FOR BACHELOR OF PHARMACY STUDENTS

By Tasisa Ketema (MSc, B.Pharm)

October, 2023

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Introduction
Functions of Blood
• Blood performs a number of functions and includes:
1. Blood transports:
– Oxygen from the lungs and nutrients from the digestive
tract
– Metabolic wastes from cells to the lungs and to kidneys for
elimination
– Hormones from endocrine glands to target organs
2. Blood maintains:
– Appropriate body temperature by absorbing and
distributing heat
– Normal pH in body tissues using buffer systems
– Adequate fluid volume in the circulatory system

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3. Blood prevents blood loss by:
– Activating plasma proteins and platelets
– Initiating clot formation when a vessel is broken
4. Blood prevents infection by:
– Synthesizing and utilizing antibodies
– Activating WBCs to defend the body against foreign
invaders

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Physical characteristics and volume
• Blood is a sticky, opaque fluid with a metallic taste
• It is a viscus fluid connective tissue.
• Color varies from scarlet (oxygen-rich) to dark red
(oxygen-poor)
• The pH of blood is 7.35–7.45 and its salt content is 0.9%
• Temperature is 38C.
• Blood accounts for approximately 8% of body weight
• Average volume of blood is 5–6 L for males, and 4–5 L for
females

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Composition of Blood
• Blood is the body’s only fluid connective tissue
• It is composed of:
 Liquid plasma (55%) and
 Formed elements (45%)

• Formed elements include:

– Erythrocytes, or red blood cells (RBCs)
– Leukocytes, or white blood cells (WBCs)
– Thrombocytes, or Platelets
• Hematocrit – the percentage or proportion of blood
volume that is RBCs.
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Plasma
• It is the liquid portion of blood
• It makes up 55% of the blood volume
Composition of plasma
Blood plasma composed of
1. Water (90%)
2. Organic constituents (9%)
– Plasma proteins: albumin, globulins, clotting proteins and
others (7%)
– Lipids, lipoproteins, phospholipids
– Hormones and enzymes
– Nutrients: CHO, vitamines, amino acids, fats
– Metabolic waste products: urea, creatinine
3. Inorganic constituents: electrolytes (1%)
4. Respiratory gases – oxygen and carbon dioxide 6
Principal plasma proteins
• There are 3 principal plasma proteins
Albumin: 4 g/dl
Globulin: 2.7 g/dl
Fibrinogen: 0.3 g/dl
• Plasma proteins are synthesized by hepatocytes,
lymphocytes, platelets and endothelial cells.
Function of plasma proteins
1. Immunologic function: γ-globulins are immunoglobulin's
(antibodies)
2. Nutritional function in starvation
3. Haemostasis: fibrinogen, prothrombin and most other
clotting factors are plasma proteins

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4. Transport of hormones, electrolytes and drugs.
5. pH regulation (buffering function)
6. Maintenance of plasma osmotic pressure
7. Enzymatic and hormonal function
Erythrocytes (Red blood cells)
Function
Transport of O2 and CO2
Regulation of acid-base balance
• Major content of RBCs is Hb (97%)
• Size: Diameter 7.5 µm
Thickness 1 and 2 µm
• Hematocrit: The percentage of blood cells
M = 42-48%
F = 38-43%
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 Hematopoiesis- is the production of circulating
erythrocytes, platelets and leukocytes from undifferentiated
stem cells
– The hemopoietic machinery resides primarily in the bone
marrow in adults, and requires constant supply of three
essential nutrients – iron, vitamin B12 and folic acid
 Anemia:- is defined as a below-normal plasma hemoglobin
concentration (12-20g/dl)
– arise from a decreased number of circulating red blood
cells or an abnormally low total hemoglobin content per
unit of blood volume.
– Anemia may occur due to deficiency of iron, vit B12 or a
folic acid 10
 Generally the different types of anemia include:-
– Aplastic anemia:-due to bone marrow abnormality
– Hemolytic anemias:- RBC loss> RBC production
– anemias caused by inherited abnormalities of RBCs (for
example, sickle cell anemia and thalassemia)
– Iron deficiency anemia
– Vitamin deficiency anemia (vitaminB12 or folic acid)
– Anemia caused by chronic (ongoing) disease
– Anemia also occur due to blood loss as in injuries
 Most cases of anemia are either iron deficient or vitamin
deficient

