5. •
•
•
•
•
Indications of
anticoagulant therapy
Established venous
thromboembolism
Prophylaxis of venous
thrombosis and
pulmonary embolism
Prosthetic heart valve
Rheumatoid mitral
valvular disease
Myocardial infarction
Contraindications
• Pre existing bleeding
disorder
• Stroke within 3 weeks
or neural / ocular
surgery
• Severe uncontrolled
hypertension
• Active peptic ulcer , IBS
• Renal failure
• Liver cirrhosis
• Pregnancy ( warfarin)

6. •
Mucopolysachharide
Heparin
Heparin is a powerful and instantaneously acting anticoagulant ,effective both
invivo and in vitro.It is not absorbed by mouth and is usually given by intravenous
or sometimes by subcutaneous injection.
MECHANISM OF ACTIONS
Heparin acts indirectly by binding to antithrombin III(AT III ,a serine proteinase
inhibitors).The heparin AT III complex then binds to clotting factors and inactivates
them ,thus by inhibits coagulation.
• Inhibits factor II, VII, IX, X, XI, XII
• Prevents conversion of prothrombin to thrombin
• Prevents conversion of fibrinogen to fibrin
• Decrease platelet aggregation at high dose
Effects:
• Anticoagulant
• Antiplatelet
• Lipemia clearing ( releasing lipoprotein lipase)

7. • Pharmacokinetics
• Route : IV/SC
• Onset of action : immediate ( within 10-15
mins )
• Plasma half life : 40-90 mins
• Metabolism : liver
• Excretion : kidney

8. USES
• Disseminated intravascular coagulation
• Deep vein thrombosis
• Pulmonary embolism
• Postoperative or after myocardial surgery
• Cardipulmonary bypass machines ( extra corporeal devices eg dialysis)
• Thrombophlebitis
• To reduce frequency of arterial embolism in patient with atrial fibrillation,
mitral stenosis or prosthetic heart valves
• Prevention of clotting during
– Blood transfusion
– Hemodialysis
– Blood sampling for lab analysis
Safe drug during pregnancy

9. ADVERSE EFFECTS
• Hemorrhage
• Hypersensitivity :
Chills,fever,urticaria,anaphylactic
shock
• Thrombocytopenia
• Transeint but reversible alopecia
• Osteoporosis
• Neuropathy
• Inhibition of aldosterone
secretion
• Slowing of wound healing
• Depression of cell mediated
immunity
CONTRAINDICATIONS
• Hypersensitive patients
• Patients having bleeding
disorders ( thrombocytopenia,
hemophilia)
• Intracranial hemorrhage
• Ulcerative lesions of GIT
• Threatened abortion
• Active tuberculosis
• Alcoholics
• Ocular and neurosurgery,
• lumbar puncture

10. DOSES
• IV bolus dose : 5,000-10,000 U
every 4-6 hours
• Child dose : 50-100U/kg
•
Infusion is best given via a
syringe pump at the rate of
25000-30000 units in 24hrs
following an initial bolus of 5000
units.If a pump is not available
the heparin can be added to
1litre of saline or 5% dextrose
and given as an infusion.
• To prevent thrombosis :5000
units in 0.2ml subcutaneously
twice daily.
UNITS
1 Unit = amount of heparin that
prevents 1 ml of citrated sheep
plasma from clotting for 1 hour
after additon of 0.2 ml of 1%
calcium chloride solution.
Heparin sodium 1 mg = 120-140U
Monitoring of heparin dose :
Blood partial thromboplastin
time with kaolin (PTTK) or aPTT .
It should increase by 2.5 -3.5
times with heparin

11. Heparinisation
1) Continuous intravenous infusion via an infusion
pump:
– Initial loading dose : 5000-10000 units
– Continuous infusion : 900 units / hour
– PTTK should be maintained at 2.5-3.5 times control
2) Intermittent intravenous administration:
– Heparin : 75-100 units /kg every 4 hours
3) Subcutaneous administration ( low dose )
– Heparin : 5000 units every 8 or 12 hours

