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Drug Class
Prototype
Action
Effect
1. Anticoagulant
Parenteral
Heparin
Inactivation of clotting factors
Prevent DVT
Oral
Warfarin
Decrease synthesis of clotting
factors
Prevent DVT
2. Antiplatelet
Aspirin
Decrease platelet aggregation
Prevent arterial
thrombosis
3. Thrombolytic
Streptokinase
Fibinolysis
Breakdown of
Thrombi
DVT: Deep venous thrombosis
Thrombus Formation
• Arterial formation:
Begins with platelet adhesion to arterial vessel
wall  Adenosine diphosphate (ADP) released
from platelets  more platelet aggregation 
Blood flow inhibited  fibrin, platelets &
RBC’s surround clot  build up of size
structure  occludes blood vessels  tissue
ischemia
• The result of Arterial Thrombus is localized
tissue injury from lack of perfusion
Thrombus Formation
• Venous Formation:
Usually from slow blood flow
Can occur rapidly  Stagnation of the blood
flow initiate the coagulation cascade
production of fibrin enmeshes RBC’s & platelets to form the
thrombus.
Venous thrombus has a long tail that can break off to produce
an embolus. These travel to faraway sites then lodge  in
lung (capillary level)  inadequate O2 & CO2 exchange occur
(i.e. pulmonary embolism & cerebral embolism)
• Oral & parenteral anticoagulants (Heparin/Warfarin)
primarily act by preventing venous thrombosis
• Antiplatelet drugs primarily act by preventing arterial
thrombosis
Hemostasis
• Involves formation of blood clots to stop
bleeding from damaged vessels, and
activation of natural anticoagulation and
fibrinolytic systems to limit clot formation to
sites of injury
• Bleeding disorders are due to defects in clot
formation or overactive fibrinolytic systems
• Hypercoagulability disorders are due to
defects in anticoagulant system or underactive
fibrinolytic systems
Normal hemostasis
• Initial step is formation of platelet plug to stop bleeding
from damaged vessel
• Then, platelet plug is reinforced by fibrin clot
• Then, fibrin clot is stabilized by activated factor XIII
(Fibrin stabilizing factor), which cross-links fibrin strands
• Fibrin clot may occur via either intrinsic or extrinsic
pathway (or both),
• Coagulation factors in intrinsic or extrinsic pathway
assemble on surface of activated platelets, which are
usually at site of vascular injury
• Many coagulation reactions also require calcium as a
cofactor
• The coagulation factors (proteins) are
manufactured by the liver.
• The liver must be able to use Vitamin K to
produce Factors II, VII, IX, and X.
• Dietary vitamin K is widely available from plant
and animal sources.
Clotting Factor
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Factor I: fibrinogen
Factor II: prothrombin
Factor III: tissue thromboplastin (tissue factor and phospholipid)
Factor IV: ionized calcium
Factor V: occasionally called labile factor or proaccelerin
Factor VI: unassigned
Factor VII: occasionally called stable factor or proconvertin
Factor VIII: antihemophilic factor or von Willebrand factor
Factor IX: plasma thromboplastin component, Christmas factor
Factor X: occasionally called Stuart-Prower factor
Factor XI: occasionally called plasma thromboplastin antecedent
Factor XII: Hageman factor
Factor XIII: fibrin-stabilizing factor
Coagulation cascade
Intrinsic Pathway
• All clotting factors are
within the blood
vessels
• Clotting: slower
Extrinsic Pathway
• Initiating factor is outside
the blood vessels: tissue
factor
• Clotting: faster in Seconds
Intrinsic pathway
• Involves factors VIII, IX, XI, XII, prekallikrein, high
molecular weight kininogen
• Merges with extrinsic pathway into common pathway
• Activated when factor XII binds to negatively charged
“foreign” surface exposed to blood
• Then sequentially activates factors XI, IX, X, then factor II
(prothrombin to thrombin), which converts fibrinogen to
fibrin
• Once extrinsic pathway is inhibited by TFPI-Xa complex,
factor VIIIa / IXa complex becomes dominant generator
of factor Xa, thrombin and fibrin
• Factor XIIa also converts prekallikrein to kallikrein, which
activates more factor XIIa; both require high molecular
weight kininogen as cofactors
Schematic showing the intrinsic and extrinsic pathways of
the coagulation cascade leading to fibrin formation.
