Drugs acting on Blood and Blood forming agents

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RAMDAS BHAT
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CHAPTER NO:01
DRUGS ACTING ON
BLOOD AND BLOOD
FORMING AGENTS
Prepared by,
RAMDAS BHAT
Assistant Professor
Srinivas college of Pharmacy
Mangalore
7795772463
Ramdas21@gmail.com

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INTRODUCTION
• Blood is the fluid connective tissue that carries oxygen, Blood also carries the dietary
elements from GIT to various body tissues.
• Blood also drains away Carbon dioxide and metabolic wastes from the tissues.
• Blood helps in maintenance of Ph and ionic balance inside the body.
The drugs acting on the blood are:
1. Coagulants and Anticoagulants
2. Antithrombotic agents
3. Haematinics
4. Plasma expanders

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COAGULANTS AND ANTICOAGULANTS
Blood is retained as the fluid in the circulation by haemostatic mechanisms they are:
1. Vascular mechanism:
• As the blood vessels gets damaged due to any trauma, blood vessels get vasoconstricted
it is termed as Transient vasoconstriction, the vasoconstriction is brought by the serotonin
released by the platelets.
• Followed by the Persistent vasodilation brought up by the Histamine.
• This causes redness, pain, heat and loss of function for some time.
• On other hand damaged blood vessels exposes the collagen to the platelets.
• Damaged blood vessels secrete VWF (Von Willebrand factor) to which Glycoprotein (GP-
Ib.) present over the platelets binds leads to platelet adhesion.
2. Platelet factors:
• Once platelet adhesion is done, Platelet now gets activated and this is termed as Platelet
Activation.
• The activated platelet now starts releasing chemicals from their granules called as ADP,
Serotonin and Thromboxane A-2 (TXA-2)
• Released TXA-2 and ADP helps in the chemotaxis of platelets towards the site of injury.
• Platelets now come to the site of the injury and attach to each-other with the help of
another glycoprotein called as the GP-IIb, IIIa.
• Aggregated platelets now form the plug called as the platelet plug and the process is
termed as Platelet plug formation.
3. Plasma coagulation factor:
Blood coagulation:
Definition: “A set of reactions in which blood istransformed from a liquid to a gel is known
as clotting or coagulation.”
• Clotting process is well described by three main pathways which are:
a) Extrinsic pathway b) Intrinsic pathway and c) Common pathways

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a) Extrinsic pathways:
• It has fewer steps than the intrinsic pathway.
• It’s a fast process than the intrinsic pathway usually takes few seconds.
During the injury
Endothelial cells which line the blood capillary get damage
So, Factor VII leaves the circulation and comes into contact with
tissue factor (TF)
It activate the clotting factor VII
Which combine with the factor X and activate
factor X
It combines with factor V in the presence of
Ca++, Platelet Phospholipid
Which form the active enzyme
PROTHROMBINASE
• Tissue factor (TF) is a complex mixture of lipoprotein and phospholipids, it releases
from the surface of damaged cells.
b) Intrinsic pathways:
• It is a more complex process than the extrinsic pathway.
• It is a slow process than the extrinsic pathway usually required several minutes
During the injury
Endothelial cells which line the blood capillary get damaged
Blood come with contact of collagen in the surrounding basal lamina (Junction between
Endothelial tissue and Connective tissue)
Activate the clotting factor XII, clotting factor XII activates
factor XI
Factor XI activates the factor IX which is also activate by extrinsic pathway factor VII
Factor IX by the help of factor VIII and platelet phospholipids activate factor X
Activated factor X combine with factor V and Ca++ (same as extrinsic pathway processes)
Which form the active enzyme PROTHROMBINASE

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c) Common pathway:
• Once prothrombinase is form it start the common pathway.
Prothrombinase convert in to thrombin by the help of Ca++
Thrombin activates factor XIII as well as convert in to Fibrinogen in the presence of Ca++
Fibrinogen converts into soluble fibrin
Soluble fibrin converts in to insoluble fibrin by the help of activated factor XIII
Clot Retraction and repair
• Process takes place after the formation of insoluble fibrin.
• Platelet from the platelet plug starts retracting the endothelium back to its normal
position.
• Retraction of endothelium is done by actin and myosin present over the platelets that pull
the endothelium present on both the sides of the injured site towards each-other.
• Process of repair happens when the platelet from the plug releases Platelet derived
growth factor that repairs damaged smooth muscles and collagen fibres of basement
membrane and Vascular derived growth factor released by platelet of plug that repairs
the damaged endothelium.
• Thus, this process causes both retraction of endothelium and repair of endothelium,
smooth muscles and collagen fibres thereby causing the sealing of the blood vessels.