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 Signs and Symptoms:
 Symptoms of anemia can be mild at first.
 They include:

» tiredness, weakness, shortness of breath, pale

skin, lightheadedness, headache, feeling cold,
rapid heartbeat and chest pain

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 Treatment may include:-
– treatment of the causative disease
– change in diet
– vitamin and mineral supplements
– medication
– blood transfusion
– transfusions -- may help treat certain types of
anemia, including anemia of chronic disease,
sickle cell anemia, and aplastic anemia
– bone marrow or stem cell transplant -- may be used
in severe cases of aplastic anemia or some cases of
sickle cell anemia

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 Agents used in Anemias
 Iron
• Iron is stored in the intestinal mucosal cells, liver, spleen,
and bone marrow as ferritin (an iron–protein complex) until
needed by the body.
• Iron is delivered to the bone marrow for hemoglobin
production by a transport protein, namely transferrin.
• Iron deficiency results from
 Reduced absorption after gastrectomy, as a result of
mucosal damage, co-administration of drugs that chelate
iron e.g. antacids, TTCs, Ciprofloxacin etc.
 Insufficient intake (nutritional deficiency) during periods
of accelerated growth in children, and in heavily
menstruating or pregnant women

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  Acute or chronic blood loss :-chronic nose bleeding,
menorrhagia, occult GI bleeding, worm infestation and
ulcers (e.g. PUD)
– blood loss- the most common cause of iron
deficiency in adults
• Thus, iron deficiency results from a negative iron balance
due to depletion of iron stores and/or inadequate intake,
resulting in hypochromic microcytic anemia (due to low
iron and small-sized red blood cells)
Mechanism of action:
• Supplementation with elemental iron corrects the iron deficiency.
• The CDC recommends 150 to 180 mg/day of oral elemental
iron administered in divided doses two to three times daily for
patients with iron deficiency anemia
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 Daily requirement of iron
 Iron requirement increases in growing children, pregnant
and lactating women
 Sources
 dietary - mostly in the organic form from meat, cereals,
etc.

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Pharmacokinetics of Iron
 Absorption
– absorbed in duodenum and proximal jejunum
– a normal individual with out iron deficiency absorbs 5-10%
of daily intakes.
– absorption is increased in states with increased
requirements , deficiencies and/or dietary factors such as
heme-iron (Fe2+) e.g from meat etc,
– Acidic conditions in the stomach keep iron in the reduced
ferrous form, which is the more soluble form.
• Its absorption increases in the presence of HCl and vitamin C
– Absorption is decreased from non heme iron (Fe3+), in the
presence of antacids and other chelators, and following
gastric resection.
– Iron crosses the intestinal mucosal cell by active transport
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 Elimination:
– Very small amount is execrated in stool by exfoliation
of intestinal mucosal cells and trace amounts are
execrated in bile, urine and sweat with total daily
excretion not more than 1mg/day.

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 Treatment of iron deficiency anemia
– The cause should always be identified and treated
whenever possible.
– Treatment of iron deficiency anemia consists of
administration of oral or parenteral iron preparation
– they should be used only when dietary measures have
failed
1. Oral Iron Therapy:
– only ferrous salts should be used because of most efficient
absorption
– Drugs: Ferrous sulfate, ferrous gluconate, ferrous
fumarate are most commonly used
– 200-400mg elemental irons should be given daily to
correct iron deficiency most rapidly
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– For best absorption, iron should be taken between
meals.
» Iron may cause stomach and intestinal
disturbances.
» Low doses of ferrous sulfate can be taken with food
and are still absorbed but with fewer side effects.
– Taking orange juice with an iron pill can help increase
iron absorption.
» Some prescribers also recommend taking a vitamin
C supplement with the iron pill
– Treatment should be continued for 3-6 months to
replenish iron stores

