4. • Anemia:- is deficiency in the oxygen-carrying
capacity of the blood due to a diminished
erythrocyte mass, size or Hg content.
• Because the main function of RBCs is
oxygenation, anemia results in varying degrees
of hypoxia
4
Sagni H
5. Causes for Anemia
1. Blood loss
Chronic-GI bleeding-ulcer and menstrual bleeding
Acute-GI bleeding
2. Bone marrow dysfunction
Low erythropoietin production- due to kidney
disease, causes normochromic anemia -[causes
normocytic/aplastic anemia]
Decreased marrow response to erythropoietin
3. Deficiencies of substances essential for RBC formation
& maturation
Iron[microcytic anemia], Vit. B12, or folic acid[both
macrocytic anemia]
4. Increased erythrocyte destruction (hemolytic anemia)
5
Sagni H
9. Red Blood Cell Development
– Begin developing in bone marrow
– Mature in blood
Four stages
1. Proerythroblasts
– Lack hemoglobin
2. Erythroblasts
– Gain hemoglobin
– Both stages reside in bone marrow.
3. Reticulocytes
– Immature erythrocytes
– Enter the systemic circulation.
4. Erythrocytes
– Full maturity
9
Sagni H
12. • Development of RBCs requires the
cooperative interaction of several factors:
1. Bone marrow
2. Erythropoietin, a stimulant of RBC maturation
3. Iron for hemoglobin synthesis
4. Vitamin B12 & folic acid to support synthesis of
DNA
• If any of these is absent or amiss→ anemia
12
Sagni H
13. Types of anemia
• Iron-deficiency anemia
• megaloblastic anemia (deficiency of Vit. B12
and folic acid)
• aplastic anemia
• hemolytic anemia
13
Sagni H
14. 1. Iron Deficiency Anemia
– most common nutritional deficiency cause of
anemia.
• When severe, it results in a characteristic
microcytic, hypochromic anemia.
14
Sagni H
16. Fates of iron
1. Metabolic Functions
– For hemoglobin synthesis(70-80%)
– For myoglobin & iron-containing enzymes (10%)
2. Uptake & Distribution
Uptake by mucosal cells of small intestine
Ferrous form of iron is more absorbed than its ferric
form
After uptake, iron may be
Stored in the form of ferritin in mucosal cells or
Bound to transferrin for distribution throughout
body
16
Sagni H
17. 3. Utilization & Storage
Transferrin bound iron, taken up by:
a. Cells of bone marrow for incorporation into
Hg
b. Liver & other tissues for storage as ferritin
c. Muscle for production of myoglobin
d. All tissues for production of iron-containing
enzymes
4. Recycling
Iron associated with Hg undergoes
continuous recycling.
Re-enters circulation
After catabolism of RBC (after 120 days)
The life span of RBC = 120 days
17
Sagni H
18. 5. Elimination
Normal physiologic loss is only very
limited amount (~ 1 gm/day)
A significant iron loss via blood loss:
Menorrhagia, hemorrhage & blood
donations
6. Regulation of Body Iron Content is via
Control of intestinal absorption
Excessive buildup is prevented through
control of iron uptake
18
Sagni H
20. Daily Requirements of iron
– Determined by the rate of erythrocyte
production
– High in infants and children (due to their
rapid growth), pregnancy (blood volume
expansion)
– adult males need 10 mg of dietary iron
each day but more for females
20
Sagni H
22. • Consequences of iron deficiency
– Anemia
– RBCs become microcytic (small) & hypochromic
(pale)
– Listlessness, fatigue & pallor of skin & mucous
membrane
– Tachycardia, dyspnea & angina
22
Sagni H
23. Oral iron preparations
Oral iron
1. Iron salts
Ferrous sulfate
Ferrous gluconate
Ferrous fumarate
• treatment of choice for iron deficiency.
• Used for prevention & treatment of iron
deficiency anemia (pregnancy & chronic
blood loss)
23
Sagni H
25. Pharmacological actions:
• Iron is part of hemoglobin, the oxygen-
carrying component of the blood.
– Iron-deficient people tire easily because their
bodies are starved for oxygen.
• Iron is also part of myoglobin.
– Myoglobin helps muscle cells store oxygen.
• As a cofactor in iron-containing enzymes
25
Sagni H
26. Clinical uses:
• For treatment or prevention of iron
deficiency anemia
1) chronic blood loss in heavy menstrution or
hemorrhoid
2) insufficient intake during periods of
accelerated growth in children, or in pregnant
women.
26
Sagni H
27. Clinical toxicity
• Acute iron toxicity
– Necrotizing gastroenteritis
– Vomiting, abdominal pain, bloody diarrhea
– Followed by shock, lethargy, dyspnea
– Severe metabolic acidosis, coma, death
• Chronic iron toxicity (hemochromatosis)
– Deposit of iron in the heart, liver, pancreas
– Can lead to organ failure and death
– Staining of teeth, dark green or black stool
27
Sagni H
28. Management of toxicity-
gastric lavage: phosphate or carbonate to
flush out unabsorbed pill
Deferoxamine (parentral) and deferasirox
(oral): potent iron chelating compounds.
To chelate already absorbed iron
28
Sagni H
29. Drug interactions
– Antacids (raise PH, and can oxidize Fe2+ to Fe3+)
• dec. absorption
– Tetracyclines (inhibit by forming anabsorbable
chelate)
• dec. absorption
– Ascorbic acid, vit. C- (reduces ferric to ferrous iron)
• inc. absorption
– Foods (meat facilitate Fe absorption by inc gastric
acid secretion)
• inc. absorption
29
Sagni H
30. Parenteral Iron
1. Iron dextran
– For clear diagnosis of iron deficiency anemia
– Used when oral iron is non-effective or non-
tolerable
– With intestinal diseases, severe blood loss.
30
Sagni H
31. • Adverse effects
– Fatal anaphylactic rxn
– Hypotension
– Circulatory failure
– Cardiac arrest
2. Iron sucrose &
3. Sodium–ferric gluconate complex
– For iron deficiency anemia in patients with
chronic kidney disease (CKD)
– Less risk of anaphylactic rxn
31
Sagni H
32. Cobalamin (Vitamin B12) Deficiency
• Cobalamin Deficiency--formerly known as pernicious
anemia (deficiency of Intrinsic factor)
• Vitamin B12 (cobalamin) is an important water-soluble
vitamin.
– Vitamin B12 : a group of cpds with similar structures
– Known as cobalamins- because of cobalt atom
• Intrinsic factor (IF) is required for cobalamin absorption
32
Sagni H
33. Relationship of folic acid and vitamin
B12 to DNA synthesis and cell
maturation
33
Sagni H
34. • Metabolic function
– For DNA synthesis (growth & division of cells)
• Absorption
– Requires intrinsic factors (IF), secreted by gastric
parietal cells
• Binds to transcobalamin II to transport to
tissues
– Stored in liver
• Elimination
– Very slow excretion
• Dietary sources
– found only in foods of animal origin: meat, liver and
dairy products.
34
Sagni H
35. • Causes of cobalamin deficiency
– Gastric mucosa not secreting IF
– GI surgery loss of IF-secreting gastric mucosal cells
– Long-term use of H2-histamine receptor blockers
cause atrophy or loss of gastric mucosa.
– Nutritional deficiency (in strict vegitarians)
– Hereditary defects of cobalamine utilization
35
Sagni H
36. Clinical manifestations of cobalamin deficiency
– General symptoms of anemia
– Disruption of DNA synthesis
Affect bone marrow, epithelial cells of mouth &
GIT
– Megaloblastic anemia
Megaloblastic-Oversized erythroblasts
Macrocytic- Oversized erythrocytes
– Neurologic Damage
Neurological demyelination
Paresthesias, loss of memory, mood changes,
hallucinations, and psychosis
– Infection and spontaneous bleeding
Loss of leukocytes and thrombocytes
36
Sagni H
37. Cobalamin Deficiency
Diagnostic Studies
• RBCs appear large
• Abnormal shapes
– Structure contributes to erythrocyte destruction
• Schilling Test: a medical investigation used for
patients with vitamin B12 deficiency. The
purpose of the test is to determine if the
patient has pernicious anemia.
37
Sagni H
38. Vitamin B12 Preparations
Cyanocobalamin
Hydroxycobalamin
– A purified, crystalline form of vitamin B12
• Adverse effects
– Hypokalemia
• Given by:
– Orally
– Intranasally
– Parenterally- IM or SC
38
Sagni H
39. Folic Acid Deficiency Anemia
• Folic acid deficiency also causes megablastic
anemia (RBCs that are large and fewer in
number)
• Folic Acid required for RBC formation and
maturation
• Causes
– Poor dietary intake
– Malabsorption syndromes
– Drugs that inhibit absorption
– Alcohol abuse
– Hemodialysis 39
Sagni H
40. • Metabolic function
– For DNA synthesis
– Dietary folic acid converted into active form in
presence of vit B12
– But at large amounts, activated via alternative
pathway
• Absorbed at small intestine
– Transported in to liver & other tissues for
storage
– Undergoes extensive enterohepatic recirculation
– Significant excretion
40
Sagni H
41. • Consequences of folic acid deficiency
1. Identical to that of vitamin B12 deficiency except
in CNS (in all people)
Megaloblastic anemia
Leukopenia
Thrombocytopenia
Injury to the oral and GI mucosa
2. Neural tube defects- spina bifida, anencephaly-
developing fetus
• Diagnosis
– Megaloplastic anemia
– Low folate levels in plasma
41
Sagni H
42. • Encourage patient to eat foods with large
amounts of folic acid
• Leafy green vegetables
• Liver
• Mushrooms
• Oatmeal
• Peanut butter
• Red beans
42
Sagni H
43. Folic acid preparations
1. Folic Acid (Pteroylglutamic Acid)
– Inactive form
– Most commonly used
Indications
1. Folic acid deficiency megaloplastic anemia
2. Prophylaxis of folate deficiency- in
pregnancy, lactation
• Given by:
– Orally
– Injection- IV, IM, SC
2. Leucovorin Calcium (Folinic Acid)
– Uncommonly used
– Active form
– Used as adjuvant in cancer chemotherapy
43
Sagni H
44. Vitamin B12 Deficiency Folate Deficiency
Cause Malabsorption from
lack of intrinsic factor
Low dietary source
Hematologic
effects
Megaloblastic anemia Megaloblastic anemia
Neurologic
effect
Damage to CNS Neural tube defects in
fetus
Diagnosis Low plasma level, low
absorption
Low plasma level
Treatment Cyanocobalamin (IM) Folic acid (PO)
Duration of
therapy
Lifelong Short term
44
Sagni H
45. Folate and Vitamin B12 Interaction
• Tetrahydrofolate is necessary for DNA synthesis
• Cobalamin and folate are cofactors for
tetrahydrofolate production
• Deficiency of either impairs cell division in the
bone marrow while RNA and protein synthesis
continues – enlarged erythrocytes
• Cobalamin deficiency – impairs synthesis of S-
adenosylmethionine – necessary for proper
nervous system functioning
45
Sagni H
46. Hemolytic Anemia
• Destruction or hemolysis of RBCs at a rate that
exceeds production
• Third major cause of anemia
Causes
1. Autoimmune disease
- IgG antibody binds to erythrocyte surface
2. In patients with G6PD deficiency
– Oxidative stress from drugs, infections or toxins
3. Infections
– Malaria, Babesiosis, Sepsis
4. Mechanical (artificial heart valves, microvascular
disease)
5. Toxins- snake venom, insect bites
46
Sagni H
47. Aplastic Anemia
• Characterized by Pancytopenia, i.e.
– ↓ of all blood cell types
• RBCs
• White blood cells (WBCs)
• Platelets
• caused by a failure of the bone marrow to
produce stem cells, the initial form of all
blood cells.
47
Sagni H
48. • Etiology
– Congenital
• Chromosomal alterations
– Acquired
• Results from exposure to ionizing radiation,
chemical agents, viral and bacterial infections
48
Sagni H
49. Aplastic Anemia
• Clinical Manifestations
– General manifestations of anemia
• Fatigue
• Dyspnea
• Pale skin
• Frequent or prolonged infections
• Nosebleed and bleeding gums
• Prolonged bleeding from cuts
• Dizziness
• headache
49
Sagni H
50. Aplastic Anemia
• Treatment
– Identifying cause
– Blood transfusions
– Antibiotics
– Immunosuppressants
• Corticosteroids
– Bone marrow stimulants
• Filgrastim (Neupogen)
• Epoetin alfa (Epogen, Procrit)
– Bone marrow transplantation
50
Sagni H
51. Erythropoietin (Epotein)
• A glycoprotein hormone
• Produced:
90% by peritubular cells in kidney
Remainder by liver and other tissues
• Is essential for normal reticulocyte
production
• Synthesis is stimulated by hypoxia/anemia
• Synthesized for clinical use
By recombinant DNA technology
51
Sagni H
53. Clinical Uses of epotein
1. Anemia associated with chronic renal failure
2. HIV-infected patients taking Zidovudine
3. Cancer chemotherapy-induced anemia
4. Anemia in Patients Facing Surgery
53
Sagni H
54. 54
Pharmacokinetics
• Route of administration --- S.C. or I.V.
• Plasma t1/2 ---- 4 - 13 hrs in patients with chronic renal
failure
• Not cleared by dialysis
Mechanism of action
• Increases rate of stem cell differentiation
• Increases rate of mitosis in red cell precursors, blast-
forming units, colony forming cells. increases release
of reticulocyte from marrow
• Increases Hb synthesis
• Its action requires adequate stores of iron
Sagni H
55. 55
Adverse effects
• Hypertension
• Cardiovascular Events (Hg ˃12 g/dl)
• Cardiac arrest
• Hypertension
• HF
• Thrombotic events- stroke and MI
• Autoimmune pure red-cell aplasia
• Severe anemia
• Can cause a complete absence of erythrocyte
precursor cells in bone marrow
• Due to production of neutralizing
antibodies
Sagni H
57. Introduction
• The endothelial lining is non-
thrombogenic
• Balance between
– Procoagulants (thromboxane, thrombin,
activated platelets, platelet factor 4) and
– anticoagulants (heparan sulfate,
prostacyclin, nitric oxide, antithrombin)
determine blood fluidity
57
Sagni H
58. Introduction…
Physiology of Coagulation
• Hemostasis is the physiologic process of
cessation of blood loss from a damaged
vessel.
• Blood clotting has four phases:
1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Fibrinolytic phase
58
Sagni H
59. 1. Vascular phase
– Manifested by vasoconstriction of damaged
blood vessels.
• Reduce blood loss by decreasing blood flow.
59
Sagni H
60. 2. Platelet phase
– Injury exposes reactive subendothelial matrix
proteins: collagen
– Platelets adhere to it & activated
– Platelets, then, secrete and synthesize
vasoconstrictors and platelet recruiting and
activating molecules
– Activation of platelets also activates their
surface receptors (glycoprotein IIb/IIIa),
• enabling it to bind to fibrinogen, w/c cross
links adjacent platelets,
– resulting in aggregation and formation of a
platelet plug
60
Sagni H
64. 3. Coagulation phase
– Transforms soluble fibrinogen to insoluble fibrin
» A thread-like protein that reinforces platelet
plug
– Produced by two major pathways:
1. Contact activation (intrinsic) pathway
2. Tissue factor (extrinsic) pathway
Both converge at a common point (at factor Xa)
Clotting factors:
Their biosynthesis is dependent on Vitamin K
Most are proteases
Normally inactive (zymogens) & sequentially activated
64
Sagni H
65. Outline of coagulation pathways showing factors affected by
warfarin and heparin
II II
a
65
Tissue
Injury
Fibrin polymer
Sagni H
69. 4. Fibrinolytic phase
• Here unwanted fibrin thrombi are removed, while
fibrin in wounds persists to maintain hemostasis.
1. Inactivation of the clotting factor
» By antithrombin (antithrombin III)
• A protein that forms a
complex with clotting factors
& inhibits their activity
2. Degradation of clots
» By activation of endogenous
protease, plasmin
» Plasminogen (inactive) converted
to plasmin (active form) by tissue
plasminogen activator
69
Sagni H
70. Pathophysiology of coagulation
• Thrombosis
– the formation of an unwanted clot within the
blood vessels or heart
– Pathologic functioning of hemostatic
mechanisms
• Arterial thrombosis (white thrombi)
– Occur at sites of high flow rate
– Adhesion of platelets to arterial wall
» due to wall damage or atherosclerotic
plaque rupture
– Platelets release ADP and TXA2
» Arterial occlusion
» Initiation of coagulation cascade
» Reinforcement with fibrin
Causes localized tissue injury
70
Sagni H
71. • Venous thrombosis (red thrombi)
– Occur at sites of slow blood flow
» Blood stagnation
» Coagulation cascades activation
» Fibrin production
» RBCs & platelets form thrombus
» thrombi can Break off travel as
embolus
» embolus blocks distant blood
vessels
Pulmonary arteries
71
Sagni H
72. Drugs for thromboembolic disorders
1. Anticoagulants
– Disrupt coagulation cascade
– Suppress production of fibrin
– Most effective against venous thrombosis
– Heparin, warfarin
2. Antiplatelet drugs
– Inhibit platelet aggregation
– Most effective at preventing arterial
thrombosis
– Aspirin, clopidogrel
3. Thrombolytic drugs
– Promote lysis of fibrin
– Cause dissolution of thrombi
– Alteplase, streptokinase
72
Sagni H
73. 1 anticoagulants
• Anticoagulants are drugs employed in
preventing blood coagulation.
• They inhibit certain clotting factors in the liver.
• The function of them is to:
– Inhibit the synthesis of clotting factors
» Vitamin K antagonists
– Inhibit the activity of clotting factors
» E.g. Xa, thrombin( ), etc
Sagni H 73
II
a
74. Classification of anticoagulants
Ⅰ.Anticoagulants both in vivo and vitro:
e.g. Heparin and its derivatives
Ⅱ.Anticoagulants in vivo: dicoumarol (e.g
warfarin)
Ⅲ .Anticoagulants in vitro: Sodium citrate,
EDTA (ethylenediamine tetra-acetic
acid),fluoride,oxalate.
Sagni H 74
75. A. Anticoagulants - Heparin
• Enhance the activity of antithrombin
» accelerate inactivation of clotting
factors: IIa, IXa, Xa, XIa, XIIa.
» Reduction of fibrin production
• Unfractionated Heparin
» Rapid-acting
» Given via injection
• Sources
» From mammalian tissues
» Lungs of cattle and intestines of
pigs
75
Sagni H
76. Anticoagulants - Heparin
• Chemistry
– Not a single molecule
– A mixture of long polysaccharide chains [mucopoly-
saccharide]
– Highly polar- many negatively charged groups
– Anticoagulant of choice for pregnant women
– Avg mol. wt - >12,000 daltons
Heparin is negatively charged
Sagni H 76
77. • 1. Anticoagulative effect
Mechanism: accelerate inactivation of clotting
factors.(IIa, IXa, Xa, XIa, XIIa ) by enhancing the
anticoagulative activity of ATⅢ ( antithrombin
Ⅲ ).
– Suppresses the fibrin formation
– Prophylaxis of venous thrombosis
– Quick anticoagulant effects (minutes)
77
Sagni H
79. Mechanism of heparin
• This reaction happens in
normal physiological
state, but it’s very slow
and weak.
• In the presence of
heparin (which acts as a
catalyst), it will be
accelerated by more
than 1,000 times
Sagni H 79
81. Characteristics of anticoagulative effect
• effective both in vivo and in vitro
• quick onset and potent effects
• efficacy positively relative to molecular weight
81
Sagni H
82. • Pharmacokinetics
– Orally inactive- b/c of degradation in GI & its
high polarity (negatively charged)
– Via injection- IV/SC
– Shows variability in plasma levels
– Has brief duration of action
– Undergoes liver metabolism- by heparinase
82
Sagni H
83. Clinical uses
1) thromboembolic disease:
deep venous thrombosis(DVT),
pulmonary embolism, unstable angina,
acute myocardial infarction, cerebral infarction
2) DIC (Disseminated intravascular coagulation): early
stage
3) extracorporal circulation
(eg. dialysis machine)
Note: Used during pregnancy-highly polar, not pass
through placenta-safe
Sagni H 83
84. Adverse reactions
• Spontaneous hemorrhage :
– antidot: protamine sulfate (a basic protein)
• 1 mg of protamine sulfate for every 100 U of
heparin
– Protamine sulfate interacts with platelets,
fibrinogen, and other clotting factors - an
anticoagulant effect – at higher doses
Sagni H 84
85. Adverse reactions …
• Heparin-induced thrombocytopenia:
– a decrease in circulating platelets
– Antibodies against complexes of heparin with
platelet
– Lower incidence with low mol wt heparin
– Can be life-threatening
• Stop heparin immediately
• Others : allergic reaction
osteoporosis
Thus, needs monitoring
85
Sagni H
87. Low Molecular Weight Heparins (LMWHs)
• Avg mol. wt 4,500 daltons - containing 15
monosaccharide units
• Weaker effect than heparin
Better absorbed - higher bioavailability
Longer biological half-life
More predictable dose-response - does not bind
to plasma proteins, macrophages, or endothelial
cells
87
Sagni H
88. LMWHs…
Can be given s.c. without lab monitoring in an
outpatient setting
No need to monitor generally
Cleared unchanged by kidney (do not use in
renal failure!) rather than by the
reticuloendothelial system
Lower risks of thrombocytopenia and bleeding
Safety and use during pregnancy not evaluated
88
Sagni H
90. LMW heparins
Dalteparin, Enoxaparin, Tinzaparin
Uses:
1. prevention of venous thromboembolism
2.Treatment of venous thrombosis, pulmonary
embolism and unstable angina
3. prophylaxis following total knee
arthroplasty(the surgical reconstruction or
replacement of joint)
Sagni H 90
91. Heparin & LMW Heparins
difference in action
Heparin
~ 45 saccaharide units
MW ~ 13,500
This reaction goes
1000 to 3000 times
faster with heparin.