12. Low molecular weight heparins
• Selectively inhibit factor Xa with little effect on IIa
• Better subcutaneous bioavailability
• Advantages
–
–
–
–
more predictable pharmacokinetic profile.
therapy may be provided in the outpatient setting
lower incidence of heparin-induced thrombocytopenia
lower risks of bleeding and osteopenia
• Once daily sc
–
–
–
–
–
–
Enoxaparin
Reviparin
Nadroparin
Dalteparin
Pamparin
Ardeparin

13. Heparin antagonist: protamine sulfate
• Strongly basic , low molecular weight protein
• 1 mg needed for every 100 U of heparin
• Rapid iv injection but rate should not exceed
50 mg in any 10 min period .

14. Other parenteral anticoagulants
•
•
•
•
•
Lepirudin
Bivalirudin
Argatroban
Danaparoid
Drotrecogin Alfa

15. Oral anticoagulants
Warfarin and its congeners acts as anticoagulant only in vivo not in
vitro.it is an oral anticoagulant.Unlike heparin, the anticoagulant
effects of warfarin are not observed until 8-12 hours of drug
administration.the anticoagulants effects of warfarin can be
overcome by the administration of vitamin K.
MECHANISM OF ACTION
It acts indirectly by interfering with the synthesis of vitamin K
dependent clotting factors in the liver. They interfere with
regeneration of active hydroquinone which carries out gamma
carboxylation of glutamate residues of prothrombin and factors VII,
IX, and X.
• Inhibits Vit K epoxide reductase

16. • USES
–
–
–
–
–
–
–
–
Deep vein thrombosis
Pulmonary embolism
Myocardial infarction
Unstable angina
Frost bite
Acute gangrene
Cerebrovascular disease
Atrial fibrillation
ADVERSE EFFECTS
–
–
–
–
–
–
–
–
–
Bleeding
Hematuria
Bleeding in GIT
Intracranial or other
internal hemorrhages
Skin rashes / transient
purpura
Drug fever
Jaundice
Purple toe syndrome
Congenital bony
abnormality in children ( if
given in pregnancy )

17. Effects of warfarin on pregnancy
• Teratogenecity
– Bony deformity
– Nasal hypoplasia
– CNS abnormality
• Abortion
• Foetal and neonatal hemorrhage
• Intrauterine death of the foetus

18. CONTRAINDICATIONS
• Should not be used during pregnancy
• Recent trauma , head injury
• Active internal bleeding ( eg active ulceration)
• Severe hyeprtension
• Major surgery
• Pre-existing bleeding disorders
• Severe renal and hepatic disease
DOSE
Warfarin sodium
Initial dose is 10-15mg ,maintenance dose 2-10mg daily for 4-7days

19. • Factors enhancing
effect:
– Malnutrition,
malabsorption,
prolonged antibiotic
therapy
– Liver diseases
– Chronic alcoholism
– Hyperthyroidism
– newborn
• Factors decreasing
effect
– Pregnancy
– Nephrotic syndrome
– Genetic warfarin
resistance
– Drugs : enzyme inducers
(OCP)

20. Monitoring of oral anticoagulant therapy
INR ( international normalised ratio) :
Prothrombin time ratio ( test/ control) based on human thromboplastin .
Optimum range should be 2.5-3.5 times normal for effective anticoagulant effect.
i) A coagulation screen and platelet count is done before starting treatment
ii) Transfusion with fresh blood is required if blood loss has been excessive.
ii) The dose of oral anticoagulant must be individualized by repeated measure of
prothrombin time

21. • Antidote:
– Immediate antagonism : plasma concentrated
with vit K dependent clotting factors ( II, VII, IX , X)
– Delayed antagonism by Inj Vitamin K ( I/ V)

24. Hemostatic agents / coagulants
1) Fresh whole blood or fresh
frozen plasma
2) Vit K
–
K1 (from plants, fat soluble )
: phytonadione (
phylloquinone )
K2 ( produced by bacteria ) :
menaquinone
K3 ( synthetic)
–
–
•
•
Fat soluble :
menadione ,
acetomenapthone
Water soluble : menadione
sodium bisulfite ,
menadione
sod diphosphate
3) Miscellaneous :
–
–
–
–
–
–
Fibrinogen
Antihemophilic factor
Adrenochrome
Monosemi carbazone
Rutin
Ethamsylate
4) Local hemostatics (styptics):
–
–
–
–
–
–
Thrombin
Fibrin
Gelatin foam
Russel viper venom
Vasoconstrictors
Astringents

25. Vitamin K
• normal physiological
function: to promote the
biosynthesis of the gcarboxy-glutamate (Gla)
forms of factors II
(prothrombin), VII, IX, and
X, anticoagulant proteins
C and S.
• Vitamin K, as KH2, the
reduced vitamin K
hydroquinone, is an
essential cofactor for gglutamyl carboxylase

26. minimum daily requirement
• 0.03 mg/kg of body
weight
DEFICIENCY
• can result from
inadequate intake,
absorption, or utilization
of the vitamin,
• or action of a vitamin K
antagonist
• increased tendency to
bleed
• Ecchymoses, epistaxis,
hematuria,
gastrointestinal bleeding,
and postoperative
hemorrhage are common
• intracranial hemorrhage
may occur. Hemoptysis is
uncommon.
• fetal warfarin syndrome
may be related to a
deficiency of the vitamin.
• deficits in bone mineral
density and fractures;

27. • menadione and its
derivatives cause
hemolytic anemia and
kernicterus in neonates,
especially in premature
infants
Uses
• correct the bleeding
tendency or
hemorrhage associated
with its deficiency.
• Oral Anticoagulant
overdose
• Hypoprothombinemia
prophylaxis

28. Toxicity
• Rapid iv injection : flushing ,breathlessness ,
hypotension, and chest constriction
• Menadione can cause hemolysis , so not used

29. Fibrinolytics / thrombolytics
• Urokinase
• Streptokinase
• Alteplase
– Recombinant tissue
plasminogen
activator)

30. Streptokinase
• It is a streptococcal exotoxin ( beta hemolytic streptococci group C)
MECHANISM OF ACTIONS
– It combines with circulating–plasminogen-liberating plasmin which breaks
down fibrin
– No intrinsic enzymatic activity but forms a stable complex with plasminogen .
This complex then converts uncomplexed plasminogen to active plasmin
which causes hydrolysis of fibrin plugs .
– Plasmin catalyses degradation of fibrinogen as well as clotting factors V and VII
USES
–
–
–
–
–
Pulmonary embolism
Peripheral arterial occlusion
Venous thrombosis
Lysis of coronary thrombosis(present use) in acute myocardial infarction
Clear occluded arterio venous cannula

31. • ADVERSE EFFECTS
–
–
–
–
–
–
Bleeding particularly at the sites of recent trauma.
Hypersensitive reactions
Anaphylaxis(especially when used second time in a patient)
Fever
Hypotension
Arrhythmias.
• PRECAUTIONS
– It should not be used if patient has had previous streptokinase
within the last 12 months
– Blood pressure should be monitored.

32. • CONTRAINDICATIONS
– Surgery within 10 days including :
• Organ biopsy
• Serious trauma
–
–
–
–
Serious GIT bleeding within 3 months
History of hypertension
Hemorrhagic disorders
Cerebrovascular accident
• DOSE
– For coronary thrombosis: 1.5 million units infused over 1hr this may be
preceded by chlorpheniramine 10mg and hydrocortisone 100mg to
reduce allergic reactions. This is combined with 300mg aspirin ,which
should be chewed before swallowing and followed by 150mg daily.

