Download Anticoagulants Drugs

Anticoagulant, Fibrinolytic and
Antiplatelet
Homeostasis: Cessation of bleeding
from an injured blood vessel
Primary Hemostasis
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This stage occurs within seconds
1. Vasospasm: Vasoconstriction of the blood vessel by
Prostacyclin (PI2), Thromboxane A2 (TXA2) and serotonin
(5-HT). Slows down the bleeding.
2. Platelet Plug: Adherence of platelets to collagen of
damaged endothelial cells. Platelet aggregation: Role of
thrombin, adenosine diphosphate (ADP), PI2, TXA2, 5-HT
and prostaglandins.
Secondary Hemostasis
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This stage takes several minutes. Stabilizes the soft clot
and maintains vasoconstriction.
3. Fibrin Clot: Conversion of prothrombin to thrombin.
Thrombin stimulates the conversion of fibrinogen (Blood
protein) to polymerized fibrin (mesh).
4. Dissolution of the clot by fibrinolysis: Plasminogen
is converted to plasmin, the enzyme that dissolves the
fibrin.
The hemostatic process is a protective mechanism
to prevent blood loss from the circulatory system.
Homeostasis: Cessation of bleeding
from an injured blood vessel
Platelet Adhesion and Aggregation
Blood Coagulation:
One Type of Hemostatic Process
Intrinsic Pathway
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Activated when the blood comes in contact with
the subendothelial surface or negatively charged
surface resulting from an injury to the blood
vessel.
The Hageman factor (factor XII) binds to the
subendothelial surface. It is then cleaved to XIIa.
XIIa activates XI to form XIa. XIa activates IX to
form IXa which then activates factor X to Xa.
Extrinsic Pathway
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Tissue factor (factor III) is located on the
membrane of most cells. Once activated, it
converts VII to its active form, VIIa. A complex of
VIIa+III+calcium+a phospholipid converts factor X
to its active form, Xa.
Common Pathway
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Factor Xa is the convergence point for both the
intrinsic and extrinsic pathways. It initiates the
common pathway.
Factor Xa converts prothrombin to active thrombin.
Thrombin is required for the conversion of soluble
fibrinogen to insoluble fibrin protein. The fibrin
meshwork is then stabilized by active factor XIIIa.
Coagulation Factors
FACTOR
Common Synonym
Dependent on Vitamin K
I
Fibrinogen
No
II
Prothrombin
Yes
III
Tissue Thromboplastin
No
IV
Calcium
No
V
Proaccelerin
No
VII
Proconvertin
Yes
VIII
Antihemophilic Factor
No
IX
Plasma Thromboplastin
Component
Yes
X
Stuart Factor
Yes
XI
Plasma Thromboplastin
Antecedent
No
XII
Hageman Factor
No
XIII
Fibrin Stabilizing Factor
No
Blood Coagulation
Extrinsic
Pathway
TF: Tissue Factor
Clotting Time
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Prothrombin Time; Prothrombin Ratio(PR) and Internationalized
Ratio(INR)
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Measures of the extrinsic/common pathway
 PT reference range: 12-15 sec; measures factors II,V,VII,X and fibrinogen.;
Used in conjunction with aPTT
 PT: blood is combined with liquid citrate (chelates calcium;
anticoagulant) in a testtube. There is a specific ratio of blood to
citrate. The mixture is centrifuged and the plasma is collected.
Thromboplastin (Tissue factor) is added to plasma and analyzed for
clotting time.
 INR normal range: 0.8-1.2
Activated Partial Thromboplastin Time (aPTT)
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Measure of the intrinsic pathway
 aPPT normal range: 25-37 seconds
 aPPT:blood is combined with liquid citrate (chelates calcium; anticoagulant)
in a testtube. There is a specific ratio of blood to citrate. The mixture is
centrifuged and the plasma is collected. A phospholipid (silica, kaolin, etc)
and calcium are added to the plasma sample and analyzed for clotting time.
 Partial Thromboplastin: thromboplastin is not added to the plasma sample.
