Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
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
gnu.i
nflibn
et.ac
.in
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:
gnu.i
nflibn
et.ac
.in
Dedicated to God, My
Family & Teachers
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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 &
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
coagulation inhibitor (LACI). gnu.i
nflibn
et.ac
.in
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 )
gnu.i
nflibn
et.ac
.in
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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
erytropoiesis. gnu.i
nflibn
et.ac
.in
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
nflibn
et.ac
.in
- 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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
Market preparation:
No. Brand name Content
1. Aprogen Aprotinin
2. Apronin Aprotinin
3. Apostate Aprotinin
4. Haemaprot Aprotinin
5. Trasylol-INF Aprotinin
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in
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.
gnu.i
nflibn
et.ac
.in