2. Introduction
Blood is a viscous (thick) fluid that varies in colour from
bright to dark red.
Its quantity differs with the size of the person; the average
adult has about 5 litres of blood, this volume accounts for
about 3.2% of the total body weight.
The circulating blood is of fundamental importance in
maintaining the internal environment in a constant state
(homeaostasis).
2
3. Introduction ----
The blood is composed of from plasma and formed
Formed elements include:
Erythrocytes: Red blood cells, which transport
oxygen.
Leukocytes: white blood cells, which protect
against infection
Platelets/thrombocytes: Are cell fragments that
participate in blood clotting by sticking together
3
4. Introduction---
Hematopoiesis: The production of circulating erythrocytes
platelets and leukocytes from undifferentiated stem cells
Produces over 200 billion new cells per day in the normal
person
The hemopoietic machinery resides primarily in the bone
marrow in adults
Requires constant supply of three essential nutrients – iron,
vitaminB12 and folic acid
4
6. Anti-anemic agents ---
• 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
6
7. Causes for Anemia
1. Blood loss
Chronic GI bleeding due to ulcer and menstrual
bleeding
Acute-GI bleeding
2. Bone marrow dysfunction
Low erythropoietin production- results from kidney
disease
Decreased marrow response to erythropoietin
3. Deficiencies of substances essential for RBC formation
& maturation
Iron[microcytic anemia], vit. B12, or folic acid[both
result in macrocytic anemia]
4. Increased erythrocyte destruction (hemolytic anemia)
7
8. Clinical Manifestations of anemia:
1. Pallor
2. Fatigue, weakness.
3. Dyspnea.
4. Palpitations, tachycardia.
5. Headache, dizziness, and restlessness.
6. Slowing of thought.
7. Paresthesia (tingling, numbness).
8
9. Red Blood Cell Development
Begin developing in bone marrow
Mature in blood
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
9
10. Types of anemia
• Iron-deficiency anemia
• Megaloblastic anemia (deficiency of Vit. B12
and folic acid)
• Aplastic anemia
• Hemolytic anemia
10
11. 1. Iron Deficiency Anemia
• Is the most common nutritional deficiency
cause of anemia.
• When severe, it results in a characteristic
microcytic, hypochromic anemia.
11
12. Daily Requirements of iron
– Determined by the rate of erythrocyte production
– High in
• infants and children (due to their rapid growth),
• pregnancy (due to blood volume expansion and
production of RBCs by the fetus)
– adult males need 10 mg of dietary iron each day
• but more for females (to replace iron lost through
menstruation)
12
14. Dietary Sources of iron
• foods of plant and animal origin
• Special iron rich foods
– liver, egg yolk, brewer's yeast, and wheat germ
• Other foods with a high iron content
– muscle meats, fish, fowl, cereal grains, beans, and
green leafy vegetables
• Foods that do not provide much iron
– milk and most nongreen vegetables.
14
15. Treatment of iron deficiency anemia
A. Oral Iron therapy: Only ferrous salts are used because of
efficient absorption.
– Ferrous gluconate-12% iron
– Ferrous fumarte- 33% iron
– Ferrous sulfate hydrated- 20% iron.
– Dried ferrous sulfate- 32% elemental iron.
• The effective dose of all of these preparations is based on iron
content.
• Treatment for oral iron should be continued for 3-6 months after
correction of the cause of the iron loss to replenish iron stores.
• Side effects: nausea, vomiting, abdominal cramps, constipation and
diarrhea.
– Take tablets immediately after or with meals to minimize SEs
– Black stool- mask the presence of GI bleeding
15
Blood Pharmacology
16. Ferrous sulfate
• Is the least expensive and prototype for oral
iron preparation
• treatment of choice for iron deficiency.
• Preferably used for prevention & treatment of
iron deficiency anemia (pregnancy & chronic
blood loss)
– When iron needs cannot be met by diet alone
16
18. Effect of food on iron absorption
• Food affects therapy in two ways
– 1. protects against iron-induced GI distress.
– 2. decreases iron absorption by 50% to 70%.
• As a rule, iron should be administered between
meals
• May be desirable to take with food
– to reduce the most intense GI effects at beginning
– to promote adherence
18
19. Pharmacological actions:
• Iron is part of hemoglobin.
– 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
19
20. 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 pregnancy.