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– Side effects: Oral iron therapy can cause nausea,
vomiting, epigastric discomfort, abdominal cramps,
constipation and diarrhea.
– Some patients have less severe gastrointestinal
adverse effects with one iron salt than another and
benefit from changing preparations
– Certain medications, including antacids, can reduce iron
absorption.
– Iron tablets may also reduce the effectiveness of other
drugs, including the antibiotics such as tetracycline,
penicillamine, and ciprofloxacin and the Parkinson's
disease drugs methyldopa, levodopa, and carbidopa.
– At least 2 hours should elapse between doses of
these drugs and iron supplements.
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2. Parenteral iron therapy:
 Drug: iron dextran , sodium ferric gluconate
complex in sucrose, iron sucrose
 may be given by deep IM or occasionally IV
 Should be reserved for patient unable to tolerate or
absorb oral iron
 Iron dextran may cause allergic reaction
» The other two are at least equally effective
and safer than iron dextran
 Side effect: - include local pain, tissue staining,
headache, light headedness, fever, arthralgia, nausea,
vomiting, urticaria, back pain, bronchospasm, and rarely
anaphylaxis and death

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 Iron dextran
– It can be given by deep intramuscular injection or by
intravenous infusion, although the intravenous route is
used most commonly.
– IV administration eliminates the local pain and tissue
staining that often occur with the IM route and allows
delivery of the entire dose of iron necessary to correct
the iron deficiency at one time
– Anaphylactic reactions to iron dextran, including fatal
reactions, have been clearly documented
– 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 are given
– The favored route of administration is i.v. infusion in
several hundred mls of normal saline over 1-2 hrs.
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 Iron-sucrose complex and iron sodium gluconate
complex
– are alternative preparations. these agents can be
given only by the iv route
– these preparations appear to be much less likely than
iron dextran to cause hypersensitivity reactions.

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 Acute iron Toxicity
 Is exclusively seen in children b/c of over ingestion
and rarely seen in adults
 Signs and symptoms
 Necrotizing gastroenteritis with vomiting, abdominal
pain and bloody diarrhea, shock, metabolic acidosis,
coma
 Treatment
 Whole bowel irrigation
 Deferoxamine- A potent iron chealating compound
should be given systemically to bind iron and promote
excretion through urine
 Given parentally (i.m., s.c. or i.v.)
 Recently, an oral iron chelator deferasirox has
been approved for treatment of iron overload.
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 Chronic iron toxicity
– Excess iron is deposited in the heart, liver, pancreas,
and other organs.
– It can lead to organ failure and death
– most commonly occurs in patients with inherited
hemochromatosis (a disorder characterized by
excessive iron absorption, and in patients who receive
many red cell transfusions over a long period of time)

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 Blood Transfusions
– Transfusions are used to replace blood loss due to
injuries and during certain surgeries.
– They are also commonly used to treat severely
anemic patients who have thalassemia, sickle cell
disease, myelodysplastic syndromes, or other types of
anemia.
– Some patients require frequent blood transfusions.
– Iron overload can be a side effect of these frequent
blood transfusions.
If left untreated, iron overload can lead to liver
and heart damage.

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– Iron chelation therapy is used to remove the excess
iron caused by blood transfusions
– For many years, deferoxamine was the only drug
used in chelation therapy
– This drug is usually injected intravenously,
using an infusion pump.
– A new drug, deferasirox , is approved as a once-daily
treatment for iron overload due to blood
transfusions.
– It does not require injections.
– Patients mix the deferasirox tablets in liquid
and drink the medicine.

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 Vitamin B12
– Daily requirement is 2-5 mg
– Source:-mainly obtained from animal products
– Ultimate source of vit B12 is from microbial
synthesis
– Importance:-serves as a co factor for essential
biochemical reaction in humans including DNA synthesis
 Pharmacokinetics
– Absorbed in distal ileum after combined with intrinsic
factor secreted by stomach
– Absorbed through a highly specific receptor mediated
transport system
– Transported/distributed to various cells of the body bound
to plasma glycoprotein, transcobalamin II
– Excess vitamin B12 is transported to the liver for
storage and excreted in the urine. 29
 Deficiency of Vit B 12- it results in:-
– Megaloblastic anemia
– Neurological syndrome involving spinal cord and
peripheral nerves
– The neurologic syndrome usually begins with
paresthesia's and weakness in peripheral nerves
and progresses to spasticity and other central
nervous system dysfunctions
 Causes of deficiency:
– defective secretion of intrinsic factor necessary for
absorption of vitB 12, partial or total gastrectomy,
diseases that affect distal ileum, malabsoption syndrome
e.g inflammatory bowel disease, small bowel resection
etc.
– Almost all cases of vit B12 deficiencies are caused by
malabsorption 30
 Treatment of Vit B 12 deficiency
» Drugs: cyanocoblamin and hydroxycobalamin
– Hydroxocobalamin is preferred because it is more
highly protein-bound and therefore remains longer in
the circulation
– may be administered orally (for dietary deficiencies)
and intramuscularly, or deep subcutaneously (for
pernicious anemia)
– patients with pernicious anemia will need life-long
therapy.

