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Anticoagulan Drugs
Anticoagulan Drugs
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
Thromboplastin
XI XIa
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
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
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