3. • Hematopoiesis: The production of erythrocytes,
platelets and leukocytes from undifferentiated stem cells
• The hematopoietic machinery:
Resides primarily in the bone marrow
Requires a constant supply of essential nutrients
Iron
Vitamin B12
Folic acid
• Hematopoietic growth factors are also very important
• Regulate proliferation and differen. of
hematopoietic cells
3
4. • Thrombocytopenia and neutropenia are not rare,
and some forms are amenable to drug therapy.
• Anemia 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%4
5. Anemia can be broadly classified based on:
• Pathophysiology
• Blood loss
• Inadequate RBC production
• Excessive RBC destruction
• Morphologic classification based on:
• RBC size: microcytic, normocytic or macrocytic
• Hb content: hypochromic, normochromic, hyperchromic
• Etiology
• Deficiency
• Central (impaired bone marrow function)
• Peripheral5
6. Classification of anemia
1.Deficiency anemia
A. Iron-deficiency anemia
• The most common form of chronic anemia
• Causes hypochromic, microcytic anemia
• Sign and symptom
• Pallor , fatigue, dizziness, exertional dyspnea, and
other generalized symptoms of tissue hypoxia
6
7. Classification…
7
B. Folic acid, VitB12 (or both) deficiency anemia
Megaloblastic anemia (large, immature &
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 & vitamin C deficiency
D. Hematopoietic growth factors deficiency
Erythropoietin
8. Classification of anemia…
2. Central : Aplastic anemia: normocytic anemia
• Severe anemia in which the capacity of bone marrow
cells to generate blood cells is diminished
• May be primary (idiopathic) or secondary
• Secondary causes may be:
o Exposure to X- ray or radiation therapy
o Idiosyncrasy to certain drugs (e.g. CAF, thiouracil)
o Reduced production of, or responsiveness to,
erythropoietin (e.g. in chronic renal failure,
rheumatoid arthritis, AIDS )8
9. 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 reactions9
10. Antianemic drugs/ hematinic agents
10
Agents effective in iron – deficiency anemia
Iron
• Iron forms the nucleus of the iron-porphyrin heme
ring, which together with globin chains forms
hemoglobin.
• In addition, it is a component of many enzymes
(e.g. myoglobin, cytochromes,
and other proteins with
diverse biologic functions.)
11. 11
Iron…
Absorption
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
12. 12
Iron…
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
increase the conversion of Fe3+ to Fe2+
13. 13
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
14. 14
Factors that influence iron absorption from GIT…
Enhancers of dietary non-haem iron absorption
• Vitamin C found in fruits and vegetables
Reduce ferric iron to ferrous
Protects ferrous form being oxidized
Stimulates iron absorption by forming soluble iron
complexes
• Fructose, succinate, citrate and various amino
acids stimulate iron absorption by forming soluble
iron complexes
15. 15
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)
16. 16
Causes of iron deficiency anaemia
Increased demand for iron (pregnant & nursing women,
infants, rapidly growing children)
Commonly manifest
Inadequate iron absorption (GIT problem, gastrectomy,
drug such as TTC, antacids…)
Inadequate dietary intake
Increased blood loss (menstruation, GI bleeding)
Iron sequestration: hemosiderosis
Hemoglobinuria
17. 17
Iron preparations
Oral iron preparations
Preferred route (normal GI absorption of iron)
• Ferrous sulfate
• Ferrous fumarate
• Ferrous gluconate
• Ferrous succinate
About 25% of oral iron given as ferrous salt can be absorbed,
18. 18
Oral iron preparations…
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
19. 19
Acute oral iron poisoning
• Commonly seen in young childen
• As few as 10 tablets of any of the commonly available oral
oral iron preparations can be lethal in young children.
• Sever necrotizing gastritis with vomiting, hemorrhage,
abdominal pain, hematoemesis, black or bloody diarrhea
• Followed by, shock, lethargy, dyspnea, severe metabolic
acidosis (leading to coma and death)
• Chronic iron toxicity (iron overload), also known as
hemochromatosis, results when excess iron is deposited in
deposited in the heart, liver, pancreas, and other organs.
