Anti coagulants and detailed pharmacology of all agents with details of fibrinolytic drugs

1. Anti-coagulants &
fibrinolytic
Dr. Fardan Qadeer
JR III

2. INTRODUCTION
HEMOSTASIS AND THROMBOSIS
Normal hemostasis comprises a series of regulated processes that
maintain blood in a fluid, clot-free state in normal vessels while
rapidly forming a localized hemostatic plug at the site of vascular
injury.
Hemostasis and Thrombosis involve three elements:
• vascular wall
• platelets
• coagulation cascade

3. NORMAL HEMOSTASIS
Vascular injury causes transient
arteriolar vasoconstriction through
reflex neurogenic mechanisms,
augmented by local secretion of
endothelin
Transient Vasoconstriction

4. ROLE OF PLATELETS
Non activated platelets do not adhere to the
endothelium
Activation of Platelets:
Injury  Exposure to the sub-endothelial ECM
Interaction to the vWF which is held in the ECM
• These interactions allow vWF to act as a sort
of molecular glue that binds platelets tightly
to denuded vessel wallsPrimary Hemostatic Plug

5. PRIMARY HEMOSTATIC PLUG
Platelet activation and aggregation:
• Change in shape of the platelets
• Release of Ca and ADP from the
platelet granules.
• Receptor activation
Platelets have 2 receptors:
• GpIb: binds to vWF leading to adhesion
• GpIIb-IIIa complex: leading to
aggregation by collagen

6. Role of Cyclooxygenase
PAR1 and PAR4 are
protease-activated
receptors that
respond to
thrombin (IIa)
P2Y1 and P2Y12 are receptors for ADP; when stimulated by
agonists, these receptors activate the fibrinogen-binding
protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to
promote platelet aggregation and secretion

7. Secondary Haemostatic Plug
• It leads to the stabilization of the platelet
plug creating an irreversibly fused mass of
platelets that constitutes the definitive
secondary hemostatic plug
• Thrombin activates a platelet surface
receptor.
• Thrombin converts fibrinogen to fibrin

8. COAGULATION CASCADE
TF exposed at sites of
vessel wall injury
initiates coagulation via
the extrinsic pathway
Formation of VIIa and TF complex
leading to activation of factor X and IX
EXTRINCIC
PATHWAY
Common pathway
Intrinsic
pathway

9. Coagulation factors

10. Fibrinolysis
u-PA
Activation of u-PA is
under inflammatory
stimuli and
extravascular

11. Natural Anticoagulant Mechanisms:
• NO
• Prostacyclin (PGI2)
Vasodilators and inhibit platelet
aggregation
Anti thrombin
Protein C homologous to factors II, VII, IX, and X

12. Drugs affecting Coagulation
Classes Drugs
Parenteral
• Indirect thrombin inhibitors
• Direct thrombin inhibitors
Heparin, LMWH and fondaparinux
Lepirudin, Bivalirudin and Argotroban

13. Heparin & its derivatives
• Heparin, a glycosaminoglycan found in the secretory granules of mast cells is
synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic
acid and N-acetyl-D-glucosamine residues
• Heparin is artificially extracted from porcine intestinal mucosa which is rich in
mast cells.
Heparin derivatives are fragments of
heparin ranging in molecular weight
from 1-10 kDa.
LMWH preparations differ from
heparin and, to a lesser extent, from
each other in their pharmacokinetic
properties.

