BLOOD

PHARMACOLOGY
By: Dawit Z. (B.Pharm, MSc.)
December 3, 2018

Department of Pharmacology,
School of Pharmacy
CHS -MU 1
 Objectives
 To discuss the various types of anemia
 To elaborate the use of iron to treat iron deficiency
anemia, the use of Vitamin B12 and folic acid to treat
megaloblastic anemia
 To discuss the indication of heparin and oral
anticoagulants
 To identify major adverse reactions associated with
heparin and other oral anticoagulant agents

2
Brainstorming Questions
 Define Hematopoiesis, Anemia?
 Write the different Classification of anemia ?
 Write at least 5 examples of Iron preparations?
 Write the definition of hemostasis, fibrinolysis,
blood coagulation, thrombosis, emboli?
 Write at least an example of coagulant ?
 List example of parenteral anticoagulant agents
and oral anticoagulant agent?
 Write the major adverse effects of Warfarin and
Heparin?
Hematopoiesis:
 Refers to the process of production of blood cells
[erythrocytes, platelets and leukocytes] from
undifferentiated stem cells.
The hematopoietic machinery resides primarily in the bone
marrow
 Requires a constant supply of three essential nutrients
 Iron
 Vitamin B12
 Folic acid
Hematopoietic growth factors are also very important
Regulate proliferation and differentiation of hematopoietic cells
4
Anemia = anemia, Greek; lack of blood
 Most common nutritional and blood disorder in the world
 Most common blood disorder too
 Characterized by  in hemoglobin or RBCs, resulting
in decreased oxygen-carrying capacity of blood
Definition of anemia: according to WHO criteria:
 Adult men
 Blood hemoglobin concentration < 13 g/dl or
 Hematocrit < 39%
 Adult women
 Blood hemoglobin concentration < 12 g/dl or
 Hematocrit < 37%
5
 Anemia can be broadly classified based on:
1. Pathophysiology
Blood loss

Inadequate RBC production

Excessive RBC destruction

2. Morphologic classification based on:

 RBC size: microcytic, normocytic or macrocytic

 Hb content: hypochromic, normochromic,

hyperchromic
3. Pregnancy/lactation induced anemia
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 Classification of anemia
1. Deficiency anemia
A. Iron-deficiency anemia
 Causes hypochromic, microcytic anemia
B. Folic acid, VitB12 (or both) deficiency anemia
 Megaloblastic anemia (large, immature and dysfunctional RBCs)
 Hyperchromic, macrocytic anemia
 Pernicious anemia: Form of megaloblastic anemia

• Due to lack of intrinsic factor responsible for the

absorption of vit. B12
C. Pyridoxine and vitamin C deficiency
D. Hematopoietic growth factors deficiency
7  Erythropoietin
Classification of anemia…

2. Aplastic anemia: normocytic anemia

• Severe anemia in which the capacity of bone marrow cells to
generate red blood cells is diminished
• May be primary (idiopathic) or secondary

• Secondary causes may be:

 Exposure to X- ray or radiation therapy

 Idiosyncrasy to certain drugs (e.g. CAF, thiouracil)

 Reduced production of, or responsiveness to, erythropoietin

(e.g. in chronic renal failure, rheumatoid arthritis, AIDS )
8
Classification of anemia…

3. Hemolytic anemia (excessive destruction of RBCs)

 Possible causes include:

 Hemoglobinopathies (such as sickle cell anemia)

 Adverse reactions to drugs (e.g. primaquine)
 Inappropriate immune reactions
 Disease condition ( Eg. Malaria)
 Hereditary (G6PD deficiency)

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 Antianemic drugs/ hematinic agents
Agents effective in iron – deficiency anemia

Iron: has several vital functions in the body, its major role being as
an oxygen carrier in blood hemaglobin and muscle myoglobin

• In addition, it is a component of many enzymes e.g. cytochromes

10
 Absorption of Iron
 5-10% absorbed in normal individual

 10-20% absorbed in anemic individual

 Dietary iron is available in two valency states, Fe2+ and Fe3+

 Only ferrous form of iron is readily absorbed

 Absorption sites are the duodenum and upper jejunum

Factors that influence iron absorption from GIT

 Valency: Ferrous (Fe2+) iron is readily absorbed than ferric (Fe3+) iron
 Fe2+ is the soluble and absorbable form of iron

 Gastric acidity
• Gastric acid lowers the pH that enhance the solubility and uptake of ferric iron

11  increase the conversion of Fe3+ to Fe2+

Factors that influence iron absorption from GIT…

 Dietary factors : Best absorbed from meat, fish and poultry

• Poorly absorbed from vegetables, grain products, dairy products & eggs

• Administration of iron therapy with a meal ↓es absorption but can be

needed to improve tolerability

 Enhancers of dietary non-haem iron absorption

• Vitamin C found in fruits and vegetables

Reduce ferric iron to ferrous , Protects ferrous form from being oxidized
and Stimulates iron absorption by forming soluble iron complexes

Fructose, succinate, citrate and various amino acids stimulate iron

absorption by forming soluble iron complexes
12
Factors that influence iron absorption from GIT…
 Inhibitors of dietary non-heme iron absorption

 Chelators / complexing agents

• Phosphates (rich in egg yolk)

• Drugs: tetracyclines, Fluoroquinolones

• Presence of cereals food in stomach (phytates)

• Coffee and tea (tannins, polyphenolic compounds )

 Alkalines (antacids): reduce iron solubility and its

reduction
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Causes of iron deficiency anaemia
 Increased demand for iron (pregnant and nursing women, infants,
rapidly growing children)
 Commonly manifest
 Inadequate iron absorption (GIT problem, gastrectomy, drug
such as TTC, Fluoroquinolone, antacids…)
 Inadequate dietary intake
 Increased blood loss (menstruation, GI bleeding)

 Iron sequestration: hemosiderosis

 Hemoglobinuria
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Iron preparations
1. Oral iron preparations
 Preferred route (normal GI absorption of iron)

• Ferrous sulfate, Ferrous gluconate, Ferrous fumarate and

Ferrous succinate
Adverse effects:
 Common: nausea, epigastric discomfort, abdominal cramps, diarrhea (GI irritant
effects of iron); black stools
 Adverse effects are usually dose-related and can often be overcome by

• Lowering daily dose and

• Taking immediately after or with meals

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2. Parenteral iron preparations
• Iron dextran, Iron sucrose complex and Iron
sodium gluconate complex
 Iron sodium gluconate and iron sucrose are with a lower risk of

anaphylaxis and appear to be better tolerated than iron dextran

Parenteral administration is indicated only for specific cases

• Oral iron is not tolerable: too much bowel upset

• Inflammatory bowel disease, chronic inflammation (RA)

• Sever deficiency with chronic bleeding

• Advanced chronic renal disease: treatment with erythropoietin to

induce rapid erythropoiesis
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Vitamin B12-deficiency anemia
 Vitamin B12 daily requirement is about 2 mcg
 Cofactor for several essential biochemical reactions
 Deoxyadenosylcobalamin and methylcobalamin are active forms in
humans
 The chief dietary source of vitamin B12 is microbially derived meat
(especially liver), eggs and dairy products
 All vit B12 comes from the diet and present in all food of animal origin
 After being ingested, vit B12 is bound to intrinsic factors (protein secreted
by gastric parietal cell)
 PO / Parenteral Cyanocobalamin and hydroxycobalamin are
vitamin B12 preparations used clinically
 It is an important cofactor for vital reaction in human body
• Haemoglobin, myelin sheath and neurotransmitters synthesis
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 Folic acid-deficiency anemia
 Inadequate dietary intake of folates, decreased absorption

 Drugs: methotrexate, phenytoin…

 Increased demand: Chronic hemolytic anemia, pregnancy, Loss:

dialysis
• The clinical features of folate-deficient megaloblastic anemia are
similar to those of vitamin B12 deficiency
• Unlike vitamin B12 deficiency, folate deficiency does not
cause characteristic neuropathy
• Alcoholics and patients with liver disease develop folic acid deficiency

