Blood Pharmacology

Sagni Hanbisa (MSc in Pharmacology)

Department of Pharmacy
Wollega University

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 Outlines
• Agents Used in Anemia
• Anticoagulants
• Antiplatelet drugs
• Fibrinolytic drugs

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 Anemia
&
Antianemic Agents

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• Anemia:- is deficiency in the oxygen-carrying
capacity of the blood due to a diminished
erythrocyte mass, size or Hg content.
• Because the main function of RBCs is
oxygenation, anemia results in varying degrees of
hypoxia

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 Causes for Anemia
1. Blood loss
 Chronic-GI bleeding-ulcer and menstrual bleeding
 Acute-GI bleeding
2. Bone marrow dysfunction
 Low erythropoietin production- due to kidney
disease, causes normochromic anemia -[causes
normocytic/aplastic anemia]
 Decreased marrow response to erythropoietin
3. Deficiencies of substances essential for RBC formation
& maturation
 Iron[microcytic anemia], Vit. B12, or folic acid[both
macrocytic anemia]
4. Increased erythrocyte destruction (hemolytic anemia)
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Clinical Manifestations of anemia:
1. Pallor.
2. Fatigue, weakness.
3. Dyspnea.
4. Palpitations, tachycardia.
5. Headache, dizziness, and restlessness.
6. Slowing of thought.
7. Paresthesia.

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Hematocyte differentiation

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 Red Blood Cell Development
– Begin developing in bone marrow
– Mature in blood
 Four stages
1. Proerythroblasts
– Lack hemoglobin
2. Erythroblasts
– Gain hemoglobin
– Both stages reside in bone marrow.
3. Reticulocytes
– Immature erythrocytes
– Enter the systemic circulation.
4. Erythrocytes Sagni H 9
Stages of red blood cell
development

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 Stem cell Committed
cell Developmental pathway
Phase 1 Phase 2 Phase 3
Ribosome Hemoglobin Ejection of
synthesis accumulation nucleus

Proerythro- Early Late Reticulo-Erythro-

Hemocytoblast blast erythroblasterythroblast Normoblast cyte cyte

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• Development of RBCs requires the
cooperative interaction of several factors:
1. Bone marrow
2. Erythropoietin, a stimulant of RBC maturation
3. Iron for hemoglobin synthesis
4. Vitamin B12 & folic acid to support synthesis of
DNA
• If any of these is absent or amiss→ anemia

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Types of anemia
• Iron-deficiency anemia

• megaloblastic anemia (deficiency of Vit. B12

and folic acid)
• aplastic anemia

• hemolytic anemia
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 1. Iron Deficiency Anemia
– most common nutritional deficiency cause of
anemia.

• When severe, it results in a characteristic

microcytic, hypochromic anemia.

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Sagni H 15
 Fates of iron
1. Metabolic Functions
– For hemoglobin synthesis(70-80%)
– For myoglobin & iron-containing enzymes (10%)
2. Uptake & Distribution
 Uptake by mucosal cells of small intestine
 Ferrous form of iron is more absorbed than its ferric
form
 After uptake, iron may be
 Stored in the form of ferritin in mucosal cells or
 Bound to transferrin for distribution throughout
body
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3. Utilization & Storage
 Transferrin bound iron, taken up by:
a. Cells of bone marrow for incorporation into Hg
b. Liver & other tissues for storage as ferritin
c. Muscle for production of myoglobin
d. All tissues for production of iron-containing
enzymes
4. Recycling
 Iron associated with Hg undergoes continuous
recycling.
 Re-enters circulation
 After catabolism of RBC (after 120 days)
 The life span of RBC = 120 days
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5. Elimination
 Normal physiologic loss is only very
limited amount (~ 1 gm/day)
 A significant iron loss via blood loss:
 Menorrhagia, hemorrhage & blood
donations
6. Regulation of Body Iron Content is via
 Control of intestinal absorption
 Excessive buildup is prevented through
control of iron uptake

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Iron cycle

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 Daily Requirements of iron
– Determined by the rate of erythrocyte
production
– High in infants and children (due to their
rapid growth), pregnancy (blood volume
expansion)
– adult males need 10 mg of dietary iron each
day but more for females
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Causes of iron deficiency

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• Consequences of iron deficiency
– Anemia
– RBCs become microcytic (small) & hypochromic
(pale)
– Listlessness, fatigue & pallor of skin & mucous
membrane
– Tachycardia, dyspnea & angina

