Drugs used for treatment of coagulate disorders

1. Drugs used for treatment of coagulate disorders 

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 • > 11,000 post surgical PE deaths per year

3. ANTITHROMBOTIC THERAPY 1) Antiplatelet therapy 2) Anticoagulant therapy 3) Thrombolytic therapy

9. INHIBITORS OF PLATELET AGGREGATION

10. Anti Platelet Drugs

11. Platelets inhibitors - ASA Kardiomagnil Daily dose - 80-300 mg

12. ANTIPLATELET THERAPYAspirin Indications 1) Stroke, TIA (transient ischemic attacks) 2) MI, recurrent MI 3) Unstable angina 4) CABG potency (coronary artery bypass graft)

13. TICLOPIDINE 1) Interferes with platelet-fibrinogen binding 2) Exerts its action for the life of the platelet 3) May prolong bleeding time • Useful for coronary artery stents and CVA (cerebrovascular accident) 5) Methylprednisolone may reverse its effect 6) Associated with TTP (thrombocytopenic purpura), neutropenia, and diarrhea

14. CLOPIDOGREL • Interferes with GP IIb/IIIa • (Glycoprotein IIb/ IIIa) binding site • 2) Exerts its action for the life of the platelet • 3) May prolong bleeding time • 4) Indicated for prevention of MI, CVA, and vascular death • 5) Fewer side effects than ticlopidine • 6) Dose: 75 mg daily

15. Abciximab (ReoPro) • Human-mouse monoclonal antibodies • Binds to GP IIb/IIIa receptor on platelets • Half-life 10 min. • May block receptor for 10 days • Indicated for prevention of closure of coronary vessels after angioplasty • May cause thrombocytopenia • Used with heparin and ASA

16. Ant platelet therapy

19. 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

24. Coagulation Factor XIIa Factor XIa Factor IXa Factor Xa Thrombin Fibrinolysis Plasmin Antithrombin III Inhibits the Following Serine Proteases Inhibitory activity against all these enzymes is substantially accelerated by heparin

25. HEPARIN (Description) 1) Discovered in 1916 by McLean; isolated from liver, thus the name heparin 2) Anionic glycosaminoglycan available as calcium or sodium salt, negative charge 3) Molecular weight 15,000 D (avg.) (3000-30000 D) 4) Prepared from porcine intestinal mucosa and bovine lung 5) Does not cross placenta 6) Little interaction with other medications 7) IV or SC administration only 8) Reversible with protamine sulfate (1 mg/200 U heparin)

26. Heparin • 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

28. HEPARIN (Action) • Binds to and potentiates antithrombin III 2) Heparin-antithrombin III complex inactivates thrombin (factor IIa) and factor Xa (Stuart-Prover) 3) Secondary effect against platelet function

29. Monitoring of Anticoagulant Therapywith Heparin Heparin s.q. – no monitoring required i.v. - APTT Activated Partial Thromboplastin Time i. v. - no less than 4 times daily or more frequent if PTT varies therapeutic goal – 2-2.5 times normal control value (-30 sec)

30. HEPARIN (Indications) Full Dose: 5000 U or 80 U/kg IV bolus, followed by 1200-1600 U/hr adjusted to therapeutic range 1) Acute deep venous thrombosis 2) Pulmonary emboli 3) Unstable angina and myocardial infarction Low Dose: 5000 U sq q12 h 1) Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedure 2) Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 3) Prophylaxis for underlying hypercoagulable state Other Dose: 1) Extracorporeal bypass 2) Hemodialysis 3) After thrombolytic therapy

31. Heparin • Pregnancy- YES

32. HEPARIN (Contraindications) 1) Thrombocytopenia 2) Aspirin or alcohol use 3) Hepatic or renal disease 4) Other platelet dysfunction 5) GI bleeding 6) Tumors

33. HEPARIN (Side Effects) 1) Major side effect is bleeding 2) Osteoporosis with prolonged use 3) Thrombocytopenia

34. HEPARIN-INDUCED THROMBOCYTOPENIA 1) Occurs in 2-5% of patients receiving standard heparin by immune mechanism • May occur with minute doses, including heparin flushes • More common with bovine than porcine heparin • Asymptomatic thrombocytopenia can occur in 30-50% of pts who develop HIT antibodies • ~20-50% of thrombocytopenic patients develop arterial or venous thrombosis that may be life threatening

35. HEPARIN-INDUCED THROMBOCYTOPENIA • Usually appears 3-15 days after starting heparin, peak incidence day 8 2) Diagnosis is largely clinical despite availability of several tests used to attempt confirmation

36. HEPARIN-INDUCED THROMBOCYTOPENIA Alternative Anticoagulants • Lepirudin • Argatroban

37. LEPIRUDIN 1) Recombinant form of hirudin 2) Highly specific direct thrombin inhibitor • Short half-life 1-2 hours • Monitored by APTT • Crosses placenta in rats, would not use in pregnancy at present • No antidote

38. LOW MOLECULAR WEIGHT HEPARIN 1) Molecular weight 3,000- 7,000 D 2) Inhibits factor Xa rather than thrombin 3) Factor Xa assay used for monitoring 4) Administered subcutaneously 2 times/d 5) Probably less antigenic than standard heparin 6) Recommended for prophylaxis and treatment

39. LOW MOLECULAR WEIGHT HEPARIN 1) PT, APTT not usually prolonged 2) May be monitored with anti-factor Xa assay

42. LOW MOLECULAR WEIGHT HEPARINS

44. Indications for and Contraindications to Parenteral Anticoagulant Agents

45. Heparin-Antibiotic Interactions • The 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.

49. ANTICOAGULANTS OF INDIRECT ACTION

50. COUMARIN (Description) 1) Isolated by Link in 1939 after previous observation that cattle developed bleeding disorder after ingestion of spoiled clover 2) Is 4-hydroxycoumarin compound, similar in structure to vitamin K 3) Administered p.o., rapid GI absorption 4) Crosses placenta easily (complications!) 5) Interacts with a variety of drugs