14. Mechanism of Action: Heparin binding to antithrombin induces
a conformational change in antithrombin
that renders its reactive site more
accessible to the target protease
Antithrombin inhibits activated
coagulation factors involved in the
intrinsic and common pathways
This induces a conformational change in
the reactive center loop of antithrombin
that accelerates its interaction with factor
Xa and IIa . To potentiate thrombin
inhibition
Inhibition of
Thrombin

15. Other Pharmacological Properties:
• High doses of heparin can interfere with platelet aggregation and thereby prolong
the bleeding time.
• Lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids.
• Heparin "clears" lipemic plasma in vivo by causing the release of lipoprotein
lipase into the circulation

16. LMWH
• Predominat effect on factor Xa
• LMWHs have greater anti-factor Xa
activity than anti-IIa activity, and the
ratio ranges from 3:1 to 2:1 depending on
the preparation.
• Given by subcutaneous route and have a
greater half life

17. Fondoxiparinux
• It is a synthetic derivative of
heparin
• It causes selective inhibition of
factor Xa
• Does not show any effect on
thrombin itself due to its
shorter polymer length
• It has lesser antiplatelet effect
hence chances of bleeding in
minimal.

18. Pharmacokinetics:
• Not absorbed through the GI mucosa and therefore must be given parenterally.
• LMWH and fondaparinux are absorbed more uniformly after subcutaneous
injection.
• Heparin appears to be cleared and degraded primarily by the reticuloendothelial
system; a small amount of undegraded heparin also appears in the urine.

19. Toxicity and Adverse Events
• Bleeding
• Major bleeding occurs in 1-5% of patients treated with intravenous heparin for venous
thromboembolism
• Incidence of bleeding is proportionate to the degree of prolongation of the aPTT
If life-threatening hemorrhage occurs, the effect of heparin can be reversed quickly by the
intravenous infusion of protamine sulfate, a mixture of basic polypeptides isolated from
salmon sperm. Protamine binds tightly to heparin and thereby neutralizes its
anticoagulant effect.
• Heparin-Induced Thrombocytopenia:
• Heparin-induced thrombocytopenia (platelet count <150,000/mL or a 50% decrease from the
pretreatment value) occurs in 0.5% of medical patients 5-10 days after initiation of therapy
with heparin
• Abnormalities of hepatic function test
• Risk of osteoporosis is lower with LMWHs or fondaparinux than it is with heparin

20. LMWH preparations
• Enoxaparin
• Dalteparin
• Tinzaparin
• Ardeparin
• Nadroparin
• Reviparin
Considerable pharmacokinetic difference

21. Protamine Sulfate
• The effect of heparin can be reversed quickly by the intravenous infusion of
protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm.
Protamine binds tightly to heparin and thereby neutralizes its anticoagulant effect
• Dose: 1 mg of Protamine Sulfate for 100 U of Heparin
• Protamine only binds long heparin molecules.
• Therefore, protamine only partially reverses the anticoagulant activity of LMWHs
and has no effect on that of fondaparinux.

22. Other Parenteral Anticoagulants
Drug Mechanism Uses
Lepirudin A direct thrombin inhibitor Used for the treatment of heparin induced
thrombocytopenia(FDA)
Desirudin A direct thrombin inhibitor Desirudin is indicated for the prophylaxis of DVT
in patients undergoing elective hip replacement
surgery
Bivalirudin A direct thrombin inhibitor Used as an alternative to heparin in patients
undergoing coronary angioplasty or
cardiopulmonary bypass surgery.
Argatroban A direct thrombin inhibitor binds reversibly to the catalytic site of thrombin.
Higher risk of bleeding, monitoring of aPTT and
PT
Danaparoid Inhibits activation of factor
Xa
Used for the treatment of heparin induced
thrombocytopenia and postoperative DVT

23. Oral Anticoagulants
Warfarin and related compounds:
Chemically various derivatives of 4-
hydroxycoumarin are available and have
activity as vitamin K antagonists

24. Mechanism of Action
Warfarin is responsible for
inhibition of vitamin K-dependent -
carboxylation of factors II, VII, IX,
and X because reduced vitamin K
serves as a cofactor for a -glutamyl
carboxylase that catalyzes the -
carboxylation process.
carboxylation of
factors VII, IX,
and X
warfarin

25. Pharmacological Properties
• The usual adult dosage of warfarin is 2-5 mg/day for 2-4 days, followed by 1-10
mg/day as indicated by measurements of the international normalized ratio
(INR)
• Because of the long t1/2 of some of the coagulation factors, in particular factor II,
the full anti-thrombotic effect of warfarin is not achieved for several days.
• Warfarin also can be given intravenously without modification of the dose.
Intramuscular injection is not recommended because of the risk of hematoma
formation.
• Warfarin is almost completely (99%) bound to plasma proteins principally
albumin.

