HAEMOSTATICS & HAEMATINICS A

Project Report

For Elective Subject

Submitted

To Hemchandracharya North Gujarat University,

Patan.

In Partial Fulfillment of the Requirement for the Degree

Certificate of Bachelor of Pharmacy YYeeaarr:: 22000066--22000077

Submitted By, DHRUV J. PATEL

Shree S.K.Patel College of Pharmaceutical

Education & Research,

Ganpat Vidyanagar,

Kherva-382711

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CERTIFICATE This is to certify that the project report for the elective subject entitled

HAEMOSTATICS & HAEMATINICS is the bonafide work of DHRUV J.

PATEL satisfactorily carried under my guidance and supervision in the

Pharmaceutical Chemistry Department of Shree S.K.Patel College of

Pharmaceutical Education and Research, Ganpat Vidyanagar, during the academic

year 2006-2007 sincerely and methodically. This work is upto my satisfaction.

Guide:

Dr. J. R. PATEL M.Pharm, Ph.D. Department of Pharmaceutical Chemistry,

Shree S.K. Patel College of

Pharmaceutical Education & Research,

Ganpat Vidyanagar.

Head of the Department:

Dr. P. U. Patel

M.Pharm, Ph.D. Department of Pharmaceutical Chemistry,

Shree S.K. Patel College of Pharmaceutical Education & Research,

Ganpat Vidyanagar.

Principal:

Dr.M.M.Patel M.Pharm, Ph.D, LLB, FIC.

Department of Pharmaceutical Technology

Shree S.K. Patel College of Pharmaceutical Education & Research,

Ganpat Vidyanagar.

Date:

Place:

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Dedicated to God, My

Family & Teachers

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ACKNOWLEDGEMENT First, I would like to express my salutation to GOD for giving me the

strength, confidence and moral boost to successful completion of this project.

“You want to do the right thing and you want to do it for the right

reasons but if u don’t have the right guidance you can never hit the right target”

It is the great pleasure and profound since of reverence that I express my

gratitude and thanks to my guide Dr.J.R.Patel for his eruptive guidance, suggestion

and encouragement during this and other project works. This work would have

been impossible without their content support and total under standing.

I also pass a special vote of thanks to Dr.M.M.Patel principal of college for

providing me the infrastructure and research facilities at college for conducting me

study.

I owe a special word of thanks to my all other teachers for extending their

help during the course of investigation.

I am thankful to my parents and my aunty who led me from darkness to light,

ignorance to enlighten and confusion to clarity through out my life.

I shall forever be grateful to my dearest brother Maulik for his sweet

deposition, motivation to work and his admirable help during entire course of my

project work.

“Your sorrows get divided and your happiness get multiplied with your

friends”

A friend is people who understand your filling, emotion and help you to be

what you to be.

It may all my friends Nirav, Hardik, Falguni and Dushyant who helped me in

hardship through the sweet fragrance of friendship without which I could not have

won all the battles.

I would also like to thank Miss Chaula computer laboratory assistant,

Mr.P.I.Patel and library staff to support me a lot.

I also thank to my all classmates for their support and helpful nature.

“May the candle be lightened forever, the joy is not of light alone, but of

presence of those, who played the role behind the curtain.”

GANPAT VIDYANAGAR DHRUV J. PATEL 2006-07 FOURTH B.PHARM

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Haemostatic

Sr

No.

Content Page

no.

1 Introduction

1.1 Definition 1

1.2 Formation of Platelet haemostatic plugs 3

1.3 Platelet Activation 4

1.4 Platelet Secretion 4

2 Blood Coagulation

2.1 Nomenclatures 5

2.2 Coagulation Cascade 6

2.3 Coagulation defects 9

2.4 Drug affecting blood coagulation 10

3 Disorder affecting blood coagulation 22

3.1 Procoagulant 10

3.2 Oral coagulation 13

3.2.1 Factor that potentiate the oral coagulation 15

3.2.2 Factor that lesson the oral anticoagulant 16

3.3 Injectable anticoagulant 18

4 Haematostatis in disease 21

5 Market Preparation 31

Haematinics

Sr.

No.

Content Page

No.

1 Introduction 24

1.1 Definition 24

2 Types of anaemia 24

3 Classification of Haematinics 24

4 Haemopoeitic growth factor 29

4.1 Use of haemopoitic growth factor 30

5 Conclusion 32

6 Reference 33

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Haemostatic:-

Definition:-

Haemostatic: - When blood vessel is damage, reaction are initiated to arrest

bleeding, that is achieve Haemostasis. The substances which

are use in haemostasis called haemostatic.

The process involves is at least four interested steps.

(i) Contraction of injured vessels

(ii) Accumulation of platelet at the site of the vessel

(iii) Activation of blood coagulation and

(iv) As a secondary event activation of fibrinolysis.

(i) Vasoconstrictions occur immediately after injury is usually transient &

stems primarily from a direct effect of the injury, upon vascular smooth

muscle cell. Distruption of endothelial cell lining the vessel, lumen bring

platelets into contact with underling subendothelial tissue & expose trace

plasma clotting proteins to materials in the vessels wall that initiate the blood

coagulation. Plates adhere to the subendothelial tissue are activated & adhere

to each other to form a growing, increasingly compacted mass, the platelets

haemostatic plug. Blood coagulation proceeds as a series of amplifying

enzymatic reaction in which plasma serine protease proenzyme serve as

substrates and then after activation as enzyme triggring further steps in this

process. Non enzymatic plasma factor & material present on the surface

membrane of activated platelets & tissue cells participates as a cofactors. The

final serine protease coagulant enzyme generated thrpmbin, split small

fibrinopeptides from fibrinogen &activates across lining cystein protease

enzyme, factor XIII. This result in the formation & stabilization of strends of

fibrin that extend out ward from the surface of the platelets & other cells.

Thus a seal is formed that is made up of a fused mass of platelets reinforced

by the meshwork of fibrin clot. More over, throbin after binding to a surface

recognition site on endothelium, acquires the ability to activate an

anticoagulant serine protein proenzyme, protein, that then inactivate key

coagulation factors. Endothelial cell also release plasminogen activators that

can activate plasminogen bound to the fibrin clot. The enzyme plasmin, which

is thus formed within the clot, dissol fibrin strends, liberating a soluble

degradation product that may reenter the circulation over a number of days

fibrin continues to be both formed & dissolved in balanced reaction at the

injury site. A haemostatic seal is thus maintained & remolded while the

proliferation of smooth muscle cells &

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Fibroblast, the deposition of new connective tissue matrix & the ingrowths of

a new luminal lining of endothelial cell repair the vessel walls.