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4. Fibrinolysis:
• Once repair is over, the fibrinolysis system is activated. This process inhibits the
clot formation in blood because in clot formation soluble fibrin is converted into
insoluble while in fibrinolysis insoluble fibrin will be converted in to soluble fibrin.
• Due to the formation of insoluble fibrin, there may be chances of formation of
bigger clot that may occlude the blood vessels thereby may causes decreased
blood flow through that blood vessel or no blood flow. It may lead to ischemia.
• Thus, endothelium of the blood vessel possesses a protein over them called as
Tissue plasminogen activator (tPA) that activates the Plasminogen in the blood
to its active form Plasmin.
• Plasmin thus formed causes dissolving of the fibers and platelets will be released
back into the blood.
Coagulants:
• Substances which promote coagulation
• Indicated in hemorrhagic states.
• Drugs used to restore homeostasis
CALCIUM SALTS:
• Calcium salts, especially Calcium intravenous injections are very popular but it does not
help much unless there isdeficiency of Calcium in the blood.
VITAMIN K:
• Fat-soluble dietary principle required for the synthesis of clotting factors
• Vit K has a basic naphthoquinone structure,
• with or without a side chain (R) at position 3.
• The side chain in K1 is phytyl,
• In K2 phenyl, while in K3 there is no side chain.
• Dietary sources are—green leafy vegetables, such as cabbage, spinach; and liver, cheese,
etc.
• MOA: Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation
proteins— prothrombin, factors VII, IX and X.
USES:
• The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of
clotting factors in the following situations
• Dietary deficiency of vit K
• Prolonged antimicrobial therapy:
• Obstructive jaundice or malabsorption syndromes
• Liver disease (cirrhosis, viral hepatitis)
• Newborns: All newborns have low levels of prothrombin and other clotting factors
• Overdose of oral anticoagulants
• Prolonged high dose salicylate therapy

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OTHER COAGULANTS:
FIBRINOGEN
• The fibrinogen fraction of humanplasma is employed to control bleeding in hemophilia,
antihemophilic globulin (AHG) deficiency and acute afibrinogenemic
ANTIHAEMOPHILIC FACTOR
• It is concentrated human AHG prepared from pooled human plasma. It is
indicated (along with human fibrinogen) in haemophilia and AHG deficiency.
• It is highly effective in controlling bleeding episodes, but action is short-lasting
(1 to 2 days).
DESMOPRESSIN ACETATE:
• Desmopressin (DDAVP) stimulates the release of von Willebrand factor (Vwf) from the
Weibel-Palade bodies of endothelial cells, thereby increasing the levels of Vwf (as well as
coagulant factor VIII) 3 to 5-fold.
• It is also used to promote the release of Vwf in patients with coagulation disorders such
as von Willebrand disease, mild hemophilia A and thrombocytopenia.
Anticoagulants:
• Clotting mechanism are formed when there is damage to the blood vessels.
• Intrinsic mechanism happens when the clotting mechanism whole mechanism of blood
clotting is governed by the blood plasma factors. This happens within the circulation.
• Extrinsic mechanism happens when there is involvement of the clotting factors that are
present outside the blood vessels.
Definition of anticoagulants:
These are the agents that prevent the Coagulation of blood.
• They act by activating the naturally occurring inhibitory elements that inhibit the clotting
mechanisms. Eg: Heparin.
• By reducing the rate of synthesis of Vitamin-K dependent clotting factors like
Prothrombin, Factor VII, IX and X. Eg: Warfarin.
• Activating fibrinolytic mechanism. Eg: Streptokinase, Urokinase.
• Antiplatelet agents: Aspirin, Cilastazole, dipyridamole, Ticlopidine, Clofibrate.
Various conditions contribute for the bleeding disorders.
1. Thrombocytopenia (Dec. in Platelets)
2. Haemophilia (Absence of clotting factors)
Thromboembolism is a condition where there is formation of Thrombus (clot) and emboli
(small piece of blood clot or fat that clogs the smaller blood vessels). It can lead to Myocardial
infarction, Stroke, Pulmonary thrombosis etc. Where there is a requirement of Anticoagulant
to dissolve or to prevent the formation of clot.

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CLASSIFICATION:
1. Vitamin K antagonist - Warfarin.
2. Heparin and related drugs:
a) Heparin.
b) LMWH (Enoxaparin, Dalteparin, Tinzaparin).
c) Synthetic heparin derivatives (Fondaparinux – longer acting).
3. Direct thrombin inhibitors:
a) Parenteral ® Hirudin, Lepirudin, Argatroban, Bivalirudin.
(b) Oral
Coumarin derivatives: Bis-hydroxy coumarin (dicumarol), Warfarin sodium
Indandione derivative: -Phenindione]
4. Active factor Xa inhibitor: Rivaroxaban, Apixaban.
5. Calcium complexing agents: Sodium citrate and Sodium oxalate.
Warfarin:
• Competitively inhibits vitamin K epoxide reductase and inhibits the post-translational
carboxylation of glutamate residues on vitamin K dependent coagulation factors II
(prothrombin), VII, IX, and X.
• They inhibit the regeneration of active vitamin K-hydroquinone (reduced form of vitamin
K). This reduced vitamin K is oxidized to vitamin K epoxide (inactive form).
• This reaction is coupled with protein carboxylation by which Des Carboxy Prothrombin
(DCP) is converted to prothrombin by carboxylation of glutamate residue.
• By the reactions of enzyme, vitamin K hydroquinone is regenerated from vitamin K -
epoxide, using NADH as a co -factor.
• Synthesis of clotting factors reduces in 2 -4 hours and the effect of anticoagulant lasts for
1 -3 days, if the synthesis of clotting factors decreases by 40-50%.

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PHARMACOKINETICS:
• Absorbed orally 100%
• Does not cross Blood brain barrier
• May lead to toxic effects in foetus
• Metabolized in liver
• Excreted in urine via kidneys.
THERAPEUTIC USE:
Warfarin is used as an anticoagulant in patients of pulmonary embolism, deep
vein thrombosis, atrial fibrillation, to inhibit thromboembolism, prosthetic valves,
primary pulmonary hypertension, and sometime in cerebrovascular disease.
ADVERSE EFFECTS:
• Haemorrhage in GIT and Urinary tract.
• Nausea/ Vomiting.
• Cutaneous necrosis.
• Alopecia
• Dermatitis
• Diarrhoea
• During pregnancy warfarin causes teratogenicity. When given in the first trimester, it can
cause fetal warfarin syndrome with bone stippling, and abnormalities of face and CNS. It
causes neonatal hypoprothrombinemia in the second and third trimester. Patients with
bleeding should not be given warfarin.
• In patients with hemorrhagic blood disorders, peptic ulcers, severe wounds, and bacterial
endocarditis, warfarin should be used very carefully.
HEPARIN:
• Heparin McLean, a medical student, discovered that liver contains a powerful
anticoagulant. Howell and Holt named it 'HEPARIN' -obtained from liver.
• Mixture of mucopolysaccharides with M W 10,000 to 20,000.
• It contains D-glucosamine-L-iduronic acid and D-glucosamine-
• D-glucuronic acid
• It carries strong electronegative charge and is the strongest organic acid present in the
body.
• Found in the secretory granules of mast cells. Richest sources are lung, liver and intestinal
mucosa.
• Commercially produced from ox lung and pig intestinal mucosa.
• Heparin produces its anticoagulant effect by binding with the plasma antithrombin III and
inhibiting factors like IIA and XA.Other actions of heparin:
1. ANTIPLATELET: -
• Higher doses inhibit platelet aggregation and prolongs bleeding time
• Thrombocytopenia

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2. LIPAEMIA CLEARING
• Injection of heparin clears turbid post-prandial lipemia by releasing a lipoprotein lipase
from the vessel wall
3. ANAGONIST:
• Protamine sulfate: It is a strongly basic, low molecular weight protein obtained from the
sperm of certain fish.
• Weight basis: I.V. 1 mg is needed for every 100 U of heparin.
• In the absence of heparin, protamine itself acts as a weak anticoagulant.
PHARMACOKINETICS
• Large, highly ionized molecule; therefore, not absorbed orally. I.V. -instantaneously, s.c.
injection -after 60 min.
• Does not cross blood-brain barrier or placenta hence safe in pregnancy
• It is metabolized in liver by heparinase fragments are excreted in urine.
LOW MOLECULAR WEIGHT HEPARIN
• Commercially prepared by fractionation (molecular weight 4000 - 6500)
Advantages over conventional heparin:
• Uniform absorption
• Longer duration of action.
• Less antigenic, less interaction with platelets- Less risk of thrombocytopenia
• Examples: Dalteparin, Danaparoid, Tinzaparin, Enoxaparin, Apixaban
DALTEPARIN
• Prophylaxis 2500 U S.C 1 hr. before surgery, then 2500 U every day for 5-7 days
• Therapeutics: 100 U/ kg BD for 5 days.
Thrombin inhibitors: Inactivates free as well as fibrin — bound thrombin, does not require
antithrombin III like heparin No antidote.
Parenteral thrombin inhibitors: Hirudin (leech), Lepirudin (Recombinant DNA)
• Orally used: dabigatran, epixaban, rivoroxiban

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FIBRINOLYTIC SYSTEM:
The process of dissolution of clot is termed as Fibrinolysis.
FIBRINOLYTICS (THROMBOLYTIC DRUGS)
• Used to lyse the thrombi / clot to recanalize the occluded blood vessel (mainly coronary
artery)
• Work by activating the Fibrinolytic system
• Eg: STREPTOKINASE. UROKINASE, RETEPLASE (analogue of alteplase), ALTEPLASE (t- PA),
TENECTEPLASE
STREPTOKINASE
• Obtained from ß-hemolytic streptococci
• Binds with circulating plasminogen to form complex that activates plasminogen to
plasmin
• t 1/2 = 30-80 min
• Antigenic, Pyrogenic
• Destroyed by circulating antistreptococcal Antibodies
• AE: Hypotension & arrhythmia can occur
t-PA
PLAMINOGEN PLASMIN
ENDOTEHLIAL CELL
FIBRIN FIBRIN split products

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Uses
• Acute myocardial infarction — 7.5 to 15 lac IU; I.V over 1 hr period
• Deep vein thrombosis, Pulmonary embolism
• Adverse effects: Bleeding, hypotension, allergic reactions, fever, arrhythmias
• Contraindications: Recent trauma, surgery, abortion, stroke, severe hypertension, peptic
ulcer, bleeding disorders
UROKINASE
• Enzyme isolated from human urine, now prepared from cultured human kidney cells
• Direct plasminogen activator
• t 1/2 = 10 to 15 min
• Non antigenic, non-allergenic
• Fever can occur but hypotension rare Indicated in patients in whom streptokinase has
been for an earlier episode
ALTEPLASE
• Recombinant tissue Plasminogen Activator(rt-PA)
• Selectively activates plasminogen bound to fibrin
• Non antigenic, not destroyed by antibodies
• Rapid acting, more potent
• Superior in dissolving old clots
• Short half-life 4-8 min
• Nausea, mild hypotension, fever may occur
• Expensive.
RETEPLASE:
• Modified rt-PA
• Longer half-life 15-20 min, but less specific for fibrin bound plasminogen
TENECTEPLASE:
• Genetically engineered mutant form of alteplase
• Higher fibrin selectivity and longer half-life — 2 hrs
• Single bolus dose 0.5 mg/kg sufficient
• Very expensive
Uses of fibrinolytics
• Acute myocardial infarction
• Deep vein thrombosis
• Pulmonary embolism
• Peripheral arterial occlusion
• Ischemic Stroke

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ANTIPLATELET DRUGS:
1. Phosphodiesterase inhibitor: Dipyridamole, cilostazole
2. Thienopyridine derivatives (ADP antagonists): Ticlopidine, clopidogrel, Dipyridamole
3. Gp-llb/llla receptor antagonists: Abciximab, eptifibatide, tirofiban
4. Prostaglandin synthesis inhibitors: Aspirin and Dazoxiben.
5. Others: PGb, daltroban, dazoxiben, clofibrate

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PHOSPHODIESTERASE INHIBITORS
• They inhibit platelet function by inhibiting cGMP phosphodiesterase activity and/or
adenosine uptake.
• It is never used alone due to its minimal antiplatelet action, thus is used along with aspirin
to enhance the antiplatelet action.
• In secondary prophylaxis of cerebrovascular diseases, dipyridamole is used along with
aspirin.
• Dipyridamole with warfarin is used after prosthetic heart valve surgery for primary
prophylaxis of thromboembolism.
ADP-Induced Platelet Aggregation Inhibitors (ADP antagonist)
The commonly used drugs that inhibit platelet aggregation are discussed below:
1) Dipyridamole: It inhibits phosphodiesterase for increasing platelet cAMP. It can also
release PG precursors from vascular endothelium. It is a vasodilator and can inhibit platelet
adhesion to thrombogenic surfaces. It can be used along with low-dose aspirin.
2) Timolol: It is a β-adrenoceptor blocker, and its concurrent use synergizes the action of
low -dose aspirin. It is used for long -term prevention of secondary myocardial infarction.
3) Clopidogrel and Ticlopidine:
• These drugs inhibit the ADP pathway of thrombocytes, and thus reduce platelet
aggregation.
• The binding of ADP to its receptors is inhibited irreversibly by these drugs.
• They do not inhibit prostaglandin synthesis.
• Clinically, they are used for treating unstable angina pectoris, acute coronary syndrome,
acute neurovascular disease, peripheral vascular disease, and for preventing thrombosis
coronary surgery.
• The dose of ticlopidine is 250mg twice daily via oral route, and that of clopidogrel is
75mg/day, with a subsequent loading dose of 300mg via oral route.
• Nearly 80% platelet activity is inhibited by these doses.
• Gastrointestinal adverse effects, leucopenia, and hemorrhage are the adverse effects of
ticlopidine,
• Whereas clopidogrel may cause hemorrhage. Because of less adverse effects and the
dosage factor, clopidogrel is preferred over ticlopidine.
4) Clofibrate:
• It is a hypolipidemic drug which may be used for reducing platelet adhesiveness.
• It does not prevent secondary myocardial infarction.
5) Dextran-70 and Dextran-75:
• These are plasma volume expanders given as IV infusions.
• They have no effect on platelet function in vitro, but damages platelet function and
fibrin polymerization in vivo. Postoperatively, they are used for preventing venous
thrombosis.

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GLYCOPROTEIN IIB/IIIA RECEPTOR INHIBITORS
• Glycoprotein IIb/IIIa receptor inhibitors are integrin or platelet surface adhesive
receptors.
• The receptor complex binds fibronectin and Von Willebrand factor, and also functions as
a receptor for fibrinogen and vitronectin. The receptor complex on activation mediates
platelet aggregation by helping the platelets to bind to the exposed collagen and also to
the adjacent platelet.
• The effect of other platelet agonist s (e.g., collagen, thrombin, TXA 2, ADP, etc.) is
inhibited by GPIIb/IIIa receptor inhibitors.
• They also inhibit the final common pathway for platelet aggregation.
• GPIIb/IIIa receptors including vitronectin receptor are blocked by abciximab (a humanized
monoclonal antibody).
• Eptifibatide and Tirofiban (chemical analogues of fibrinogen) block fibrinogen binding.
These drugs are parenterally administered as a short course therapy in percutaneous
coronary intervention and acute coronary syndrome.
Therapeutic Uses
Anti-platelet drugs prevent arterial thromboembolism in the following situations:
1. Coronary Artery Diseases
i) Unstable Angina: The risk of death and myocardial infarction is reduced by aspirin in 75-
325mg/day dose. However, aspirin along with clopidogrel (75mg/day) is preferred. Abciximab
via intravenous route due to its rapid action is used as a short -term therapy for the same
purpose. Maintenance therapy is given for an indefinite period by oral aspirin or clopidogrel
in 75mg/day dose.
ii) Acute Myocardial Infarction: Survival (30% reduction in mortality) and thrombolytic
therapy is improved by oral aspirin in 325mg dose (1 tablet) followed by a maintenance dose
of 75mg/day.
iii) Post MI Patients: Aspirin in 75mg/day dose is administered for an undefined period as a
secondary prophylactic agent for reducing the risk of infarction by 25%. A suitable alternative
can be Clopidogrel administered in the same dose orally.
* *
2. Cerebrovascular Diseases:
• Aspirin in 75-325mg/day dose is used as a secondary prophylactic agent for preventing
transient ischemic attacks and strokes.
3. Prosthetic Heart Valves and Arteriovenous Shunts:
• Dipyridamole and oral anticoagulants prevent microthrombi formation on artificial heart
valves. They also reduce embolism. Aspirin is not a drug of choice in combination with
warfarin due to the adverse drug reactions that may occur.
4. Venous Thromboembolism: Anticoagulants are used to prevent venous
thromboembolism, while anti-platelet drugs are unimportant.
Adverse Effects
The adverse effects of anti-platelet drugs include stomach upset, heartburn, nausea,
constipation, flushing, dizziness, weakness, headache, bloody stools, GI bleeding, rashes, liver
impairment, and anaphylactic shock.