20. 20
Treatment of acute iron poisoning
• Whole bowel irrigation
• Iron chelating agents:
Deferoxamine (not absorbed orally, given IM, IV)
Deferasirox (orally absorbed)
• Supportive therapy
For CV – collapse and dehydration --- IV fluid
Metabolic acidosis--- Sodium bicarbonate
Convulsions --- Benzodiazepines
21. 21
Parenteral iron preparations
• Iron dextran
• Iron sucrose complex
• 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 (a small test dose is given)
22. 22
Parenteral iron preparations…
Parenteral administration is indicated only for specific cases
cases
• Oral iron is not tolerable: too much bowel upset
• Malabsorption syndrome
• Inflammatory bowel disease, chronic inflammation
• Sever deficiency with chronic bleeding
• Advanced chronic renal disease: PLUS treatment with
erythropoietin to induce rapid erythropoiesis
• with advanced chronic kidney disease who are undergoing
23. 23
Parenteral iron toxicity
• Local toxic effect: pain at site of injection, skin
discoloration, local inflammation
• Systemic toxic effects: headache, muscle and joint
pain, tachycardia, bronchospasm, hypotension,
encephalopathy, convulsion, rash, anaphylactic reaction
(more on iron dextran)
24. Vitamin B12-deficiency anemia…
Vitamin B12
• Cofactor for several essential biochemical reactions
• Deoxyadenosylcobalamin and methylcobalamin
are active forms in humans
• The ultimate source is microbial synthesis
• The chief dietary source of vitamin B12 is microbially
derived meat (especially liver), eggs and dairy
products
• It is an important cofactor for vital reaction in human
body
24
25. Vitamin B12 absorption
25
Absorption
After being ingested, vit B12 is bound to intrinsic factors
(protein secreted by gastric parietal cell)
The complex gets absorbed by distal ileum by highly
specific receptor mediated transport system
Transportation
Bound to transcobalamin II
A total vitamin B12 storage pool is 3000–5000 mcg in
average adult
Daily requirement is about 2mcg.trace amount being
lost so to develop megaloblastic anemia it would take
app.5years provided no absorption at all
28. Vitamin B12 deficiency anemia…
Causes:
↓ed production of intrinsic factors: pernicious
anemia
Gastric mucosal damage due to:
• Chronic gastritis
• H.Pylori infection
• Gastric carcinoma
• Gastrectomy
Malabsorption: damaged intestinal mucosa,
competitive intestinal parasites (Schilling test to
detect malabsorption)
Increased demand28
29. Vitamin B12 deficiency anemia…
Clinical manifestations
Hematological manifestations
• Macrocytic, hyperchromic RBCs
• Associated mild or moderate leukopenia or
thrombocytopenia (or both),
The neurologic syndrome associated with vitamin B12 deficiency
usually begins with
o Paresthesias and weakness in peripheral nerves and
Progresses to
o Spasticity, ataxia, and other central nervous system
dysfunctions
29
30. Treatment
Oral / parenteral vitamin B12
Preparation
• Cyanocobalamin
• Hydroxocobalamin (highly protein-bound )
• Daily or every other day for 1–2 weeks to replenish
body stores. Maintenance intramuscularly once a
month for life
Almost all cases of vitamin B12 deficiency are caused by
malabsorption
Lack of intrinsic factor or
Malfunction of the specific absorptive30
31. Folic acid-deficiency anemia
Folic acid: provide precursors for the synthesis of
amino acids, purines, and DNA.