Factor III - tissue thromboplastin
(tissue factor)
Factor IV – ionized Ca++
(Factor I)
Extrinsic pathway
• Involves tissue factor (TF), originally considered “extrinsic”
to blood since it is present on cell surfaces not normally in
contact with (i.e. extrinsic to) the circulatory system
• The primary mechanism of the coagulation pathway in vivo
is tissue factor binding to activated factor VII (factor VIIa)
• TF-Factor VIIa complex activates factors X and IX
• Activated factor IX activates more factor X,
• Activated factor X converts prothrombin to thrombin, with
activated factor V, anionic phospholipids and calcium as
cofactors
• After initial activation, pathway is inhibited by the binding
of tissue factor pathway inhibitor (TFPI) to factor Xa, which
inhibits TF-VIIa complex, and further coagulation is
dependent on the intrinsic pathway
Common pathway
• Involves fibrinogen (factor I), factors II
(prothrombin), V, X
• Thrombin converts soluble fibrinogen to
insoluble fibrin; remaining fibrin monomers
polymerize to form fibrin; thrombin also binds
to antithrombin, which inhibits thrombin to
prevent excessive clotting
• Factor XIII cross links fibrin to increase stability
of fibrin clot
Drug Class
Prototype
Action
Effect
1. Anticoagulant
Parenteral
Heparin
Inactivation of clotting factors
Prevent DVT
Oral
Warfarin
Decrease synthesis of clotting factors
Prevent DVT
2. Antiplatelet
Aspirin
Decrease platelet aggregation
Prevent arterial
thrombosis
3. Thrombolytic
Streptokinase
Fibinolysis
Breakdown of
Thrombi
DVT: Deep venous thrombosis
Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
Thromboplastin
XIa
XI
IXa
IX
Xa
X
Factors affected
By Heparin
VIIa
Prothrombin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Fibrinogen
XIII
VII
X
Thrombin
Fribrin monomer
Fibrin polymer
Definition of Anticoagulation
• Therapeutic interference ("blood-thinning")
with the clotting mechanism of the blood to
prevent or treat thrombosis and embolism.
Indications of Anticoagulant Therapy
• Treatment and Prevention of Deep Venous Thrombosis
• Pulmonary Emboli
• Prevention of stroke in patients with atrial fibrillation,
artificial heart valves, cardiac thrombus.
• Ischemic heart disease
• During procedures such as cardiac catheterisation and
apheresis.
1. Standard Heparin
• Heterogenous mixture of polysaccharide chains
• MW 3,000 to 30,000
Administration
Parenteral:
only IV or deep s.c.
Do not inject IM (danger of hematoma formation)Metabolism
Partially in the liver by heparinase to uroheparin, which has only
slight antithrombin activity.
Adverse effect
haemorrhage - antidote - protamine sulphate
Mechanism of action:
• Primarily: interaction with antithrombin III: alters the
molecular configuration of antithrombin III, making it
1,000 to 4,000 times more potent as an inhibitor of
thrombin formation: limits conversion of fibrinogen to
fibrin: prolongs aPTT (activated partial thromboplastin
time)
• Also inhibits the effects of factor Xa on the coagulation
cascade & limits platelet aggregation.
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Complications of Heparin
• Haemorrhage (bleeding from ruptured blood vessels)
• Heparin-induced thrombocytopenia (HIT) [an abnormally
low amount of platelets]
• Most significant adverse effect of heparin after
haemorrhage
• Begins 3 - 15 days after start of heparin
• Treatment
• Stop heparin immediately: Platelet count returns 4
days after stopping heparin
• Use other drugs for anticoagulation
• Osteoporosis (long-term only) [thinning of bone tissue
and loss of bone density ]
Low Molecular Weight Heparin
Advantages
• Standard (Unfractionated) heparin 3k to 30k
• LMWH contains polysaccharide chains MW 5k
• Same incidence of bleeding
• Lower incidence of thrombocytopenia
• Lower incidence of bone loss
• Safe for use during pregnancy {does not cross the
placenta}
• Higher Bioavailability: 90% Vs 30%
• Longer Plasma Half life: 4-6 h Vs 0.5-1 h
Renal (Slower) Vs Hepatic clearance
LMWH Administration
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Subcutaneous injection
Once every 12 or 24 hours
Outpatient
Patients that need monitoring
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Pregnant
Pediatric
Renal
Prolonged therapy
Those at risk for bleeding
Mechanism of action
Primarily by inhibiting factor Xa, which is higher in the
coagulation cascade than antithrombin: LMWH is more
efficient than UFH (Un-fractionated).
{the molecular configuration of antithrombin III is not altered
by LMWH}
2. Oral anticoagulants
Vitamin K-Dependent Clotting Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of Non
Functional
Coagulation
Factors
Warfarin
Enhances
Antithrombin Activity
PT: Prothrombin time
aPTT: Activated partial thromboplastin time
Warfarin:
Major Adverse Effect—Haemorrhage
• Factors that may influence bleeding risk:
– Intensity of anticoagulation
– Concomitant clinical disorders
– Concomitant use of other medications
– Quality of management
Warfarin-induced
Skin Necrosis
Warfarin
Dosing & Monitoring
• Start low
– Initiate 5 mg daily
– Educate patient
• Stabilize
– Titrate to appropriate INR (International normalized ratio)
– Monitor INR frequently (daily then weekly)
• Adjust as necessary
Relative Contraindications
• Pregnancy
• Situations where the risk of hemorrhage is greater than
the potential clinical benefits of therapy
– Uncontrolled alcohol/drug abuse
– Unsupervised dementia/psychosis
Signs of Warfarin Over dosage
• Any unusual bleeding:
– Blood in stools or urine
– Excessive menstrual bleeding
– Bruising (Minor hematoma)
– Excessive nose bleeds/bleeding gums
– Persistent oozing from superficial injuries
– Bleeding from tumor, ulcer, or other lesion
Why do we need new anticoagulation
drugs?