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 Oral iron preparations
 Oral iron
1. Iron salts
 Ferrous sulfate
 Ferrous gluconate
 Ferrous fumarate
• treatment of choice for iron deficiency.
• Used for prevention & treatment of iron
deficiency anemia (pregnancy & chronic blood
loss)
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Pharmacokinetics:

Absorption: Fe2+ (ferrous iron)

Increased by: Vitamin C, amino acid,
gastric acid
Decreased by: phosphorus, calcium,
Tannic acid, Antacids, H2-receptor blockers,
Proton pump inhibitors, Tetracyclines

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 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.

• As a cofactor in iron-containing enzymes

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 Clinical uses:

• For treatment or prevention of iron

deficiency anemia
1) chronic blood loss in heavy menstrution or
hemorrhoid

2) insufficient intake during periods of accelerated

growth in children, or in pregnant women.

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 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
– Staining of teeth, dark green or black stool
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 Management of toxicity-
 gastric lavage: phosphate or carbonate to
flush out unabsorbed pill
 Deferoxamine (parentral) and deferasirox
(oral): potent iron chelating compounds.
 To chelate already absorbed iron

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 Drug interactions
– Antacids (raise PH, and can oxidize Fe2+ to Fe3+)
• dec. absorption
– Tetracyclines (inhibit by forming anabsorbable
chelate)
• dec. absorption
– Ascorbic acid, vit. C- (reduces ferric to ferrous
iron)
• inc. absorption
– Foods (meat facilitate Fe absorption by inc gastric
acid secretion)
• inc. absorption
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 Parenteral Iron
1. Iron dextran
– For clear diagnosis of iron deficiency anemia
– Used when oral iron is non-effective or non-
tolerable
– With intestinal diseases, severe blood loss.

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• Adverse effects
– Fatal anaphylactic rxn
– Hypotension
– Circulatory failure
– Cardiac arrest
2. Iron sucrose &
3. Sodium–ferric gluconate complex
– For iron deficiency anemia in patients with chronic
kidney disease (CKD)
– Less risk of anaphylactic rxn

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Cobalamin (Vitamin B12) Deficiency
• Cobalamin Deficiency--formerly known as pernicious
anemia (deficiency of Intrinsic factor)

• Vitamin B12 (cobalamin) is an important water-soluble

vitamin.

– Vitamin B12 : a group of cpds with similar structures

– Known as cobalamins- because of cobalt atom

• Intrinsic factor (IF) is required for cobalamin absorption

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Relationship of folic acid and vitamin
B12 to DNA synthesis and cell
maturation

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• Metabolic function
– For DNA synthesis (growth & division of cells)
• Absorption
– Requires intrinsic factors (IF), secreted by gastric
parietal cells
• Binds to transcobalamin II to transport to
tissues
– Stored in liver
• Elimination
– Very slow excretion
• Dietary sources
– found only in foods of animal origin: meat, liver
and dairy products.
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• Causes of cobalamin deficiency
– Gastric mucosa not secreting IF

– GI surgery loss of IF-secreting gastric mucosal

cells

– Long-term use of H2-histamine receptor blockers

cause atrophy or loss of gastric mucosa.
– Nutritional deficiency (in strict vegitarians)

– Hereditary defects of cobalamine utilization

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Clinical manifestations of cobalamin deficiency
– General symptoms of anemia
– Disruption of DNA synthesis
 Affect bone marrow, epithelial cells of mouth & GIT
– Megaloblastic anemia
 Megaloblastic-Oversized erythroblasts
 Macrocytic- Oversized erythrocytes
– Neurologic Damage
 Neurological demyelination
 Paresthesias, loss of memory, mood changes,
hallucinations, and psychosis
– Infection and spontaneous bleeding
 Loss of leukocytes and thrombocytes
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 Cobalamin Deficiency
Diagnostic Studies
• RBCs appear large
• Abnormal shapes
– Structure contributes to erythrocyte destruction
• Schilling Test: a medical investigation used for
patients with vitamin B12 deficiency. The
purpose of the test is to determine if the patient
has pernicious anemia.