Cause
Inadequate dietary intake of folates
Decreased absorption
Drugs: methotrexate, phenytoin…
Increased demand
•Chronic hemolytic anemia,
•Alcoholism, Liver disease
•pregnancy, exfoliative skin disease
•Loss: dialysis31
32. • Alcoholics and patients with liver disease develop folic
acid deficiency
Poor diet
Diminished hepatic storage of folate
• 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
32
33. 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
33
34. Folic acid deficiency during pregnancy → fetal neural
tube defect like Spina bifida and anencephaly
34
Also called
• cleft
spine
• open
spine
• rachischi
sis
• spinal
dysraphis
m
35. 35
Hematopoietic growth factors
Glycoprotein hormones that regulate the proliferation and
differentiation of hematopoietic progenitor cells in the bone
marrow
The 1st factor to be identified
CSFs (colony stimulating factor )
Stimulate growth of various progenitor cells
Erythropoietin (epoetin alfa, epoetin beta)
Granulocyte colony-stimulating factor (G-CSF)
Granulocyte-macrophage colony-stimulating factor (GM-CSF),
and
36. 36
Erythropoietin
• Produced by the kidney
• Produced and released in response to blood loss/or low
tissue oxygen tension
• Regulates RBCs production
• Two forms of recombinant human erythropoietin
Epoetin alfa – given iv or sc
Darbepoetin alfa (longer duration, 3X) - given iv or
sc
37. 37
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
• Anemia due to primary bone marrow disorder and 20
anemia
Adverse effects:
• Hypertension, thrombotic complications, iron
38. 38
Colony stimulating factors/ MYELOID Growth
factors
Granulocyte – CSF (G-CSF)
• Stimulates proliferation and differentiation of progenitors
already committed to neutrophil lineage
• Activates the phagocytic activity of mature neutrophils
neutrophils
• Mobilize hematopoietic stem cells, ie, to increase their
their concentration in peripheral blood
Useful for hematopoietic stem cell transplantation
• Recombinant human G-CSF: filgrastim (rHuG-CSF in a
bacterial expression system), pegfilgrastim (longer serum
serum half-life ), Lenograstim
39. 39
Colony stimulating factors…
Granulocyte – macrophages CSF (GM-CSF)
• Stimulate proliferation and differentiation of progenitor cells
of :
Granulocytes
Erythroid cells
Megakaryocytes
• It also stimulates the function of mature neutrophils
• GM-CSF acts together with interleukin-2 to stimulate T-cell
cell proliferation and appears to be a locally active factor at
at the site of inflammation.
• Recombinant human GM-CSF: Sargramostim (rHuGM-
CSF
41. 41
Colony stimulating factors…
Adverse effects
• G-CSF
Bone pain (clears when the drug is discontinued)
• GM-CSF
Fever, malaise, arthralgias, myalgias, and a capillary
capillary leak syndrome characterized by peripheral
peripheral edema and pleural or pericardial effusions
effusions
Allergic reaction (infrequent, but serious)
42. MEGAKARYOCYTE GROWTH
FACTORS
42
platelet transfusion is commonly used to treat
thrombocytopenia
A recombinant form of IL-11 FDA approved for
treatment of thrombocytopenia.
Oprelvekin, the recombinant form of IL-11 is produced by
expression in Escherichia coli. The half-life of IL-11 is 7–8
hr
Romiplostim: nonimmunogenic peptide agonists of the
thrombopoietin receptor, approved by the FDA for
idiopathic thrombocytopenic purpura.
43. 43
DRUGS USED IN DISORDERS OF COAGULATION
Coagulants and anti –coagulants
44. 44
Hemostasis
The arrest of blood loss from damaged vessels
The main phenomena:
Vascular contraction
Platelet activation, aggregation
Blood coagulation (fibrin formation) and
Platelet activation leads to formation of a haemostatic
plug
Stops bleeding and is subsequently reinforced by
48. Blood Coagulation
• The coagulation cascade is a stepwise series of
enzymatic reactions that results in the formation of a
fibrin mesh
Cement blood component together
• Can be triggered via either the intrinsic or extrinsic
pathways
48
49. Blood Coagulation…
Intrinsic/contact path
way Extrinsic pathway
49
• Activated by vessel injury
• Also activated when shed
blood comes into contact
with an artificial surface
such as glass
• Relatively slow process
• All components are
present in blood
• Activated by vessel
injury
• Faster process
• Some components
come from outside
the blood
50. Blood coagulation cascade & sites of action of
anticoagulant drugs
50
The main initiator of coagulation in vivo is the TF
52. 52
Blood coagulation…
Controlled by enzymatic inhibitors and fibrinolysis
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
53. 53
Blood coagulation…
Fibrinolysis/ Thrombolysis
Physiological pathway by which Clots are dissolved
Important for reestablishment of blood flow & 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
54. Drugs that act on the coagulation
cascade
Drugs are used when there is defect in coagulation
or unwanted coagulation
• Coagulation defects
Genetically determined deficiencies of clotting
factors
Classic haemophilia (haemop. A) - lack of
factor VIII
Haemophilia B (Christmas disease)- lack of
factor IX
Treatment54
55. Drugs that act on the coagulation cascade…
Acquired coagulation defects
More common than hereditary ones
• Liver disease
• Vitamin K deficiency
• Excessive oral anticoagulant therapy
o Result in bleeding
55
56. Coagulants
Vitamin K:
Fat-soluble vitamin
• Vit k1 (phytomenadione)
Found in plants, available for oral and parenteral
adm.
