Drugs Used in

Disorders of
blood
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.
 ANTICOAGULATION
COAGULATION
BALANCE

FLUID CLOT
AT-III Thrombin
Proteins C,S Fibrinogin
 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.
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.
 Intrinsic Pathway Extrinsic Pathway
All clotting factors Initiating factor is
are within the blood outside the blood
vessels vessels - tissue factor
Clotting slower
Clotting - faster - in
Activated partial Seconds
thromboplastin test
(aPTT) Prothrombin test (PT)
 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

XIIa Tissue Factor

XII

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer
Vit. K dependent Factors Fibrin polymer
Affected by Oral Anticoagulants XIII
 Classes Of Drugs Used in the
Treatment of Clotting
Disorders
Drugs used in clotting disorders

To reduce clotting To facilitate clotting

(anticlotting drugs)

Thrombolytics Anticoagulants Antiplatelet drugs Replacement factors Plasminogen inhibitors

(VII, IX, etc.

Antithrombin III Leech proteins Oral anticoagulants Heparin Phosphodiestrase Glycoprotein ADP receptor Cyclooxygenase
(lepirudin) (warfarin) inhibitors IIb/IIIa receptor antagonists inhibitors
antagonists (aspirin)
 1. Anticoagulant Drugs
Reduce the formation of fibrin clots.
Oral anticoagulant drugs : Coumarin
anticoagulants (warfarin - dicumarol)
Parenteral anticoagulant drugs:
Heparin - Hirudin)
 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.
Oral anticoagulants 4-hydroxycoumarins

Vitamin K

Coumarins
Coumarins act here
act here
Coumarins are
competitive
inhibitors
 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).
 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.
 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.
 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.
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
 Heparin - Structure
Average molecular wt of 12,000 daltons (40 glucose
units) with the following structure:
 Heparin binds to antithrombin III
(ATIII) and enhances its proteolytic
activity

Active clotting factors Active clotting factors

(IIa, IXa, Xa, XIa, XIIa, XIIIa (IIa, IXa, Xa, XIa, XIIa, XIIIa

Rapid AT III +
Slow AT III
(1000x) heparin

Inactive factors Inactive factors

A. No Heparin B. With Heparin

 Heparin mechanism of action

Heparin

Antithrombin III Thrombin

 Mechanism of action of
Heparin
Heparin binds to antithrombin III and
enhances its proteolytic activity by 1000-
fold.
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.
 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.
 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
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.
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.
 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.
 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.
 Platelet aggregation and
sites
Vascular Endothelium
of drug action

Collagen vWF Aspirin

GP GP Granules Inhibits
Ia Ib Synthesis
Platelet ......
.... TXA2
... .. ADP
GP
Abciximab IIb/IIIa Ticlopidine
5-HT
Binds Inhibits
Fibrinogen Effects
GP
IIb/IIIa
GP
GP
 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)
Therapeutic uses of Aspirin
Prophylactic for transient
cerebral ischemia
Reduce the incidence of
recurrent MI
Decrease mortality in
postmyocardial infarction
patients.
 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).
 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
 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.
 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.
 Fibrinolysis and sites of
drug action
Streptokinase
Plasminogen Urokinase
Alteplase
Aminocaproic acid (Tissue plasminogen
Activator)

Fibrin Fibrinogen

Plasmin

Fibrin split products Degradation products

 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.
 Mechanisms of action
Urokinase and the recombinant forms of t-
PA (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).
 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.
 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.
 Hematopoietic Drugs
Anemia:
It is a subnormal concentration of RBCs 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
 Iron Metabolism

Ingested Fe Myoglobin and enzymes

Plasma (transferrin) Ferritin stores

120 days
Bone marrow

Erythrocytes (hemoglobin) Reticuloendothelial cells

 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.
 Vitamins

Folic acid or vitamin B12 deficiency may

cause megaloblastic anemia.
Both are cofactors in many enzymatic
reactions involving the addition of single-
carbon units.
 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.
 VITAMIN B12
Used to treat pernicious anemia.
Common B12 preparations include:
Cyanocobalamin
Hydroxocobalamin
 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.
 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.
 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).
 VITAMIN B12
Drug interactions:
Alcohol may decrease the absorption of oral
cyanocobalamin.
Adverse reactions:
No dose-related adverse reactions.
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
 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, chemotherapy-
induce anemia in cancer patients, AZT-
induced anemia in HIV infected patients).
 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/L.