Normal haemostatic function prevents excessive bleeding after the minor

tissue injury of daily living. Platelets haemostatic plugs are particularly

important in controlling bleeding from capillaries & small venules in erosion

of mucosal surfaces. Abnormal bleeding from the gastrointestinal or

genitourinary tract is source of concern in a thrombocytopenia patient. When

an effective fibrin clot can not be formed either because of impaired of blood

coagulation or excessive fibrinolysis, a trivial tissue injury may cause

extensive bleeding for example, a patient with haemophilia may bleed

massively into the soft tissue of an extremely from minor trauma that ina

normal person, might cause a bruise no longer than 50% piece.

If a large artery is served by a lacerating injury, tourniquet must be applied

immediately to prevent the injured person from bleeding to death until the

vessel can be surgical repaired. During procedure many small arteries are

served, each is occurred with a surgical instrument & then sutured very large

number of arterioles, capillaries & venules are also severed; bleeding from the

vessel ceases spontaneously as the result of haemostatic process. If

haemostatic is impaired from any cause, bleeding from the myriad of the

small vessels that are not sutured may result in serious blood loss during

surgery moreover bleeding may reoccur during the first 2 weeks of the post

operative period.

Although essential for survival haemostatic reactions are harmful when they

cause a clot to form with in lumen of the blood vessels. Patient at risk of

thrombosis are often treated with drug that impair haemostatic by interfering

with platelet function of slowing blood coagulation patient with an acute

thrombosis of coronary artery are given a plasminogen activator in an attempt

to reopen the occluded vessels.

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Formation of platelets haemostatic plugs :

Platelets are nonmucleated cells, 2 to 4 micrometer in diameter present in

blood concentration of 150-400 x 109 per litre. When vascular endothelium is

disturbed, platelets adhere to the exposed subendothelium which is the initial

step in the formation of platelet haemostatic plug.

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At high rate of wall shear presents in blood vessels. This platelet adhesion

required the participation of von willebrand factor (VWF), a protein

synthesized in vascular endothelial cells both into the plasma & albuminally

into superficial layer of sub endothelial VWF contributed to platelets adhesion

but is insufficient in itself for normal adhesion.

Platelets activation:-

As platelets adhere to exposed sub endothelium they become activated.

Platelets arriving subsequently at the injury site also begin to activated,

adhering to platelet already present. Thus platelet mass start to grow. As

platelets activate they undergo a series of progressive overlapping event,

shape change, aggregation, liberation & oxidation of arachidonic acid

secretion of α granule & dense granules contents, recognization of surface

membrane phospholipids, which make phosphotidylserine available on the

outer surface of bilayer, where it can participate coagulation reaction & an

oriented centripetal contraction of actinomyosin of the platelet cytoskeleton.

The early event of platelet activation shape change & the primary phase of

aggregation – are reversible & loosely aggregated platelets may break away

from the haemostatic plugs to reenter the circulation. However as platelets

activation progresses an increasing contraction of platelet cytoskeleton.

Platelet secretion:

Platelets contain three types of granules:

i. α granules

ii. Dense granules

iii. Lysosomal granules

Distributed randomly in the unstimulated platelet, they move to center of the

platelet after platelet activation. The content of granules are secreted through

the open canalicular system. First term α and dense granse granules & later as

the platelet appear to break down & fuse from the lysosomal granules. The

dense granules contain ADP, ATP, calcium &secretion. Although a

vasoconstrictor & a weak platelet agonist, Serotonin has no recognized

function in haemostasis. Depleting dense granules of serotonin with the drug

reserpin does not impair with haemostatic patient with hare dietary disorder

that prevent the storage of normal quantities of ADP in the dense granules

have mild to moderate bleeding diathesis resulting from impaired formulation

of haemostatic plug.

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Blood coagulation:-

Nomenclature:

Numbers &letter & trivial names are use to identify different components of

the blood coagulation Roman numerals to the then recognized clotting factor.

The Roman mineral nomenclature was accepted for most but not all factor are

rarely.

Properties of Moieties Involving in Blood Coagulation

Type Name M.W.

(dal)

Plasma conc.

g/ml nM

I.V.

Half time,

Contact

system

proenz.

Vitamin K-

dependent

coagulant

proenz

Co-factor

Factor of

fibrin

deposition

inhibitors

F XIII

F XI

F VII

F IX

Prothronbin

Tissue factor

Fibrinogen

F XIII

Protein C

80,000

160,000

50,000

57,000

70,000

340,000

320,000

62,000

29

45

0.5

4

150

0

2500

8

4

360

510

10

70

2100

0

7000

25

66

2

-

0.2

1

3

-

4.5

7

0.3

Referred to as factor I,II, III. When a Roman numeral clotting factor is in its

activated form of factor IX is written factor IXa or a simply Ixa. Two proteins

that participate both in contact activation of blood coagulation & in the

generation of kinin, prekallikrein & high molecular weight kininogen & two

more recently identified vit. K dependent proteins and it have not been given

Roman numeral names. The major protease inhibitor of blood coagulation

which neutralizes thrombin factor Xa & factor Ixa. Is called as antithrombin

III, a name carried over from a time when the name antithrombin, followed by

Roman numeral was use to distinguish between different thrombin

neutralizing activities, in clotting mixture. A recently identified factor Xa

dependent inhibitor of catalytic activity if the factor V IIa / tissue factor

complex does not yet have a generally accepted name. It has been referred to

as the extrinsic pathway inhibitor (EPI) & as the lipoprotein associated

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Coagulation Cascade:-

Definition:-Blood coagulation means the conversion of fluid blood to a solid

gel or clot.

The main event is conversion of soluble fibrinogen to insoluble strands of

fibrin. The last step in the complex enzyme cascade. The components are

present in blood is inactive precursor of proteolytic enzymes & co-factor.

They are activated by proteolysis, the active forms being designated by the

suffix “a”. Factor XIIIa, XIa, Ixa, Xa &throbin (IIA) are also serin proteases.

