This document discusses drugs used to treat disorders of blood clotting and bleeding. It describes three classes of anticoagulant drugs that reduce clotting: oral anticoagulants like warfarin that inhibit vitamin K-dependent clotting factors; injectable anticoagulants like heparin and hirudin that inhibit thrombin; and antiplatelet drugs like aspirin and clopidogrel that decrease platelet aggregation. It also discusses fibrinolytic drugs like tissue plasminogen activator that dissolve blood clots, and hematopoietic drugs used to treat anemia, such as iron supplements, folic acid, and vitamin B12.

1. Drugs Used in
Disorders of
blood

2. Objectives:
• To understand the process of
clotting.
• To describe three major classes of
anticlotting drugs.
• To describes three different drugs
used to treat disorders of excessive
bleeding.

3. ANTICOAGULATION –
COAGULATION
BALANCE
FLUID
AT-III
Proteins C,S
CLOT
Thrombin
Fibrinogin

4. Normal Hemostasis
When a small blood vessels is injured, hemorrhage is
prevented by:
• Vasospasm (reduces blood flow and
facilitates platelet aggregation and
coagulation).
• The formation of platelet plug (platelet
aggregation) to arrest bleeding.
• The formation of a fibrin clot (exposure of
the blood to tissue factors) to arrest
bleeding until the vessel is repaired.
• Fibrinolysis (the removal of the clot) after
the vessel is repaired.

5. Pathological Thrombus Formation
• A clot that adheres to a vessel wall = thrombus
• A clot that floats within the blood = embolus
• Both thrombi and emboli are dangerous because
they may occlude blood vessels and deprive
tissues of oxygen and nutrients
• Anticoagulants are drugs that retard coagulation
and thereby prevent the occurrence of a
thrombus.

6. Intrinsic Pathway
• All clotting factors
are within the blood
vessels
• Clotting slower
• Activated partial
thromboplastin test
(aPTT)
Extrinsic Pathway
• Initiating factor is
outside the blood
vessels - tissue factor
• Clotting - faster - in
Seconds
• Prothrombin test
(PT)

7. Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
Thromboplastin
XIa
XI
IXa
IX
Xa
X
Factors affected
By Heparin
VIIa
Prothrombin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Fibrinogen
XIII
VII
X
Thrombin
Fribrin monomer
Fibrin polymer

8. Classes Of Drugs Used in the
Treatment of Clotting
Disorders
Drugs used in clotting disorders
To reduce clotting
(anticlotting drugs)
Thrombolytics
Antithrombin III
To facilitate clotting
Anticoagulants
Leech proteins
(lepirudin)
Oral anticoagulants
(warfarin)
Antiplatelet drugs
Heparin
Phosphodiestrase
inhibitors
Glycoprotein
IIb/IIIa receptor
antagonists
Replacement factors
(VII, IX, etc.
ADP receptor
antagonists
Plasminogen inhibitors
Cyclooxygenase
inhibitors
(aspirin)

9. 1. Anticoagulant Drugs
• Reduce the formation of fibrin clots.
• Oral anticoagulant drugs : Coumarin
anticoagulants (warfarin - dicumarol)
• Parenteral anticoagulant drugs:
Heparin - Hirudin)

10. A. Oral anticoagulants
(Coumarin anticoagulants)
• Chemistry and mechanisms:
– They are structurally related to vitamin k
– These drug inhibit the synthesis of clotting
factors II (prothrombin), VII, IX, and X.
– Warfarin blocks the reduction of oxidized
vitamin K and thereby prevents the
posttranscriptional carboxylation of the above
four factors.

11. Action of Coumarins
Oral anticoagulants – 4-hydroxycoumarins
Vitamin K
Coumarins
act here
Coumarins
act here
Coumarins are
competitive
inhibitors

12. Pharmcokinetic and
Pharmacological Effects
(coumarin)
• Extensively metabolized, highly bound to
plasma proteins
• Cross the placenta, may cause fetal
hemorrhage and malformations. Pregnant
women with thrombosis should be treated
with standard or low molecular weight
heparin.
• The onset of action is 3-5 days (time
required to deplete the pool of circulating
clotting factors).

13. Adverse Effects of
Coumarins
• Bleeding
– Minor bleeding: withdrawal of the drug and
administer vitamin K1.
– Severe bleeding: fresh frozen plasma or factor
IX concentrate
• Cross the placenta:
Teratogenic （ damaging to the
developing fetus ）
• must not be given to pregnant women.

