tissues.
• Transferrin binds only two iron atoms.
• Normally, 20–45% of transferrin binding sites are filled (measured as percent transferrin
saturation [TS]).
Iron Transport
IRON USE IN THE BODY
• 75% of absorbed iron is bound to proteins such as hemoglobin that
are involved in oxygen transport.
• About 10% to 20% of absorbed iron goes into a storage pool that is
also recycled in erythropoiesis, so storage and use are balanced.
IRON STORAGE
• Iron is initially stored in ferritin molecules.
• A single ferritin molecule can store up to 4,000 iron
atoms.
• When excess dietary iron is absorbed, the body
responds by producing more ferritin to facilitate iron
storage.
FERRITIN MOLECULES
STORE THOUSANDS OF
IRON ATOMS WITHIN THEIR
MINERAL CORE. WHEN
EXCESS DIETARY IRON IS
ABSORBED, THE BODY
RESPONDS BY PRODUCING
MORE FERRITIN TO
FACILITATE IRON STORAGE.
IRON FORMULATIONS
ORAL:
Ferrous sulfate
Ferrous gluconate
Ferrous fumarate
PARENTERAL:
Iron Dextran
Iron-sucrose complex
Iron sodium gluconate complex
ORAL IRON THERAPY
Treatment with oral iron should be continued for 3–4 months
after correction of the cause of the iron loss. This corrects the
anemia and replenishes iron stores.
Common adverse effects of oral iron therapy include:
• Nausea
• epigastric discomfort
• abdominal cramps
• Constipation
• diarrhea.
These effects are usually dose-related and can often be overcome
by lowering the daily dose of iron or by taking the tablets
immediately after or with meals
PARENTERAL IRON THERAPY
Reserved for patients with documented iron
deficiency who are unable to tolerate or
absorb oral iron.
For patients with extensive chronic blood loss
who cannot be maintained with oral iron alone
• Postgastrectomy conditions
• Previous small bowel resection
• Inflammatory bowel disease
• Malabsorption syndrome
• Iron-dextran: iv or im (50mg/ml)
• Iron sucrose complex: iv or im
• Iron-sodium gluconate: iv or im
• Iron-sorbitol-citrate: only im
Iron dextran:
• A stable complex of ferric hydroxide and low-molecular-
weight Dextran.
• Can be given by deep intramuscular injection or by
intravenous Infusion
• Intravenous administration eliminates the local pain and
tissue staining
• Adverse effects of intravenous iron dextran therapy
include:
Side effects
• Headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain,
flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death.
• Hypersensitivity reactions may be delayed for 48–72 hours after administration.
• Owing to the risk of a hypersensitivity reaction, a small test dose of iron dextran
should always be given before full intramuscular or intravenous doses.
• Iron-sucrose complex and iron sodium gluconate complex are alternative
preparations.
• These agents can be given only by the intravenous route.
• These preparations appear to be much less likely than iron dextran to cause
hypersensitivity reactions
• Body requirement of iron
• Hb has 33% of iron (50 mg in 100 ml of blood)
• Daily requirement
Male: 0.5-1 mg
Female: 1-2 mg
Children: 25 mg
Pharmacokinetics of iron
• Iron absorbs by active transport across intestinal mucosa.
• Converted Fe2+ to Fe3+
• Apoprotein-iron complex (ferritin)
• Release on demand
• Absorption depends on apoprotein to ferritin ratio.
• Transferrin binds with free Fe2+ or Fe3+ from ferritin and carries to bone marrow
• Haemosiderin granules seen with iron overload & gives rise to
haemosiderosis or bronze diabetes.
Treatment of iron deficiency anaemia
• Oral iron therapy: ferrous salts of sulfate, fumerate, gluconate, lactate, succinate
and glycine sulfate etc.
• Ferric salts: ferric ammonium citrate, iron polysaccharide and ferric hydroxide
polymaltose complex.