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 Vitamin B12 Preparations
 Cyanocobalamin
 Hydroxycobalamin
– A purified, crystalline form of vitamin B12
• Adverse effects
– Hypokalemia
• Given by:
– Orally
– Intranasally
– Parenterally- IM or SC

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 Folic Acid Deficiency Anemia
• Folic acid deficiency also causes megablastic
anemia (RBCs that are large and fewer in
number)
• Folic Acid required for RBC formation and
maturation
• Causes
– Poor dietary intake
– Malabsorption syndromes
– Drugs that inhibit absorption
– Alcohol abuse
– Hemodialysis
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• Metabolic function
– For DNA synthesis
– Dietary folic acid converted into active form in
presence of vit B12
– But at large amounts, activated via alternative
pathway
• Absorbed at small intestine
– Transported in to liver & other tissues for storage
– Undergoes extensive enterohepatic recirculation
– Significant excretion

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• Consequences of folic acid deficiency
1. Identical to that of vitamin B12 deficiency except
in CNS (in all people)
 Megaloblastic anemia
 Leukopenia
 Thrombocytopenia
 Injury to the oral and GI mucosa
2. Neural tube defects- spina bifida, anencephaly-
developing fetus
• Diagnosis
– Megaloplastic anemia
– Low folate levels in plasma
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• Encourage patient to eat foods with large
amounts of folic acid
• Leafy green vegetables
• Liver
• Mushrooms
• Oatmeal
• Peanut butter
• Red beans

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 Folic acid preparations
1. Folic Acid (Pteroylglutamic Acid)
– Inactive form
– Most commonly used
 Indications
1. Folic acid deficiency megaloplastic anemia
2. Prophylaxis of folate deficiency- in
pregnancy, lactation
• Given by:
– Orally
– Injection- IV, IM, SC
2. Leucovorin Calcium (Folinic Acid)
– Uncommonly used
– Active form
– Used as adjuvantSagni
in Hcancer chemotherapy 43
 Vitamin B12 Folate Deficiency
Deficiency
Cause Malabsorption from Low dietary source
lack of intrinsic factor

Hematologic Megaloblastic anemia Megaloblastic anemia

effects
Neurologic Damage to CNS Neural tube defects in
effect fetus
Diagnosis Low plasma level, low Low plasma level
absorption

Treatment Cyanocobalamin (IM) Folic acid (PO)

Duration of Lifelong Short term

therapy Sagni H 44
 Folate and Vitamin B12 Interaction
• Tetrahydrofolate is necessary for DNA synthesis
• Cobalamin and folate are cofactors for
tetrahydrofolate production
• Deficiency of either impairs cell division in the
bone marrow while RNA and protein synthesis
continues – enlarged erythrocytes
• Cobalamin deficiency – impairs synthesis of S-
adenosylmethionine – necessary for proper
nervous system functioning

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 Hemolytic Anemia
• Destruction or hemolysis of RBCs at a rate that exceeds
production
• Third major cause of anemia
Causes
1. Autoimmune disease
- IgG antibody binds to erythrocyte surface
2. In patients with G6PD deficiency
– Oxidative stress from drugs, infections or toxins
3. Infections
– Malaria, Babesiosis, Sepsis
4. Mechanical (artificial heart valves, microvascular
disease)
5. Toxins- snake venom, insect
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bites 46
 Aplastic Anemia
• Characterized by Pancytopenia, i.e.
– ↓ of all blood cell types
• RBCs
• White blood cells (WBCs)
• Platelets
• caused by a failure of the bone marrow to
produce stem cells, the initial form of all
blood cells.

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• Etiology
– Congenital
• Chromosomal alterations

– Acquired
• Results from exposure to ionizing radiation,
chemical agents, viral and bacterial infections

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 Aplastic Anemia
• Clinical Manifestations
– General manifestations of anemia
• Fatigue
• Dyspnea
• Pale skin
• Frequent or prolonged infections
• Nosebleed and bleeding gums
• Prolonged bleeding from cuts
• Dizziness
• headache

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 Aplastic Anemia
• Treatment
– Identifying cause
– Blood transfusions
– Antibiotics
– Immunosuppressants
• Corticosteroids
– Bone marrow stimulants
• Filgrastim (Neupogen)
• Epoetin alfa (Epogen, Procrit)
– Bone marrow transplantation

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 Erythropoietin (Epotein)
• A glycoprotein hormone
• Produced:
 90% by peritubular cells in kidney
 Remainder by liver and other tissues
• Is essential for normal reticulocyte production
• Synthesis is stimulated by hypoxia/anemia
• Synthesized for clinical use
 By recombinant DNA technology

