Anticoagulant

drugs
 Anticoagulants
General Overview
 Drugs that help prevent the clotting
(coagulation) of blood
 Coagulation will occur instantaneously once a
blood vessel has been severed
 Blood begins to solidify to prevent
excessive blood loss and to prevent
invasive substances from entering
the bloodstream
A Blood Clot
 Consists of platelets
meshed into fibrin
 A web-like
accumulation of strands
with RBCs
 There are two major
facets of the clotting
mechanism – the
platelets, and the
thrombin system
 Blood Clotting
 Vascular Phase
 Platelet Phase
 Coagulation Phase
 Fibrinolytic Phase
Vascular Phase
 Vasoconstriction
 Exposure to tissues activate Tissue factor and initiate
coagulation

Tissue Factor
Platelet phase
 blood vessel wall (endothelial cells) prevent platelet adhesion and
aggregation
 platelets contain receptors for fibrinogen and von Willebrand
factor
 after vessel injury Platelets adhere and aggregate.
 Release permeability increasing factors (e.g. vascular
permeability factor, VPF)
 Loose their membrane and form a viscous plug
 Coagulation Phase
 Two major pathways
 Intrinsic pathway

 Extrinsic pathway

 Both converge at a common point

 13 soluble factors are involved in clotting

 Biosynthesis of these factors are dependent on Vitamin K1 and K2

 Normally inactive and sequentially activated

 Hereditary lack of clotting factors lead to hemophilia -A

 Coagulation Factors
Factor Name Factor Name
I Fibrinogen X Stuart or Stuart-
II Prothrombin Prower factor
III Tissue Factor or XI Plasma thomboplastin
thromboplastin antecedent
IV Ca++ XII Hageman factor,
V Proaccelerin contact factor
VII Proconvertin XIII Fibrin stabilizing factor
VIII Antihemophilic A factor Prekallikrein factor
IX Antihemophilic B factor or High-molecular-
Christmas factor weight kininogen
 Extrinsic Pathway
Intrinsic Pathway
Blood Vessel Injury Tissue Injury

XII XIIa Tissue Factor

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X
Prothrombin Thrombin
Factors affected
Fibrin monomer
By Heparin Fibrinogen
Vit. K dependent Factors Fibrin polymer
Affected by Oral Anticoagulants XIII
 Intrinsic Pathway Extrinsic Pathway
 All clotting factors are  Initiating factor is outside the
within the blood blood vessels - tissue factor
vessels

 Clotting slower  Clotting - faster - in Seconds

 Activated partial  Prothrombin test (PT)
thromboplastin test
(aPTT)
Anticoagulants
Inhibit clotting factor activation reactions in the blood
 CURRENT DRUGS TARGETED FACTOR
 Unfractionated Heparin______________ Antithrombin (indirectly Xa and IIa)
 Low Molecular Weight Heparin________ Antithrombin (indirectly Xa and IIa)
 Lepirudin (DTI)____________________ Thrombin (IIa)
 Bivalirudin (DTI) ___________________ Thrombin (IIa)
 Argatroban(DTI)____________________Thrombin (IIa)
 Danaparoid_______________________ Antithrombin
 Drotrecogin Alfa____________________Va, VIIIa
 Vitamin K antagonists (Warfarin)_______
Prothrombin (II), VII, IX, X
 NEW/ in DEVELOPMENT DRUGS
 Fondaparinux_____________________ Xa
 Idraparinux_______________________ Xa
 SSR 126517______________________ Xa
 Rivaroxaban______________________ Xa
 Apixaban_________________________ Xa
 LY517717________________________ Xa
 YM150__________________________ Xa
 DU-176b_________________________ Xa
 Betrixaban________________________ Xa
 Ximelagatran*_____________________ Thrombin (IIa)
 Dabigatran etexilate________________Thrombin (IIa)