Low Mol. Wt.
Heparin
~ 15 saccaharide
units
MW ~ 4,500
circulates in the plasma -
rapidly inhibits thrombin
only in the presence of
heparin
Antithrombin
inhibits thrombin,
Xa, IXa and to a
lesser extent VIIa
Sagni H
92. Other parenteral anticoagulants
Danaparoid (ORGARAN)
• nonheparin glycosaminoglycans (84% heparan
sulfate)
Promotes inhibition of Xa by antithrombin
Prophylaxis of deep vein thrombosis
In patients with heparin-induced thrombocytopenia
Lepirudin (REFLUDAN)
recombinant derivative of hirudin (a direct
thrombin inhibitor in leech)
In patients with heparin-induced
thrombocytopenia
Sagni H 92
93. Coumarin derivatives
Oral anticoagulants
• Warfarin and Dicoumarin
• These agents are often referred to as oral
anticoagulants
– because they are administered orally, which
exists as the main difference from heparin.
• Small & lipid-soluble molecules
• Structurally related to vitamin K
– vitamin K antagonists
• Isolated from clover leave
93
Sagni H
94. • MOA
• Oral anticoagulants antagonize VitK →inhibiting the
synthesis of Vitamin K–dependent clotting
factors:Ⅱ,Ⅶ,Ⅸ,Ⅹ
» Inhibits vitamin K–epoxide reductase
• →inhibiting coagulation
94
Sagni H
96. Pharmacokinetics
• Absorption: rapid and complete (warfarin)
• Distribution: plasma albumin bound - 99%
– small Vd
• Elimination: liver
• Excretion: kindney
• Warfarin crosses placenta – is teratogenic – birth defects
and abortion
– Category X
Sagni H 96
97. characteristics
• oral administration
• effective in vivo, not in vitro
• slow onset, long duration
• Takes 4-5 days to become effective – active
carboxylated factors in plasma need to be cleared
Warfarin - Antidote
–Vitamin K (oral or parenteral)
Sagni H 97
98. clinical uses:
• For long term prophylaxis of acute deep vein
thrombosis or pulmonary embolism
• Prevent venous throboembolism in patients
undergoing orthopedic or gynecological surgery
• Prevent systemic embolization in patients with
– myocardial infarction,
– prosthetic heart valves or
– chronic atrial fibrillation
98
Sagni H
99. adverse effects
• Spontaneous hemorrhage :
– needs monitoring
– Treatment: withdrawal of the drug;
– administration of vitamin K and fresh blood
• others:
– Fetal hemorrhage & teratogenesis-birth
defects
• Category X
– Risks outweighs any possible benefits
– Allergic reaction
Sagni H 99
101. Drug interactions
1. Drugs that increase anticoagulant effects
– By displacement from albumin- salicylates &
sulfonamides
– By enzyme inhibition- acetaminophen,
amiodarone, azole, cimetidine, disulfiram,
sulfonamide
– Decreased synthesis of clotting factors-
cephalosporins
101
Sagni H
102. Drug interactions…
2. Drugs that promote bleeding
– By inhibition of platelet aggregation- NSAIDs
– By inhibition of coagulation cascade-
antimetabolites, heparin
– By generation of GI ulcers- aspirin, glucocorticoids,
indomethacin, phenylbutazole
3. Drugs that decrease anticoagulant effects
– By enzyme induction- anticonvulsants
– By increasing clotting factors synthesis- oral
contraceptives, vit K1
– By inhibition of its absorption- cholestyramine,
colestipol
102
Sagni H
103. Contraindication
– Like heparin
– Severe thrombocytopenia
– Uncontrollable bleeding
– Vitamin k deficiency
– Liver disease
– Alcoholism
– Pregnancy & lactation
103
Sagni H
104. Features Heparin Warfarin
Route Injection PO
MOA Inactivates
thrombin &
factor Xa
Inhibits clotting
factors
synthesis
Onset Rapid (mins) Delayed (hrs)
Duration Brief (hrs) Prolonged
(days)
Monitori
ng
aPTT PT
Antidotes Protamine Vitamin K
Summary of Contrasts b/n Heparin and
Warfarin
104
Sagni H
105. Antiplatelet Drugs
• Drug that inhibits platelets from aggregating to
form a plug.