 Poor diet or diminished hepatic storage of folate

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 Oral folic acid is well absorbed even in patients with
malabsorption syndrome
• Parenteral route rarely used

 Folic acid supplementation to prevent folic acid deficiency

should be considered in high risk patients
• Alcoholic dependence

• Hemolytic anemia

• Liver disease

• Certain skin diseases

• Patients on dialysis
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 Folic acid deficiency during pregnancy → fetal neural
tube defect like Spinal bifida (congenital defect in which a
vertebra is malformed) and anencephaly (A defect in brain
development resulting in small or missing brain hemispheres).

20 02-Dec-18
Hematopoietic growth factors
 Glycoprotein hormones that regulate the proliferation and
differentiation of hematopoietic progenitor cells in the bone marrow
 Erythropoietin

• Produced by the kidney

• Produced and released in response to blood loss/or low tissue oxygen

tension and Regulates RBCs production
• Two forms of recombinant human erythropoietin

 Epoetin alfa – given iv or sc

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 Darbepoetin alfa (longer duration) - given iv or sc
Therapeutic uses
• Anemia of Chronic Renal Failure

• Anemia during chemotherapy for cancer

• Prevention of anemia that occurs in premature infants

• Anemia of AIDS (exacerbated by zidovudine therapy)

• Anemia of chronic inflammatory conditions

Adverse effects:

• Hypertension, thrombotic complications, iron

deficiency
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 DRUGS USED IN DISORDERS
OF COAGULATION

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 Hemostasis
 The arrest of blood loss from damaged vessels while maintaining
blood fluidity
 The main phenomena:

• Platelet activation, aggregation

• Blood coagulation (fibrin formation) and

• Vascular contraction

 Platelet activation leads to formation of a haemostatic plug

• Stops bleeding and is subsequently reinforced by fibrin

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 Regulation of Hemostasis
 Clotting (Blood coagulation) Regulation Mechanism

 Clotting Inhibitors or enzymatic inhibitors

 Fibrinolytic System

These mechanisms involve

Prostacyclin Antithrombin
(PGI2) III Proteins C and S

Tissue Factor Tissue-type

Pathway Inhibitor Plasminogen Activator
(TFPI) (t-PA)
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 Regulation of Hemostasis continued…
Enzymatic inhibitors

• Antithrombin III: an endogenous anticoagulant and is a

member of the serine protease inhibitors

 Inactivates the serine proteases: IIa, IXa, Xa, XIa

and XIIa

• Protein C and protein S: attenuate blood-clotting

cascade by proteolysis of the two factors Va and VIIIa
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 Regulation of Hemostasis continued…

, XIa and XIIa

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 Regulation of Hemostasis continued…
Fibrinolysis/ Thrombolysis
 Physiological pathway by which Clots are dissolved
 It starts shortly after its formation…to allow blood flow to be
reestablished & tissue repair

 Plasmin (fibrinolysin): digests fibrin strands, fibrinogen,

factors(II,V &VIII), other proteins
 Plasminogen activators: activate plasminogen to plasmin
• Tissue type plasminogen activators - tPA and
• Urinary-type plasminogen activator (uPA)

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 Regulation of Hemostasis continued…
• Thrombosis is unwanted formation of a hemostatic plug or
thrombus consisting of platelets, fibrin, red cells and white cells in the
arterial or venous circulation
• Emboli: is when the formed thrombosis is broken and move from its
site of formation to other part of the vascular system
 Cause ischemia and infarction, tissue necrosis

• Factors that increase risk of thrombosis

 Vascular injury
 Altered blood flow, turbulence
 Increased blood coagulation
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 Regulation of Hemostasis continued…
Blood Coagulation
A process by which fibrin strand form and create a meshwork that

cement blood component together

A stepwise series of enzymatic reactions that results in the

formation of a fibrin mesh

Most plasma coagulation factors circulate as inactive proenzymes ⇒

activated through proteolytically cleavage by the activated factors

that precede them in the cascade

• Can be triggered via either the intrinsic or extrinsic pathways

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 Blood Coagulation…
Intrinsic/contact path way Extrinsic pathway