Activation of small amount of one factor catalyses the formation of still large

amount at the next & so on so the cascade provides a mechanism of

amplification termed „intrinsic‟ & other „extrinsic‟ ( because some

components come from outside the blood )

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The extrinsic pathway is especially imp in controlling blood coagulation in the

body & can accurately be called the in vivo pathway. The intrinsic pathway is

activated when blood come into contact with an artificial surface such as glass

in vivo (extrinsic) pathway initiated by tissue factor which is the cellular

receptor & co-factor for factor VII, which undergo an active site transition on

binding to tissue factor in presence of calcium ion, enhancing in rapid

autocatalytic activation of VII to VIIa. The tissue factor VIIa complex

activates factor IX & X. Acidic phospholipids function as surface catalyst.

They are provided during platelets activation, which exposed phospholipids

that co-localize & activate various clotting factor. Platelets also contribute be

secreting coagulation factor including factor Va & fibrinogen. Coagulation is

sustained by further generation factor Xa by Ixa-VIIa calcium phospholipids

complex. This is needed because this tissue factor pathway inhibitor & by

antithrombin III. Factor Xa, in presence of calcium, phospholipids & factor

Va activate prothrombin to thrombin; the main enzyme of cascade.

The Role of thrombin:

Thrombin cleaves fibrinogen, producing fragments that polymerize to form

fibrin. It also activate factor XIII a fibrinoligase, which strengthens fibrin to

fibrin link, there by stabilizing the coagulum. In addition to its coagulation

action, thrombin also cause platelet aggregation, stimulates cell proliferation

& modulates smooth muscle contraction.

The contact pathway commences when factor XII (hagman factor) adhere to a

negatively charge surface & converages with the in vivo pathway at the stage

of factor X activation. The proximal part of this pathway is not crucible for

blood coagulation in vivo. The two pathway are not entirely separated even

before they converage & various positive feedback promote coagulation.

At might be expected this accelerating enzyme cascade has to be controlled by

inhibitors, since otherwise all the blood in the body would sodify within

minute of initiation of the haemostatis one of the most imp inhibitors inan

alpha 2 globulin antithrombin III which nuetralise all the serine protease in the

cascade. Another heparin cofactor II, inhibit only thrombin, vascular

endothelium also actively limits thrombus extension.

o The clotting system consists of cascade of proteolytic enzyme & cofactor.

o Inactivate precursors are activated in series, each giving rise to more of the

next.

o The last enzyme, thrombin derived from prothrombin (II) convert soluble

fibrinogen (I) in an insoluble meshwork of fibrin in which blood cells are

trapped forming the clot.

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o There are two pathways in the cascade.

The extrinsic pathway which operate in vivo.

The intrinsic or contact pathway which operate in vitro.

o Both pathway result inactivation of factor X, which then convert

prothrombin to thrombin

o Calcium or negatively charged phospholipids are essential for three step

namely the action of ,

Factor IXa on X

Factor VIIa on X

Factor Xa on II

o Phospholipids is provided by activated platelets adhering to the damaged

vessels

o Some factor promotes coagulation by binding to PL and serine protease

factor, e.g. factor Va in activation of II by Xa VIIa in the activation of X by

Ixa.

o Blood coagulation is controlled by,

Enzyme inhibitors e.g. antithrombin III

Fibrinolysis.

Drug that act on coagulation cascade:-

Drugs are use to modify the cascade either when there is a defect in

coagulation or when there unwanted coagulation.

Coagulation Defects:-

Genetically determine deficiencies of clotting factor are rare. Examples are

classical hemophilia, caused by lack of factor VIII & even rarer form of

hemophilia, caused of lack of factor IX. Missing factor can be supplied by

giving fresh plasma or concentrated preparation of factor VIII or factor IX. In

the past these have transmitted viral infects HIV & hepatitis B. Pure form of

several factor are now available.

Some aquired clotting defects are more common than hereditary ones. These

include liver disease vitamin K deficiency universal in neonate & excessive

oral anticoagulation therapy, each of which may require treatment with

vitamin K.

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Drug affecting blood coagulation:-

1. Procoagulant drug: Vitamin K.

The reduced form of vitamin K is a cofactor in post translation α-

carboxylation of cluster of glutamic acid residues in each of factor II, VII,

IX, & X vitamin K is oxidized during the reaction. The α-carboxylated

glutamic acid residues are essential for the interaction these factor calcium

& negatively charged phospholipids.

2. Oral anti-coagulant e.g. Warfarin

These inhibit the reduction of vitamin k, thus inhibiting the α-

carboxylation glu. In II, VII, IX, & X.

They act only in vivo & the factor is delayed.

Many factor modify their action, drug interaction are especially imp.

There is wide variation in response, their effect is monitored by measuring

the INR & the dose individualized accordingly.

3. Injectable anti coagulants :

E.g. Heparins, low molecular wt. heparin (LMWHS)

( I ) Procoagulant drug vitamin k

Vitamin k is water soluble occurring naturally in two form – as

vitamin k (phytomenadione) in plants & as vit K2 which synthesized by

bacteria in the g.i.trect vit. K2 is not a single compound but a series of

substances with side chain at varying lengths.

Vitamin K is essential for formation of clotting factor II, VII,

IX & X. These are all glycoprotein with several α-carboxyglutamic acid

residues clustered at the N-terminal end of peptide chain. The α-

carboxylation occurs after the synthesis of the chain & the carboxylase

requires vit. K as a cofactor. The role of vitamin k is clarified by

considering the interaction of factor Xa & prothrombin with calcium and

phospholipid binding does not occur in the absence of α-carboxylation.

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Vitamin K

O+

O+

PO

O

O

PO

O

O

Na

Na

Na

Na

Menidol sodium phosphate

O

OH

CH3

OC6H5

O warfarin

Vitamin K, its congeners & warfarin (as an anticoagulant drug)

5

8

6

7

3

2

4

1

R

CH3

O

O

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Warfarin, a vitamin K antagonist is used as oral anti coagulant drug.

The activation of prothrombin (factor II) by factor Xa.

Enzymic sites -carboxy glutamic

Acid residues

Activation site if cleavage of

peptides II by Xa

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Reduced vitamin K is an essential co-factor in the carboxylation of glutamate

residues.

Administration & pharmacokinetic aspects :-

Natural vitamin K (phylloquinone) may be given orally or in intramuscular or

intravenous injection. It is given by mouth, it require bill salt for absorption &

this occure by suitable energy requiring process in the part of small

intenstine. A synthetic preparation menadiol sodium phosphate is also

available. It is water soluble & thus does not require bile salt for its

preparation. This synthetic compound takes longer act than phytomendione. It

is metabolized to more polar subs that are excreted in the urine & in the bile.