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Heparin-induced thrombocytopenia
Heparin prophylaxis is imperfect
Heparin-associated osteoporosis
Warfarin takes several days for its effect
Warfarin interacts with many other drugs
Warfarin is dangerous if not monitored
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Direct Thrombin Inhibitors
Synthetic pentasaccharide
Enhanced Protein C pathway
Tissue Factor Pathway Inhibitor (TFPI)
Thrombolytic Drugs
Antiplatelet Drugs
Direct Thrombin Inhibitors
• Advantages
– Bound thrombin readily inhibited
– More predictable patient response
– Not neutralized by PF4 (Platelet factor 4)
• Disadvantages
– Higher cost of the drugs
Ximelagatran
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Promising oral direct thrombin inhibitor
Converted to the active form melagatran in vivo
No dosing problems
No monitoring needed.
Recent atrial fibrillation study showed it to possibly be
superior to warfarin.
Enhances
Ximelagatran
Antithrombin Activity
Dabigatran etexilate
• Oral dosing
– Absorbed from GI tract
– Transforms to active dabigatran
• Future – replace warfarin
– Wider therapeutic range
– Acceptable bleeding risk
– Little or no lab monitoring
Argatroban
• Small molecule
• A synthetic derivative of L-arginine with antithrombotic
activity
• univalent and direct inhibitor of fibrin-bound thrombin
• Used to treat HIT
Hirudin and Derivatives
• Hirudin is a naturally occurring peptide in the salivary
glands of medicinal leeches (such as Hirudo medicinalis)
• has a blood anticoagulant property
• Thrombin is produced from prothrombin.
• A key event in the final stages of blood coagulation is the
conversion of fibrinogen into fibrin by the thrombin.
• Fibrin is then cross linked by factor XIII to form a blood
clot.
• The principal inhibitor of thrombin in normal blood
circulation is antithrombin III.
• Similar to antithrombin III, the anticoagulatant activity of
hirudin is based on its ability to inhibit the procoagulant
activity of thrombin.
• Hirudin is the most potent natural inhibitor of thrombin.
• Therefore, hirudin has therapeutic value in blood
coagulation disorders, in the treatment of skin
hematomas, either as an injectable or a topical
application cream.
• It is difficult to extract large amounts of hirudin from
natural sources, so a method for producing and purifying
this protein using recombinant biotechnology has been
developed. This has led to the development and
marketing of a number of hirudin-based anticoagulant
pharmaceutical products, such as lepirudin (Refludan),
and desirudin (Revasc/Iprivask).
• Several other direct thrombin inhibitors are derived
chemically from hirudin.
Hirudin and Derivatives
1. Lepirudin (Refludan)
– It is almost identical to hirudin extracted from
Leech saliva of Hirudo medicinalis
– Cleared by kidneys
– Inhibits clot bound thrombin
– Clot associated Xa will trigger generation of
more thrombin once treatment stops
Hirudin and Derivatives
2. Bivalirudin (Angiomax)
– Semisynthetic
– Cleared by liver
– Half-life
• Shorter than lepirudin
– Safer drug
– No risk of HIT
Hirudin and Derivatives
• Indications:
– HIT (heparin-induced thrombocytopenia )
– Cardiopulmonary bypass
– Hip replacement surgery
– Unstable angina
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Direct Thrombin Inhibitors
Synthetic pentasaccharide
Enhanced Protein C pathway
Tissue Factor Pathway Inhibitor (TFPI)
Thrombolytic Drugs
Antiplatelet Drugs
Synthetic Pentasaccharide
E.g. Fonaparinux (Arixtra)
• Synthetic, single molecular entity
• Targets Factor Xa
• Does not cause thrombocytopenia
• Shown promise in DVT prevention during
orthopedic procedures.
• Also being examined in ischaemic heart disease
• Approved for surgery prophylaxis
– General
– Total hip replacement
– Total knee replacement
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Direct Thrombin Inhibitors
Synthetic pentasaccharide
Enhanced Protein C pathway
Tissue Factor Pathway Inhibitor (TFPI)
Thrombolytic Drugs
Antiplatelet Drugs
The protein C/protein S anticoagulant pathway
Thrombin-thrombomodulin (TM) complex activates protein C. Activated protein C with its
cofactor, free protein S, degrades factors Va and VIIIa. In addition, when thrombin binds
thrombomodulin, thrombin loses its procoagulant functions.
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Direct Thrombin Inhibitors
Synthetic pentasaccharide
Enhanced Protein C pathway
Tissue Factor Pathway Inhibitor (TFPI)
Thrombolytic Drugs
Antiplatelet Drugs
Inhibition of VIIa/TF
• TFPI – tissue factor pathway inhibitor

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