• Ferrous salts better absorbed than ferric salts.
• Ferrous salts: 100mg provides 20% of elemental iron
• Ferrous fumerate: 33%
• Ferrous sulfate:19%
• Ferrous succinate: 12%
• Adult: 200mg of elemental iron administered in 2-3 divided doses after meal
• Children:3-5mg/kg in 3 divided doses
• 325mg tablets of ferrous sulfate, thrice a day
• Ferrous sulfate: FERSOLATE 200mg tab
• Ferrous fumerate: NORI-A 200mg tab
• Ferrous gluconate:FERRONICUM 300mg tab
• Collodial ferric hydroxide: NEOFERRUM 200 mg tab. 400mg/5ml syrup
Vitamin B12
• Cyanocobalamine
• Hydroxycobalamine
• Methylcobalamine
• 5’ deoxyadenosyl cobalamine
Cobalamine…
• Pharmacokinetics of cobalamine
• Intrinsic factor (IF)
• Transcobalamine-II
• Metabolic functions
• Therapeutic uses
• Daily requirement: 2-3 μg/day
• Therapeutic dose: 100-1000ug/day i.m
Cobalamine…
• Cyanocobalamine
• REDISOL, MACRABIN 100µg, 500µg/day
• Hydroxocobalamine
• REDISOL-H, MACRABIN-H 500µg, 1000µg per vial inj.
• Methylcobalamine
• METHYLCOBAL 500µg tab, NEUROKIND-OD 1500µg tab., 500µg/ml
inj.
Folic acid
• Pteroylglutamic acid
• Pharmacokinetics
• Metabolic functions
• Deficiency
• Therapeutic uses
• Daily requirement: 50µg
• Therapeutic doses: 1-5mg/day
• Folic acid
FOLVITE, FOLITAB 5mg tab
• Folinic acid
RECOVORIN 15 mg tab., 75mg/ml, 10mg/ml inj.
Haematopoietic growth factors
• Erythropoietin: epoietin 100 IU/kg s.c or i.v 3 times a week,
darbepoetin.
• Preparations available
• EPOX, ZYROP,EPREX 2000IU, 4000IU/ml inj.
• Colony stimulating factor (CSF)
• G-CSF & GM-CSF
• Filgrastim & pegfilgrastim 300µg/inj.
• Megakaryocyte growth factors
• Interleukin-11
Vitamins
• Fat soluble vitamins: A, D, E and K
• Water soluble vitamins
B-complex group: B1,B2,B3,B5,B6 and Biotin
Haematopoietic B-complex vitamins
Folic acid and cyanocobalamin
Non B-complex group: Ascorbic acid (vitamin-C)
Ascorbic acid (Vitamin C)
• Dietary sources
• Physiological role
• Deficiency symptoms: Scurvy (defect in collegen formation)
• Prophylactic doses:50-500mg/day
• Therapeutic doses:1-1.5g/day
• As antioxidant:100mg/day
• Haematinic formulations 150mg/day
• Preparations available:CELIN,CHEWCEE,REDOXON 500mg tab
Erythropoietin
• Cytokine produced in juxtatubular cells in the kidney and also in
macrophages.
• Produced by recombinant technology.
• Available as epoeitin α and β.
• 25-100 IU/kg, s.c. or i.v. 3 times a week.
Uses of Erythropoietin
Anaemia due to:
• Chronic renal failure.
• Cancer chemotherapy.
• AIDS.
• Premature infants.
• Blood transfusion
• Adverse effects: flu-like symptoms, mild hypertension, encephalopathy,
occasionally convulsions, risk of thrombosis due to hematocrit rises.
Erythropoietin preparations available
• Erythropoietin, EPOX, ZYROL, EPREX 2000 IU, 4000 IU/ml inj.