Clinical uses of vitamin K:-

The treatment and prevention of,

Bleeding due to oral anti coagulant drug ( warfarin)

Haemorrhagic disease of the new born.

Vitamin K deficiency.

Sprue, celiac disease steatorrhea

Lack of bile

(II) Oral anti coagulants:- Warfarin

Oral anti coagulation become available as an indirect result of a change in

agricultural policy in North America in the 1920s. Sweet clover was

substituted for corn in cattle- feed and an epidermis of deaths of cattle from

haemorrhage ensued. This turned out to be due to bis hydroxyl coumarin in

spoiled sweet clover. One the first uses to which this observation was put that

the development of such compounds at rat poisons. Related compounds were

developed for clinical used.

Warfarin is the most important of these, other anti coagulant e.g. phenindione

are now used only in rare patient who experience idiosyncratic adverse

reaction to warfarin.

Mechanism:-

Oral anticoagulants act only in vivo & have no effect on clotting if added to

blood in vitro. They interfere with the post transitional αcarboxylation of

glutamic acid residue in clotting factor II, VII, IX & X. They do this by

preventing the reduction of vitamin K. the structural similarity of warfarin to

vitamin K is illustrated in fig. Their effect takes several days to develop

because

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of the taken for degradation of carboxylated factor. Their onset of action thus

depends on the elimination half life of relevant factor. Factor VII with a

Half life of 6 hrs is affected first, then IX, X, & II with half lives of 24,40 &

60 hrs respectively

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Administration and pharmacokinetics aspects:-

Warfarin is given orally & is absorbed quickly & totally from the

gastrointestinal tract. It has a small distribution volume being strongly bound

to plasma albumin. The peak concentration in the blood occurs within an hour

of ingestion but because of the mechanism of action this doesn‟t coincide with

the peak pharmacological effect which occur about 48 hrs. Later. The effect of

single dose doesn‟t start for 12-16 hours & last 45 days warfarin is metabolized by the

hepatic mixed function oxidase p450 system & its half life is very variable being of

order of 40 hours in many individuals.

Oral anticoagulant cross the placenta & are not given in first month of

pregnancy because they are teratogenic, nor in later stages because they cause

intracranial haemorrhage in the baby during delivery. They also appear in the

milk during lactation. This could theoretically be important because new born

infant are naturally deficient in vitamin K because of in adequate synthesis of

vitamin K in the bowel, however infants are routinely prescribed vitamin K to

prevent haemorrhagic disease, & warfarin treatment of the mother does not

generally possess a risk to breast feed infants.

The therapeutic use of warfarin requires a careful balance between giving too

little having unwanted coagulation uncheckes & giving too much there by

causing haemorrhage. Therapy is complicated not only became the effect of

particular dose is only seen 2 days after giving it but also because of numerous

condition that modify sensitivity to warfarin, including interaction with other

drug. The effect is monitored by measuring the prothrombin time which is

expressed as International normalized ratio (INR). Dosage is usually adjusted

to give an INR of 2-4, the precise target depending on the clinical situation.

Factor that potentiate oral anticoagulants:-

Variouse disease ane drug potentiate warfarin, increasing the risk of

haemorrhage.

Diseases:-

Liver disease interferes with synthesis of clotting factor condition on

which there is a high metabolic rate such as fever & thyrotoxicosis, increasing

the effect of anti coagulants by increasing degradation of clotting factors.

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Drugs:-

Many drugs potantiate warfarin including:

(i.) Agent that inhibit the drug metabolism e.g. climitidin, imipramine,

cotrimoxazole, chloramphenicol, ciprofloxacin, amiodarone, & many

antifungal agents.

(ii.) Drugs that inhibit platelet function:- e.g. Non steroid anti inflammatory

drugs, Moxalactum and carbenicillin.

(iii.) Drugs that displace warfarin from binding site on plasma albumin result in

transient increasing the concentration of free warfarin in plasma.

e.g. including some of nonsteroid anti inflammatory drugs &

chloral hydrate.

(iv.) Drug that inhibit the vitamin K:- e.g. cephalosporin

(iv.) Drugs that decrease the vitamin K:- e.g. Broad spractum antibiotics &

some sulfonamides.

Factor that lessens the effect of oral anticoagulants:-

Physiological state/ disease:-

There is decreased response to warfarin in condition where is increased

coagulation factor synthesis. Similarly the effect of oral anticoagulation is

lessened in hypothyroidism, which is associated with reduced degradation of

coagulation factor.

Drugs:-

Several drugs reduced the effectiveness of warfarin, this lead to increased

doses being used to achieve the target INR. If the dose of warfarin is not

reduced when the interacting drug is discontinued this can result in over

anticoagulant & hemorrhage.

Vitamin K is present in some parental feeds & vitamin preparation.

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Drugs that induce hepatic p450 enzyme increase the degradation of

warfarin e.g. rifampicin, carbamazepam, barbiturate, griseofulvin.

Drugs that reduce the absorption e.g. cholestyramine.

Unwanted effect:-

Haemorrhage is main hazard. Haemorrhages occur especially into the bowel

or the brain. Depending on the urgency of the situation, treatment may

consist of with holding warfarin, administration of vit K or fresh plasma or

coagulation factor concentration oral anticoagulants are teratogenic.

Hepatotoxicity is common necrosis of soft tissue due a thrombosis in

vennules occurs rarely shortly after starting treatment & is attributed to

inhibition of biosynthesis of protein c which is shorter elimination half life

than do the vit K dependant coagulation factor. This result in a procoagulant

state soon after starting treatment. Treatment heparin is usually started

before warfarin avoiding this problem.

Injectable anticoagulant:-

Heparin & low molecular weight heparins.

Heparin was discovered in 1919 by a second year medical student at johns

Hopkins hospital. During a vacation project in which he was attempting to

extract thromboptastic substance from various tissues, he found instead a

powerful anticoagulant activity. This was named „heparin‟ because it was

first extracted from liver.

Heparin is not a single substance but a family of sulphated gycosamino

glycans (mucopolysaccharide) with a range of molecular weight up to

40000. It is present together with histamine in the granules of mast cells. It

is extracted from beaf lungs or hog intestine & since preparation differ in

potency assayed biologically against an agreed international std.: doses are

specified in units of activity rather than of mass.

Heparin fragments, referred to as low molecular weight heparin (LMWHS),

are used increasingly in place of UN fractionated heparin. The molecular

weight of different preparation very from 4000 to15000.

