Anticoagulant, antithrombotic and anti platelet drugs

1. Anticoagulant, Antithrombotic
and Anti-Platelet Drugs
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2. Clinical Thrombosis
•>2.5 million cases of deep venous
thrombosis (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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3. Indications For Antithrombotic Therapy
•Venous thromboembolic disease
–Deep venous thrombosis (DVT)
–Pulmonary embolism (PE)
–Primary prophylaxis of DVT or PE
•Arterial thromboembolic disease
•Prosthetic heart valves
•Mitral valve disease, especially with atrial fibrillation
•Congestive cardiomyopathies, especially with atrial fibrillatio
•Atrial fibrillation
•Mural cardiac thrombi
•Transient ischemic attacks
•Stroke in evolution
•Disseminated intravascular coagulation
•Maintenance of patency of vascular grafts, shunts, bypasses
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11. Recombinant Human Activated
Protein C
•Drotrecogin alfa (activated)- Xigris
•Indicated for Severe Sepsis in Adults with
Acute Organ Dysfunction with High Risk
of Death
•Reduction in Death as Primary End
Point
•Antithrombotic, Antiinfammatory,
Profibrinolytic Properties
•Serious Bleeding is Major Side Effect
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20. Antithrombin III Inhibits the
Following Serine Proteases
•Coagulation
•Factor XIIa
•Factor XIa
•Factor IXa
•Factor Xa
•Thrombin
•Fibrinolysis
•Plasmin
Inhibitory activity against all these enzymes is substantially accelerated by heparin
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21. Heparin
•Heterogeneous; 3,000-30,000 d
•Average=15,000 d (~45monosaccharide
chains)
•About 1/3 of dose binds to AT III
•To form the AT III:Heparin:Clotting Factor
Complex- requires at least 18 saccarides
except
•Unique high affinity pentasaccaride heparin
sequences catalyze inhibition of Xa by AT
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23. Anticoagulant Properties of Heparin
1.Inhibits the thrombin-mediated conversion
of fibrinogen to fibrin
2.Inhibits the aggregation of platelets by
thrombin
3.Inhibits activation of fibrin stabilizing
enzyme
4.Inhibits activated factors XII, XI, IX, X
and II
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24. Heparin
•Biologic Sources
•Bioavailability
•Metabolism
•Elimination
•Side Effects
•Overdose
•Contraindications
•Pregnancy- YES
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26. Unfractionated Heparin
•High Dose
–Treatment of venous/arterial thrombi
–Requires monitoring
–IV- 5,000 Units bolus, then 30,000-35,000
units/24 hrs
–80 Units/kg bolus, then 18 Units/kg/hr to
maintain aPTT in therapeutic range
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28. Monitoring of Anticoagulant
Therapy
Heparin
s.q. – no monitoring required
i.v. - partial thromboplastin time (P.T.T.)
*daily or more frequent if PTT varies
mechanism – measures intrinsic pathway
therapeutic goal – 2-2.5 times normal
control value (-30 sec)
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30. 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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34. Indications for and Contraindications to
Parenteral Anticoagulant Agents
Anticoagulant AgentClass Approved & Appropriate
Indications
Contraindication
Unfractionated heparin
Enoxaparin
(Lovenox)
Dalteparin
(Fragmin)
Tinzaparin
(Innohep)
Antithrombin III
inhibitor
Low-molecular-
weight heparin
Low-molecular-
weight heparin
Low-molecular-
weight heparin
Treatment of venous
thromboembolism or unstable
angina; used when rapid reversal is
important
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 anesthesia
Pregnancy
Prosthetic Heart Valves
Regional anesthesia
Regional anesthesia
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35. Indications for and Contraindications to
Parenteral Anticoagulant Agents (cont’d)
Ardeparin
Lepirudin
Argatroban
Danaparoid
Bivalirudin
Fondaparinux
(Arixtra)
Low-molecular-weight
heparin
Hirudin derivative
Direct thrombin inhibitor
Heparinoid
Hirudin derivative
Synthetic factor Xa
inhibitor
Approved; not being
marketed
Heparin-induced
thrombocytopenia with
thrombosis
Heparin-induced
thrombocytopenia with
thrombosis
Prophylaxis against
thrombosis in heparin-
induced
thrombocytopenia
Unstable angina or
angioplasty
Prophylaxis in high-
risk patients?
Regional anesthesia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Unknown
Unknown
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37. Heparin-Antibiotic Interactions
•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 vivo
and competitively inhibit vitamin K action, leading to
prolongation of the prothrombin time and bleeding.
•- This side chain is also associated with a disulfiram-like
reaction to alcohol.
•- Clinical bleeding has been less frequently reported with
Cefotetan than with cefoperazone or cefamandole.
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39. Mechanisms of HIT
•Type 1: In most of these cases, the fall in platelet count occurs within
the first two days after heparin initiation, often returns to normal with
continued 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 receiving heparin
develop an immune thrombocytopenia, mediated by antibodies to a
heparin-platelet factor 4 complex. One study, for example, randomly
assigned 665 patients to therapy with unfractionated heparin or LMW
heparin. Type 2 HIT developed in 2.7 percent of patients treated with
unfractionated heparin but in none of those receiving LMW heparin.
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41. 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 HIT
that is complicated by thrombosis; these agents
should also be considered for prophylactic therapy in
patients with HIT without thrombosis until the
platelet count has recovered
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49. Warfarin
•Bioavailability
•Metabolism
•Serum Protein Binding
•Vitamin K Status
•Protein C Effects
•Elimination
•Side Effects
•Overdose
•Contraindications
•Pregnancy- NO
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59. Contraindications to Antithrombotic
Therapy
•General risk factors
-Pre-existing coagulation or platelet defect, thrombocytopenia, or
other bleeding abnormality
-Inaccessible ulcerative lesion (e.g., gastrointestinal tract lesion)
-Central 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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60. Contraindications to Antithrombotic
Therapy
•Specific 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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61. Contraindications to Antithrombotic
Therapy
•Specific to thrombolytic agents
-Recent thoracic, abdominal, or central
nervous system surgery
-Recent cerebrovascular accident, trauma, or
neoplasm
-Bleeding ulcer
-Hypertension
-Anticipated invasive procedures (arterial
punctures, biopsies, central lines)
-Concurrent hemostatic dysfunction
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62. Platelet Receptor Mediated
Pathways: Drugs
Arachidonic Acid ASA
NSAIDs
ADP Ticlopidine
Clopidogrel
Thrombin
-Final Common Pathway
-Promotes Platelet
Adhesion (Fibrinogen,
vWF)
GP IIB/IIIA Inhibitors
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban
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63. Anti Platelet Drugs
Drug Mechanism Uses
Aspirin Permanently
inhibits COX-1
and COX-2
CAD
Stroke-TIAs
NSAIDs Reversibly
inhibits COX-1
Limited
DipyridamoleInhibits PDE;
increases cAMP
TIAs
Ticlopidine
Clopidrgrel
Inhibits ADP
PlatAg;active
metabolite
TIAs;Stroke
CAD;PVD
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