*taken off the market Italics are Oral Drugs

 Standard Heparin
 Heterogenous mixture of polysaccharide chains
 MW 3k to 30k
 Active in vitro and in vivo
 Administration - parenteral- Do not inject IM - only IV or
deep s.c.
 Half-life 1 - 2 hrs - monitor APTT
 Adverse effect : haemorrhage  antidote - protamine
sulphate
 Monitoring Heparin
 Activated Partial Thromboplastin Time (APTT)
 Normal range: 25-40 seconds
 Therapeutic Range: 55-70 seconds
 Timing
 4-6 hours after commencing infusion
 4-6 hours after changing dosing regimen
 Low Molecular Weight Heparin
Changed management of venous
thromboembolism
Standard (Unfractionated) heparin 3k to 30k
LMWH contains polysaccharide chains MW 5k
Enriched with short chains with higher anti-Xa:IIa
ratio
 Low-molecular weight heparin
 Low-molecular weight heparin is gradually replacing heparin for
treatment of most patients with venous thromboembolism and
acute coronary syndromes because it has more convenient and
cost-effective
 It has similar results to heparin
 Administered by subcutaneous
injection
 LOVENOX® is an example
Fondaparinux
 Fondaparinux is given via injection once daily
 It is licensed for initial treatment of deep vein
thrombosis (DVT) and pulmonary embolism (PE) and for
venous thromboembolism prevention in patients
undergoing surgery for hip fracture or hip/knee
replacement
 Differences in Mechanism of Action
Any size of heparin chain can inhibit the action of
factor Xa by binding to antithrombin (AT)
In contrast, in order to inactivate thrombin (IIa),
the heparin molecule must be long enough to
bind both antithrombin and thrombin
Less than half of the chains of LMWH are long
enough
Complications of Heparin
 Haemorrhage
 Heparin-induced thrombocytopaenia (HIT)
 Osteoporosis (long-term only)
Vitamin K-Dependent Clotting Factors

Vitamin K

VII
Synthesis of
IX Functional
Coagulation
X Factors

II
Warfarin Mechanism of Action
Vitamin K

Antagonism VII
of Synthesis of Non
Vitamin K IX Functional
Coagulation
X Factors

II

Warfarin
Warfarin: Major Adverse Effect—
Haemorrhage
Factors that may influence bleeding
risk:
Intensityof anticoagulation
Concomitant clinical disorders
Concomitant use of other medications
Quality of management
Prothrombin Time (PT)
 Historically, a most reliable and “relied upon”
clinical test
However:
 Proliferation of thromboplastin reagents with widely
varying sensitivities to reduced levels of vitamin K-
dependent clotting factors has occurred
 Problem addressed by use of INR (International
Normalised Ratio)
INR: International Normalised Ratio
A mathematical “correction” (of the PT ratio) for
differences in the sensitivity of thromboplastin
reagents
 INR is the PT ratio one would have obtained if the
“reference” thromboplastin had been used
 Allows for comparison of results between labs
and standardises reporting of the prothrombin
time
 Changing over from Heparin to Warfarin
May begin concomitantly with heparin therapy
Heparin should be continued for a minimum of four
days
 Timeto peak antithrombotic effect of warfarin is
delayed 96 hours (despite INR)
When INR reaches desired therapeutic range,
discontinue heparin (after a minimum of four days)
 Warfarin: Dosing & Monitoring
Start low
 Initiate 2-5 mg daily
 Educate patient

Stabilise
 Titrate to appropriate INR
 Monitor INR frequently (daily then weekly)

Adjustas necessary
Monitor INR regularly (every 1–4 weeks) and adjust
 Relative Contraindications to Warfarin Therapy
 Pregnancy
 Situations where the risk of hemorrhage is
greater than the potential clinical benefits of
therapy
Uncontrolledalcohol/drug abuse
Unsupervised dementia/psychosis
 Signs of Warfarin Overdosage
Any unusual bleeding:
Blood in stools or urine
Excessive menstrual bleeding
Bruising
Excessive nose bleeds/bleeding gums
Persistent oozing from superficial injuries
Bleeding from tumor, ulcer, or other lesion
Reversing action of warfarin
Plasma
Rapid but short-lasting
Vitamin K
Not rapid, but lasts 1-2 weeks. Do not use if
wishing to restart warfarin within next week.
The future for anticoagulants
Limitations of warfarin have fostered a great
interest in the development of novel
anticoagulants for oral use to potentially replace
warfarin
The design of specific inhibitors against molecular
targets that play a pivotal role in the coagulation
cascade are in development
The future for anticoagulants
 Molecular targets are factor IIa (thrombin) and
factor Xa
 The two candidate compounds, one direct
thrombin inhibitor (dabigatran etexilate) and one
direct factor Xa inhibitor (rivaroxaban) are
hoping to be approved as new oral
anticoagulants in the near future
Why do we need new anticoagulation
drugs?
 Heparin-induced thrombocytopenia
 Heparin prophylaxis is imperfect
 Heparin-associated osteoporosis
 Warfarin takes several days for its effect
 Warfarin is not as effective in some situations e.g
antiphospholipid syndrome
 Warfarin interacts with many other drugs
 Warfarin is dangerous if not monitored
The ideal anticoagulant
 Effective
 Minimal complications/side effects
 Convenient administration (ie: oral for outpatients)
 Rapid absorption
 Fast on and offset action
 Predictable pharmacokinetics
 No interactions with food or drugs
 No HIT
 No coagulation monitoring
Conclusion
 Anticoagulant therapy is use extensively.
 Current mainstays of treatment are heparin or
heparin-like drugs and oral warfarin.
 Both have problems but when monitored closely
are generally safe.
 New anticoagulation drugs are arriving
THANK YOU