• Activated by vessel injury • Activated by vessel injury

• Also activated when shed blood • Faster process

comes into contact with an
• Some components come
artificial surface such as glass
from outside the blood
• Relatively slow process

• All components are present in

blood
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 Coagulation Defects
 Congenital coagulation disorders (genetic)
 Classic hemophilia or Hemophilia A: FactorVIII deficiency

 Hemophilia B: Factor IX deficiency

Treatment

 Replacement of missing factors by giving fresh plasma

 Supplement with concentrated preparation of factors VIII or IX

 Acquired clotting defects

 More common

 Causes may include: liver disease, vitamin K deficiency and excessive

oral anticoagulant therapy
 These condition may require treatment with vitamin K
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 Interference Through Hemostasis

 Coagulants

 Anticoagulants

 Fibrinolytic/thrombolytics

 Anti-fibrinolytic drugs

 Anti-platelet drugs

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 COAGULANTS
VITAMIN K
 A fat soluble vitamin occurring naturally as

 Vitamin K1, or phytonadione (AKA phylloquinone) is found in

plants

 A series of bacterial menaquinones (vitamin K2) Vit k2

(menaquinone)

 Considerable synthesis occurs in gram (+) bacteria

 Intestinal flora (gut flora) synthesize it in human

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 COAGULANTS continued…

 It is essential for the formation of clotting

factors II, VII, IX and X [glycoproteins with

γ-carboxyglutamic acid (Gla) residues] in
liver

 Required for post-translational modifications of

glutamic acid residues on clotting factors that

allow these proteins to bind to the membranes

 γ-carboxylation occurs after the synthesis of the

amino acid chain, and the carboxylase enzyme

requires Vitamine k (reduced form – hydroquinone)

35
as a cofactor
 COAGULANTS continued…
Preparation
 Vitamine k1 (phytomenadione) -available orally or parenterally
 Synthetic preparation: menadiol sodium diphosphate – is a water
soluble
Clinical use of Vitamin K
 Treatment and /or prevention of bleeding
 Bleeding due to excess oral anticoagulants (e.g. Antidote for
warfarin)
 Hemorrhagic disease of newborns (low level of prothrombin & other
clotting factors)
 For vitamin k deficiencies in adults i.e. absorption problems
 Chronic antimicrobial therapy
 Liver disease and Obstructive jaundice

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 Anticoagulants
A. Substances which remove ionic calcium

Ca precipitant: oxalates of potassium and sodium

 Use to prevent blood clotting in vitro system

Drugs which diminish ionizable calcium

 Sodium citrate and edetate

 Form soluble non ionizable chelate

 3.8% of sodium citrate is used to maintain the fluidity of

blood for transfusion

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Anticoagulants…
B. Substances which interferes with synthesis of factors,
II,VII, IX and X (Oral anticoagulants)
 Warfarin, dicumarol, acenocoumarol,
phenoprocoumon
C. Substances which inhibit thrombin

 Heparin, Fondaparinux: activates antithrombin III

 Hirudin, lepirudin, bivalirudin: direct thrombin

inhibitors
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 Oral anticoagulants
 Warfarin: the prototype drug for the groups.
 Anticoagulant of choice for long-term or extended anticoagulation
 An oral anticoagulant with a delayed onset of effect that acts as a
vitamin K antagonist
 Active only in vivo
Mechanism of action
 Inhibit vitamin K epoxide reductase (VKOR) which is responsible
for the cyclic interconversion of vitamin K in the liver
 Reduced vitamin K is a cofactor required for the γ-carboxylation of
clotting factors: II, VII, IX, and X, as well as for the synthesis of
endogenous anticoagulant proteins C and S
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 Mechanism of warfarin

