Transcript ANTICOAGULANT DRUGS

ANTICOAGULANT DRUGS
Dr.V.V.Gouripur
Clotting Process
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Formation of a blood clot (thrombus) in blood
vessels or the heart.
may be life saving (when it plugs a severed vessel)
or life-threatening if it occludes a vessel supplying a
vital structure.
may break loose to create an embolus that flows
downstream to lodge at a distant site.
The potential consequence is ischemic necrosis of
cells and tissues known as infarction.
Cerebral vascular accidents (stroke), myocardial
infarction and pulmonary embolisms are examples
of disorders resulting from thrombosis or embolism.
• Thrombophlebitis is the term used for a
venous thrombosis with associated
inflammation.
• 1. Arterial thrombosis—Result is localized
tissue injury owing to lack of perfusion
• 2. Venous thrombosis—Usually develops
when blood flow is slow; this initiates
coagulation cascade; part can become
embolus
Hemostasis
Physiologic process by which bleeding is
stopped
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Stage 1: formation of a platelet plug—
Begins when platelets come in contact
with collagen on exposed surface of
damaged vessel, adhere to area, release
adenosine diphosphate (ADP) and
thromboxane A2 platelet plug and
bleeding stopped. Platelet aggregation
ends with fibrinogen bridges
Stage 2: coagulation (reinforcement of platelet
plug with fibrin)—Occurs in series of cascading
reactions from extrinsic and/or intrinsic systems.
Four of the coagulation factors (VII, IX, X and
prothrombin) require vitamin K for synthesis
Stage 3. Keeping hemostasis under control—
Antithrombin III prevents widespread
coagulation
Stage 4. Physiologic removal of clots—Essential
in healing process using plasmin
Physical Process of Clotting
injured tissue
exposure of
subendothelial cells
vasoconstriction
blood
subendothelial cells
platelets
platelets adhere to
exposed cells
platelets aggregate
and form a “plug”
Chemical Process of Clotting
IXa and VIIIa work together to
convert X into Xa.
Xa and Va work together to convert II into IIa.
IIa works on a number of steps.
HMWK and TF are initiation points
CLOT is the end point
Anti-coagulants
• Anti-coagulants are molecules that prevent
blood from clotting.
• They inhibit the chemical process of
proteolytic formation of the threedimensional fibrin polymer.
• These include heparin, low molecular
weight heparin, coumarins, and 1,3indanediones.
anti-platelet agents.
• Molecules that do not allow platelets to
aggregrate and thus prevent clotting,
especially in the arteries, are called antiplatelet agents
• These include aspirin, sulfinpyrazone,
dipyridamole, and ticlopidine.
Fibrinolytic agents.
• Molecules that disintegrate a pre-formed
clot are called fibrinolytic agents.
• Some examples are
-streptokinase
-Altaplase
-Tenactaplase
Coagulation factors
Factor
I
II
III
IV
V
VII
VIII
IX
XI
XII
XIII
Name
Fibrinogen
Prothrombin
Tissue Factor or thromboplastin
Ca++
Proaccelerin
Proconvertin
Antihemophilic A factor
Christmas factor or Stuart-Prower factor
Plasma thomboplastin antecedent
Hageman factor
Fibrin stabilizing factor
HMWK- High molecular weight kininogen
Endogenous Inhibitors of Clotting
• Thrombin plays a pivotal role in blood
coagulation and
• Nature has designed several serine
protease inhibitors (SERPINS) to regulate
the its activity.
• These include
- antithrombin (major),
-Protein C
-Thrombomodulin
• Antithrombin Antithrombin is present in the
plasma ,primarily neutralizes factor Xa and
thrombin, in addition to inhibiting most active
serine proteases of the clotting system..)
• Protein C is another plasma protein that limits
clotting by being activated by thrombin to
proteolytically inactivate proaccelerin (V) and
antihemophilic factor (VIII).
• Thrombomodulin, a cell membrane bound
glycoprotein lining the vascular endothelium,
specifically binds thrombin so as to convert it to
a form with decreased ability to catalyze clot
formation but with a >1,000-fold increased
capacity to activate protein C.
Heparin
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Heparin is a naturally occurring, strongly acidic
mucopolysaccharide found in granules of mast
cells and basophils.
These polysaccharides possess a wide range
of molecular weights (3000 to 30,000) and are
negatively charged making them highly polar
and unable to readily cross membranes.
The dosage is measured in units of activity
determined by its ability to prevent clotting of
plasma standards.
In contrast to coumarin derivatives, it is only
administered parenterally.
Mechanism of action
–Acts by combining with an antithrombin
III.
–Heparin-antithrombin complex combines
with, and neutralizes, thrombin within
seconds.
–This complex also inhibits the action of
activated factors XIIA, IXa, VIIA, and Xa.
• Action - prolongs clotting time in vivo and in vitro.
• Monitoring is via the activated partial
thromboplastin time (APTT)
• Duration of action <4hrs
Low-Molecular-Weight (LMW) Heparins
Enoxaparin (Lovenox
Lepirudin (Refludan)
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These are heparins with shorter
molecules than those found in standard
(unfractionated) heparin.
They are as effective as standard
heparin and do not require APTT
monitoring
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Only for prophylaxis of DVT after hip or
abdominal surgery
Adverse Reactions
• Hemorrhage
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Thrombocytopenia
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Chemical antagonism occurs with
protamine sulfate, a strongly basic
protein that neutralizes heparin.
Coumarin Derivatives
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Warfarin
Dicoumarol
Coumarin
4-Hydroxycoumarin
Coumarin Derivatives (Warfarin
[Coumadin®])
Mechanism
– Vitamin K antagonist
– Inhibit formation of prothrombin (factor II) and factors
VII, IX and X, which are synthesized in the liver, and
the synthesis, is dependent upon vitamin K.
• Action
– Absorbed rapidly from GI tract
– Lowering of prothrombin occurs slowly. Monitoring is via
the prothrombin time (PT) or the international
normalized ratio (INR)
– Duration of action – 2-3 days
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Other Agents-Anisindione—Like warfarin but
greater side effects
Biochemical Mechanism of
Action
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Coumarins are competitive inhibitors of vitamin K in the
biosynthesis of prothrombin.
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The coagulation cascade relies on the conversion
of prothrombin to thrombin in a very important step.
However, this conversion depends on the presence of 10
g-carboxyglutamic acid (GLA) residues in the N-terminus
of prothrombin.
• The multiple Gla residues form a binding site for Ca+2.
Under normal circumstances 10 glutamic acid (Glu)
residues of prothrombin are converted to Gla residues in
a post-translational modification.
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Biochemical Mechanism of
Action
• This post-translation modification is catalyzed by an
enzymes vitamin K reductase and vitamin K epoxide
reductase.
• Vitamin K is a co-factor in this conversion reaction.
• Thus it cycles between a reduced form and an epoxide
form. Because of their structural similarity with vitamin K
coumarins are thought to bind the enzymes, vitamin K
reductase and vitamin K epoxide reductase, without
facilitating the conversion of Glu residues of prothrombin
to Gla.
• Thus prothrombin cannot be acted upon by factor Xa.
Adverse Reactions
–mild diarrhea, soft stools
–Hemorrhage
–Treatment of overdose
»Vitamin K1 is the antagonist to the coumarins,
and administration of phytonadione (emulsion
of vitamin K1) will restore prothrombin level after
period of hours
»When an immediate effect is desired,
prothrombin is given (fresh blood, freeze dried
plasma).
–Possible risk of "rebound" with abrupt cessation of
therapy,
• Contraindications
Bleeding or hematological diseases
• Drug Interactions
» Stimulation of coumarin metabolism by administration of drugs
that induce microsomnzymes (barbiturates, meprobamate and
other sedative-hypnotic drugs; griseofulvin).
» Inhibition of metabolism (e.g., allopurinol [Zyloprim®]); disulfira
(Antabuse®).
» Displaced from binding sites by phenylbutazone, phenytoin,
sulfinpyrazone, clofibrate and other drugs.
» Others
» Salicylates, indomethacin
» Oral Contraceptives
» Acetaminophen (Tylenol)inhibits warfarin degradation
» Effect of anticoagulants on other drugs Coumarin agents prolon
and intensify action of chlorpropamide, tolbutamide, phenytoin
and phenobarbital.
Comparison of Heparin and warfarin
Heparin
warfarin
Onset of action
Immediate Gradual to peak at 48hrs
Duration
< 4 hours
2 – 5 days
Route of adm.
Parenteral
Oral
Lab.control of dose- [APTT]
Prothrombintime[PT]/INR
Antidote
Protamine/Fresh blood
Vitamin K1
Cost Expensive
Inexpensive
Active in vitro
Yes
No
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