Antiplatelet and Anticoagulation Therapy
Antiplatelet Therapy:
Targets
Clopidogrel bisulfate Dipyridamole
Ticlopidine hydrochloride Cilostasol
Prasugrel hydrochloride Phosphodiesterase
Ticagrelor
ADP
ADP
Gp 2b/3a Inhibitors
Collagen
Activation Thrombin
TXA2
COX
TXA2
Aspirin
ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2
Source: Schafer AI. Antiplatelet Therapy. Am J Med 1996;101:199–209
Mechanism
Classes
Antiplatelets Drug (Brand)
Cyclooxygenase-1 Inhibitor Aspirin
ADP Inhibitors/P2Y12 Clopidogrel (Plavix)
Inhibitors Prasugrel (Effient)
Ticagrelor (Brillinta)
Cangrelor (Kengreal)
Phosphodiesterase Inhibitor Dipyridamole/ASA (Aggrenox)
Cilostazol (Pletal)
GP IIb/IIIa Inhibitors Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban (Aggrastat)
Classes
Anticoagulants Drug (Brand)
Heparin Unfractionated heparin
Enoxaparin (Lovenox)
Vitamin K Antagonists Warfarin (Coumadin)
Factor Xa Inhibitors Apixaban (Eliquis)
Rivaroxaban (Xarelto)
Edoxaban (Savaysa)
Fondaparinux (Arixtra)
Direct Thrombin Inhibitors Dabigatran (Pradaxa)
Bivalirudin (Angiomax)
Argatroban
Antiplatelet Anticoagulant
Stroke Stroke prophylaxis
prophylaxis/treatment
Acute coronary syndromes Acute coronary syndromes
Peripheral vascular disease Atrial fibrillation/flutter
DVT (Deep Vein Thrombosis)
prophylaxis/treatment
Pulmonary embolism
Heart valve replacement
Antiplatelet
• ADP Inhibitors/P2Y12 Inhibitors
• Drugs: clopidogrel,
prasugrel, ticagrelor,
cangrelor (IV)
• Clopidogrel most
commonly used
– 15-40% of patients are poor
responders
– Prasugrel not impacted by reduced
CYP enzyme function
Antiplatelet
• Drug specific
contraindications
Medication Contraindications
Prasugrel History of stroke/TIA (Transient
ischemic attack), weight <60
kg, severe renal/hepatic
impairment, age >75
Ticagrelor History of intracranial
hemorrhage, Concurrent use
with aspirin >100mg daily
Anticoagulant
• Heparin
– Unfractionated heparin
– low molecular weight
heparin
• Warfarin
– Monitoring: titrated based on
INR (International Normalized
Ratio)
Anticoagulant
• Factor Xa Inhibitors
• Drugs: apixaban,
rivaroxaban, edoxaban,
fondaparinux (SQ)
• Renal patients: apixaban
preferred
• Administration
– May crush and mix with
apple sauce or water
Anticoagulants
Warfarin vs new oral
anticoagulants
• Advantages
– Reversible
– Mechanical heart valves
• Disadvantages
– Monitoring
– Higher risk of major bleeding
Anticoagulant
• Direct Thrombin Inhibitors
• Drugs: dabigatran, bivalirudin
(IV), argatroban (IV)
• Bridging to warfarin with
bivalirudin or argatroban
– Elevates PT/INR; requires
specific holding instructions and
modified INR goal while bridging
Combination
Therapy
• Dual antiplatelet therapy (DAPT)
– Aspirin + ADP inhibitor
– PCI w/drug eluting stent
• Double vs triple antithrombotic
therapy
– Anticoagulant + aspirin or ADP
inhibitor
– Atrial fibrillation + drug eluting
stent (Aspirin + clopidogrel for 6-12
months followed by aspirin )
Major Contraindications
• Trauma
• Active bleeding
• Intracranial
hemorrhage
• GI bleed
• Bleeding disorders
Monitoring
• Signs/symptoms of bleeding or
bruising
• Hemoglobin
• Platelets
• Drug-specific side effects
• Drug-specific lab tests (i.e.
INR for warfarin)