Mechanism:- Heparin inhibits coagulation both in vivo and in vitro by activating

antithrombin III. Antithrombin III inhibit thrombin & other serine proteases

by binding to the

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Active serine site. Heparin modifies this interaction by binding via a unique

pentasaccharide sequence to antithrombin III changing its conformation &

accelerating its rate of action.

Thrombin is considerably more sensitive to the inhibitory effect of the heparin

antithrombin III complex than is factor X. To inhibit thrombin, it is necessary

Heparin pentasaccharide

The pentasaccharide sequence in heparin which is the binding site for

antithrombin III

For heparin to bind to the enzyme as well as to antithrombin III to inhibit

factor X, it is only necessary for heparin to bind to antithrombin III.

Antithrombin III deficiency is very rare cause of resistant to heparin therapy.

Low molecular weight heparin increase the action of antithrombin III on

factor Xa but not its action on thrombin, since the molecules are too small to

bind both enzyme & inhibitor, essential for inhibitor of thrombin but not a

factor Xa.

The anticoagulant action of heparin is modified platelets, fibrin and plasma

protein. Not only do platelets release a heparin neutralizing protein, platelet

factor IV, but factor Xa, when newly generated on the platelet surface, is

protected from the action of heparin antithrombin III complex. Thrombin

when bound fibrin is likewise protected from the action of complex.

Administration & pharmacokinetic effects:-

Heparin is not absorbed from the gut because of its charge & large size & is

therefore given intravenously or subcutaneously (intramuscular injection of

bolus haematomas). After iv injection of bolus dose there is a phase of rapid

elimination followed by more gradual disappearance due to both to saturable

process (involving binding to sites on endothelial cells & macrophages) &

slower first order process including renal excretion. Heparin acts immediately

following iv administration but the onset is delayed up to 60 minutes, when it

is given subcutaneously. The elimination half life is approx 40-90

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minutes. In urgent situation it is therefore usual to start treatment with a

intravenous doses, followed by constant rate of infusion. The activated partial

thromboplastin time (APTT) or other in vitro clotting test, is measured & the

dose of unfractionated heparin adjusted to achieve a valvu a target range (e.g.

-1.5-2.5 time control).

LMWHS are given subcutaneously. They have a longer elimination half life

than unfractionated heparin & this is independent of dose, so the effect are

more predictable & dosing less frequent concentration or twice a day.

LMWHS don‟t prolong the APTT, their quality is consistent & unlike

unfractionated heparin, the effect of standard dose is sufficiently predictable

that monitoring is not read routinely. They are not neutralized by platelet

factor IV & are eliminated mainly by renal excretion. They are at least as safe

& effective unfractionated heparin & are more convenient to use, since patient

can be taught to inject themselves at home & there is generally no need for

blood tests & dose adjustment.

Unwanted effect:-

The main hazard is haemorrhage which is treated by stopping therapy & if

necessary giving protamine sulphate. The heparin antagonist is strongly basic

protein that forms an inactive complex with heparin & is given intravenously.

The dose is estimated from the dose of heparin that has been administered

recently & it is important not to give too much as this can it self cause

bleeding. If necessary, an in vitro neutralization test is performed on a sample

of blood from the patient to provide a more precise indication of the required

dose.

Thrombosis is an uncommon but serious adverse effect of heparin & as with

warfarin necrosis may be misattributed to the natural history of disase for

which heparin is being administered. Paradoxically, it is associated with

thrombocytopenia.

A transitory early decrease in platelet number is not uncommon & is not

clinically important. More serious thrombocytopenia occurring 2-14 days after

of therapy is rare & is cause by IgM or IgG antibodies against complex of

heparin & platelet factor IV circulating immune complexes bind to Fc

receptor on circulating platelet, ther by activating them & releasing more

platelet factor IV & causing thrombocytopenia antibody also bind to platelet

factor IV complexed with glycosaminoglycans on the surface on endothelium

cells, leding to immune injury of the vessel wall, thrombosis & disseminated

intravascular coagulation. LMWHS are less liable than standard heparin to

activate platelet t release platelet factor IV & bind less widely to platelet

factor IV.

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Osteoporosis with spontaneous factor has been reported with long term ( 6

mouth or more ) treatment with heparin (usually during pregnancy ). Its

explanation is unlike hypoaldosteronism (with consequent hyperkalrmia) has

also been describes but is extremely rare.

Hypersensitivity reactions to heparin are rare but are more common with

LMWHS.

Newer thrombin- related agent:-

Dermatan sulfate is glycoaminoglycan related to heparin. It

potentiates heparin cofactor II which inhibit thrombin selectively, so it is

hoped that it may cause less bleeding than heparin. Its safely & efficiency has

yet to be compared with LMWHS.

Antithrombin III independent anticoagulant:-

Several direct inhibitors of thrombin are under investigation including

hirudin, hirugen argatroban & a tripeptide chloromethane ketone inhibitor,

PPACK.

Hirudin, the anticoagulant from the medicinal leach has been

synthesized by recombinant DNA techniques. Clinical trials, including

GUSTO-2 & TIMI-9 have been some what disappointing. Hirudin is synthetic

decapeptide derived from hirudin. Argatroban, an arginin – based compound

is a weak competitive inhibitor of thrombin PPACK alkylates the active site in

in thrombin inhibiting it irreversibly. The latter three compounds can reach &

inactivate thrombin that is bound to fibrin but it is unknown whether this will

prove clinically advantageous. These drugs may have a niche in the treatment

of patients who have developed immune thrombocytopenia / cytopenia

thrombosis during treatment with heparin, from they are immunological quite

distinct.

The clinical use of anticoagulant:-

Uses relate mainly to venous thrombosis & include

Prevention of deep vein thrombosis ( e.g. perioperiatively)

Preventing extension of established deep vein thrombosis or

reoccurrence of pulmonary embolus.

Preventing thrombosis & embolisation in patient with a trial

fibrillation.

Preventing thrombosis on prosthetic heart valves.

Prevention of clotting in extra corporeal circulation (e.g. during

haemodialysis or bypass surgery).

In addition, heparin is also use in unstable angina heparin is used

acutely for short term action & warfarin for prolonged therapy.

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Haemostatics in disease :-

Screening test of haemostasis:-

Haemostatic function is examined in clinical medicine to evaluate the

possibility of abnormal bleeding & to obtain information for the diagnosis &

management of disease, whose manifestation include disturb haemostasis.