40
 Oral anticoagulants Contd…
 The time required for warfarin to achieve its pharmacologic effect is

dependent on the elimination half-lives of the coagulation proteins

 It takes ~5 to 7 days to kick off its antithrombotic effect

 Warfarin usually is started concurrently, and the heparin or heparin

derivative is continued for at least 5 days until effect of warfarin

commences

41
Oral anticoagulants…
Pharmacokinetics

• Warfarin is absorbed rapidly and completely from GIT

• Strong affinity to plasma albumin (99%)

• Warfarin crosses the placenta (concentration in fetal plasma

approaches the maternal values)

• Secreted into milk in a very small amount

 Poses little risk to breastfed infants

42
 Drug interactions with oral anticoagulants
Drugs that reduce their effect:
• Enzyme inducers: Rifampin, barbiturates, griseofulvin,
carbamazepine …
• Cholestyramine: Interfere with absorption

• Increased Vit k level

• Other factors: physiological state/ disease

 Pregnancy (↑ coagulation factors synthesis)

 Hypothyroidism (↓ed turnover rate of clotting factors)

 Contraindication : GI bleeding or open wounds ,
hypersensitivity, severe liver or kidney disease, pregnancy,
43
Drug interactions with oral anticoagulants…
Drugs that enhance their effect:
• Enzyme inhibitors: Cimetidine, CAF, metronidazole,
allopurinol, disulfiram, erythromycin, amiodarone,
antifungal azoles etc...
• Drugs that inhibit platelet function: aspirin

• Inhibition of Vitamin k synthesis: oral cephalosporins

• Inhibition of Vitamin K absorption e.g. liquid paraffin

• Displacement from the binding sites on plasma albumin

 Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides,

diazoxide, clofibrate
44
Adverse effects of warfarin
 Risk of bleeding:
 To shorten the time to correction of overanticoagulation
 Withhold warfarin, adjusting the dose of warfarin, and administer a small oral
dose of vitamin K…for minor problems
 Patients with warfarin-associated major bleeding require administration of
fresh frozen plasma or coagulation factor concentrates and
supplementation with high-dose IV vitamin K (10 mg) via slow IV injection
 Skin Necrosis
 Warfarin-induced skin necrosis is a rare condition characterized by painful
discoloration of the breast, buttocks, thigh, or penis within 3 to 6 days of the
initiation of warfarin therapy
 Purple toe syndrome…a reversible, sometimes painful, blue-
tinged discoloration of the plantar surfaces and sides of the toes
 Warfarin causes a birth defect, abortion, neonatal intracranial
hemorrhage, intrauterine death, still birth
• Contraindicated (C/I) to pregnant woman
45
 ANTICOAGULANTS: Parenteral Agents
HEPARIN (Standard heparin (unfractionated heparin [UFH])

 A glycosaminoglycan found naturally in the granules of mast cells

(heterogeneous mixtures of sulfated glycosaminoglycans)

 Commercially obtained from bovine lungs or porcine intestinal

mucosa

 Inhibits coagulation, both in-vivo and in-vitro

 Strongly acidic and carries strong electronegative charge

 A rapid-acting anticoagulant that is administered IV or SC

46
 Mechanism of Action of Standard Heparin
 UFH binds to antithrombin-III through its specific pentasaccharide

sequence ⇒ provoking a conformational change ⇒ accelerates

antithrombin interaction with clotting factors
 The Heparin-antithrombin complex is 100 to 1,000 times more

potent than antithrombin alone

 The heparin-AT complex irreversibly inactivates factor IIa
(thrombin) and factor Xa, as well as activated factors IX, XI, and
XII…thrombin and Xa are most sensitive to inhibition