• Vit k2 (menaquinone)
Found in human tissue & synthesized by
intestinal micro flora
• Menadiol sodium phosphate
a water soluble synthetic preparation
Essential for the synthesis of clotting factors II, VII, IX56
58. Clinical use of vitamin K
• Treatment & /or prevention of bleeding
From excessive oral anticoagulants (e.g. warfarin)
Hemorrhagic disease of newborns( low level of
prothrombin & other clotting factors)
• Vitamin K deficiencies in adults
Sprue, coeliac disease, steatorrhoea
• Long term antimicrobial therapy: alter intestinal flora
• Liver disease & obstructive jaundice
58
59. Clotting factors & hemostatics
Antihemophilic factor (AHF) - used to treat
patients with deficiency of clotting factor VIII,
hemophilia A
Human factor IX complex: tx hemophilia B
Topical hemostatic agents
Oxidized cellulose
Gelatin (Gelfoam)
60. Anti fibrinolytic agents
• Agents which inhibit plasminogen activation
1. Aminocaproic acid, tranexamic acid
• Competitively inhibit plasminogen activation
• Enhances blood coagulation/used to tx severe bleeding
60
61. Anti fibrinolytic agents…
2. Aprotinin
• Serine protease inhibitor
• Inhibits plasmin and thus fibrinolysis
• Approved use
Patients undergoing coronary artery bypass
grafting who are at high risk of excessive blood
blood loss
61
62. Desmopressin (DDAVP )
62
Vasopressin and desmopressin increase plasma levels
of
factor VIII and von Willebrand factor,
presumably by V2 receptor-mediated release from
storage sites in vascular endothelium .
Because of this, desmopressin is sometimes used
after minor trauma or before elective dent al surgery in
patients with mild hemophilia A who have
demonstrated responsiveness.
DDAVP induces an increase in plasma levels of
von Willebrand factor (VWF)
coagulation factor VIII (FVIII), and
tissue plasminogen activator (t-PA)
In spite of its extensive clinical use, its cellular
63. Anticoagulants
63
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
64. 64
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
Indirect Thrombin inhibitor: Heparin, Fondaparinux: activates
antithrombin III
Direct Thrombin inhibitor : Hirudin, lepirudin, bivalirudin
D. Fibrinolytic agents
Streptokinase, Alteplase…
E. Antiplatelet aggregation
Aspirin, Dipyridamole, Ticlopidine, Clopidogrel, abciximab
66. Oral anticoagulants
Warfarin – prototype
Active only in vivo
Mechanism of action
• Competitive inhibitors of the reduction of oxidized
vitamin K that regenerates active vitamin K
(hydroquinone)
• Their effect takes several days to develop until
the preformed clotting factors are depleted
66
67. 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
67
68. Drug interactions with oral anticoagulants
Drugs that reduce their effect:
• Enzyme inducers: rifampin, barbiturates,
griseofulvin…
• Cholestyramine: Interfere with absorption
• Increased Vit k level
• Other factors: physiological state/ disease
Pregnancy (↑ coagulation factors synthesis)
Hypothyroidism (↓ turnover rate of clotting
68
69. Drug interactions with oral
anticoagulants…
Drugs that enhance their effect:
• Enzyme inhibitors: cimetidine, CAF, metrinidazole
• Drugs that inhibit platelet function: aspirin
• Inhibition of Vit k synthesis: oral cephalosporins
• Inhibition of Vit K absorption e.g. liquid paraffin
• Displacement from the binding sites on plasma
Phenylbutazone, salicilates, sulfonamides,
clofibrate
69
70. 70
Adverse effects of warfarin
Risk of bleeding:
• Management
Stopping the drug
Giving Vit k
Fresh plasma/or whole blood or coagulation
factors
Warfarin causes a birth defect, abortion, neonatal
intracranial hemorrhage, intrauterine death, still birth
• Contraindicated to pregnant woman
71. 71
Warfarin- sole oral anticoagulant for 60 years.
Limitations-
• Narrow therapeutic index
• Delayed onset & offset of action
• Mandatory lab monitoring
• Drug interactions
Why new oral anticoagulants ?