14. Drug Interactions
• Aspirin and Phenylbutazone (displace
warfarin from albumin, inhibit of platelet
aggregation).
• Antibiotics (decrease microbial vit. K
production in the intestine, inhibition of
metabolism of warfarin).
• Barbiturates and rifampin (decrease warfarin
effectiveness by inducing microsomal P450
system.
• Oral contraceptives (decrease warfarin
effectiveness by increasing plasma clotting
factors and decreasing antithrombin III.

15. Therapeutic uses of
Coumarins
• Long-term management of patients
with deep vein thrombosis or atrial
fibrillation or artificial heart valve.
• In conjunction with heparin for the
treatment of MI.

16. 2. Parenteral Anticoagulants
A. Heparin
• Chemistry and Mechanisms: It is a
polymeric mixture of sulfated
mucopolysaccharides.
• It is highly negatively charged at
physiological pH. Can be neutralized by
basic molecules such as protamine.
• Heparin is synthesized as a normal
product of many tissues including the
lung, intestine, and the liver. Commercial
preparations are derived from bovine lung
or porcine intestinal extracts (average

17. Heparin - Structure
Average molecular wt of 12,000 daltons (40 glucose
units) with the following structure:

18. Heparin binds to antithrombin III
(ATIII) and enhances its proteolytic
activity
Active clotting factors
(IIa, IXa, Xa, XIa, XIIa, XIIIa
Slow
AT III
Inactive factors
A. No Heparin
Active clotting factors
(IIa, IXa, Xa, XIa, XIIa, XIIIa
Rapid
(1000x)
AT III +
heparin
Inactive factors
B. With Heparin

19. Heparin mechanism of action
Heparin
Antithrombin III
Thrombin

20. Mechanism of action of
Heparin
• Heparin binds to antithrombin III and
enhances its proteolytic activity by 1000fold.
• Heparin has a direct anticoagulant activity
(can inhibit clotting in vitro).
• Heparin releases lipoprotein lipase from
vascular beds, which accelerate clearing
of lipoproteins from the plasma.

21. Pharmacokinetic and
Pharmacological Effects
(Heparin)
• Heparin must be given parenterally by
slow infusion or deep subcutaneous
injection. It is not injected IM due to the
potential of hematoma
• Heparin is metabolized in the liver by
heparinase to smaller molecular-weight
compounds, which are excreted in the
urine.

22. Adverse Effects of Heparin
• Bleeding
– Minor bleeding: drug withdrawal
– Severe bleeding: Protamine sulfate (a
highly positively charged mixture of
peptides)
• Thrombocytopenia (25% of patients). Oral
anticoagulant should be used.
• Hypersensitivity reactions (chills, fever,
urticaria, anaphylaxis). Obtained from
animal sources (antigenic)
• Reversible alopecia
• Osteoporosis

23. Therapeutic uses of Heparin
• Preoperative prophylaxis against
deep vein thrombosis.
• Heparin is administered following MI
or pulmonary embolism.
• Heparin prevents clotting in arterial
and heart surgery, during blood
transfusion, and in renal dialysis and
blood sample collection.

24. Contraindications and Drug
Interactions with Heparin
• Heparin is contraindicated in patients who
are bleeding, patients with hemophilia,
thrombocytopenia and hypertension.
• Heparin is contraindicated before and
after brain, spinal cord or eye surgery.
• Heparin should not be administered with
aspirin or other drugs that interfere with
platelet aggregation.
• Positively charged drugs and
aminoglycosides can reduce the
effectiveness of heparin therapy.

25. B. Hirudin and Related
Drugs
• Hirudin is a natural anticoagulant
obtained from Hirudo medicinalis,
the medicinal leech.
• It is a direct inhibitor of thrombin.
• These drugs are undergoing clinical
trials for the treatment of unstable
angina and acute MI.

26. 3. Antiplatelet Drugs
• Platelet aggregation plays a central role in
the clotting process (esp.. clots that form
in the arterial circulation).
• Platelet aggregation is facilitated by
thromoboxane, ADP, fibrin and serotonin.
Platelet aggregation is inhibited by
prostacyclin and increased cAMP
• Antiplatelet drugs are agents that
decrease platelet adhesiveness induced
by collagen.
• They are useful in preventing arterial
thrombi since they are of platelet origin.