• They are used to prevent clotting and alter the
natural course of atherosclerosis.
• Principal indication is for prevention of
thrombosis in arteries
» A platelet core constitutes the bulk of an arterial
thrombus
105
Sagni H
106. Classification
1. Cyclooxygenase inhibitors- Aspirin
2. PDE inhibitors
3. ADP receptor antagonists
» Both affect only one pathway in platelet
activation
» Limited antiplatelet effect
4. GP IIb/IIIa receptor antagonists
» Block the final common step in platelet
activation
» Powerful antiplatelet effects
106
Sagni H
109. 1. Aspirin
• Aspirin is a classic old drug which is used as a
NSAIDs for more than 100 years.
• Besides antipyretic, analgesic and anti-
inflammatory activities, it can inhibit platelet
aggregation.
109
Sagni H
111. Aspirin…
– Aspirin also inhibits synthesis of prostacyclin
(PGI2)
• By blood vessel wall
• w/c has opposite effect to TXA2, i.e.
Suppression of platelet aggregation
Promotion of vasodilation
But at high doses
111
Sagni H
113. Pay attention!
• at small dose (50～75mg/d): inhibit the
synthesis of TXA2 – which causes platelet
aggregation
• at higher doses (> 320 mg/day): inhibits the
synthesis of PGI2 – which inhibits platelet
aggregation.
Sagni H 113
114. • Clinical indications
– Prophylaxis after cardiac operation
– to reduce the incidence of recurrent
myocardial infarction (MI)
– Prophylaxis for transient ischemic attacks
(TIA) or post TIA
– Chronic stable angina and unstable angina
Reduces morbidity & mortality
Adverse effects
– GI bleeding
– Hemorrhagic stroke
114
Sagni H
115. ⅱ PDE inhibitors : Dipyridamole
Mechanism :
1) ↓PDE → cAMP ↑ ↓ aggregation
2) ↓ the uptake of adenosine →↑AC
Clinical use: Substitute of aspirin
prosthetic heart valves, etc.
Sagni H 115
116. 2. ADP Receptor Antagonists
• Include:
a. Clopidogrel
b. Ticlopidine
c. Prasugrel
• Irreversible blockade of ADP receptors on
the platelet surface
» Prevent ADP-stimulated platelet
aggregation
• For stroke and acute coronary syndromes
116
Sagni H
117. a. Clopidogrel
» Oral antiplatelet drug
• Pharmacokinetics
» Orally active
» 50% bioavailable
» Prodrug
117
Sagni H
118. • Clinical use
– Prevent blockage of coronary artery
stents
– Reduce thrombotic events
» MI
» Ischemic stroke
» Vascular death
• Adverse effects
» Similar to aspirin
» Abdominal pain, dyspepsia,
diarrhea, and rash.
» Less intracranial hemorrhage &
less GI bleeding vs aspirin
118
Sagni H
119. • Drug interactions
» Heparin
» Warifarin
» NSAIDs- aspirin
b. Ticlopidine
– Similar action as clopidogrel
– Prevention of thrombotic stroke
– Life-threatening hematologic reactions
» Neutropenia
» Agranulocytosis, etc
– GI disturbances & dermatologic reactions
c. Prasugrel
» Investigational drug
» Prodrug
119
Sagni H
120. 3. Glycoprotein IIb/IIIa Receptor
Antagonists
• activation of glycoprotein receptor on
platelet membrane is the final
common pathway for platelet
aggregation.