Two test are often to form carried out to screen for the adequacy of

information of haemastasis plug – the platelet count & the bleeding time. The

bleeding time measure the time is take to form platelet drug plugs that stop

bleeding (against a pressure of 40 mmHg transmitted to from an inflated blood

pressure cuff on the upper arm) from tiny vessels severed by making a cut of

1mm due to in the skin of the forearm. It is used to screen for condition other

than thrombocytopenia that can impair the formation of haemostatic plug.

Two tests are used to screen for the adequacy of blood coagulation. One test

the prothrombin time, measure the adequancy of the reaction that clot plasma

when a very high concentrated of tissue factor is present. The other test the

activated partial thromboplastin time (APTT), measure the adequacy of the

clotting reaction that clot plasma when a reagent optimizing the contact

activation reaction & providing procoagulant phospholipids is present.

The platelet count bleeding time, prothombin time & APTT will usually

provide a satisfactory screen of haemostatic function. In cirtain circumstance

other tests are added, e.g. a secondary bleeding time after giving a patient

aspirin or a test of stability of plasma clots incubated in saline & in a urea

solution to look for evidence of excessive fibrinolysis & factor XIII

deficiency. When screening test is abnormal, the pattern of abnormality plus

the patient‟s other clinical finding provide the information needed to proceed

with specific test of platelet function or specific coagulation actor assays.

Disorder affecting function of haemostatic plugs:-

Thrombocytopenia:-

Where as hereditary thrombocytopenia is very rare, acquired

thrombocytopenia is the most commonest cause of impaired haemostatic

function. It may result from failure of platelet production or from accelerated

platelet destruction. Moreover, moderate thrombocytopenia, in the 60000-

1,50,000 per micro range may result from the pooling of platelet in an

enlarged spleen.

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Thrombocytopenia due to a decreased production usually occurs in patients

with very serious bone marrow disease, for e.g. leukemia or aplasia.

Thrombocytopenia from accelerated peripheral destruction most often stems

from clotting platelets with IgG & removal of coated platelets by mononuclear

phagocytes in the spleen, liver and bone marrow. The IgG may be true auto

antibody to a platelet antigen, an antibody to an epitope formed when a drug

bind to the surface of the platelet or IgG in immune complex with some gram

negative bacteria infection also frequently become thrombocytopenia. This

apparently result from the several processes, disposition of platelet on

activated vascular endothelium, activation by endotoxin of complement on the

platelet surface, binding of immune complexes to platelets & consumption of

platelet in intravascular coagulation.

Disorders with normal platelet counts but impaired formation of

haemostatic plugs:-

Hereditary disorder affecting the formation of haemostatic plugs. Include von

willebrand‟s disease in which the abnormality is in the plasma & a group of

intrinsic platelet disorders, von willebrand‟s disease an autosomal dominant

disorder is most common hereditary haemostatic disorder. In most patients it

stems from an inability to make a normal amount of von willebrand factor

molecules. The usual patient with von willebrand‟s mild bleeding disorder

with prolong bleeding time & concordant moderate reduction in the plasma

level of von willbrand factor antigen & factor VIII clotting activity. The latter

reflects the need for factor VIII to circulate in plasma bound to von willebrand

factor.

The formation of haemostatic plug may be impaired despite a normal platelet

count in number of despite a normal platelet in a number of acquired

conditions. In myelodysplastic or certain myeloproliferative disease, abnormal

megakaryocytic may make defective haemostatic function. Certain therapeutic

agent, particularly penicillin & penicillin derivative when given in high dose

may coat platelet & and interfere with their function. Uremic patient

frequently have prolong bleeding time despite a normal or moderately platelet

count. This reason yet not clears.

Disorder affecting blood coagulation:-

Hereditary deficiency states have been identified for each of the known

plasma coagulation factors. As mention earlier, factor XII deficiency,

prokallikrein deficiency and high molecular weight kininogen deficiency

prolong coagulation in glass tubes but do not cause abnormal bleeding. The

other disorders are all

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associated with abnormal bleeding. Except for Hemophilia A (factor VIII

deficiency) hemophilia B (factor XI deficiency) & factor XI deficiency the

hereditary deficiency states are rare autosomal recessive disorder in which

heterozygotes do not bleed abnormally. Factor XI deficiency is also a

autosomal recessive disorder but has an unusually high genes for factor VIII

and factor IX are located on X chromosome. The hemizygote male who

receive an abnormal gene from his mother is not protected by a normal X

chromosome and develop the disease. Hemophilia therefore is most common

hereditary bleeding disorder due a coagulation factor deficiency but it

confined to makes.

There are four major causes of acquired abnormalities of blood coagulation.

Vitamin K deficiency

Liver disease

Disseminated intravascular coagulation

Acquired antibodies against clotting factor

Vitamin k deficiencies usually result from the combination of inadequate

dietary intake plus the administration of broad spectrum antibiotics that

suppress bacterial synthesis of vitamin k in the gut. Vitamin k is a fat soluble

vitamin & patient with gi tract disorder interfering wit fat absorption are at

particular risk for developing vitamin k deficiency. In liver disease seriously

impairing the ability to hepatocytes to synthesize proteins, patient develop to

bleeding tendency secondary to fall in plasma concentration of all clotting

factors except factor VIII & to fall in the plasma concentration of the plasma

inhibitor, alpha 2 antiplastin. Patient wit advancement liver disease may bleed

uncontrollably from relative minor lesion in gastrointestinal tract.

Disseminated intravascular coagulation (DIC) may occur as a complication of

pregnancy, of malignancy or of infection usually from gram negative bacterial

infection. In DIC tissue factor, activated clotting enzyme or both gain access

to the blood in sufficient concentration to cause fibrin to be formed within the

flowing blood. Bleeding may result from the depletion of plasma fibrinogen

factor VIII & v plus the antihemostatic effect of extensive secondary

fibrinolysis. Antibody of clotting factor may develop as a complication of

known autoimmune disorder or without warning in patient with no known

underlying disease antibodies that neutralizing the coagulant activity of factor

VIII & non neutralizing antibody that cause hypoprothrombinemia because of

the rapid cellular clearance of prothrombine antiprothrombin immune

complexes are the most common cause of bleeding secondary to clotting

factor antibodies.

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Haematinics:-

Definition: - Haematinics are antianamics that increase the haemoglobin

content of blood through erythropoeisis or through increase the haemoglobin

content of erythrocytes. The choice of haematinics critically depends upone

the nature of anemia. The hypo chromic anemia‟s all iron deficiency anemia

in character & are treated with iron preparatory.