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 Folic acid
– Daily requirement is 50 -100μg
– Folic acid deficiency is not uncommon
 Sources
– include yeast, liver, kidney and green vegetables
 Physiologic functions
– required for essential biochemical reactions that provide
precursors for the synthesis of amino acids, purines and
DNA
 Deficiency
– Common among elderly patients, poor patients, pregnant
ladies.
– It results in megaloblastic anemia.
– The causes are dietary deficiency, alcoholics with liver
disease, hemolytic anemia, malabsorption syndrome,
drugs such as methotrexate 32
 Phamacokinetics
– folic acid is readily and completely absorbed in the
proximal jejunum.
– 5 -20 mg of folates are stored in the liver and other
tissues
– Body stores of folates are relatively low and daily
requirement is high
– hence folic acid deficiency and magaloblasitc anemia
can develop within 1 -6 months after the in take of
folic acid stops

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 Treatment

– Folic acid 1mg orally per day

 N.B

– Folic acid supplementation to prevent folic acid

deficiency should be considered in high-risk
individuals including pregnant women, alcoholics and
patients with hemolytic anemia, liver disease, certain
skin disease, and patients on renal dialysis.

– The administration of folic acid in the setting of vitB12

deficiency will not prevent neurological manifestation
even though it will largely correct the anemia caused
by the vitamin B12 deficiency.
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 Erythropoietin (Epoetin alpha)
– Erythropoietin is a glycoprotein normally made by the
kidney, that regulates red blood cell proliferation and
differentiation in bone marrow
– Erythropoietin deficiency results in a normocytic anemia
– Epoetin alfa is a glycoprotein manufactured by
recombinant DNA technology, and has the same
biological effects as endogenous erythropoietin
– is effective in the treatment of anemia caused by end-
stage renal disease, anemia associated with HIV, and
anemia in some cancer patients
– erythropoietin has had a significant positive impact for
patients with anemia of chronic renal failure
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 Pharmacokinetics:
– given IV or SC Half life of 4-13 hrs in patients with
chronic renal failure.
 Side Effects:
– a rapid increase in hematocrit & hemoglobin may
cause hypertension & thrombotic complications.
These can be minimized by raising the hematocrit
slowly and treating the hypertension.
 Contraindications:
– Uncontrolled hypertension
 Novel erythropoiesis stimulating protein (NESP), also
called darbepoetin alfa , lasts longer in the blood than
epoetin alfa and requires fewer injections.

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Thrombogenesis
 Hemostasis is the spontaneous arrest of
bleeding from damaged blood vessel
 The immediate haemostatic response of a
damaged vessel is vasospasm

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MECHANISMS OF BLOOD COAGULATION
 A clot that adheres to a vessel wall is called a thrombus,
whereas an intravascular clot that floats in the blood is
termed an embolus, a detached thrombus becomes an
embolus
 Both thrombi and emboli are dangerous, because they may
occlude blood vessels and deprive tissues of oxygen and
nutrients
 Physical trauma to the vascular system, such as a puncture
or a cut, initiates a complex series of interactions between
platelets, endothelial cells, and the coagulation cascade
 This results in the formation of a platelet-fibrin plug (clot)
at the site of the puncture

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 The creation of an unwanted thrombus involves many of the
same steps as normal clot formation, except that the
triggering stimulus is a pathologic condition in the vascular
system rather than an external physical trauma.
 At resting condition
 Platelets circulate freely since chemical signal indicate that
there is no vascular system damage.
 Prostacyclin binds to platelet membrane receptors,
causing synthesis of cAMP
 cAMP stabilizes inactive GP IIb/IIIa receptors and inhibits
release of granules containing platelet aggregation agents
or Ca2+.
• This results in decrease in thromboxane A2,
adenosine, serotonin, platelet activating factor ].
 When endothelium injured, platelets activated and trigger
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series of chemical reaction
 intrinsic pathway
Ⅻ Ⅻa
process of normal blood coagulation
+
Ⅺ Ⅺa
extrinsic pathway
+

Ⅸ Ⅸa Ⅲa,Ⅶa Ⅲ, Ⅶ

+ +
ⅩIII
Ⅹ Ⅹa Ⅹ

+ +

Prothrombin(Ⅱ) Thrombin(Ⅱa) ⅩIIIa

+ +
Fibrin Fibrin
fibrinogen (soluble) ( Insoluble)

Fibrin clot 40
Factor Common Name
Number
I Fibrinogen
II Prothrombin
III Tissue Factor
IV Ca2+
Va Proaccelerin
VII Proconvertin
VIII Antihemophilic Factor
IX Christmas Factor
X Stuart Factor
XI Plasma thromboplastin antecedent
XII Hageman factor
XIII Fibrin Stabilizing Factor

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Clotting Disorders /Coagulation Disorder
 Drugs used in abnormal clotting and bleeding are
shown blow:

Treatment
Disorder
Anti-platelets
Abnormal
clotting Anticoagulants
Coagulation
Disorders
Thrombolytics
Abnormal
bleeding
Coagulants

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2.1. Anti clotting Drugs
A) Antiplatelet Drugs
Platelet aggregation
 Is facilitated by thromboxane, ADP, fibrin, 5-HT,
and other substances.
 Inhibited by Prostacyclin and increased cAMP
Antiplatetes includes
NSAID (aspirin)
ADP receptor antagonist (Ticlopidine and Clopidogrel)
Glycoprotein IIb/IIIa receptor antagonist (abciximab)

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Aspirin
 NSAID inhibits thromboxane synthesis by blocking the
enzyme cyclo-oxygenase
 Inhibition by aspirin persists until new platelets are
formed (several days)
 Aspirin prevent further infarcts myocardial infarction,
transient ischemic attacks (TIAs), ischemic strokes and
other thrombic events
 Low dose aspirin used

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Ticlopidine and Clopidogrel
Ticlopidine:
Inhibit platelet aggregation by inhibiting ADP pathway
involved in binding of platelets to fibrinogen.
Used orally
Can cause bleeding and neutropenia so reserved for patients
who cannot tolerate aspirin.
Clopidogrel:
 Analog of ticlopidine and prevents ADP-mediated activation
of the glycoprotein complex GPIIb/IIIa, thereby inhibiting
platelet aggregation.
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Abciximab
 Glycoprotein IIb/IIIa receptor antagonist.
 It is a monoclonal antibody that inhibits the receptors that
form the final common pathway for platelet aggregation
 It can reduce platelet aggregation by more than 90%.
 It is given IV as an adjunct to percutaneous coronary
intervention for prevention of cardiac ischemic
complications.
 It is given with heparin and aspirin
Dipyridamole
 Coronary vasodilator, used prophylactically with aspirin to
treat angina.
 It increases intracellular levels of cAMP by inhibiting
phosphdiesterase.
 It is combined with warfarin
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Antiplatelet Drugs: Eptifibatide and Tirofiban
 Act similarly to Abciximab, blocking the GPIIb/IIIa
receptor.
 They mimic the arginine-glycine-aspartic acid
sequence of fibrinogen, which accounts for their
specific antagonism at this receptor.
 They decrease the incidence of thrombotic
complications associated with acute coronary
syndromes
 Used IV

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Toxicity of anti-platelates
 Aspirin: gastrointestinal
disturbances
 GP IIb/IIIa inhibitors:
bleeding and
thrombocytopenia
 Ticlopidine: bleeding and
neutropenia
 Dipyridamole: headache
and palpitation

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B) THROMBOLYTICS
 Rapidly lyse thrombi by catalyzing the formation
plasmin from its precursor plasminogen
 Create a generalized lytic state when administered
intravenously.
 Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
 Thrombolytic drugs reduce the mortality of acute
myocardial infarction
 Can be either endogenous tissue plasminogen
activators(t-PA): alteplase, teneplatase, reteplase or
protein synthesized by streptococi (Streptokinase)

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 The process of dissolution of clot is called
fibrinolysis

Endothelial
t-PA cells

Plasminogen Plasmin

fibrin Fibrin degraded

products

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 Plasminogen

Streptokinase + - EACA
Urokinase Tranexamic acid
Alteplase Aprotinin

Fibrinolytics Plasmin Antifibrinolytics

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Streptokinase
 Streptokinase is a non-enzyme protein isolated from
streptococci; it binds to plasminogen to catalyze the
conversion of plasminogen to active plasmin.
 It acts on both circulating plasminogen and fibrin-bound
plasminogen.
 It is used in AMI and stroke, acute pulmonary embolism,
DVT, and reperfusion of occluded peripheral arteries.
 It is also used to clear occluded venous catheters.

Adverse effects: systemic bleeding, allergic reactions

in patients having streptococcal antibodies

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Urokinase
 A protease originally isolated from urine; the drug is now
prepared in recombinant form from cultured kidney cells.
 Urokinase activates circulating and fibrin-bound
plasminogen
 Urokinase is approved for the treatment of pulmonary
embolism.
 It is less antigenic than streptokinase and is indicated in
patients sensitive to streptokinase

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Clinical Use of Thrombolytics
Acute Myocardial Infarction
Pulmonary Embolism
Deep Vein Thrombosis [DVT]
Arterial Thrombosis or Embolism

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C) ANTICOAGULANTS
 These are drugs which interfere with the coagulation
of blood either in vivo or in vitro
 They are used clinically to prevent the extension of
an existing thrombus and stop formation of new
thrombi in the vascular bed

Classification of anticoagulants
A. Parenteral anticoagulants
B. Oral anticoagulants

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I. Parenteral anticoagulants
 Substances which inhibit conversion of prothrombin to
thrombin and interfere with the action of thrombin on
fibrinogen
Indirect thrombin inhibitors
Heparin and Low molecular weight heparin
Direct thrombin inhibitors
lipirudin and Danaparoid
II. Oral anticoagulants:
 Substances which interfere with synthesis of
prothrombin and factor VII, IX and X.
 These agents comprises:
 Coumarins, e.g. Warfarin, Dicoumarol,
Tromexan, Cyclocoumar

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Indirect thrombin inhibitors
- Include unfractionated heparin (UFH = heparin) & low
molecular weight heparin (LMWH)
Mechanism of action of Heparin
A. It acts indirectly by markedly increasing the activity of
antithrombin-III (heparin- antithrombin-III complex)
that inhibits several activated clotting cofactors,
namely; IIa, IXa, Xa, XIa & XIIa); most importantly
thrombin & factor Xa
B. Antithrombin III then inhibits the conversion of
prothrombin to thrombin

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Low Molecular Weight Heparin (LMWH)
Low molecular weight heparin is synthesized by
depolymerization of heparin
unlike heparin which has equivalent activity against factor Xa &
thrombin, LMWHs have greater activity against factor Xa
DIRECT THROMBIN INHIBITORS
Lepirudin, Danaparoid:
Directly bind to the active site of thrombin inhibiting thrombin's
downstream effects thus exerting their antithrombotic activity
Anticoagulant in vivo only
Advantages over UFH:
Useful in patients with heparin – induced thrombocytopenia

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Anticoagulants: Heparin
 Mucopolysaccharide
 Metabolized partially in the liver to uroheparin by
heparinase, which has only slight antithrombin activity.
 20-50 % is excreted unchanged.
 The heparin polysaccharide chain is degraded in the
gastric acid administered IV or SC
 Heparin should not be given IM {due to danger of
hematoma formation}.

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Anticoagulants: Heparin
Unfractionated heparin (UFH)
 Mol weight: 3000-30000
 Also inhibits the effects of factor Xa on the
coagulation cascade & limits platelet aggregation.
 Heparin-induced thrombocytopenia
 is systemic hypercoagulable state
 platelet count falls below the lower limits of normal
or by 50% but remains in the normal range.
 Platelets are activated by Immunoglobulin G causing
platelet aggregation

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ORAL ANTICOAGULANTS ( VIT. K antagonists)
 Coumarin anticoagulants include warfarin and dicumarol
Mechanism of action:
 It inhibits vitamin K reductase & vitamin K epoxide reductase
enzymes, so blocking the activation of vitamin K
 This leads to inhibition of the synthesis of factors II, VII, IX & X
Adverse drug reaction
Hemorrhage
Teratogenicity
Hair loss (alopecia)
Hypersensitivity
Cutaneous necrosis
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Warfarin: indication
Warfarin is given orally.
After absorption from intestine, it is largely bound 99%
to plasma albumin
It is eliminated by liver metabolism, and its t½ is about
36 h .
To adjust the dose, Lab. control of anti-coagulation is
done using INR
Therapeutic uses of Warfarin
I. DVT: Treatment is started with Heparin for 5-7
days (either LMW heparin SC OR IV UFH ( in case PE
is also present ) , and then continue anti-coagulation
with warfarin (INR 2.5- 3) for about 6 weeks in
case of DVT alone, OR 3 months in cases complicated
by PE ; the aimis to maintain anti-coagulation in order
to prevent recur