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PROSTAGLANDIN SYNTHESIS (PG) INHIBITORS
• Some common PG inhibitors are discussed below:
1. Aspirin: In low doses (75 -300mg/day), it is used as a prophylaxis of myocardial infarction
and also as a prophylaxis against secondary myocardial infarction. Aspirin acts through
irreversible acetylation of platelet cyclooxygenase. Its mechanism of action is blocking of
COX-1 pathway and thus blocking formation of TXA2 that is required for platelet
aggregation. In low doses, it produces a nominal and transient effect on vascular
cyclooxygenase. It has been proved that aspirin in low doses reduces the occurrence of
non-fatal myocardial infarction and re -infarction; however, the overall mortality rate is
left unaffected. Scientifically, low doses of aspirin can be used for long -term prevention
of myocardial infarction. Its effects can be improved by using it along with dipyridamole.
2. Dazoxiben: It is a thromboxane synthetase inhibitor, thus selectively decreases TxA-2. It
does not inhibit platelet aggregation when given alone; however, with aspirin it produces
considerable effects.
3. Epoprostenol (PGI2): It is a potent inhibitor of platelet aggregation; but its use has been
prohibited due to its very short half-life. It may be used during renal dialysis or cardiac
bypass surgery.
4. Sulphinpyrazone: It is a uricosuric drug and a cyclooxygenase inhibitor. It is not selective
for platelets. Earlier it was used in low doses to prevent myocardial re -infarction (like
aspirin), but after multi-centric long -term trials, it has been withdrawn.
5. Diet: Dietary therapy can be adjunctive in the prophylaxis of thrombosis. The Eskimos
intake high amounts of dietary eicosapentaenoic acid (an unsaturated fatty acid), thus
they generate PGI3 that is an anti -aggregating substance like PGI2.
HEMATINICS
• HEMATINICS are involved in the formation of blood and are used in the treatment of
Anaemia (a condition in which blood lacks healthy RBCs or hemoglobin).
• Hemoglobin is a major part of the red blood cells to which oxygen molecules get bound.
• Body cells do not get sufficient amount of oxygen, if a n individual has a few or abnormal
red blood cells, or the hemoglobin level is low or abnormal.
• The main symptom of Anaemia is fatigue which occurs if organs do not get sufficient
amount of oxygen that is required for different body functions.
Etiology:
Anaemia occurs when,
A. Blood loss (acute or chronic)
B. Impaired red formation due to;
a) Deficiency of iron, vit. B12 folic acid.
b) Bone marrow depression.
C. Increased destruction of RBCs.

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Classification: -
1) Iron & it's compound: - Eg: - Ferrous succinate, Ferrous sulfate, Ferrous gluconate etc.
2) Maturation factor: - Eg: - Cyanocobalamin, Hydroxycynocobalamine.
3) Miscellaneous: - Eg: - Copper, Cobalt, Riboflavin.
IRON
• According to Greek thought MARS is the god of strength & IRON is dedicated to it.
• Source of iron: - Rich Liver, egg yolk, dry bean, dry fruit. Medium: - Meat, chicken, fish,
banana, apple. Poor: - Milk & it's product.
• Daily requirement: - Adult male: - 0.5-1mg(13ug/kg). Adult Infant: -60ug/kg. Children: -
25ug/kg. Pregnancy: - 3-5mg(80ug/kg).
Iron absorption
• Its absorption occurs all over the intestine.
• In the stomach containing HCL & reducing agent are convert the ferric to ferrous.
• Two separate iron transporters in the intestinal mucosal cells function to effect iron
absorption.
• At the luminal membrane the divalent metal transporter 1 (DMTI) carries ferrous iron
into the mucosal cell.
• The ferroportin (Iron transporter) are bound with ferrous iron & pass-through mucosal
cell directly into the blood steam.
Factor affecting absorption: -
1. Achlorhydria (Achlorhydria is a condition in which the stomach does not produce
hydrochloric acid, one of the components of gastric acid.
2. Alkaline pH
3. Presence of food in stomach
4. Complex with tetracycline & phosphate.
TRANSPORT, UTILIZATION, STORAGE AND EXCRETION
• As such, on entering plasma it is immediately converted to the ferric form and
complexed with a glycoprotein transferrin (Tf).
• Iron is transported into erythropoietic and other cells through attachment of transferrin
to specific membrane bound transferrin receptors (Tf Rs).
• The complex is engulfed by receptor mediated endocytosis.
• Iron dissociates from the complex at the acidic pH of the
intracellular vesicles.
• The released iron is utilized for hemoglobin synthesis or other purposes.
• Tf and T f R are returned to the cell surface to carry fresh loads.
STORAGE: -
1. Reticulo endothelial cell in liver.
2. Spleen
3. Bone marrow
4. Hepatocytes and
5. Myocytes
EXCRETION: -