47
 Pharmacokinetics: Unfractionated heparin:UFH
 Poor oral bioavailability…should be given i.v or s.c
 Has a dose-dependent half-life of ~ 30 to 90 mins, in high doses
to as much as 150 mins
 The SC bioavailability is dose dependent and ranges from 30% at
low doses to as much as 70% at high doses
 Binds to plasma proteins
 Onset of anticoagulant effect is usually 1-2 hrs after SC injection
 Degraded primarily by the reticuloendothelial system; Small
amount of intact heparin appears in the urine
 Unfractionated heparin (High molecular weight) is
preferred in patients with severe renal insufficiency
48
 Bleeding Adverse Drug Reactions: UFH
 The most common bleeding sites are the GI tract, urinary tract, and soft tissues.
 If major bleeding occurs, UFH should be discontinued immediately and IV
protamine sulfate slow IV infusion over 10 minutes (1mg/100 units of UFH
infused during the previous 4 hours; maximum 50 mg).
 Thrombocytopenia (platelet count less than 150,000/mm3)
 Heparin-associated thrombocytopenia is a benign, transient, and
mild
 Heparin-induced thrombocytopenia (HIT) is a serious immune-
mediated
 Reductions in platelet count of>50% from baseline
 A rare drug-induced immunologic reaction
 Occurs more frequently with bovine lung heparin
 A life-threatening condition with high morbidity and mortality though
low incidence
 Can lead to significant venous and arterial thrombosis, as well as
thromboembolic stroke, acute MI, skin necrosis, and thrombosis of other
major arteries
 Adverse Drug Reactions: UFH
 Bruising, local irritation, mild pain, erythema, histamine-
like reactions, and hematoma can occur at the site of
injection

 Osteoporosis

 Hyperkalemia (due to hypoaldosteronism)…rare

 Hypersensitivity Reactions…rare

 Urticaria, chills, fever, rash, rhinitis, conjunctivitis,

asthma, and angioedema

 Priapism, and a reversible temporal alopecia

Measures to manage heparin hemorrhage

 Stop therapy

Specific antidote (heparin antagonist)

oProtamine sulfate– as strong basic protein which forms

an inactive complex with heparin – given IV as 1% solution

oNB. Large dose of protamine sulfate cause bleeding

 Fresh blood transfusion (if excessive blood loss)

51
LOW-MOLECULAR-WEIGHT HEPARINS
• AKA: Fractionated heparin

• LMWH fragments produced by either chemical or

enzymatic depolymerization of UFH
• Enoxaparin, dalteparin, tinzaparin
• Inhibit factor Xa with lesser effect on factor IIa

• Administered SC.

• In comparison to UNFRACTIONATED HEPARIN (UFH), LMWH has:

 Equal efficacy, ed bioavailability, less frequency of

52
administration and lesser antiplatelet action
 LOW-MOLECULAR-WEIGHT HEPARINS
Low-Molecular-Weight Heparins
 LMWHs has a similar mechanism of action as UFH, but with reduced
(LMWHs)
inhibitory activity against thrombin (because they cannot bind
both AT and thrombin simultaneously) relative to factor Xa

 To inactivate factor Xa, only the Antithrombin component of the

heparin-AT complex is required to bind to factor Xa

Advantages of LMWHs over UFH

–
•Predictable anticoagulation dose response
• Improved SC bioavailability
• Dose-independent clearance
• Longer biologic half-life
• Lower incidence of thrombocytopenia, and
53 • Reduced need for routine laboratory monitoring
 Pharmacokinetics: LMWHs
 LMWH has a more predictable anticoagulation response

 Bioavailability ~ 90% after SC

 Anticoagulation effect is seen in 3 to 5 hrs

 Elimination is renal

 Half-life 3 to 6 hrs

 Clearance is independent of dose

54
 Therapeutic uses of anticoagulants
 Prevent clot formation or extension of the clot

 No effect on the preformed clots

 Treatment of thromboembolic disease

• MI (coronary thrombosis)

• Venous thrombosis

• Thrombosis of central retinal vein or artery

• Cerebral thrombosis or embolism

• Pulmonary embolism
55
 Therapeutic uses of anticoagulants…

 Prophylactically to prevent thromboembolic complication

following surgery

• Minimum dose of heparin – deep vein thrombosis and

pulmonary embolism

 To prevent blood clotting during transfusion

 To prevent embolism in patient with long standing

atrial fibrillation
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 Fibrinolytic/ thrombolytic agents
• Agents that promote dissolution of thrombi / emboli

