This document provides information on various anticoagulant drugs including heparin, low molecular weight heparins, synthetic heparin derivatives like fondaparinux, direct thrombin inhibitors, and oral vitamin K antagonists like warfarin. It discusses their mechanisms of action, indications, dosing, advantages and disadvantages, interactions, and adverse effects. Key anticoagulants covered are heparin, enoxaparin, fondaparinux, dabigatran, rivaroxaban, and warfarin.
3. Coumarin derivatives: warfarin,
acenocumarol, ethyl biscoumacetate and
dicumarol
Indanedione group: phenindione and
Anisindione
4. Factor Name
I Fibrinogen
II Prothrombin
III Tissue Factor or thromboplastin
IV Ca++
V Proaccelerin
VII Proconvertin
VIII Antihemophilic A factor
IX Christmas factor or
X Stuart factor
XI Plasma thomboplastin antecedent
XII Hageman factor
XIII Fibrin stabilizing factor
5.
6. INTRINSIC PATHWAY
All clotting factors are
within the blood vessels
Clotting slower
Activated partial
thromboplastin test (aPTT)
EXTRINSIC PATHWAY
Initiating factor is outside
the blood vessels - tissue
factor
Clotting - faster - in
Seconds
Prothrombin test (PT)
7.
8. Heparin is a non-uniform mixture of straight chain
mucopolysaccharide molecules
The mean molecular weight of heparin is 15,000 D
Strongest organic acid present in body
Source- mast cells lung, liver, Int.mucosa
Actions –acts both in-vivo and invitro
Antithrombin III (ATIII) binding is necessary for its
anticoagulant activity
9. Antithrombin III (ATIII) is a slow endogenous progressive
inhibitor of thrombin and other clotting enzymes.
Higher doses inhibits
platelet aggregation and
Prolongs bleeding time.
Lipaemia clearing
10. Large, highly ionised molecule,
Bioavailability- sc -variable, IV
Does not cross –BBB or placenta
Excreted in urine
T1/2-1-4 hrs
1000, 5000 u/ml 5ml vials
Should not be mixed with penicillin,
tetracyclines.
11. Bleeding: they both lead to bleeding but the
bleeding is less in LMWH
To treat bleeding: inject antidote protamine sulphate
(1mg IV for each 100 units of UFH) (reversal effect)
Thrombosis: heparin ↓ ATIII ↑risk of
thrombosis
12. Thrombocytopenia: Heparin-induced thrombocytopenia
(HIT) is a life threatening immune reaction
HIT ↑ platelet activation platelet aggregation
thrombosis.
HIT endothelial damage
HIT may occur in the early stages of treatment (within 5
days) but it’s non-immune reaction (not life threatening)
LMWHs, though of lower risk, are contraindicated with
HIT.
Osteoporosis, hyperkalemia, hypersensitivity
13. Bleeding or hemophilia
Severe hypertension
Thrombocytopenia or purpura-HIT
Intracranial hemorrhage
Recent surgery-ocular, neuro, lumbar
Hypersensitivity to heparin
TB
GIT ulcer
Hepatic or renal disease, chronic alcoholics
Use of digoxin
14. M.Wt 2000-8000 Da ( avg 4500 Da )- prepared from SH by
fractionation & enzymatic degradation .
Commercial preprn : Enoxaparin, Dalteparin, Ardeparin,
Tinzaparin, Reviparin, Nadroparin
Routes : SC (OD)
High anti-Xa and low anti-IIa activity↔ greater
antithrombotic and lower anticoag activity
Low anti-IIa activity, hence, aPTT, TT are not ideal for
monitoring. Anti-Xa assay ideal
Less complicated, dose independent clearance and more
predictable anticoagulant response than UFH.