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• Daily excretion in adult male is 0.5-1 mg, mainly g.i. mucosal cells, some RBCs and in bile
from feces.
• Other routes are skin, very little in urine and sweat.
• In menstruating women, monthly menstrual loss may be averaged to 0.5-1 mg/ day.
ADVERSE EFFECTS: -
1. Epigastric pain.
2. Heartburn.
3. Nausea, vomiting.
4. Staining of teeth.
5. Metallic taste.
6. Constipation.
PREPARATIONS AND DOSE: -
1. Ferrous succinate
2. Iron choline citrate
3. Ferric ammonium citrate
4. Ferric gluconate
5. Ferrous fumarate
Parenteral iron: -
Iron therapy by injection is indicated only when:
1. Oral iron is not tolerated: bowel upset is too much.
2. Failure to absorb oral iron: malabsorption.
3. Non-compliance to oral iron.
4. In presence of severe deficiency with chronic bleeding.
5. Along with erythropoietin
Preparations for parenteral use are:
1. Iron- dextran.
2. Iron-sorbitol-citric acid
Therapeutic use: -
1. Iron deficiency Anaemia.
2. Megaloblastic Anaemia.
3. As an astringent: - Ferric chloride is used in throat paint.
4. Miscellaneous: -
a) Copper: - Haem synthesis is interfered in copper Deficiency. Dose 0.5-5 mg of copper
sulphate.
b) Cobalt: - It stimulates erythropoiesis transiently, probably by inducing tissue hypoxia
increased erythropoietin production.
c) Riboflavin: - Hypoplastic Anaemia occurs in riboflavin deficiency

19. PHARMACOLOGY-II
RAMDAS BHAT
SRINIVAS COLLEGE OF PHARMACY 19
MATURATION FACTORS
VITAMIN-B12 (Cyanocobalamin)
• Vit B12 occurs as water soluble, thermostable red crystals.
• It is synthesized in nature only by microorganisms; plants and animals acquire it from
them.
• Dietary sources: -Liver, kidney, sea fish, egg yolk, meat, cheese.
• Daily requirement: 1-3 ug, pregnancy and lactation 3-5 ug.
METABOLIC FUNCTIONS: -
• Vit B12 is essential for the conversion of homo-
cysteine to methionine.
• Purine and pyrimidine synthesis.
• Methymalonyl-CoA to Succinyl-CoA.
• Useful in cell growth and multiplication
UTILIZATION OF VIT B12
• Intrinsic factor secreted by stomach forms a complex with B12 attaches to specific
receptors present on intestinal mucosal cells and is absorbed by active carrier mediated
transport.
• Vit B12 is transported in blood in combination with a specific globulin transcobalamin Il
(TCII).
• Vit B12 is especially taken up by liver cells and stored about 2/3 to 4/5 of body's content
(2—8 mg) is present in liver.
• Vit B12 is not degraded in the body. It is excreted mainly in bile (3—7 ug/ day); all but
0.5—1 ug of this is reabsorbed — considerable entero-hepatic circulation occurs.
• The absence of intrinsic factor or when there is malabsorption.
• From Parentral rout (i.m/s.c) is mainly excreted via urine.
DEFICIENCY: -
1. Pernicious Anaemia.
2. Other cause of gastric mucosal damage.
3. Malabsorption.
4. Nutritional deficiency
Manifestations of deficiency are: -
• Megaloblastic Anaemia
• g.i. disturbances
• Neurological degeneration.
Preparations, dose, administration: -
• Cyanocobalamin: - MACRABIN 35 gg/5ml
• Hydroxocobalamin: -REDISOL-H,
• Methyl cobalamin: -METHYLCOBAL 0.5 mg tab.

20. PHARMACOLOGY-II
RAMDAS BHAT
SRINIVAS COLLEGE OF PHARMACY 20
Therapeutic use: -
1. Pernicious Anaemia.
2. Malabsorption syndromes.
3. Nutritional deficiency.
4. Neurological condition.
5. Psychiatric disorder.
Adverse drug reaction: - Allergic reactions have occurred by injection.
FOLIC ACID
• Folic acid (Pteroyl glutamic acid) is a member of the B complex group of vitamins.
• Dietary sources: - Liver, green leafy vegetables (spinach), egg, meat, milk.
• Daily requirement: - 0.2 mg/ day
Metabolic functions
1. Conversion of homocysteine to methionine.
2. Generation of thymidylate, an essential constituent of DNA.
3. Conversion of serine to glycine.
4. Purine synthesis.
5. Histidine metabolism.
Deficiency & manifestation: -
1. Megaloblastic Anaemia.
2. Nutritional deficiency.
3. Malabsorption.
4. Epithelial damage.
5. Weight loss.
Therapeutic use: -
1. Megaloblastic Anaemia.
2. Improve absorption.
3. Protect epithelial cell.
4. Growth factor.
Adverse effects: -
• Hypersensitivity reaction occur by injection.
Preparations and dose
• Folic acid: -liquid oral.
• Injectable.
• Tablet (5mg/day)
• Folinic acid: -CALCIUM LEUCOVORIN 3 mg/ml inj.