Type of Anamia:-

Definition:- Anemia is defined as a reduced concentration of haemoglobin in

the blood. It may give rise to symptoms of fatigue but if it is chronic, it often

surprising asymptomatic. The commonest cause is blood loss related to

menstruation & child bearing but there are several different types of anemia

and different diagnostic levels. Microscopical examination of a stained blood

smear of blood allowed characterized into,

Hypo chromic, mocrocytic anemia (small red cells with

haemoglobin due to iron deficiency).

Macrocytic anemia (large red cells, few in number).

Nor mochromic normocytic anemia (fewer normalized red cells

with normal haemoglobin).

Mixed pictures.

The commonest anemias are due to deficiencies of nutrients.

The use of agent which stimulate the proliferation & maturation of red &

white blood cells & platelets will also cover. The use of haematinics is often

only in adjunct to treatment of underlying cause of anemias.

Widely prescribed haematinics are –

(i.) Iron

(ii.) Folic acid and vitamin B12

(iii.) Pyridoxine, vitamin C

(i) iron:-

Iron is transition metal with two important properties relevant to its biological

role

the ability to exist in several oxidation states

the tendency to form stable co-ordination complex.

The body of 70 kg man contains about 4 gm of iron 65% of which circulate in

the blood as the oxygen transporting molecules hemoglobin. About one-half

of

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The reminder is store in the liver, spleen & bone marrow. The iron in these

molecules is available for haemoglobin synthesis. The rest, which is not

available for haemoglobin synthesis is present in myoglobin, cytochromes &

various enzymes.

The distribution of iron in an average normal adult male is under.

The distribution of iron in the body of a normal 70-kg. Male

Protein Tissue Iron content(mg)

Haemoglobin

Myoglobin

Enzyme

Transferin

Ferritin & haemosiderin

Erythrocytes

Muscle

Liver & other tissue

Plasma & extra cellular

fluids

Liver

2600

400

25

8

410

The valvu of an average female would be about 55% of these. Since most of

the iron in the body is either part of or destined to be part of the haemoglobin

in red blood cell, the most obvious clinical result of the iron deficiency is

anemia & the indication for therapy with iron is to provide material for

haemoglobin synthesis.

Haemoglobin is made up four proteins chain subunits, each of which contains

one haem moiety. Haem consist of tetrapyrole porphyrin ring containing

ferrous (Fe+2

) iron.

Clinical use of iron:-

Iron deficiency anemia which can be due to:-

Chronic blood loss (e.g. with menorrhagia )

Increased demand ( e.g. in pregnancy & early infancy )

In adequate dietary intake or absorption.

Administration:-

Iron is usually given orally but may be given parentally.

Several different preparation of ferrous iron salt available for oral

administration. The main one is ferrous sulfate.

Parental iron is rarely given but who are not able to absorb iron because or

malabsorption syndromes or as a result of surgical procedure of inflammatory

condition involving gastrointestinal tract. E.g. iron sorbital or iron dextran.

Iron dextran is given by slow intravenous infusion.

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Unwanted effects:-

The unwanted effects of oral iron administration are dose related & include

nausea, abdominal cramps & diarrhea.

Due to acute iron toxicity may produce vomiting, haemorrhage &

diarrhea followed by circulating collapse.

Chronic iron toxicity or iron overload is virtually always due to

cause other than ingestion of iron salts.

Treatment:-

The treatment of acute & chronic iron toxicity involves. The use of iron

chelators desferrioxamine which is given both intragastrically &

intramuscularly. Desferrioxamine form a complex with ferric ion which is

excreted in the urine.

(ii) folic acid & vitamin B12

Vitamin B12 & folic acid are necessary constituents of the man‟s diet being

essential for DNA synthesis & cell proliferation. The main manifestation of

vitamin B12 or folate deficiency is megaloblastic haemopoiesis in which there

is marked disorder of eration & defective erythropoiesis.

The principal use of vitamin B12 deficiency is decrease absorption of the

vitamin due to either to lack of intrinsic factor or to condition which interfere

with its absorption in the ileum.

Intrinsic factor is a protein secreted by the stomach & is essential for vitamin

B12 absorption. It is lacking in patient with pernicious anemia & in

individuals who have had total gastrectomies. There is often a concurrent

neurological disorder sud acute combined degeneration of spinal cord caused

by the deficiency of B12. castle & his associates subsequently established that

liver contained an extrinsic factor & that this together with intrinsic factor

present in normal gastric juice was necessary for normal maturation of red

cells.

Other conditions resulting in B12 deficiency include disorder of the terminal

ileum & various inflammatory condition of the bowel.

Folic acid:-

Folic acids consist of pteridin ring, p-amino benzoic acid & glutamic acid.

Different states of reduction of the pteridine ring may occur several one-

carbon unit may be attached to N5-N

10 or both & additional glutamic acid

residue may be attached to glutamate moiety by unusual α-peptide bond

giving folate polyglutamates.

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NH

N

N

N

NH2

NH

O

NH

COOH

HOOC

| Pteridine | PABA |glutamic acid|

Folic acid (pteroylgutamic acid).

The average daily diet in Western Europe & the USA contains about 600 mg

of folate of which about 100 mg is absorbed. The folates in food are in form

of polyglutamates. They are converted to the monoglutamate before

absorption and are transported in blood in this form. The folates in tissue are

mostly polyglutamate.

Actions:-

Folic acid essential for DNA synthesis in that they are co-factor in

the synthesis of purines & pyrimidines.

They are also necessary for reactions involved in amino acid

metabolism.

Folate must be a tetra hydro form, in which it is maintained by

enzyme dihydrofolate reductase. This enzyme reduce dietary folic

acid to tetra hydro folate in two step reaction & also reduce the

dihydrofolate (FH2) produced from the FH4. During thymidylate

synthesis folate antagonist act by inhibiting dyhydrofolate

reductase.

DHF

FH4 FH2

DUNP DTMP

Thymidylate

Sythatase

(O)

FH2 FH4

The clinical use of folic acid:-

Folic acid is needed for DNA synthesis. Deficiencies mainly affect

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P‟cokinetic aspects:-

Folic acid is usually given orally but preparation for parenteral use is

available. In the intestine, folic acid is absorbed unchanged folinic acid a

synthetic tetrahydrofolic acid is converted much more rapidly to the poly

glutamate form.