26. Drug Polymorphism:
• Polymorphisms in two genes, CYP2C9 and VKORC1(vitamin K epoxide reductase
complex, subunit 1) account for most of the genetic contribution to the variability
in warfarin response
CYP2C9 Pharmacokinetics Common variations in the
CYP2C9 gene are associated
with higher drug
concentrations and reduced
warfarin dose requirements
VKORC1 Pharmacodynamics Polymorphism in VKORC1 explains
30% of the variability in warfarin
dose requirements.

27. Drug Interactions
• There is enhanced the risk of hemorrhage in patients taking oral anticoagulants include
decreased metabolism due to CYP2C9 inhibition:
• Displacement from protein binding sites
• Loop diuretics
• Valproate.
• Relative deficiency of vitamin K may result from elimination of intestinal flora by
antimicrobial agents. Gut bacteria synthesize vitamin K and are an important source of
this vitamin.
• Consequently, antibiotics can cause excessive PT prolongation in patients adequately
controlled on warfarin
Amiodarone Cimetidine Clopidogrel
Azole antifungals Cotrimoxazole Fluoxetine

28. Adverse Effect and Toxicities:
• Haemorrhage:
• INR should be maintained between 2-3 and risk of bleeding is potentiated beyond INR 3.
• Risk of Intracranial haemorrhage, GI bleeding, intraperitoneal, retroperitoneal increases
• Vitamin K supplementation(iV/oral) is required when INR >5 with temporary discontinuation
of drug
• Birth defects:
• Administration of warfarin during pregnancy causes birth defects and abortion.
• A syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that
resemble chondrodysplasia punctata may result from maternal ingestion of warfarin during the
first trimester
• Skin necrosis: Rare
• Purple Toe Syndrome: painful, blue-tinged discoloration of the plantar surfaces and
sides of the toes that blanches with pressure and fades with elevation of the legs.

29. Other Vitamin K Antagonists
Phenprocoumon It has a longer plasma t1/2 (5 days) than warfarin, as well as a
somewhat slower onset of action and a longer duration of action
(7-14 days).
Acenocoumarol It has a shorter t1/2 (10-24 hours), a more rapid effect on the PT,
and a shorter duration of action (2 days). The maintenance dose is
1-8 mg daily.
Indandione It is similar to warfarin in its kinetics of action, has higher chances
of Hypersensitivity

30. New Oral Anticoagulants:
• Dabigatran
• Reversibly blocks the active site of thrombin.
• Used in the prevention of venous
thromboembolism after elective hip or knee
replacement surgery.
• Rivaroxaban
• Oral factor Xa inhibitor
• This drug is given in fixed doses and does not
require coagulation monitoring.

31. Therapeutic Uses:
• Prevention and treatment of Deep Vein Thrombosis and Pulmonary Embolism
• For established venous thrombosis: I.V. inj Heparin 5000-10000 IU bolus followed by I.V.
infusion of 1000 IU/hr followed by warfarin
• Myocardial Infarction
• Unstable angina: warfarin is used along with antiplatelet drugs
• Rheumatic Heart Disease: due to the higher chances of thrombosis due to AF
• Cerebrovasclar disease
• DIC
• To prevent clotting in extracorporeal circulation in haemodialysis
• During cardiac bypass surgery

32. Thrombosis
• Pathological opposite to
Hemostasis is Thrombosis
• Formation of a solid mass
from the constituents of blood
within the vasculature (blood
vessels / chambers of heart)

33. Pathogenesis
Injury
• Exposure of subendothelial collagen
• Adherence of platelets
• Exposure to tissue factor
• Local depletion of prostacyclin and
plasminogen activator Formation of Thrombus