EMBOLISM
THROMBOSIS
T
H
R
A thrombus is a blood clot in an intact
blood vessel. It forms under normal
physiological and pathological
conditions. When a thrombus dislodges,
it becomes an embolus.
Anticoagulants (Parental)
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Heparin Sodium, Heparin Calcium
Anticoagulants (Parental)
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Heparin Sodium, Heparin Calcium: Unfractionated: 5000-30,000 g/mol.
Naturally occurring mixture of sulfated muccopolysaccharides produced
by mast cells and basophils.
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Clinical Use: Prevention and treatment of embolism (i.e., post-op or following
myocardial infarction), deep vein thrombosis, pulmonary embolism. Initial
management of unstable angina or acute myocardial infarction.
MOA: Increases the activity of antithrombin III and inactivates thrombin.
High doses will inhibit platelet aggregation.
Pharmacokinetics: Administration: Not absorbed from the gut; i.v. and s.c..
Immediate onset (30-60 mins); Hepatic elimination and excretion, some
excreted unchanged in urine. Dosage is determined by the activated partial
thromboplastin time (aPPT; 1.5-2 times is normal).
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Side effects: Thrombocytopenia (early or delayed), hemorrhage.
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Contraindications: existing bleeding condition or bleeding tendency.
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Drug Interactions: Risk of bleeding is increased by salicylates
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In case of overdose: protamine sulfate (positive charge binds heparin).
Anticoagulants (Parental) cont.
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Enoxaparin: Heparin
Analog; Fractionated,
Low molecular weight
heparin (LMWH; 20009000 g/mol)
Factor IIa is thrombin
Anticoagulants (Parental)
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Enoxaparin: Heparin Analog; Fractionated, Low molecular weight
heparin (LMWH; 2000-9000 g/mol)
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Clinical Use: Prevention and treatment of embolism (i.e., postop or following myocardial infarction), deep vein thrombosis.
MOA: Inhibits factor Xa, very little effect on factor IIa; aPPT is
not used to measure its anticoagulant activity. Binds less to
plasma proteins.
Pharmacokinetics: Administration: i.v. and s.c. outpatient
basis for DVT patients. Immediate onset (30-60 mins); Hepatic
elimination and excretion, some excreted unchanged in urine.
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Side effects: Thrombocytopenia (early or delayed),
hemorrhage.
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Contraindications: existing bleeding condition or bleeding
tendency.
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In case of overdose: protamine sulfate (positive charge binds
heparin).
Anticoagulants (Oral)
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Coumarins: dicumarol and warfarin; warfarin is
structurally related to vitamin K.
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Clinical Use: Treatment of embolism, deep vein thrombosis or atrial
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MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the
fibrillation, patients with prosthetic valves (at risk for thrombosis).
production of active vitamin K.
Active
form
Anticoagulants (Oral)
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Coumarins: dicumarol and warfarin; warfarin is
structurally related to vitamin K.
Pharmacokinetics: Route of administration: p.o.; 100% absorbed; 99%
bound to plasma proteins; slow onset of activity; Hepatic elimination and
excreted in the urine. Dicumarol is incompletely absorbed from the gut.
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Side effects: Hemorrhage.
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Contraindications: Patients with Hemophilia.
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Drug Interactions: Drugs that inhibit CytoP450
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Enzymes will increase levels, ie cimetidine,
Macrolide antibiotics, antifungal agents. Drugs that induce
CytoP450 enzymes will decrease levels, ie rifampin and
Barbituates.
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In case of overdose: Vitamin K (phytonadione)
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Fibrinolytic Drugs (Thrombolytics)
These agents are enzymes or large proteins that dissolve clots,
ie., an existing thrombus in pts with myocardial infarction,
thrombotic stroke or pulmonary embolism.
Fibrinolytic Drugs:
(Thrombolytics)
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Tissue Plasminogen Activator (t-PA); alteplase and reteplase
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MOA: It is a serine protease which activates plasminogen (bound to
fibrin) and increases plasmin levels. Clot specific and must bind to
fibrin.
2 anti-plasmin
Fibrinolytic Drugs:
(Thrombolytics)
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Urokinase; enzyme obtained from urine
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MOA: Directly activates plasminogen; isolated from human
kidney, therefore less chance of evoking an allergic reaction.
Streptokinase: protein obtained from streptocci;
anistreplase (a preformed complex of streptokinase and
plasminogen)
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MOA: Combines with plasminogen to form an active complex
that converts plasminogen to plasmin to dissolve the fibrin.
Thrombolytics
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Pharmacokinetics: Parental administration, i,.v.
Side effects: hemorrhage, hypersensitivity reactions and
reperfusion arrythmias.
Contraindications: Bleeding disorders; recent surgery;
severe hypertension.
Drug Interactions: Increases risk of bleeding with
dicumarol, warfarn, heparin, aspirin, ticlopidine,
abciximab.
In case of overdose: Aminocaproic acid inhibits
fibrinolysis by competitively blocking plasminogen
activation.
Antiplatelet Agents
GP: glycoprotein
vWF: von Willebrand’s factor
Antiplatelet Agents
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Aspirin
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Clinical Use: Prevention of atherosclerosis, thrombosis,
transient ischemic attacks; unstable angina.
MOA: Irreversible cyclooxygenase inhibitor and inhibits the
formation of thromboxane A2.
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Pharmacokinetics: Oral administration
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Side effects: Bleeding; gastrointestinal irritation,
hypersensitivity reactions and thrombocypenia.
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Contraindications: Bleeding disorders, hypersensitivity and
Reye’s syndrome.
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Drug Interactions: Increased hypoglycemic effects of
sulfonylureas, inhibits uricosuric effect of probenecid.
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In case of overdose: Forced Alkaline Diuresis
Antiplatelet Agents
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Dipyridamole
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Clinical Use: Prosthetic valves; may be used as an adjunct
with aspirin therapy.
MOA: Lowers platelet calcium and increases the formation of
cAMP (weak antiplatelet drug) , coronary vasodilator.
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Pharmacokinetics: Oral administration
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Side effects: GI distress, headache, dizziness and rash.
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Contraindications: Hypersensitivity to this drug
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Drug Interactions: Increases risk of bradycardia with Beta
adrenergic receptor antagonists.
Antiplatelet Agents
 Clopidogrel
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(Plavix®)
Clinical Use: Prevention of atherosclerosis, thrombosis,
transient ischemic attacks; unstable angina.
MOA: Inhibits the binding of ADP to its receptor which
is involved in the activation of platelet glycoprotein
receptors binding to fibrinogen.
Pharmacokinetics: Oral administration; eliminated in
urine and feces.
Side effects: Bleeding, neutropenia and
thrombocytopenia.
Antiplatelet Agents
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Ticlopidine (Ticlid ®)
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Clinical Use: Patients intolerant to aspirin; prevents
thrombotic stroke.
MOA: Inhibits ADP-induced expression of platelet glycoprotein
receptors and reduces fibrinogen binding and platelet
aggregation. Effects on platelet function are irreversible.
Pharmacokinetics: Oral administration; eliminated in the urine
and feces
Side effects: Bleeding; mild to moderate neutropenia,
increased cholesterol and triglyeride levels.
Contraindications: Bleeding disorders, severe liver disease
Drug Interactions: Inhibits cytoP450 drug metabolizing
enzymes.
Antiplatelet Agents
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Abciximab
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Clinical Use: Percutaneous transluminal coronary
angioplasty as adjunct with aspirin and heparin.
MOA: Binds to platelet glycoprotein IIb/IIIa receptors
and prevents binding to fibrinogen.
Pharmacokinetics: Parental administration, i.v.
Side effects: Bleeding, thrombocytopenia, hypotension
and bradycardia.
Contraindications: Aneurysm, bleeding, recent surgery,
stroke
Drug Interactions: Unknown
Hemostatic Agents
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Aminocaprioic acid, Tranexamic acid,
Antihemophilic factor, Antiinhibitor
coagulants, Factor IX complex and
Desmopressin
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Clinical Use: Decrease bleeding which may be due to
hereditary deficiencies, surgery, or thrombolytic
overdose.