72. 72
Features of an ideal anticoagulant
• High efficacy to safety index
• Predictable dose response
• Administration by parenteral and oral routes
• Rapid onset of action
• Availability of a safe antidote
• Minimal side effects
• Minimal interactions
74. 74
• Competitive and reversible direct thrombin inhibitor.
• Inhibits thrombin activity, thrombin generation and platelet
activation.
• Prolongs aPTT, Prothrombin time.
• No action on other serine proteases
• Prodrug of melagatran
• About 20% of oral dose is absorbed.
• Tmax - 2-3 hrs, t1/2 – 4-5 hrs
• Eliminated via kidney (80%)
• Kinetics not influenced by sex, body weight and ethnicity
Ximelagatran
75. 75
• Administered orally at Fixed doses
• Coagulation monitoring not required
• Immediate action
• More predictable anticoagulant response
• Wider safety margin
• Less inter subject variability
• Minimal drug interactions
Disadvantage
• Hepatotoxicity
• No antidote available (but dialysis can hasten
Advantage
76. Dabigatran
Given orally
Elimination renal
Half life 12 h
Substrate for P-glycoprotein in
kidney, GIT
77. Activated partial thromboplastin time
(aPTT) & prothrombin time (PT)
Blood clots in 4-8 min in a glass tube
Chelation of ca2+ prevents clotting
Recalcified plasma clots in 2-4 min
Addition of negatively charged phospholipids and kaolin
(aluminium silicate) shortens clotting time to 26-33 sec –
aPTT
Addition of ‘thromboplastin’ (a saline extract of brain –
tissue factor and phospholipids) shortens clotting time to
12-14 sec – prothrombin time (PT)
78. 78
Heparin (UFH or LMWH)
UFH
• Commercial heparin is extracted from porcine intestinal
mucosa and bovine lung
• It is a mucopolysaccharide
• Administered IV or SC
• Strongly acidic and carries strong electronegative charge
-essential for its activity
• Effective in vivo and in-vitro
Indirect Thrombin Inhibitor
79. 79
Heparin…
Mechanism of action
• Heparin binds to ATIII, an inhibitor of coagulation
factors (IIa, IXa, and Xa)
Accelerates the binding of ATIII to factors Xa and
IIa
Enhance ATIII activity
• Congenital defect of ATIII in an individual, will cause
thrombophilia and resistance to heparin therapy
81. 81
Adverse effects of heparin
• Hemorrhage (major ADR)
• hypersensitivity reaction
• Increased loss of hair and reversible alopecia
• Osteoporesis and spontaneous fracture (long term use)
• Hypoaldosteronism
• Heparin induced thrombocytopenia
• Systemic hypercoagulable state that occur in 1-4% of pts
treated with UFH (unfractionated heparin) for a minimum of 7
82. 82
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)
83. Low molecular weight heparins (LMWH)
• Fractionated heparin
• Enoxaparin, dalteparin, tinzaparin
• Inhibit factor Xa with lesser effect on factor IIa
• Administered Sc.
• In comparison to UFH, LMWH has:
Equal efficacy, ed bioavailability, less frequency
of adm. and lesser antiplatelet action, low
thrombocytopenia
83
84.
85.
86.
87. 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
87
88. 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
88
89. Apixaban
Direct Factor Xa inhibitor
Oral bioavailability 60%
Half life 12 h
Elimination hepatic > renal
Other Xa Inhibitors…..
91. D. 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
91
93. 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
93
94. Fibrinolytic/ thrombolytic agents…
2. Urokinase
• Proteolytic enzyme formed by kidneys & found in
urine
• Derived from human urine
• Converts plasminogen to plasmin
• Non-antigenic
94
99. Antiplatelet drugs
99
Drugs that prevent
platelet aggregation
Aspirin
• Inhibits COX enzyme irreversibly leading to inhibition of
the production of TXA2 (potent vasoconstrictor and platelet
aggregator)
• 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??????
100. 100
Antiplatelet drugs…
Dipyridamole
• Inhibits platelet PDE enzyme leading to ↑cAMP
Prevents platelet aggregation
Augment the antiadhesive effect of prostacyclins
• Has also vasodilator and anti - anginal effect
Epoprostenol (PGI2)
• Inhibits platelet aggregation through elevation
elevation of cAMP
102. 102
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