Post on 10-Apr-2018
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Anticoagulant, Antithromboticand Anti-Platelet Drugs
Department of Pharmacology
Robert Taylor, MD, Ph.D .
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Clinical Thrombosis
>2.5 million cases of deep venousthrombosis (DVT) per year >600,000 cases of pulmonary embolism(PE) per year >50,000 deaths per year from PE
PE contributes to another 150,000 deaths per year > 11,000 postsurgical PE deaths per year
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I ndications For Antithrombotic Therapy
Venous thromboembolic disease Deep venous thrombosis (DVT) Pulmonary embolism (PE) Primary prophylaxis of DVT or PEArterial thromboembolic disease
Prosthetic heart valves
Mitral valve disease, especially with atrial fibrillationC ongestive cardiomyopathies, especially with atrial fibrillatioAtrial fibrillationMural cardiac thrombiTransient ischemic attacksStroke in evolution
Disseminated intravascular coagulationMaintenance of patency of vascular grafts, shunts, bypasses
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Recombinant Human ActivatedProtein C
Drotrecogin alfa (activated)- XigrisIndicated for Severe Sepsis in Adultswith Acute Organ Dysfunction with HighRisk of DeathReduction in Death as Primary End Point
Antithrombotic, Antiinfammatory,Profibrinolytic PropertiesSerious Bleeding is Major Side Effect
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Antithrombin III Inhibits theFollowing Serine Proteases
C oagulation
Factor X II aFactor X I aFactor I Xa
Factor XaThrombin
Fibrinolysis
Plasmin
Inhibitory activity against all these enzymes is substantially accelerated by heparin
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HeparinHeterogeneous; 3,000-30,000 dAverage=15,000 d (~45monosaccharidechains)
About 1/3 of dose binds to AT IIITo form the AT III: Heparin :C lotting Factor
C omplex- requires at least 18 saccarides
except Unique high affinity pentasaccaride heparinsequences catalyze inhibition of Xa by AT
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Anticoagulant Properties of Heparin1. I nhibits the thrombin-mediated conversion
of fibrinogen to fibrin
2. I nhibits the aggregation of platelets bythrombin
3. I nhibits activation of fibrin stabilizing
enzyme4. I nhibits activated factors X II , X I , I X, Xand II
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HeparinBiologic SourcesBioavailability
MetabolismEliminationSide EffectsOverdoseContraindicationsPregnancy- YES
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Unfractionated HeparinHigh Dose Treatment of venous/arterial thrombi Requires monitoring I V- 5,000 Units bolus, then 30,000-35,000
units/24 hrs
80 Units/kg bolus, then 18 Units/kg/hr tomaintain aPTT in therapeutic range
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Monitoring of Anticoagulant
TherapyHeparin
s.q. no monitoring requiredi.v. - partial thromboplastin time (P.T.T.)
*daily or more frequent if PTT varies
mechanism measures intrinsic pathwaytherapeutic goal 2-2.5 times normalcontrol value (-30 sec)
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Low Dose Unfractionated Heparin
Surgical Prophylaxis 5,000 Units SQ 2 hr preop 5,000 Units SQ every 12 hours
Medical Prophylaxis 5,000 Units SQ every 12 hours
No monitoring required
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I ndications for and C ontraindications toParenteral Anticoagulant Agents
Anticoagulant Agent Class Approved & AppropriateIndications
Contraindication
Unfractionated heparin
Enoxaparin( Lov eno x)
Dalteparin( Fragmin )
Tinzaparin( Inn oh ep)
Antithrombin III inhibitor
L ow-molecular-weight heparin
L ow-molecular-
weight heparin
L ow-molecular-weight heparin
Treatment of venousthromboembolism or unstableangina; used when rapid reversal isimportant
Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina
Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina
Prophylaxis in moderate-risk or high-risk patients, treatment of
venous thromboembolism
? Prophylactic treatment
Regional anesthesiaPregnancyProsthetic Heart Valves
Regional anesthesia
Regional anesthesia
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I ndications for and C ontraindications toParenteral Anticoagulant Agents (contd)
Ardeparin
L epirudin
Argatroban
Danaparoid
Bivalirudin
Fondaparinux A rixtra
L ow-molecular-weight
heparin
Hirudin derivative
Direct thrombin inhibitor
Heparinoid
Hirudin derivative
Synthetic factor Xainhibitor
Approved; not being
marketed
Heparin-inducedthrombocytopenia withthrombosis
Heparin-inducedthrombocytopenia withthrombosis
Prophylaxis againstthrombosis in heparin-inducedthrombocytopenia
Unstable angina or angioplasty
Prophylaxis in high-risk patients?
Regional anesthesia
Thrombocytopenia other than heparin-inducedthrombocytopenia
Thrombocytopenia other than heparin-inducedthrombocytopenia
Thrombocytopenia other than heparin-induced
thrombocytopenia
Unknown
Unknown
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Heparin-AntibioticInteractions
The second-generation cephalosporins- cefamandole,cefotetan, and cefoperazone, contain an N-
methylthiotetrazole (NMTT) side chain. This NMTT group can:- Dissociate from the parent antibiotic in solution or in vivoand competitively inhibit vitamin K action, leading toprolongation of the prothrombin time and bleeding.
- This side chain is also associated with a disulfiram-likereaction to alcohol.
- Clinical bleeding has been less frequently reported withCefotetan than with cefoperazone or cefamandole.
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Mechanisms of HIT
Type 1: In most of these cases, the fall in platelet count occurs withinthe first two days after heparin initiation, often returns to normal withcontinued heparin administration, and is of no clinical consequence.The mechanism of the thrombocytopenia is non-immune and appears
to be due to a direct effect of heparin on platelet activation.
Type 2: Approximately 0.3 to 3 percent of patients receivingheparin develop an immune thrombocytopenia, mediated byantibodies to a heparin-platelet factor 4 complex. One study, forexample, randomly assigned 665 patients to therapy withunfractionated heparin or LMW heparin. Type 2 HIT developed in 2.7percent of patients treated with unfractionated heparin but in none of those receiving LMW heparin.
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Therapy of HIT
There are two recommended approaches: Use of the heparinoid danaparoid The direct thrombin inhibitor lepirudin (recombinant
hirudin) Based upon the data published to date, either
danaparoid or lepirudin should be used to treat HITthat is complicated by thrombosis; these agentsshould also be considered for prophylactic therapy in
patients with HIT without thrombosis until theplatelet count has recovered
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W arfarinBioavailabilityMetabolismSerum Protein Binding
Vitamin K StatusProtein C EffectsEliminationSide EffectsOverdoseContraindicationsPregnancy- NO
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C ontraindications to AntithromboticTherapy
General risk factors-Pre-existing coagulation or platelet defect, thrombocytopenia, or
other bleeding abnormality-Inaccessible ulcerative lesion (e.g., gastrointestinal tract lesion)
-C entral nervous system lesion (e.g., caused by stroke, surgery,trauma)-Spinal anesthesia or lumbar puncture-Malignant hypertension-Bacterial endocarditis-Advanced retinopathy
-Old age (relative)-Aspirin or other antiplatelet drugs-Neoplastic disease
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C ontraindications to Antithrombotic
TherapySpecific to warfarin (ambulatory patients)
-Early and late pregnancy-Poor patient cooperation,
understanding, reliability-Unsatisfactory laboratory or patient
follow-up-Occupational risk to trauma
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C ontraindications to Antithrombotic
TherapySpecific to thrombolytic agents
-Recent thoracic, abdominal, or centralnervous system surgery
-Recent cerebrovascular accident, trauma, or neoplasm
-Bleeding ulcer -Hypertension-Anticipated invasive procedures (arterial
punctures, biopsies, central lines)-C oncurrent hemostatic dysfunction
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Platelet Receptor MediatedPathways : Drugs
Arachidonic Acid ASA NSA I Ds
ADP TiclopidineC lopidogrel
Thrombin-Final C ommon Pathway
-Promotes PlateletAdhesion (Fibrinogen,vWF)
GP II B/ III A I nhibitorsAbciximab (ReoPro)
Eptifibatide ( I ntegrilin)Tirofiban
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Anti Platelet DrugsDrug Mechanism Uses
Aspirin Permanentlyinhibits C OX-1and C OX-2
C ADStroke-T I As
NSA I Ds Reversiblyinhibits C OX-1
L imited
Dipyridamole I nhibits PDE;
increases cAMP
TI As
TiclopidineC lopidrgrel
I nhibits ADPPlatAg;activemetabolite
TI As;StrokeC AD;PVD