34. Fate of Thrombus
Resolution
Thrombus Propagation
Recanalization

35. Fibrinolytic Drugs:
Thromobolytic drugs act by
converting inactive
plasminogen into plasmin
leading to dissolution of
fibrin clot
• Venous thrombi are more
easily lysed than the
arterial thrombi

36. Streptokinase:
• Streptokinase was the first thrombolytic agent approved for clinical use, and it has been
used extensively.
• Streptokinase is a purified bacterial protein isolated from Lancefield group C strains of
b-hemolytic streptococci.
• This produces a conformational change that exposes the active site on plasminogen that
cleaves Arg560 on free plasminogen to form plasmin.
• Due to its bacterial origin, streptokinase stimulates an immune response and the
production of antibodies in humans. Because circulating (neutralizing) antibodies can
inactivate the drug, streptokinase cannot be re-administered for at least 6 months

37. Tissue Plasminogen Activator and R-tpa
• It is a poor plasminogen activator in the absence of fibrin
• t-PA activates fibrin-bound plasminogen several hundredfold more rapidly than it
activates plasminogen in the circulation
• Alteplase(ACTIVASE) is produced by recombinant DNA technology.
• The currently recommended regimen for coronary thrombolysis
• 15-mg intravenous bolus, followed by
• 0.75 mg/kg of body weight over 30 minutes
• 0.5 mg/kg (up to 35 mg accumulated dose) over the following hour
• Reteplase: is a recombinant form of TPA having a longer half life.

38. Urokinase:
• It is a protease enzyme obtained from human urine and is now produced by
cultured human kidney cells.
• It is a direct plasminogen activator and degrades both fibrinogen and fibrin.
• Half life is 20 min
• It has more fibrin specificity than Streptokinase.

39. Hemorrhagic Toxicity of Thrombolytic Therapy
• The major toxicity of all thrombolytic agents is hemorrhage, which results from two
factors:
1) The lysis of fibrin in hemostatic plugs at sites of vascular injury, and
2) The systemic lytic state that results from systemic plasmin generation, which produces
fibrinogenolysis and degradation of other coagulation factors (especially factors V and
VIII).
• Intracranial hemorrhage is by far the most serious problem. Hemorrhagic stroke occurs
with all regimens and is more common when heparin is used

40. Contraindications
Absolute Contraindications
• Prior intracranial hemorrhage
• Known structural cerebral vascular lesion
• Known malignant intracranial neoplasm
• Ischemic stroke within 3 months
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant closed-head trauma or facial trauma within 3 months
Relative Contraindications
• Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)
• Traumatic or prolonged CPR or major surgery within 3 weeks
• Recent (within 2-4 weeks) internal bleeding
• Non compressible vascular punctures
• For streptokinase: prior exposure (more than 5 days ago) or prior allergic reaction to streptokinase
• Pregnancy
• Active peptic ulcer
• Current use of warfarin and INR >1.7

41. Inhibitors of Fibrinolysis
• Aminocaproic Acid
• Aminocaproic acid is a lysine analog that competes for lysine binding
sites on plasminogen and plasmin, blocking the interaction of plasmin
with fibrin.
• Aminocaproic acid is thereby a potent inhibitor of fibrinolysis
and can reverse states that are associated with excessive
fibrinolysis.
• For intravenous use, a loading dose of 4-5 g is given over 1
hour, followed by an infusion of 1-1.25 g/hour until bleeding
is controlled.
• No more than 30 g should be given in a 24-hour period.
• Rarely, the drug causes myopathy and muscle necrosis.

42. Tranexamic Acid:
• Tranexamic acid is a lysine analog that, like
aminocaproic acid, competes for lysine binding
sites on plasminogen and plasmin, thus blocking
their interaction with fibrin.
• The FDA approved oral tranexamic acid tablets
for treatment of heavy menstrual bleeding in
2009.
• When used for this indication, tranexamic acid
usually is given at a dose of 1 g four times a day
for 4 days.

43. Summary: