PHARMACOLOGY - Parenteral Anticoagulants


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PHARMACOLOGY - Parenteral Anticoagulants

  1. 1. PHARMACOLOGY: Parenteral AnticoagulantsnianderthalNOTES
  2. 2. PARENTERAL ANTI-COAGULANTSHEPARIN:-Biochemistry: -glycosaminoglycan found in the secretory granules of mast cells-Heparan Sulfate: -synthesized from the same disaccharide precursor but undergoes less modification; contains less sulfate groups but more glucoronic acid and N-acetylglucosamine
  3. 3. PARENTERAL ANTI-COAGULANTSHEPARIN:-Source: -commonly extracted from porcine intestinal mucosa or bovine lung -low-molecular-weight heparins are isolated from standard heparin by: a. gel filtration chromatography b. precipitation with ethanol c. Partial depolymerization with nitrous acid and other chemical enzymatic reagents *the biologic activity of low molecular weight heparin is generally measured with a factor Xa INHIBITION ASSAY, which is mediated by antithrombin
  4. 4. PARENTERAL ANTI-COAGULANTSHEPARIN:-Mechanism of Action: -catalyzes the inhibition of several coagulation proteases by antithrombin -increases the rate of the thrombin-antithrombin reaction by serving as a catalytic template to which the inhibitor and protease bind -induces conformational change in antithrombin that makes the reactive site more accessible to the protease -Heparin molecules containing less than 18 monosaccharide units do not catalyze inhibition of thrombin -antithrombin – inhibits activated coagulation factors of the intrinsic and common pathways including thrombin, Xa and IXa.; has little activity agains VIIa
  5. 5. PARENTERAL ANTI-COAGULANTSHEPARIN:-Pharmacological Effects: -interfere with platelet aggregation and thus prolongs bleeding time -clears lipemic plasma in vivo by release of lipoprotein lipase; may occur at concentrations of heparin below those necessary to produce anticoagulant effect -lipoprotein lipase – hydrolyzes triglycerides to glycerol and free fatty acids
  6. 6. PARENTERAL ANTI-COAGULANTSHEPARIN:-Clinical Use: -initiate treatment of VENOUS THROMBOSIS and PULMONARY EMBOLISM because of its rapid onset of action -started concurrently with an oral anticoagulant, and is continued 4-5 days to allow oral anticoagulant to achieve its full Rx effect -Unstable Angina -Myocardial Infarction -DIC
  7. 7. PARENTERAL ANTI-COAGULANTSHEPARIN:-LMW HEPARIN vs STANDARD HEPARIN: -LMW heparin has a more predictable pharmacokinetic profile, which allows weight adjusted subcutaneous administration WITHOUT laboratory monitoring -LMW heparin have longer biological half-lives than do standard preparations of the drug-HEPARIN vs WARFARIN: -In contrast to WARFARIN, HEPARIN DOES NOT cross placenta and is not associated with fetal malformations, HEPARIN IS DRUG OF CHOICE FOR ANTICOAGULATION DURING PREGNANCY -Heparin should be discontinued 24 hours before delivery to minimize postpartum bleeding
  8. 8. PARENTERAL ANTI-COAGULANTSHEPARIN:-Absorption and Pharmacokinetics: -NOT ABSORBED through GI mucosa and must be GIVEN by CONTINUOUS IV infusion or SQ injection -immediate onset of action thru IV; delay of 1-2 hours SQ -LMW heparin are absorbed more uniformly DOSE ADMNISTERED IV PLASMA HALF-LIFE (t1/2) *Half-life is… SHORTENED: 100 units/kg 1 hour -Pulmonary Embolism 400 units/kg 2.5 hours PROLONGED: 800 units/kg 5 hours -Hepatic cirrhosis -ESRD
  9. 9. PARENTERAL ANTI-COAGULANTSHEPARIN:-Absorption and Pharmacokinetics: -degraded primarily by the reticuloendothelial system; a small amount of undegraded heparin appears in the urine
  10. 10. PARENTERAL ANTI-COAGULANTSHEPARIN:-Administration and Monitoring: -Venous thromboembolism: bolus injection of 5000 units -therapy is monitored routinely by aPTT, the target is an elevation 1.8-2.5 times the normal value -Initially, apTT should be measured and infusion rate readjusted EVERY 6 HOURS, if steady dosage schedule is established, daily monitoring is sufficient -DVT prophylaxis – low dose therapy every 8 hours in a hospital setting, NO NEED for LABS
  11. 11. PARENTERAL ANTI-COAGULANTSHEPARIN:-Administration and Monitoring: -SQ heparin can be used for long term management of patients of whom warfarin is contraindicated
  12. 12. PARENTERAL ANTI-COAGULANTSHEPARIN:-LMW Heparin Preparations: -Enoxaparin, dalteparin, tinzaparin etcall differ in composition and may have different anti-factor Xa activity -SQ weight adjusted regimen: 1-2 times daily
  13. 13. PARENTERAL ANTI-COAGULANTSHEPARIN:-Synthetic heparin derivatives: -Fondaparinux (Arixtra) is a synthetic pentasaccharide based on the structure of antithrombin binding region of heparin -inhibits factor Xa by antithrombin but DOES NOT inhibit thrombin d/t its short polymer length -Administered SQ; reaches peak plasma level in 2 HOURS -URINE t1/2: 17-21 hours  NOT USED IN PATIENTS WITH RENAL FAILURE -given OD at fixed dose WITHOUT LAB MONITORING -low incidence of thrombocytopenia -indications: PE, DVT -thromboprophylaxis: hip or knee surgery
  14. 14. PARENTERAL ANTI-COAGULANTSHEPARIN:-Toxicities: 1. Bleeding -PRIMARY UNTOWARD EFFECT -less with LMW heparin -anticoagulant effect of heparin disappears within HOURS after drug discontinuation -effects of heparin can be antigonized by slow IV infusion of PROTAMINE SULFATE (1mg PS / 100 units heparin up to 50mg over 10 minutes)
  15. 15. PARENTERAL ANTI-COAGULANTSHEPARIN:-Toxicities: 2. Heparin-induced Thrombocytopenia -platelet count <150,000 uL or a 50% decrease from pretreatment value -occurs 5-10 days after Rx of standard heparin -venous thromboembolism is MOST COMMON -may be d/t the development of IgG antibodies against complexes of platelet factor 4 leading to thrombin generation -discontinued immediately if unexplained thrombocytopenia occurs -Dx confirmed through heparin-dependent platelet activation assay
  16. 16. PARENTERAL ANTI-COAGULANTSLEPIRUDIN: -direct thrombin inhibitor -excreted by the kidneys with a t1/2 of 1.3 hours -used cautiously in patients with renal failure -daily monitoring of aPTT -no antidote -alternative in patients with risk of developing heparin-induced thrombocytopenia
  17. 17. PARENTERAL ANTI-COAGULANTSBIVALIRUDIN: -IV administration -used as an alternative to heparin in patients going coronary angioplasty -t1/2: 25 minutes in patients with normal renal function -dosage must be reduced for patients with moderate or severe renal impairment
  18. 18. PARENTERAL ANTI-COAGULANTSARGATROBAN: -binds REVERSIBLY to the catalytic site of thrombin -IV administration -metabolized by hepatic CYPs and excreted in the bile  dosage reduction in hepatic insufficiency - t1/2: 40-50 minutes -alternative to lepirudin in patients with risk of developing heparin-induced thrombocytopenia
  19. 19. PARENTERAL ANTI-COAGULANTSDANAPAROID: -mixture of nonheparin glycosaminoglycan -heparan sulfate -dermatan sulfate -chondroitin sulfate -used for prophylaxis of DVT -mainly promotes the inhibition of factor Xa but DOES NOT prolong the PT or a PTT -prophylaxis: SQ with fixed dosage -full anticoagulation: IV at a higher wt adjusted dose
  20. 20. PARENTERAL ANTI-COAGULANTSDROTRECOGIN ALFA: -recombinant form of human activated protein C that inhibits coagulation by proteolytic inactivation of factors Va and VIIIa -has anti-inflammatory effects -MAJOR ADVERSE EFFECT: BLEEDING