» The most effective antiplatelet drugs
3 drugs are available:
» Abciximab
» Tirofiban
» Eptifibatide
– Administered by IV
– Reversible blockade of platelet GP IIb/IIIa
receptors
– Inhibit the final step in aggregation
– Prevent aggregation stimulated by all
factors
120
Sagni H
121. • Clinical uses
– Prevent ischemic events
» Acute coronary syndromes (ACSs)
» Percutaneous coronary
intervention (PCI)
a. Abciximab
» A purified Fab fragment of a
monoclonal antibody
» Risk of bleeding
b. Eptifibatide
» A small peptide drug
» Risk of bleeding
c. Tirofiban
» Isolated from snake venom
» Risk of bleeding
121
Sagni H
122. Fibrinolytic drugs
(thrombolytic agents)
• These agents can activate the conversion of
plasminogen to plasmin,
– a serine protease that hydrolyzes fibrin and thus
dissolves clots.
• Mainly used in acute thrombolism
122
Sagni H
123. Include:
Ⅰ Plasminogen activator from human body
Urokinase (UK) , Alteplase (t-PA)
Ⅱ Plasminogen activator form bacteria
Streptokinase (SK) , Anistreplase,
Stephylokinase
Ⅲ Plasminogen activator from snake
Snake venom antithrombus enzyme,
Ancrod, Acutase
123
Sagni H
124. SHARED CHARACTERISTICS
• ACTION
– All act either directly or indirectly to convert
plasminogen to plasmin, which in turn
cleaves fibrin, thus lysing thrombi.
• Clot dissolution occurs with a higher
frequency when therapy is initiated early
after clot formation.
Sagni H 124
127. 2. Urokinase(UK)
• mechanism: activating plasminogen
directly
• clinical uses: Same use as SK, especially
cerebral embolism
• adverse reactions: bleeding, but no
antigenicity
Sagni H 127
128. plasminogen
inhibitors - + UK
plasmin
+ +
Degration
fibrin splits
products fibrinogen fibrin
products
Sagni H 128
129. 3.tissue plasminogen activator (t-PA)
or Alteplase
Mechanism: act directly
Charateristics:
• act selectively , risk of bleeding ↓
(High affinity to plasmnogen bound to
fibrin in the embolism ，low affinity to
free plasmnogen)
• superior to SK and UK
Sagni H 129
130. 4. anistreplase (anisoylated plasminogen
streptokinase activator complex)
• a complex of purified human plasminogen
and bacterial streptokinase that has been
acylated to protect the enzyme’s active site.
• When administered, the acyl group
spontaneously hydrolyzes, activating
streptokinase-proactivator complex.
• greater clot selectivity (ie, more activity on
plasminogen associated with clots than on
free plasminogen in the blood)
Sagni H 130
In aplastic anaemia, the red cells, white cells, and platelets in the blood are all reduced in number. The condition is caused by a failure of the bone marrow to produce stem cells, the initial
form of all blood cells.
Iron is an essential component of myoglobin; heme enzymes such as the cytochromes, catalase, and peroxidase; and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme a-glycerophosphate oxidase.
Iron deficiency can affect metabolism in muscle independent of the effect of anemia on O2 delivery, possibly due to a reduction in the activity of iron-dependent mitochondrial enzymes. Iron deficiency also has been associated with behavioral and learning problems in children, abnormalities in catecholamine metabolism, and impaired heat production.
Heme iron, which constitutes only 6% of dietary iron, is far more available and is absorbed independent of the diet composition; it represents 30% of iron absorbed.
Orally administered ferrous sulfate is the treatment of choice for iron deficiency. Ferrous salts are absorbed about three times as well as ferric salts, and
the discrepancy increases at high dosages.
COAGULATION IN VITRO The time in which recalcified plasma will clot after addition of kaolin is termed the activated partial thromboplastin time (aPTT); normal values are from 26 to 33 seconds.
Alternatively, the time required for recalcified plasma to clot after the addition of “thromboplastin” (a mixture of tissue factor and phospholipids is termed the prothrombin time (PT); a normal value is from 12 to 14 seconds.
aPTT = Activated partial thromboplastin time.
PT = Prothrombin time.
Test results are reported as a PT ratio or an INR (international normalized ratio).
