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Anticoagulant, Antithrombotic and Anti-Platelet Drugs

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INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com

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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 www.indiandentalacademy.com


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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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 www.indiandentalacademy.com


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Antithrombin III Inhibits the Following Serine Proteases • Coagulation

• Fibrinolysis

• • • • •

• Plasmin

Factor XIIa Factor XIa Factor IXa Factor Xa Thrombin

Inhibitory activity against all these enzymes is substantially accelerated by heparin www.indiandentalacademy.com


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 www.indiandentalacademy.com


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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 www.indiandentalacademy.com


Heparin • • • • • • • •

Biologic Sources Bioavailability Metabolism Elimination Side Effects Overdose Contraindications Pregnancy- YES www.indiandentalacademy.com


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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 www.indiandentalacademy.com


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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) www.indiandentalacademy.com


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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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Indications for and Contraindications to Parenteral Anticoagulant Agents Anticoagulant Agent

Class

Approved & Appropriate Indications

Contraindication

Unfractionated heparin

Antithrombin III inhibitor

Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important

? Prophylactic treatment

Enoxaparin (Lovenox)

Low-molecularweight heparin

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Dalteparin (Fragmin)

Low-molecularweight heparin

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Regional anesthesia

Low-molecularweight heparin

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism

Regional anesthesia

Tinzaparin (Innohep)

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Regional anesthesia Pregnancy Prosthetic Heart Valves


Indications for and Contraindications to Parenteral Anticoagulant Agents (cont’d) Ardeparin

Low-molecular-weight heparin

Approved; not being marketed

Regional anesthesia

Lepirudin

Hirudin derivative

Heparin-induced thrombocytopenia with thrombosis

Thrombocytopenia other than heparin-induced thrombocytopenia

Argatroban

Direct thrombin inhibitor

Heparin-induced thrombocytopenia with thrombosis

Thrombocytopenia other than heparin-induced thrombocytopenia

Danaparoid

Heparinoid

Prophylaxis against thrombosis in heparininduced thrombocytopenia

Thrombocytopenia other than heparin-induced thrombocytopenia

Bivalirudin

Hirudin derivative

Unstable angina or angioplasty

Unknown

Fondaparinux (Arixtra)

Prophylaxis in highSynthetic factor Xa risk patients? inhibitor www.indiandentalacademy.com

Unknown


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Heparin-Antibiotic Interactions • The second-generation cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an Nmethylthiotetrazole (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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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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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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Warfarin • • • • • • • • • •

Bioavailability Metabolism Serum Protein Binding Vitamin K Status Protein C Effects Elimination Side Effects Overdose Contraindications Pregnancy- NO www.indiandentalacademy.com


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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 www.indiandentalacademy.com


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 www.indiandentalacademy.com


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 www.indiandentalacademy.com


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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Anti Platelet Drugs Drug

Mechanism

Uses

Aspirin

Permanently inhibits COX-1 and COX-2

CAD Stroke-TIAs

NSAIDs

Reversibly inhibits COX-1

Limited

Dipyridamole

Inhibits PDE; TIAs increases cAMP

Ticlopidine Clopidrgrel

Inhibits ADP TIAs;Stroke PlatAg;active CAD;PVD metabolite www.indiandentalacademy.com


Thank you www.indiandentalacademy.com Leader in continuing dental education

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