27. Platelet aggregation and
sites of drug action
Vascular Endothelium
vWF
Collagen
GP
Ia
GP
Ib
Platelet
Abciximab
Binds
GP
IIb/IIIa
GP
IIb/IIIa
GP
GP
Granules
Aspirin
Inhibits
Synthesis
.
.
...
...
.. …
.. .. …… TXA2
.
…
…
…
… ADP Ticlopidine
5-HT Inhibits
Fibrinogen
Effects
⊕

28. A. Aspirin
• Mechanisms and Pharmacological effects
– Aspirin and most other NSAIDs inhibit the
synthesis of prostaglandins:
• Decrease endothelial synthesis of PGI2
(prostacyclin)
• Decrease thromoboxane A2 production
in platelets by inhibiting cyclooxygenase
type I and type 2.
• Irreversible inhibition of cyclooxygenase
and platelet aggregation for the life of
the platelet.
• It may cause bleeding, especially in the
GI, and hypoprothrombinemic effect
(high doses)

29. Therapeutic uses of Aspirin
• Prophylactic for transient
cerebral ischemia
• Reduce the incidence of
recurrent MI
• Decrease mortality in
postmyocardial infarction
patients.

30. B. Ticlopidine
• Mechanisms and Pharmacological effects:
– It inhibits adenosine diphosphate (ADP)-induced
expression of platelet glycoprotein receptors and
reduces fibrinogen binding and platelet
aggregation.
– It can be used in patients who are unresponsive to
aspirin to prevent thrombotic stroke.
– After oral ingestion, it is extensively bound to
plasma proteins and undergoes hepatic
metabolism.
– Can cause mild to severe neutropenia (frequent
complete blood count is advisable).

31.  Dipyridamole (PERSANTINE) –
 *inhibits platelets adhesion to damaged
blood vessels
 *may increase the antiaggregating effect of
prostacycline
 *↑ dosage ⇒ increase in platelets c-AMP
formation and ↓ platelet Ca which inhibits
platelets aggregation
 pt. with intolerant to aspirin

32. C. Abciximab
• It is Fab fragment of a chimeric
human-murine monoclonal antibody.
• It is used solely for the prevention of
thrombosis in patients undergoing
coronary angioplasty.
• It binds to platelet glycoprotein
IIb/IIIa receptors and prevents
binding by fibrinogen.

33. C. Fibrinolytic Drugs
• Recently formed thrombus is easily lysed by
these drugs.
• Aged thrombi (72 hrs) are usually resistant.
• They are primarily used to dissolve clots in
patients undergoing MI, thromotic stroke or
pulmonary embolism.

34. Fibrinolysis and sites of
drug action
Plasminogen
Aminocaproic acid
 ⊕
Fibrin
Streptokinase
Urokinase
Alteplase
(Tissue plasminogen
Activator)
Fibrinogen
Plasmin
Fibrin split products
Degradation products

35. Fibrinolytic Drugs
• Chemistry and Mechanisms:
– Altephase: recombinant forms of human
tissue plasminogen activator (t-PA).
– Urokinase: a protein obtained from
human urine.
– Streptokinase: a protein obtained from
streptococci.
– Anistreplase: a performed complex of
streptokinase and plasminogen.

36. Mechanisms of action
• Urokinase and the recombinant forms of tPA (altepase) directly convert
plasminogen to plasmin.
• Streptokinase must combine with
plasminogen first to form an activator
complex that convert the inactive
plasminogen to plasmin.
• Anistreplase (anisoylated plasminogen
streptokinase activator complex, APSAC).

37. Adverse effects
• Bleeding: Fibrinolytic drugs may lyse
both normal and pathologic thrombi. Less
effect is seen with t-PA (selectively
activates plasminogen that is bound to
fibrin) than streptokinase. Bleeding can
be controlled by Aminocaproic acid
(inhibits plasminogen activation)
• Hypersensitivity reaction: streptokinase
• Arrhythmias (bradycardia,tachycardia):
Free radicals generated after fibrinolysis.

38. Hematopoietic Drugs
• Hematopoiesis:
– Mature blood cells is formed in the
bone marrow, removed from
circulation by RE cells in the liver and
spleen. This process is called
hematopoiesis.
– This process requires minerals,
vitamins and regulated by
hematopoietic growth factors.