Unwanted effect:-

Unwanted effects don‟t occur even with large doses of folic acid – except

possibility in the presence of vitamin B12 deficiency. Because of vitamin B12

deficiency is treated with folic acid, and the blood picture may improve and

the appearance of cure while the neurological lesions get worse. It is there for

important to determine whether a megaloblastic anemia is due a folate or a

vitamin B12 deficiency

Vitamin B12:-

Vitamin B12 is complex cobalamin compound. The vitamin B12 is used

medicinally hydroxocobalamin. In act the principle source of vita B12 are

meats particularly liver, eggs & dairy product. All cobalamins, dietary &

therapeutic, must be converted to methanocobalamin (methyl B12) or 5-

deoxyadenosylcobalamins (ado-B12) for activity in body. The average daily

diet in Western Europe contains 5-25 mg of B12 & the daily required is 2-3

mg.

B12 is carried in plasma by B12 binding protein called transcobalamins (TCs).

Action:-

Vitamin B12 required for two main biochemical reaction in man.

- the conversion of methyl FH4 to FH4

- conversion of methylmalonyl co-A to succinyl co-A

The clinical uses of vitamin B12:-

Vitamin is needed for synthesis of DNA. Deficiencies affect mainly

erythropoiesis.

Administration & pharmacokinetic aspect:-

When vitamin B12 is used therapeutically, it is almost given by intramuscular

injection. Since vitamin B12 deficiency is virtually always due to

malabsorption of vitamin patient with pernicious anemia required lifelong

therapy. Unwanted effect do not occur.

Clinical use of folic acid & hypoxocobalamin:- gnu.i

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- folic acid is used

- To treat magaloblastic anemia due to folate deficiency which can be cause

by,

- poor diet

- Malabsorption syndromes.

- To treat or prevent toxicity from methotrexate, a folate antagonist

- Prophylactically in individuals at hazard from depending folate deficiency.

For e.g.

- Pregnant women ( especially if there is a risk of birth defects)

- Premature infants.

- Patient with severe chronic haemolytic anemia including

haemoglobino pathies (e.g. sickle cell anemia).

Clinical uses of vitamin B12 (hydroxycobalamin) :-

- to treat pernicious anemia & other cause of vitamin B12 deficiency.

- Prophylactically after surgical operation which remove the site of

production of intrinsic factor.

Haemopoietic growth factor:-

The haemopoietic growth factor regulates the proliferation and differentiation

of progenitor stem cells. Found in bone marrow. They are glycoprotein that

binds to specific cell surface receptor, resulting sequence of events

culminating in haematopoeisis. Recombinant DNA technology has allowed

the manufacturing of sufficient quantities of this factor to enable clinical

patients‟ erythropoietin, which stimulate red cells production, was the first

human haematopoietic growth factor to be isolated. It improves the anemia

associated with several clinical conditions. Several of colony stimulating

factors also have been purified, molecularly cloned & expressed as

recombinant patients. Clinical trial in progress are evaluating their

effectiveness in treating patient for variety of haematological disorder two of

the colony stimulating factor- granulocyte colony stimulating factor ( G-CSF)

& granulocyte macrophage- colony stimulating factor (GM-CSF) are

efficacious in the management of bone marrow hypoplasia, particularly after

myelosupressive chemotherapy. They not only stimulate the progenitor cell

target but also result in some functional activation of the mature cell. It is

anticipated that future therapy was use addition haematopoeitic growth factors

in various condition involving altering haematological status.

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Clinical use of epoietin:-

- The main use is for anemia, chronic renal failure, in this condition there is

decrease in erythrocytes due to the decrease in production of

erythropoietin by the disease kidney & also to the blood loss associated

with dialysis.

- Other potential futures are the anemia of AIDS, the anemia of chronic

inflammatory condition such as rheumatoid arthritis, the anemia of cancer,

the anemia which occurs in premature treatments.

Antihaematopoeitic drugs:-

Polycythemia & erythrocytosis are condition in which there is an incease in

the number of circulating erythrocytes. The cause is usually the result of

deficient oxygenation of the arterial blood & either condition may be

corrected by management of underlying primary disorder several

antineoplastic drugs such as the nitrogen mustard, the antifolic acid, arsenic or

rediophosphate may be employed. The leukemia result from excessive

leukocytic haematopoeitic activity of neoplastic nature, either the bone

marrow or lymphatic tissue may be involved. In myelogenous leukemia there

may be anemia because the erythropoeitic cells are crowded present by

leukopoietic cells.

Use of haemopoeitic growth factor:-

Erythropoietin:-

- regulate red cells production.

- It given intravenously, subcutaneous, intraperitoneally.

- Can cause transient flu like symptoms, hypertension iron deficiency and

increase blood viscosity.

- It available as epoietin.

Granulocyte colony stimulating factor (G-CSF):-

- It stimulates nuetrophil progenitors.

- It available as filgrastim: given intravenously, subcutaneously.

Granulocyte macrophage- colony stimulating factor (GM-CSF):-

- Stimulate development of many types of progenitor cells.

- It available as malgramostim, given intravenously, subcutaneously.

- Can cause fever, rashes bone pain, hypotension GIT symptoms & arterial

oxygen desaturation.

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Market preparation:

No. Brand name Content

1. Aprogen Aprotinin

2. Apronin Aprotinin

3. Apostate Aprotinin

4. Haemaprot Aprotinin

5. Trasylol-INF Aprotinin

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Conclusions:-

Haemostatic is used to arrest the bleeding & haemotinics are enhancing the

haemostasis process. So it is used in the minor injury & during operation

when bleeding is occurring.

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Reference:

1. Remington, The science and practice of pharmacy. 20th

edition.

Volume II, publisher Lippincott. Williams & Wilkins. Page- 1243-

1248.

2. Goodman & Gillman. The pharmacological basic of therapeutics, 9th

edition. Publisher-McGraw Hill (health profession division). Page –

1311-1342.

3. H.P.Rang. M.M.Dale, J, M, Ritter, The book of pharmacology, 4th

edition, publisher- Churchill Livingstone, page-310-315.

4. Harsion internal medicine. 15th

edition, volume I publisher Mac-graw

Hill. Page-653-660.

5. Willson & Griswold‟s. Text book of organic medicinal & p‟cal

Chemistry, 10th

edition. Publisher- lippincott-Revar. Page -809-873.

6. Bertram G. Kaotzung. Basic & clinical p‟cology. 6th

edition.

Publisher- A large medical book. Page-567-570.

7. K.D.Tripathi, Essential medical p‟cology. 4th

edition. Publisher-

jaypee brothers. Page-580-585.

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