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II. Long-term use of Warfarin : for about 12 months
a. Recurrent DVT or recurrent PE ( INR 3-4)
b. Prosthetic cardiac valves (INR 3-4)
c. Atrial fibrillation esp. if chronic or recurrent or
complicating mitral valve disease (INR 2.5-
d. Myocardial infarction in young men (< 50 year

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Adverse effects of Warfarin
1. Overdose bleeding : stop drug for few days; the
specific antidote is vitamin K given in dose of 5 mg IV
for serious bleeding OR 0.5-2 mg for mild bleeding ; it
takes about 3-5 h to induce synthesis of effective clotting
factors by liver. In urgency : transfusion of blood or fresh
plasma or prothrombin complex concentrate ( contains
factors II, IX, and X) is needed to stop the bleeding
 Note : Vitamin K IV may render patient resistant to
warfarin anti-coagulation for about 1-2 weeks , but
heparin remains effective during this period

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2. Teratogenicity : warfarin passes across the placental
barrier to reach the fetus during pregnancy; its use may be
associated skeletal malformations; CNS malformations,
probably due to intra cerebral bleeds. The anticoagulant
action render fetus susceptible to bleeding. It should be
stopped before labor and heparin substituted.
3. Skin necrosis : may occur early with its use & esp. in
those patients with hereditary deficiency of protein C or S
4. Allergy : include skin rashes; these are rare

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Warfarin: disease-drug-interaction
 Decreased absorption due to diarrhea or binding
to cholestyramine
 Hepatic microsomal enzyme induction : e.g. use
of phenobarbital, phenytoin, Rifampin
 Hereditary resistance : due to reduced
sensitivity of epoxide reductase to warfarin
 Hypothyroidism
 Pregnancy or use of combined estrogen cont

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 Hepatic microsomal enzyme inhibitors e.g.
cimetidine, ciprofloxacin, imidazole antifungals, protease
inhibitors for HIV, OR competitive inhibition of
warfarin metabolism by other drugs e.g.
cotrimoxazole, metronidazole
 Hyperthyroidism : due to increased turnover of
plasma clotting factors
 NOTE : NSAIDs may cause gastric irritation and
erosions and also inhibit platelet aggregation so
increase the risk of bleeding from warfarin; thus NSAIDs
should be avoided

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 Increased anti-coagulant effect (with increased risk of
bleeding) occurs with :
 Vitamin K deficiency due to malabsorption
resulting from biliary obstruction or intestinal
disease, or from prolonged use of broad spectrum
antimicrobials e.g. tetracyclines
 Displacement of warfarin from binding to
plasma albumin by salicylates and other
NSAIDs, anti-microbials such as sulfonamides
 Liver disease

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2.2. Drugs used to treat bleeding/ Coagulants
 Bleeding problems may have their origin in naturally
occurring pathologic conditions, such as hemophilia, or
as a result of fibrinolytic states that may arise after
gastrointestinal surgery or prostatectomy
 The use of anticoagulants may also give rise to
hemorrhage
 Certain natural proteins and vitamin K, as well as
synthetic antagonists, are effective in controlling this
bleeding
 For example, hemophilia is a consequence of a
deficiency in plasma coagulation factors, most
frequently Factors VIII and IX.
 Concentrated preparations of these factors are
available from human donors.
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A. Aminocaproic acid: inhibit plasminogen
activation, are orally active, and excreted in the
urine. A potential side effect of treatment is
intravascular thrombosis.
B. Protamine sulfate: antagonizes the anticoagulant
effects of heparin and is derived from fish sperm or
testes and is high in arginine content, which explains
its basicity. The positively charged protamine interacts
with the negatively charged heparin, forming a stable
complex without anticoagulant activity.
C. Vitamin K: Important for clotting factor synthesis
D. Aprotinin: Stop bleeding by blocking plasmin

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