• Stimulate the activation of endogenous plasminogen to plasmin

which subsequently degrades the fibrin matrix, fibrinogen, clotting

factors (II, V and VIII)

1. Streptokinase (Stk)

• Protein derived from β hemolytic streptococci group C bacteria

• Inactive as such, Stk combined with plasminogen form enzymatic

complex
57
 The fibrinolytic/ antifibrinolytic system

58
Fibrinolytic/ thrombolytic agents…

• The complex convert plasminogen to plasmin

• Antistreptococcal antibodies present due to past infections

inactivate considerable fraction of the initial dose of Stk

• Stk is antigenic; can cause hypersensitivity reaction and

anaphylactic shock , especially when used for 2nd time

 It should be used after 1 year of a previous use

• Repeated doses are less effective due to neutralization.

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Fibrinolytic/ thrombolytic agents…
2. Urokinase
• Proteolytic enzyme formed by kidneys & found in urine

• Derived from human urine

• Converts plasminogen to plasmin

• Non-antigenic

3.Tissue plasminogen activators (tPA):

 Alteplase, Duteplase, Reteplase ,Tenecteplase

 Proteases preferentially activate fibrin bound plasminogen

• Avoid systemic activation “clot selective”

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• Facilitate fibrinolysis to the formed thrombus
Fibrinolytic/ thrombolytic agents…
Therapeutic uses
• Acute Myocardial Infarction {MI} (Coronary
thrombosis)
• Deep vein thrombosis {DVT}

• Pulmonary embolism

Adverse effects
• Hemorrhage (GIT & Stroke)

• Allergic RXN (Streptokinase)

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Anti-fibrinolytic agents
 Prevent plasminogen activation and dissolution of clot
Aminocaproic acid, tranexamic acid
• Competitively inhibit plasminogen activation
Clinical uses
 Treatment of bleeding from fibrinolytics
 Adjunct therapy in hemophilia
 Treatment of postsurgical and postprostatectomy bleeding
 Treatment of bladder haemorrhage secondary to radiation and drug
induced cystitis
Aprotinin
• Inhibits plasmin and thus fibrinolysis

• Approved use for Patients undergoing coronary artery bypass grafting

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who are at high risk of excessive blood loss
 Antiplatelet drugs
 Drugs that prevent platelet aggregation

Aspirin
 It acetylates and irreversibly inhibits cyclooxygenase (primarily COX-1)
both in platelets, preventing the formation of TxA2, and in endothelial cells,
inhibiting the synthesis of PGI2
 Goal of therapy with aspirin to selectively inhibit the synthesis of platelet
TxA2

• Small doses of aspirin are used as a prophylactic therapy against

cardiac and cerebral ischemic vascular disease
• Increased doses of ASA: benefit from high dose??????
63
Antiplatelet drugs… • Inhibits ADP-dependent platelet

 Dipyridamole aggregation

• Inhibits platelet PDE enzyme Epoprostenol (PGI2)

leading to ↑cAMP  Inhibits platelet aggregation
through elevation of cAMP
 Prevents platelet aggregation
 Others: abciximab, tirofiban,
 Augment the antiadhesive effect
eptifibatid
of prostacyclins
 Block platelet glycoprotein
• Has also vasodilator and anti -
IIb/IIIa receptors
anginal effect
 Ticlopidine, Clopidogrel

• Irreversibly block ADP

64 receptor on platelets
 Therapeutic uses of antiplatelet drugs
 The main drug is Aspirin. Other drugs are used as adjunct
or used to replace aspirin in patients who are intolerant.
• Prevention of myocardial infarction
• Prevention of thrombosis in patients undergoing placement
of coronary stent (clopidogrel/ticlopidine)
• Prevention of recurrence of transient cerebral ischaemic
attack, thrombotic stroke or unstable Angina pectoris
• Prevention of thromboembolism in patients having atrial

65
fibrillation, if oral anticoagulant is contraindicated
66