This Slide share deals with drugs used for the treatment of anemia, bleeding, and anticoagulants.

1. Drugs acting on Diseases
of the Blood
1
By:
Kald Beshir (MSc in Pharmacology)
Mekelle University Ethiopia

2. Drug treatment of anemia
2

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

26. The two essential enzymatic reactions that
require vit B12
26

27. 27

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

40. 40
Colony stimulating factors…
Therapeutic uses
• Cancer chemotherapy induced neutropenia
• Congenital neutrpenia
• Neutropenia associated with myelodysplasia, & aplastic
anemia

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

45. 45
Under normal circumstances, repair of
vascular injury occurs without thrombosis

46. Platelet adhesion
and aggregation
Platelet activation

47. Processes of hemostasis
47

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

51. 51
++
+
+
+
+ = upstream activation

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

57. Mechanism of vitamin K and warfarin
57

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

65. Fibrin
Prothrombin Thrombin
Fibrinogen
X Xa
IX IXa
VII VIIa- TF
Tissue factor (TF)
Heparin
Warfarin VIIIa
Va
TFPI,NAPc2
-
-
-
-
-
-
-
-
Anticoagulants

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

73. 73
Parenteral DTIs:
Bivalent:
• Hirudin
• Bivalirudin
• Lepirudin
Monovalent:
• Argatroban
• Melagatran
Oral DTIs:
• Ximelagatran
• Dabigatran
Direct Thrombin Inhibitor
Thrombin Inhibitor

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

80. Heparin mechanism of action
Heparin
Antithrombin III
Thrombin

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

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…..

90. Rivaroxaban
Direct Factor Xa inhibitor
Oral bioavailability 80%
Half life 7-11 h
Elimination renal > hepatic

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

92. The fibrinolytic/ antifibrinolytic system
92

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

95. Fibrinolytic/ thrombolytic agents…
3.Tissue plasminogen activators (tPA):
 Alteplase, Duteplase, Reteplase ,Tenecteplase
 Proteases preferentially activate fibrin bound
plasminogen
• Avoid systemic activation “clot selective”
• Facilitate fibrinolysis to the formed thrombus
95

96. Fibrinolytic/ thrombolytic agents…
Therapeutic uses
• Acute MI (Coronary thrombosis)
• Deep vein thrombosis
• Pulmonary embolism
Adverse effects
• Hemorrhage (GIT & Stroke)
• Allergic RXN (Streptokinase)
96

97. Antiplatelet drugs

98. Antiplatelet drugs
clotting
Increased cAMP
Prevents clotting
ADP
P2Y receptor
Lowers cAMP
Clopidogrel
ticlopidine
inhibit
stimulates
TXA2 recep
Arachidonic acid
Aspirin
Thromboxane
(from activated platelets)
GpIIb-IIIa
Receptor for
fibrinogen and
platelet adhesion
Ca2+
Dipyridamole
(prevents
breakdown by
phosphodiesterase)
clotting
Eptifibatide
Abciximab
Tirofiban

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

101. 101
Antiplatelet drugs…
Ticlopidine, Clopidogrel
• Irreversibly block ADP receptor on platelets
• Inhibits ADP-dependent platelet aggregation
Others: abciximab, tirofiban, eptifibatid
• Block platelet glycoprotein IIb/IIIa receptors

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

103. PDE Inhibitor Dipyridamol