33. FIBRINOLYTIC INHIBITORS:
•
•
•
•
AMINOCAPROIC ACID
TRANEXAMIC ACID
PHYTOMENADIONE
APROTININ
• Aminocaproic acid (EACA)- chemically similar to the amino acid
lysine
• It competitively inhibits plasminogen activation It is rapidly
absorbed orally and is cleared from the body by the kidney. The
usual oral dosage of EACA is 6 g four times a day. When the drug is
administered intravenously, a 5 g loading dose should be infused
over 30 minutes to avoid hypotension.
• Tranexamic acid is an analog of aminocaproic acid and has the
same properties. It is administered orally with a 15 mg/kg loading
dose followed by 30 mg/kg every 6 hours

34. Anti thrombotic drugs / antiplatelet
drugs
• Drugs interfering with platelet function:
–
–
–
–
–
–
–
–
–
–
–
–
–
Aspirin
Sulfinpyrazole
Ticlopidine
Eptifibatide
Tirofiban
Dextran-70
Dazaxiben
Dipyridamole
Epoprostenol
Clofibrate
Clopidogrel
Abciximab
Glycoprotein IIb/IIIa Inhibitors

35. Aspirin
• In platelets, the major cyclooxygenase product
is thromboxane A2, a labile inducer of platelet
aggregation and a potent vasoconstrictor.
• Aspirin blocks production of thromboxane A2
by acetylating a serine residue near the active
site of platelet cyclooxygenase (COX-1), the
enzyme that produces the cyclic endoperoxide
precursor of thromboxane A2.
• 50 to 320 mg per day

36. Ticlopidine.
• Platelets contain two purinergic receptors, P2Y1 and
P2Y12; both are GPCRs for ADP. The ADP-activated
platelet P2Y1 receptor couples to the Gq-PLC-IP3-Ca2+
pathway and induces a shape change and aggregation.
The P2Y12 receptor couples to Gi and, when activated
by ADP, inhibits adenylyl cyclase, resulting in lower
levels of cyclic AMP and thereby less cyclic AMPdependent inhibition of platelet that inhibits the P2Y12
receptor
• dose is 250 mg twice per day
• common side effects are nausea, vomiting, and
diarrhea. The most serious is severe neutropenia .

37. Blood and plasma Volume expanders
• High molecular weight substances that exert
colloidal osmotic pressure and when infused
iv retain fluid in the vascular compartment.
• Substances:
– Human albumin
– Dextran
– Degraded gelatin polymer
– Hydroxyethyl starch ( HES) , hetastarch
– Polyvinyl pyrrolidone (PVP)

38. • Desirable properties of plasma expanders :
– Should exert osmotic pressure comparable to
plasma
– Should remain in circulation and not leak out in
tissues or be too rapidly disposed
– Should be pharmacodynamically inert
– Should be non pyrogenic or antigenic
– Should not interfere with grouping or cross
matching of blood
– Should be stable , easily sterilizable , and cheap

39. Human albumin
• Obtained from human pooled plasma
• 100 ml of 20% human albumin equivalent to 400 ml of
fresh frozen plasma or 800 ml of whole blood .
• Uses:
–
–
–
–
–
–
Dehydration
Burns , hypovolemia
Shock
Acute hypoproteinemia
Acute liver failure
Dialysis
• Febrile reaction may occur
• Expensive

40. Dextran
• Polysachharide obtained from
sugar beat.
• Dextran-70 ( MW- 70,000)- 6%
solution in dextrose or saline
• Expands plasma volume for 24
hours and is excreted through
kidney and oxidation.
• May interfere with blood
grouping
• May cause allergic reactions :
urticaria , itching ,
bronchospasm, hypotension
and anaphylactic reaction.
• Can prolong bleeding time , so
should not be given in
hypofibrinogenemia, or
thrombocytopenia
• Dextran-40 ( MW- 40,000) –
10% solution I dextrose or
saline
• Reduces blood viscosity
• Acts for a shorter period and
quickly eliminated through
kidney
• Used in stroke , and for
prophylaxis of deep vein
thrombosis and pulmonary
infarction.