20
21. Adverse effects of Ferrous sulfate
• GI disturbances- nausea, pyrosis (heartburn),
bloating, diarrhea, constipation, dark green or
black stool (harmless)
– Aggravate peptic ulcers
• Staining of teeth
• Anti-dot: Deferoxamine (parentral) and
deferasirox (oral): potent iron chelating
compounds.
To chelate already absorbed iron
If the plasma level of iron is high (above 350 to 500
mcg/dL),
21
22. Drug interactions
Antacids (raise PH, and can oxidize Fe2+ to Fe3+)
• Decrease absorption
Tetracyclines (form unabsorbable chelate)
• dec. absorption
Ascorbic acid, vit. C- (reduces ferric to ferrous iron)
• Increase absorption
Meat facilitate Fe absorption by inc gastric acid
secretion
• inc. absorption
22
23. Parenteral Iron
Drugs include
Iron dextran
Iron sucrose
Sodium–ferric gluconate complex
Iron dextran
– The rate of response is equal to that of oral iron
– Risk for fatal anaphylactic reactions
– Used
• when oral iron is not effective or not tolerable
• With intestinal diseases (when unable to absorb oral iron)
• severe blood loss (500 to 1000 mL/wk).
– oral iron cannot be absorbed fast enough to meet hematopoietic needs
23
24. Iron dextran---
• Adverse effects
– Fatal anaphylactic rxn
– Hypotension
– Circulatory failure
– Cardiac arrest
To reduce risk
• Whenever iron dextran is administered,
– injectable epinephrine and facilities for resuscitation should be
at hand.
• Furthermore, each full dose should be preceded by a small
test dose.
• Do not combine d/t iron preparations at a time
– oral + parenteral = iron toxicity
24
25. Cobalamin (Vitamin B12) Deficiency
• Cobalamin Deficiency--formerly known as pernicious anemia
(deficiency of Intrinsic factor)
• Intrinsic factor (IF) is required for cobalamin absorption
• Known as cobalamins- because of cobalt atom
• Vitamin B12 (cobalamin) is an important water-soluble
vitamin.
25
27. Cobalamin deficiency-----
• Causes of cobalamin deficiency
– Gastric mucosa not secreting IF
– GI surgery loss of IF-secreting gastric mucosal
cells
– Nutritional deficiency (in strict vegitarians)
– Hereditary defects of cobalamine utilization
27
28. Clinical manifestations of cobalamin deficiency
• General symptoms of anemia
• Disruption of DNA synthesis, and affect rapidly
replicating cells
bone marrow, epithelial cells of mouth & GIT
• Megaloblastic anemia
Megaloblastic-Oversized erythroblasts
Macrocytic- Oversized erythrocytes
• Neurologic Damage
Neurological demyelination
loss of memory, mood changes, hallucinations, and
psychosis
• Infection and spontaneous bleeding
Loss of leukocytes and thrombocytes
28
29. Vitamin B12 Preparations
Cyanocobalamin
Hydroxycobalamin
– A purified, crystalline form of vitamin B12
• Adverse effects
– Hypokalemia
• Erythrocytes incorporate significant amounts of potassium
• Given by:
– Orally
– Intranasally
– Parenterally- IM or SC
• Lifelong treatment is required
29
30. Folic Acid Deficiency
• 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 30
31. Folic Acid-----
• Metabolic function
– For DNA synthesis
• Dietary folic acid (inactive) converted into active form in
presence of vit B12
• But at large amounts, activated via an alternative
pathway
• Absorbed at small intestine
– Transported into liver & other tissues for storage
– Significant excretion
31
32. • Consequences of folic acid deficiency
1. Identical to that of vitamin B12 deficiency except
the CNS effect.
Megaloblastic anemia
Leukopenia
Thrombocytopenia
Injury to the oral and GI mucosa
2. Neural tube defects- spina bifida, anencephaly-
in the developing fetus
32
33. Dietary recommendation
• Encourage patient to eat foods containing
large amounts of folic acid
• Leafy green vegetables
• Liver
• Mushrooms
• Peanut butter
• Red beans
33
34. Folic acid preparations
1. Folic Acid (Pteroylglutamic Acid)
– Inactive form
– Most commonly used
Indications
1. Treatment of folic acid deficiency
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
34
35. 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. Toxins- snake venom, insect bites
35
36. 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.
36
37. Aplastic Anemia---
• Etiology
– Congenital
• Chromosomal alterations
– Acquired
• Results from exposure to ionizing radiation,
chemical agents, viral and bacterial infections
37
38. Aplastic Anemia
• Treatment
– Identifying cause
– Blood transfusions
– Antibiotics
– Immunosuppressants
• Corticosteroids
– Bone marrow stimulants
• Epoetin alfa (Erythropoietin)
• Produced by recombinant DNA technology
– Bone marrow transplantation
38
40. Introduction
Blood fluidity is determined by the balance between
– Procoagulants (thromboxane, thrombin, activated platelets,
platelet factor 4) and anticoagulants (heparan sulfate,
prostacyclin, nitric oxide, antithrombin)
• -If this balance is disturbed, there will be thrombi
formation or spontaneous bleeding.
40
41. Introduction…
Physiology of coagulation
• Hemostasis is the physiologic process of
cessation of blood loss from damaged vessel.
• Blood clotting has four phases:
1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Fibrinolytic phase
41
42. Introduction…
Vascular phase
– Manifested by vasoconstriction of damaged blood vessels.
• Decreases blood flow to the site of injury - Reduce
blood loss.
Platelet phase: Platelets adhere to & activated
Coagulation phase
– Transforms soluble fibrinogen to insoluble fibrin
Fibrinolytic phase
• unwanted fibrin thrombi are removed
42
43. Outline of coagulation pathways showing factors
affected by warfarin and heparin
II IIa
43
Tissue
Injury
Fibrin polymer
45. Pathophysiology of coagulation
Thrombosis
– the formation of unwanted clot within the blood vessels
or heart
– Pathologic functioning of hemostatic mechanisms
Arterial thrombosis (white thrombi)
– Begins with adhesion of platelets to arterial wall
» due to wall damage or atherosclerotic plaque
rupture
– Platelets release TXA2 (attract additional platelets)
» Arterial occlusion
» Initiation of coagulation cascade
» Reinforcement with fibrin
Causes localized tissue injury due to lack of perfusion
45
46. Venous thrombosis (red thrombi)
– Occur at sites of slow blood flow
» Blood stagnation
» Coagulation cascades activation
» Fibrin production
» Traps RBCs & platelets to form thrombus
» thrombi can Break off & travel as embolus
» embolus blocks distant blood vessel
46
47. Drugs for Thromboembolic Disorders
General MOA:
Prevent formation of thrombi (intravascular
blood clots) and
Dissolve thrombi that have already formed.
Act By:
• Suppressing coagulation,
• inhibiting platelet aggregation, and
• promoting clot degradation.
47
48. Drugs for Thromboembolic --
1. Anticoagulants (eg. heparin, warfarin)
– Disrupt coagulation cascade
– Suppress production of fibrin
– Most effective against venous thrombosis
2. Antiplatelet drugs (e.g Aspirin, clopidogrel)
– Inhibit platelet aggregation
– Most effective at preventing arterial thrombosis
3. Thrombolytic drugs (e.g. Alteplase, streptokinase)
– Promote lysis of fibrin
– Cause dissolution of thrombi
48
49. Anticoagulants
• Are drugs employed in preventing blood
coagulation.
• Drugs include:
– Inhibit the activity of clotting factors
» E.g. heparin
– Inhibit the synthesis of clotting factors in the
liver
» E.g warfarin
50. A. Heparin (Unfractionated)
• Mechanism of action
– Accelerate inactivation of clotting factors (IIa and
Xa) by enhancing the anticoagulative activity of
ATⅢ ( ant thrombin Ⅲ ).
• Suppresses the fibrin formation
• Quick anticoagulant effects (within minutes)
50
52. Pharmacokinetics
• Orally inactive- too large & highly polar (negatively
charged)
– Given via injection- IV/SC
• Does not traverse the placenta and does not enter breast milk
(Anticoagulant of choice for pregnant women)
• Plasma levels can be highly variable (monitoring is
required) – due to plasma protein binding
• Undergoes liver metabolism (by heparinase) and renal
excretion
– Has brief duration of action
52
54. Adverse reactions
• Spontaneous hemorrhage :
– Antidot: Protamine sulfate (a basic protein)
• 1 mg of protamine sulfate for every 100 U of heparin
– Protamine sulfate
• Has multiple positively charged groups.
– At higher doses - Protamine sulfate interacts with
platelets, fibrinogen, and other clotting factors –
result in an anticoagulant effect.
• Aggravates the bleeding .
55. Adverse reactions …
• Heparin-induced thrombocytopenia:
– a decrease in circulating platelets
– Due to production of antibodies against heparin-platelet
complex.
• The incidence is low with low mol wt heparin
– Can be life-threatening
• Stop heparin immediately
• Others : allergic reaction
osteoporosis
• Drug interactions
– Aspirin and other antiplatelet drugs aggravate bleeding
55
56. B. Low Molecular Weight Heparins
(LMWHs)
• Weaker effect than heparin – weak on IIa
inhibition
Higher bioavailability - not bind to proteins and
tissues
More predictable dose-response r/n ship
-Plasma levels do not vary
Longer biological half-life - slower clearance
56
57. 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!)
Lower risks of thrombocytopenia and bleeding
Safety to use during pregnancy is not evaluated
57
59. LMW heparins
Uses:
1. prevention of venous thromboembolism
2. Treatment of venous thrombosis,
pulmonary embolism and unstable angina
60. Advantages of LMWH over UH
• No need for laboratory monitoring
– When given on a weight adjusted basis, the LMWH
anticoagulant response is predictable and
reproducible
• Higher bioavailability- 90% Vs 30%
• Longer plasma halflife
– 4-6 hrs Vs 0.5 to 1 hr
• Less inhibtion of platlet function
– Potentially less bleeding risk
• Lower incidence of thrombocytopenia and
thrombosis
60
Blood Pharmacology
61. Oral anticoagulants
• Warfarin
• Often referred to as oral anticoagulant
– because it is administered orally, which exists as
the main difference from heparin.
• Small & lipid-soluble molecule
• Structurally related to vitamin K
– Act as vitamin K antagonist
• warfarin was used to kill rats.
61
62. Warfarin-----
• MOA
• inhibits the synthesis of Vitamin K–dependent clotting
factors: protrombin (II), VII, IX, and X
By Inhibiting vitamin K–epoxide reductase →Inhibit
carboxylation of in active prothrombin to active thrombin →
thereby inhibit coagulation
62
63. Warfarine--
Pharmacokinetics:
• Absorption: rapid and complete
• Distribution: 99% bound to plasma albumin
• Onset of effect is delayed until the decay of already formed clotting factors
in plasma - Takes several days.
– not useful in emergencies
• Warfarin crosses placenta – is teratogenic – can cause birth defects and
abortion
• Warfarin antidote is Vitamin K (oral or parenteral)
63
64. Warfarin---
:
• 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
64
65. Warfarin----
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
66. Signs of Warfarin Overdosage
• Any unusual bleeding:
– Blood in stools or urine
– Excessive menstrual bleeding
– Excessive nose bleeds/bleeding gums
– Persistent oozing from superficial injuries
– Bleeding from tumor, ulcer, or other lesion
• Why warfarin is active only invivo where
as heparin both invivo and invitro??
66
Blood Pharmacology
67. Drug interactions
1. Drugs that increase anticoagulant effects
– By displacement from albumin- salicylates &
sulfonamides
– By enzyme inhibition- ketoconazole, cimetidine,
disulfiram, sulfonamide
– By decreasing synthesis of clotting factors-
cephalosporins
67
68. 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- phenytoin, phenobarbital,
etc
– By increasing clotting factors synthesis- oral
contraceptives, vit K
– By inhibition of its absorption- cholestyramine,
colestipol
68
69. Contraindication
– Patients on heparin therapy
– Severe thrombocytopenia
– Uncontrollable bleeding
– Vitamin k deficiency
– Liver disease
– Alcoholism
– Pregnancy & lactation
69
70. 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
70
72. 1. Cyclooxygenase inhibitor (Aspirin)
• Aspirin is a classic old drug which is used as a
NSAID for more than 100 years.
• Besides antipyretic, analgesic and anti-
inflammatory activities, it can inhibit platelet
aggregation.
72
74. Aspirin…
• At small dose (50～75mg/day): inhibits the
synthesis of TXA2 – inhibits platelet
aggregation
• At higher doses (> 320 mg/day): inhibits the
synthesis of PGI2 (platelet aggregation
inhibitor) – enhances platelet aggregation.
75. Aspirin…
• Clinical indications
– Prophylaxis after cardiac operation
– to reduce the incidence of recurrent myocardial
infarction (MI)
– Chronic stable angina and unstable angina
Reduces morbidity & mortality
Adverse effects
– GI bleeding
– Abdominal pain, dyspepsia, diarrhea, and rash.
75
77. Fibrinolytic drugs
(thrombolytic agents)
• Activate the conversion of plasminogen to
plasmin,
– plasmin is a serine protease that hydrolyzes fibrin
to dissolve clots.
• Mainly used in acute thromboembolism
78
78. 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
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