21. PHARMACOLOGY-II
RAMDAS BHAT
SRINIVAS COLLEGE OF PHARMACY 21
PLASMA EXPANDERS:
• These are high molecular weight substances which exert colloidal osmotic pressure, and
when infused IV retain fluid in the vascular compartment.
• They are used to correct hypovolemia due to loss of plasma/ blood.
Ideal properties of a plasma expander are:
• Should exert oncotic pressure comparable to plasma.
• Should remain in circulation and not leak out in tissues.
• Should be pharmacodynamically inert.
• Should not be pyrogenic or antigenic.
• Should be stable, easily sterilizable.
DEXTRAN
• It is a polysaccharide obtained from sugar beet.
Dextran-70
• The more commonly used preparation is dextran- 70.
• It expands plasma volume for nearly 24 hours.
• It is slowly excreted by glomerular filtration as well as oxidized in the body over weeks.
• Some amount is deposited in RE cells.
• Dextran has nearly all the properties of an Ideal plasma expander.
Dextran-40
• It acts more rapidly than dextran-70.
• It reduces blood viscosity.
• Microcirculation may improve.
Polyvinyl pyrrolidone (PVP)
• It is a synthetic polymer (average MW 40,000) used as a 3.5% solution.
• It interferes with blood grouping and cross-matching and is a histamine releaser.
• PVP is slowly excreted by kidney and small amounts by liver into bile.
• It is stored in RE cell.
USE OF PLASMA EXPANDERS: -
1. Plasma loss.
2. Burn
3. Hypovolemic & endotoxin shock.
4. Sever trauma & extensive tissue damage
5. Whole blood loss.
CONTRAINDICATIONS
1. Severe Anaemia.
2. Cardiac failure.
3. Pulmonary edema.

22. PHARMACOLOGY-II
RAMDAS BHAT
SRINIVAS COLLEGE OF PHARMACY 22
Sl No Chapter
Name
Long Essay Short Essay Short
Answer
Total Marks Duration
allotted
1 Pharmacolo
gy of Drugs
acting on
Blood and
blood
forming
agents
- 01 01 07 05
SHORT ESSAYS:
1. Classify anticoagulants with examples. Mention in-vitro anticoagulants.
2. Compare the pharmacology of heparin and warfarin.
3. What is heparin? Write its mechanism of action and therapeutic uses.
4. Write mechanism of action, adverse effects and therapeutic uses of warfarin.
5. Write mechanism of action, advantages and uses of Low Molecular Weight Heparins.
6. What are thrombolytics? Give examples. Write their mechanism of action and
therapeutic uses.
7. Classify antiplatelet agents on the basis of mechanism of action with examples.
8. What is GP IIb/IIIa antagonists? Give examples. Write their mechanism of action and
uses.
9. Write mechanism of action and uses of aspirin and clopidogrel combination.
10. Write mechanism of action and uses of aspirin and dipyridamole combination.
11. Enlist antiplatelet agents? Write the mechanism of action and therapeutic uses of aspirin
as an antiplatelet agent.
12. Write sources, mechanism of action and therapeutic uses streptokinase and urokinase.
13. How do you treat iron deficiency Anaemia? Explain with examples.
14. What are recombinant tissue plasminogen activators? Write their mechanism of action
and uses.
15. Write briefly on different classes of agents used for the treatment of Anaemia
SHORT ANSWERS:
1. Mention any four low molecular weight heparins.
2. Mention antagonists for heparin and warfarin along with their uses.
3. Write four therapeutic uses of anticoagulants.
4. Mention two common adverse effects and two contraindications of anticoagulants.
5. Mention four oral anticoagulants.
6. What are Low Molecular Weight Heparins? Give two examples.
7. Write significance of GP IIb/IIIa antagonists and give two examples.
8. Write mechanism of antiplatelet action of aspirin.
9. Write any four prophylactic uses of clopidogrel.
10. Write mechanism of action of thrombolytic agents.
11. Name four fibrinolytic agents.
12. What are plasma expanders? Give two examples.
13. Name two plasma expanders. Mention their uses.
14. What is megaloblastic Anaemia? Mention two drugs used in its treatment.

23. PHARMACOLOGY-II
RAMDAS BHAT
SRINIVAS COLLEGE OF PHARMACY 23
15. What is microcytic hypochromic Anaemia? Mention two drugs used in its treatment.
16. What are Haematopoietic growth factors? Give two examples.
17. Mention four parenteral iron preparations.
18. Write indications for parenteral iron preparations.
REFERENCES:
1. Essentials of Medical Pharmacology Seventh Edition KD TRIPATHI.
2. Pharmacology II Thakur publication.
3. Lippincott® Illustrated Reviews: Pharmacology South Asian Edition.
4. Goodman Gilman, A., Rall, T.W., Nies, A.I.S. and Taylor, P. Goodman and Gilman’s The
pharmacological Basis of therapeutics.
THANKYOU