15. 1. Heparin –IV -5000-10000 units
2. Low dose regimen-sc-DVT
LMWH-
1. Prophylaxis and trmt of DVT, pulm. Embolism-
enoxaparin -30mg sc
2. Unstable angina and MI-
3. To maintain patency of canula and shunts
4. RHD
5. Cerebrovascular diseases
6. DIC
7. Anticoagulation in pregnancy
8. Treatment of peripheral embolism
16. Dabigatran etexilate is a new oral direct thrombin
inhibitor and the prodrug of Dabigatran
Rivaroxaban is an orally available, small-molecule,
active site-directed factor Xa inhibitor
Knee replacement surgeries
Equivalent to LMWH
17. first selective factor Xa inhibitor,
55% better than enoxaparin (LMWH) at reducing risk
of VTE
synthetic pentasaccharide: “represents the
oligosaccharide consensus sequence of heparin”
Indirect inhibition: binds to antithrombin and
increases antithrombin’s affinity for factor Xa by
300-fold
18. Fondaparinux is given –sc- once daily
Long elimination t 1/2 (20 hrs). Renal clearance
Uses
1. Initial treatment of deep vein thrombosis (DVT)
2. pulmonary embolism (PE) and for
3. Venous thromboembolism prevention in patients
undergoing surgery for hip fracture or hip/knee
replacement
19. Lepirudin (DTI) derived from hirudin from leech
salivary glands.
-ischemic conditions associated with unstable angina
Better in hepatic insufficiency patients
Bivalirudin (DTI) approved for use during heparin-
induced thrombocytopenia (HIT) & percutaneous
coronary interventions
Argatroban (DTI) can be used in patients with risk of
(HIT)
Desirudin -DVT
20. Danaparoid-84% heparan sulphate+12% dermatan
sulphate+ 4% chondroitin sulphate
Drotrecogin Alfa
Human recombinant activated protein C
used in patients with sepsis; recombinant form of
activated protein C that inhibits f Va and f VIIIa
21. Vitamin K Antagonists (The Coumarins)
Vitamin K is co-factor for the hepatic
synthesis of clotting factors II, VII, IX & X
Warfarin inhibits Vit. K reductase
no active form of Vit. K
no synthesis of clotting factors
Clinical anticoagulant activity needs
several days to develop (due to the
already circulating clotting factors)
So the action of warfarin will appear
after the elimination of prior
clotting factors.
22. Onset: starts after 12-16 hours
lasts for 4-5 days
Elimination time (factor II needs: 60 hours factor
X: 40 hours)
Overlap heparin & warfarin therapy taken
together until the effect of warfarin appears
(after 5 days) then stop taking heparin.
23. Warfarin has 100% oral bioavailability,
plasma protein binding-99% &
long plasma t1/2 of 36 hours
A high loading dose followed by an adjusted
maintenance dose
Contraindicated with pregnancy -is teratogenic in
the first trimester & and induce intracranial
hemorrhage in the baby during delivery
Warfarin is metabolized by hepatic Cytochrome
P450 enzymes with half-life of 40 hrs
25. Prophylaxis and/or treatment of:
Venous thrombosis and its extension-2-2.5
Pulmonary embolism
Thromboembolic complications associated with AF
and cardiac valve replacement-
Post MI, to reduce the risk of death, recurrent MI,
and thromboembolic events such as stroke or
systemic embolization-3-3.5
Prevention and treatment of cardiac embolism.
26. INR= patients PT in seconds
mean normal PT in seconds
ISI
INR = International Normalized Ratio
ISI = International Sensitivity Index
27. Food and drug interactions
Genetic variation in metabolism
narrow therapeutic window
slow onset of action
overlap with parenteral drugs
dosage adjustments &
freq. monitor with INR
28. 1. Induce microsomal enzymes (barbiturates,
meprobamate and other sedative-hypnotic drugs;
griseofulvin).
2. Inhibition of metabolism (e.g., allopurinol disulfiram.
3. Displaced from binding sites by phenylbutazone,
phenytoin, sulfinpyrazone, clofibrate, Salicylates,
Indomethacin, Oral Contraceptives
4. Acetaminophen inhibits warfarin degradation
5. Effect of anticoagulants on other drugs -Coumarin
agents prolong and intensify action of chlorpropamide,
tolbutamide, phenytoin and phenobarbital.
Hinweis der Redaktion
The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway).
Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII).
The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X.
Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin.
Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide.
Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.