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Erythropoietin action

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 Clinical Uses of epotein

1. Anemia associated with chronic renal failure

2. HIV-infected patients taking Zidovudine
3. Cancer chemotherapy-induced anemia
4. Anemia in Patients Facing Surgery

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 Pharmacokinetics
• Route of administration --- S.C. or I.V.
• Plasma t1/2 ---- 4 - 13 hrs in patients with chronic renal
failure
• Not cleared by dialysis
 Mechanism of action
• Increases rate of stem cell differentiation
• Increases rate of mitosis in red cell precursors, blast-
forming units, colony forming cells. increases release of
reticulocyte from marrow
• Increases Hb synthesis
• Its action requires adequate stores of iron

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 Adverse effects
• Hypertension
• Cardiovascular Events (Hg ˃12 g/dl)
• Cardiac arrest
• Hypertension
• HF
• Thrombotic events- stroke and MI
• Autoimmune pure red-cell aplasia
• Severe anemia
• Can cause a complete absence of erythrocyte
precursor cells in bone marrow
• Due to production of neutralizing
antibodies

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 Anticoagulant,
Antiplatelet
&
Thrombolytic Drugs

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 Introduction
• The endothelial lining is non-
thrombogenic
• Balance between
– Procoagulants (thromboxane, thrombin,
activated platelets, platelet factor 4) and
– anticoagulants (heparan sulfate,
prostacyclin, nitric oxide, antithrombin)
determine blood fluidity
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 Introduction…
Physiology of Coagulation
• Hemostasis is the physiologic process of
cessation of blood loss from a damaged vessel.
• Blood clotting has four phases:
1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Fibrinolytic phase

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 1. Vascular phase
– Manifested by vasoconstriction of damaged blood
vessels.
• Reduce blood loss by decreasing blood flow.

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2. Platelet phase
– Injury exposes reactive subendothelial matrix
proteins: collagen
– Platelets adhere to it & activated
– Platelets, then, secrete and synthesize
vasoconstrictors and platelet recruiting and
activating molecules
– Activation of platelets also activates their surface
receptors (glycoprotein IIb/IIIa),
• enabling it to bind to fibrinogen, w/c cross
links adjacent platelets,
– resulting in aggregation and formation of a
platelet plug
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 Platelets
activation
processes involve
three steps:
1.adhesion to the
site of injury
2.release of
intracellular
granules:
3.aggregation of
the platelets.

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• Glycoprotein IIb/IIIa receptor
stimulated by:
1. Thromboxane A2 (TXA2)
2. Thrombin
3. Collagen
4. Platelet activation factor, PAF
5. ADP
• After activation, binds with
fibrinogen
– Causes aggregation to form Platelet
plug
• stops bleeding

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3. Coagulation phase
– Transforms soluble fibrinogen to insoluble fibrin
» A thread-like protein that reinforces platelet plug
– Produced by two major pathways:
1. Contact activation (intrinsic) pathway
2. Tissue factor (extrinsic) pathway
 Both converge at a common point (at factor Xa)
 Clotting factors:
 Their biosynthesis is dependent on Vitamin K
 Most are proteases
 Normally inactive (zymogens) & sequentially activated

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Outline of coagulation pathways showing factors affected by
warfarin and heparin

Tissue
Injury

Surface
Contact

II II
a
Fibrin polymer

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Hemostasi
s: injury
1. Vessel

2. Vascular spasm

3. Platelet plug formation

4. Coagulation
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 Hemostasis
(+ feedback)

Clotting
thromboplastin
Factors
Prothrom Thromb
bin in

Fibrinoge Fibrin
n Traps RBC & platelets

Sagni H Platelets release thromboplastin 67

Blood
Clot
RBC

Platelet

Fibrin thread

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4. Fibrinolytic phase
• Here unwanted fibrin thrombi are removed, while
fibrin in wounds persists to maintain hemostasis.
1. Inactivation of the clotting factor
» By antithrombin (antithrombin III)
• A protein that forms a complex
with clotting factors & inhibits
their activity
2. Degradation of clots
» By activation of endogenous
protease, plasmin
» Plasminogen (inactive) converted
to plasmin (active form) by tissue
plasminogen activator

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 Pathophysiology of coagulation
• Thrombosis
– the formation of an unwanted clot within the
blood vessels or heart
– Pathologic functioning of hemostatic mechanisms
• Arterial thrombosis (white thrombi)
– Occur at sites of high flow rate
– Adhesion of platelets to arterial wall
» due to wall damage or atherosclerotic
plaque rupture
– Platelets release ADP and TXA2
» Arterial occlusion
» Initiation of coagulation cascade
» Reinforcement with fibrin
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• Venous thrombosis (red thrombi)
– Occur at sites of slow blood flow
» Blood stagnation
» Coagulation cascades activation
» Fibrin production
» RBCs & platelets form thrombus
» thrombi can Break off travel as
embolus
» embolus blocks distant blood
vessels
 Pulmonary
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 Drugs for thromboembolic disorders
1. Anticoagulants
– Disrupt coagulation cascade
– Suppress production of fibrin
– Most effective against venous thrombosis
– Heparin, warfarin
2. Antiplatelet drugs
– Inhibit platelet aggregation
– Most effective at preventing arterial thrombosis
– Aspirin, clopidogrel
3. Thrombolytic drugs
– Promote lysis of fibrin
– Cause dissolution of thrombi
– Alteplase, streptokinase
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 1 anticoagulants
• Anticoagulants are drugs employed in preventing
blood coagulation.
• They inhibit certain clotting factors in the liver.
• The function of them is to:
– Inhibit the synthesis of clotting factors
» Vitamin K antagonists
– Inhibit the activity of clotting factors
» E.g. Xa, thrombin, etc

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Classification of anticoagulants
Ⅰ.Anticoagulants both in vivo and vitro:

e.g. Heparin and its derivatives

Ⅱ.Anticoagulants in vivo: dicoumarol (e.g

warfarin)

Ⅲ .Anticoagulants in vitro: Sodium citrate,

EDTA (ethylenediamine teraacetic acid)
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A. Anticoagulants - Heparin
• Enhance the activity of antithrombin
» accelerate inactivation of clotting
factors: IIa, IXa, Xa, XIa, XIIa.
» Reduction of fibrin production
• Unfractionated Heparin
» Rapid-acting
» Given via injection
• Sources
» From mammalian tissues
» Lungs of cattle and intestines of
pigs

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 Anticoagulants - Heparin
• Chemistry
– Not a single molecule
– A mixture of long polysaccharide chains [mucopoly-saccharide]
– Highly polar- many negatively charged groups
– Anticoagulant of choice for pregnant women
– Avg mol. wt - >12,000 daltons

 Heparin is negatively charged

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• 1. Anticoagulative effect

Mechanism: accelerate inactivation of clotting

factors.(IIa, IXa, Xa, XIa, XIIa ) by enhancing the
anticoagulative activity of ATⅢ ( antithrombin Ⅲ ).
– Suppresses the fibrin formation

– Prophylaxis of venous thrombosis

– Quick anticoagulant effects (minutes)

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ATⅢ: a plasma protease inhibitor

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Mechanism of heparin
• This reaction happens
in normal
physiological state,
but it’s very slow and
weak.
• In the presence of
heparin (which acts as
a catalyst), it will be
accelerated by more
than 1,000 times
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 Characteristics of anticoagulative effect

• effective both in vivo and in vitro

• quick onset and potent effects
• efficacy positively relative to molecular weight

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• Pharmacokinetics
– Orally inactive- b/c of degradation in GI & its
high polarity (negatively charged)
– Via injection- IV/SC
– Shows variability in plasma levels
– Has brief duration of action
– Undergoes liver metabolism- by heparinase

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Clinical uses
1) thromboembolic disease:
deep venous thrombosis(DVT),
pulmonary embolism, unstable angina,
acute myocardial infarction, cerebral infarction
2) DIC (Disseminated intravascular coagulation):
early stage
3) extracorporal circulation
(eg. dialysis machine)
Note: Used during pregnancy-highly polar, not pass
through placenta-safe

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 Adverse reactions
• Spontaneous hemorrhage :
– antidot: protamine sulfate (a basic protein)
• 1 mg of protamine sulfate for every 100 U of
heparin

– Protamine sulfate interacts with platelets,

fibrinogen, and other clotting factors - an
anticoagulant effect – at higher doses

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 Adverse reactions …
• Heparin-induced thrombocytopenia:
– a decrease in circulating platelets
– Antibodies against complexes of heparin with
platelet
– Lower incidence with low mol wt heparin
– Can be life-threatening
• Stop heparin immediately
• Others : allergic reaction
osteoporosis
Thus, needs monitoring
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• Drug interactions
– Aspirin
 Heparin overdose
– Protamine sulfate

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 Low Molecular Weight Heparins
(LMWHs)
• Avg mol. wt 4,500 daltons - containing 15
monosaccharide units
• Weaker effect than heparin
 Better absorbed - higher bioavailability
 Longer biological half-life
 More predictable dose-response - does not bind
to plasma proteins, macrophages, or endothelial
cells
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 LMWHs…
 Can be given s.c. without lab monitoring in an
outpatient setting
 No need to monitor generally

 Cleared unchanged by kidney (do not use in

renal failure!) rather than by the
reticuloendothelial system
 Lower risks of thrombocytopenia and bleeding
 Safety and use during pregnancy not evaluated

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 MOA
 Preferentially inactivates factor Xa

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 LMW heparins
 Dalteparin, Enoxaparin, Tinzaparin

Uses:
1. prevention of venous thromboembolism
2.Treatment of venous thrombosis, pulmonary
embolism and unstable angina
3. prophylaxis following total knee arthroplasty

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 circulates in the plasma -
Heparin & LMW Heparins rapidly inhibits thrombin
difference in action only in the presence of
heparin
Heparin
~ 45 saccaharide units
MW ~ 13,500
This reaction goes
1000 to 3000 times
faster with heparin.

Antithrombin
inhibits thrombin,
Xa, IXa and to a
lesser extent VIIa

Low Mol. Wt.

Heparin
~ 15 saccaharide
units
MW ~ 4,500
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 Other parenteral anticoagulants
Danaparoid (ORGARAN)
• nonheparin glycosaminoglycans (84% heparan
sulfate)
 Promotes inhibition of Xa by antithrombin
 Prophylaxis of deep vein thrombosis
 In patients with heparin-induced
thrombocytopenia

Lepirudin (REFLUDAN)
 recombinant derivative of hirudin (a direct thrombin
inhibitor in leech)
 In patients with heparin-induced thrombocytopenia
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 Coumarin derivatives
Oral anticoagulants
• Warfarin and Dicoumarin
• These agents are often referred to as oral
anticoagulants
– because they are administered orally, which exists
as the main difference from heparin.
• Small & lipid-soluble molecules
• Structurally related to vitamin K
– vitamin K antagonists
• Isolated from clover leave
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• MOA
• Oral anticoagulants antagonize VitK →inhibiting
the synthesis of Vitamin K–dependent clotting
factors:Ⅱ,Ⅶ,Ⅸ,Ⅹ
» Inhibits vitamin K–epoxide reductase
• →inhibiting coagulation

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 Oral anticoagulants
Gamma glutamic acid residues of clotting factors must be
carboxylated for enzyme activity

Action of Coumarins
factors
II, VII,
IX, X,
Protein
C and S
Vitamin
K

Coumarins are
competitive
inhibitors

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 Pharmacokinetics
• Absorption: rapid and complete (warfarin)

• Distribution: plasma albumin bound - 99%

– small Vd

• Elimination: liver

• Excretion: kindney

• Warfarin crosses placenta – is teratogenic – birth defects and

abortion
– Category X
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 characteristics
• oral administration
• effective in vivo, not in vitro
• slow onset, long duration
• Takes 4-5 days to become effective – active
carboxylated factors in plasma need to be cleared
Warfarin - Antidote
–Vitamin K (oral or parenteral)

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 clinical uses:
• For long term prophylaxis of acute deep vein
thrombosis or pulmonary embolism
• Prevent venous throboembolism in patients
undergoing orthopedic or gynecological
surgery
• Prevent systemic embolization in patients with
– myocardial infarction,
– prosthetic heart valves or
– chronic atrial fibrillation
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adverse effects
• Spontaneous hemorrhage :
– needs monitoring
– Treatment: withdrawal of the drug;
– administration of vitamin K and fresh blood
• others:
– Fetal hemorrhage & teratogenesis-birth
defects
• Category X
– Risks outweighs any possible benefits
– Allergic reaction
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Sagni H 100
 Drug interactions
1. Drugs that increase anticoagulant effects
– By displacement from albumin- salicylates &
sulfonamides
– By enzyme inhibition- acetaminophen,
amiodarone, azole, cimetidine, disulfiram,
sulfonamide
– Decreased synthesis of clotting factors-
cephalosporins

Sagni H 101
 Drug interactions…
2. Drugs that promote bleeding
– By inhibition of platelet aggregation- NSAIDs
– By inhibition of coagulation cascade-
antimetabolites, heparin
– By generation of GI ulcers- aspirin,
glucocorticoids, indomethacin, phenylbutazole
3. Drugs that decrease anticoagulant effects
– By enzyme induction- anticonvulsants
– By increasing clotting factors synthesis- oral
contraceptives, vit K1
– By inhibition of its absorption-
cholestyramine, colestipol

Sagni H 102
 Contraindication
– Like heparin
– Severe thrombocytopenia
– Uncontrollable bleeding
– Vitamin k deficiency
– Liver disease
– Alcoholism
– Pregnancy & lactation

Sagni H 103
Summary of Contrasts b/n Heparin and
Warfarin
Features Heparin Warfarin
Route Injection PO
MOA Inactivates Inhibits clotting
thrombin & factors synthesis
factor Xa
Onset Rapid (mins) Delayed (hrs)
Duration Brief (hrs) Prolonged
(days)
Monitorin aPTT PT
g
Antidotes Protamine Vitamin K
Sagni H 104
 Antiplatelet Drugs
• Drug that inhibits platelets from aggregating to
form a plug.
• They are used to prevent clotting and alter the
natural course of atherosclerosis.
• Principal indication is for prevention of
thrombosis in arteries
» A platelet core constitutes the bulk of an arterial
thrombus

Sagni H 105
 Classification
1. Cyclooxygenase inhibitors- Aspirin
2. PDE inhibitors
3. ADP receptor antagonists
» Both affect only one pathway in platelet
activation
» Limited antiplatelet effect
4. GP IIb/IIIa receptor antagonists
» Block the final common step in platelet
activation
» Powerful antiplatelet effects

Sagni H 106
Sagni H 107
Sagni H 108
 1. Aspirin
• Aspirin is a classic old drug which is used as a
NSAIDs for more than 100 years.
• Besides antipyretic, analgesic and anti-
inflammatory activities, it can inhibit platelet
aggregation.

Sagni H 109
 Aspirin…
• MOA
– Irreversible COX inhibitor
• Thus, Inhibits Synthesis of TXA2, thereby
» Inhibits platelet activation
» Inhibits vascular smooth muscle
vasoconstriction
– Suppress platelet aggregation
– Reduce risk of arterial thrombosis
– Effect lasts for platelets life-span (7-10 days)

Sagni H 110
 Aspirin…
– Aspirin also inhibits synthesis of prostacyclin
(PGI2)
• By blood vessel wall
• w/c has opposite effect to TXA2, i.e.
 Suppression of platelet aggregation
 Promotion of vasodilation
 But at high doses

Sagni H 111
Sagni H 112
 Pay attention!
• at small dose (50 ～ 75mg/d): inhibit the
synthesis of TXA2 – which causes platelet
aggregation
• at higher doses (> 320 mg/day): inhibits the
synthesis of PGI2 – which inhibits platelet
aggregation.

Sagni H 113
• Clinical indications
– Prophylaxis after cardiac operation
– to reduce the incidence of recurrent myocardial
infarction (MI)
– Prophylaxis for transient ischemic attacks (TIA)
or post TIA
– Chronic stable angina and unstable angina
 Reduces morbidity & mortality
 Adverse effects
– GI bleeding
– Hemorrhagic stroke

Sagni H 114
ⅱ PDE inhibitors : Dipyridamole
Mechanism :
1) ↓PDE → cAMP ↑ ↓ aggregation

2) ↓ the uptake of adenosine →↑AC

Clinical use: Substitute of aspirin

prosthetic heart valves, etc.

Sagni H 115
 2. ADP Receptor Antagonists
• Include:
a. Clopidogrel
b. Ticlopidine
c. Prasugrel
• Irreversible blockade of ADP receptors on the
platelet surface
» Prevent ADP-stimulated platelet
aggregation
• For stroke and acute coronary syndromes
Sagni H 116
a. Clopidogrel
» Oral antiplatelet drug
• Pharmacokinetics
» Orally active
» 50% bioavailable
» Prodrug

Sagni H 117
• Clinical use
– Prevent blockage of coronary artery
stents
– Reduce thrombotic events
» MI
» Ischemic stroke
» Vascular death
• Adverse effects
» Similar to aspirin
» Abdominal pain, dyspepsia,
diarrhea, and rash.
» Less intracranial hemorrhage &
less GI bleeding vs aspirin

Sagni H 118
• Drug interactions
» Heparin
» Warifarin
» NSAIDs- aspirin
b. Ticlopidine
– Similar action as clopidogrel
– Prevention of thrombotic stroke
– Life-threatening hematologic reactions
» Neutropenia
» Agranulocytosis, etc
– GI disturbances & dermatologic
reactions
c. Prasugrel
» Investigational
Sagni H drug 119
3. Glycoprotein IIb/IIIa Receptor
Antagonists
• activation of glycoprotein receptor on
platelet membrane is the final common
pathway for platelet aggregation.
» The most effective antiplatelet drugs
 3 drugs are available:
» Abciximab
» Tirofiban
» Eptifibatide
– Administered by IV
– Reversible blockade of platelet GP IIb/IIIa
receptors
– Inhibit the final step in aggregation
– Prevent aggregationSagni H stimulated by all 120
• Clinical uses
– Prevent ischemic events
» Acute coronary syndromes (ACSs)
» Percutaneous coronary intervention
(PCI)
a. Abciximab
» A purified Fab fragment of a
monoclonal antibody
» Risk of bleeding
b. Eptifibatide
» A small peptide drug
» Risk of bleeding
c. Tirofiban
» Isolated from snake venom
» Risk of bleeding
Sagni H 121
 Fibrinolytic drugs
(thrombolytic agents)
• These agents can activate the conversion of
plasminogen to plasmin,
– a serine protease that hydrolyzes fibrin and thus
dissolves clots.
• Mainly used in acute thrombolism

Sagni H 122
 Include:
Ⅰ Plasminogen activator from human body
Urokinase (UK) , Alteplase (t-PA)
Ⅱ Plasminogen activator form bacteria
Streptokinase (SK) , Anistreplase,
Stephylokinase
Ⅲ Plasminogen activator from snake
Snake venom antithrombus enzyme,
Ancrod, Acutase
Sagni H 123
 SHARED CHARACTERISTICS
• ACTION
– All act either directly or indirectly to convert
plasminogen to plasmin, which in turn cleaves
fibrin, thus lysing thrombi.
• Clot dissolution occurs with a higher
frequency when therapy is initiated early
after clot formation.

Sagni H 124
1. Streptokinase(SK)
• mechanism: acts indirectly
SK-plasminogen complex →
activate plasminogen
• clinical uses:
thrombolytic therapy: early,< 6h
intravenous route: DVT, multiple pulmonary emboli
intra-arterial route: myocardial infarction
• adverse reactions:
– bleeding, hypotension, allergic
reaction (has antigenicity)
Sagni H 125
 plasminogen

inhibitors - + SK-
plasminogen
complex
plasmin
＋ +
Degration fibrin
splits
products fibrinogen fibrin
products

Sagni H 126
2. Urokinase(UK)
• mechanism: activating plasminogen
directly

• clinical uses: Same use as SK, especially

cerebral embolism

• adverse reactions: bleeding, but no

antigenicity

Sagni H 127
 plasminogen

inhibitors - + UK

plasmin
+ +
Degration
fibrin splits
products fibrinogen fibrin
products
Sagni H 128
3.tissue plasminogen activator (t-PA)
or Alteplase

Mechanism: act directly

Charateristics:
• act selectively , risk of bleeding ↓
(High affinity to plasmnogen bound to
fibrin in the embolism ， low affinity to
free plasmnogen)
• superior to SK and UK

Sagni H 129
4. anistreplase (anisoylated plasminogen
streptokinase activator complex)
• a complex of purified human plasminogen
and bacterial streptokinase that has been
acylated to protect the enzyme’s active site.
• When administered, the acyl group
spontaneously hydrolyzes, activating
streptokinase-proactivator complex.
• greater clot selectivity (ie, more activity on
plasminogen associated with clots than on
free plasminogen in the blood)
Sagni H 130
THANK
YOU !!!