39. Hematopoietic Drugs
• Anemia:
– It is a subnormal concentration of RBC’s or
hemoglobin in the blood.
– Can be caused by chronic blood loss, bone
marrow abnormalities, increased hemolysis,
infections, malignancy.
– Drugs can cause toxic effects on blood cells.
– Nutritional anemias are caused by dietary
deficiencies of iron, folic acid and vitamin B12

40. Iron Metabolism
Ingested Fe
Myoglobin and enzymes
Plasma (transferrin)
Ferritin stores
120 days
Bone marrow
Erythrocytes (hemoglobin)
Reticuloendothelial cells

41. Iron Preparations
• They are used to prevent and treat iron deficiency
anemia.
– Ferrous sulfate and related compounds:
• They administered orally
• A typical daily dose is 100-200 mg iron/day (only
25% of orally administered iron is absorbed)
• May require 3-6 months to replenish body stores.
– Iron dextran:
– In patients who are intolerant of or
unresponsive to oral therapy.
– May cause anaphylactic reactions.

42. Vitamins
• Folic acid or vitamin B12 deficiency may
cause megaloblastic anemia.
• Both are cofactors in many enzymatic
reactions involving the addition of singlecarbon units.

43. 1. Folic acid
• Folic acid deficiency may be caused by:
– Dietary deficiency during pregnancy and
lactation
– Poor absorption caused by pathology of the
small intestine
– Alcoholism
• Folic acid deficiency may lead to megaloblastic
anemia. It is important to evaluate the basis of
megaloblastic anemia prior to instituting
therapy because vitamin B12 deficiency can
cause symptoms of the same disorder. In this
case, folic acid therapy will not correct the
neurologic damage associated with B12
deficiency.

44. VITAMIN B12
•
•
•
•
Used to treat pernicious anemia.
Common B12 preparations include:
Cyanocobalamin
Hydroxocobalamin

45. VITAMIN B12
• Pharmacokinetics:
• Administered orally or parenterally.
• When a person has a deficiency of intrinsic
factor, which is secreted by the gastric
mucosa and is needed for vitamin B12
absorption, vitamin B12 deficiency
pernicious anemia develops.
• These people require vitamin B12
injections.

46. VITAMIN B12
• Stored in the liver; excreted in the urine.
• Pharmacodynamics:
• Essential for cell growth and replication and
for the maintenance of myelin throughout
the nervous system.

47. VITAMIN B12
• Pharmacotherapeutics:
• Used to treat pernicious anemia, which is a
megaloblastic anemia characterized by
decreased gastric production of
hydrochloric acid and the deficiency of the
intrinsic factor (normally secreted by the
parietal cells of the gastric mucosa and is
essential for vitamin B12 absorption).

48. VITAMIN B12
• Drug interactions:
• Alcohol may decrease the absorption of oral
cyanocobalamin.
• Adverse reactions:
• No dose-related adverse reactions.

49. IV. Hematopoietic Growth Factors
• Endogenous growth factors:
– Colony-stimulating factors (CSF) and
erythropoietin are glycoproteins that
stimulate the differentiation and maturation
of bone marrow progenitor cells.
• Growth factor preparations:
– Epoetin alfa
– Filgrastim and sargramostin

50. Growth factor preparations
• Epoetin alfa:
– It is a form of erythropoietin produced by
recombinant DNA technology. Natural
erythropoietin is secreted by the kidneys to
stimulate erythroid cell differentiation and
proliferation.
– It is used in the treatment of anemia that is
due to inadequate erythropoiesis (patients
with chronic renal failure, chemotherapyinduce anemia in cancer patients, AZTinduced anemia in HIV infected patients).

51. Growth factor preparations
• Filgrastim and sargramostin:
– Filgrastim is recombinant human granulocyte
colony stimulating factor (G-CSF), Sargramostin is
recombinant human granulocyte-macrophage
colony-stimulating factor (GM-CSF).
– Both are primarily used to treat neutropenia
associated with cancer chemotherapy and bone
marrow transplantation (to accelerate granulocyte
and myeloid cell recovery following chemotherapy
or bone marrow transplantation).
– Both can be administered IV or subQ until the
neutrophil count has reached 10,000/µL.