Drugs used in coagulation disorders

-patients with defects in formation of primary platelet plug ( def. primary hemostasis): bleeding from surface sites like gingiva, skin, heavy menses; common in von Willebrandt disease

-patients with defects in clotting mechanisms ( seconadry hemostasis): bleeding into deep tssues (joints, muscles, peritoneum), appartently without any incidentic reason ( haemophilia A)

INR= prothrombin time ration= patient prothrombin time/ mean of normal prothrombin time for lab) do potęgi ISI

ISI: international sensitivity index

ANTICOAGULANtS

1) INDIRECT THROMBIN INHIBITORS

- interact with antithrombin binding to it and enhancing inhibiting of factor proteases (esp.thrombin) thus inactivation of factor Xa, IXa

-require monitoring by aPTT ( activated partial thromboplastin time, also called PTT) esp. in patients receiving UFH

*HEPARIN: heterogenous mixture of sulfated monasaccharides; mechanism of action: heparin + antithrombin III=> conformational change of antithrombin-> activated antithrombin rapidly reacts with proteases. Heparin acts as an cofactor in this reactions! than heparin is released intact. Irreversibly inactivates the coagulation factors thrombin and factor Xa

-UFH: UNFRACTIONATED HEPARIN

-LMWH: LOW MOLECULAR WEIGHT HEPARIN: ENOXAPARIN, DALTEPARIN, TINZAPARIN= more selective anti X activity, more reliable pharmacokinetics with renal elimination, less risk of thrombocytopenia

#CLINICAL APPLICATION: used in venous thrombosis, pulmonary embolism, MI, unstable angina, adjuvant to percutaneous coronary intervention (PCI) and thrombolytics

#ADMINISTRATION: PARENTERALLY

#TOXICITIES: bleeding ( must be monitored with aPTT), thrombocytopenia ( heparin induced thrombocytopenia= HIT), osteoporosis ( in chronic use); elderly women and renal failure patients are more prone to develop hemorrhages; may cause problem in alergics ( its a drug of animal origin)

#CONTRADICATIONS: patients with HIT, active bleeding, haemophilia, thrombocytopenia, purpura, severe hypertension, intracranial hemorrhages, infective endocarditis, active tuberculosis, ulcers of GI, advanced hepatic and renal disease

#REVERSAL OF HEPARIN ACTION: protamine sulphate

2) ORAL DIRECT FACTOR X INHIBITORS

-these drugs inhibit factor Xa in the final common pathway of clotting by binding to active site of factor Xa

-do not require monitoring

-rapid onset of actions

-shorter half lifes than warfarin

*RIVAROXABAN:

#CLINICAL APPLICATION: prevention of venous thrombosis following knee or hip surgery, pulmonary embolism, prevention of stroke in patients with atrial fibrillation

#ADMINISTRATION: ORALLY, fixed dose no routine monitoring ( factor Xa test)

# TOXOCITIES: bleeding, no specific reversal agents

3) DIRECT THROMBIN INHIBITORS

-bind to the active site of thrombin, inhibiting thrombin's downstream effects. Can bind to both catalytic and active site ( hirudin, bivalirudin) and only to the active site ( argatroban, melagatran)

* LEPIRUDIN: binds to thrombin's active site and inhibits its enzymatic action, has little effect on PLTs, excreted by kidneys

#CLINICAL APPLICATIONS: anticoagulation in patients with HIT

#ADMINISTRATION: IV, requires monitoring (a PTT)

#TOXICITY: bleeding, anaphylactic reactions

*DABIGATRAN: binds to thrombin's active site and inhibits its enzymatic action

#CLINICAL APPLICATIONS: anticoagulation in patients with HIT, prevention of venous thromboembolism in patients after knee/hip surgery

#ADMINISTRATION: ORALLY, requires monitoring (aPTT)

#TOXICITY: bleeding

-its effects can be increased by amiodarone, quinidine, clopidogrel, ketoconazole

4) COUMARIN ANTICOAGULANTS

-block gamma-carboxylation of several glutamate residues in prothrombin and factors VII, IX and X as well as the endogenous anticoagulant proteins C and S. Protein carboxylation is related to vit. K oxidation. Oxidation is proceeding when vit. K is reduced.

*WARFARIN: inhibits vitamin K poxide reductase and thereby interferes with production of functional vitamin K-dependent clotting and anticlotting factors ( reductive metabolism of vit. K is inhibited!)

#CLINICAL APPLICATIONS: venous thrombosis, pulmonary embolism, prevention of thromboembolic complications of atrial fibrillation or cardiac valve replacement

#ADMINISTRATION: ORALLY, delayed onset and offset of anticoagulant activity, many drug interactions

#TOXICITY: bleeding (must be monitored with PT, vit.K1 is reversal agent), thrombosis ( in early theraphy), teratogenic ( corsses placenta)

THROMBOLYTICS

*ATELEPTASE ( recombinant human tissue plasminogen activator [t-PA]: converts plasminoge to plasmin which degrades the fibrin in thrombin

#CLINICAL APPLICATION: coronar artery thrombosis, ischaemic stroke, pulmonary embolism

#ADMINISTRATION: PARENTERAL

#TOXICITIES: bleeding, especially cerebral hemorhhage

*RETEPLASE,TENECTAPLASE : longer half life

*STREPTOKINASE: bacterial protein that forms a complex with plasminogen that rapidly converts plasmonogen to plasmin. Subject to inactivating antibodies and allergic reactions

ANTIPLATELET DRUGS

*COX INHIBITOR=ASPIRIN: noncelective, irreversible COX inhibitor, reduces platelet production of thromboxane A2, a potent stimulator of PLT aggregation; dose required for antithrombotic effect is lower than anti-inflammatory dose

#CLINICAL APPLICATION: prevention and treatment of arterial thrombosis

#ADMINISTRATION: ORAL

#TOXICITIES: GI toxicity, nephrotoxicity, hypersensitivity reactions due to increased leukotrienes; tinnitus; hyperventilation, metabolic acidosis, hypothermia, coma in overdosage

*GLYCOPROTEIN IIb/IIIa inhibitors

*ABCIXIMAB: inhibits PLT aggregation by interfering with GP IIb/IIIa binding to fibrinogen and other ligands

#CLINICAL APPLICATIONS: used during PCI to prevent restenosis, ACS

#ADMINISTRATION: PARENTERAL

#TOXICITIES: bleeding, thrombocytopenia with prolonged use

*EPTIFIBATIDE, TIROFIBAN: REVERSIBLE GP IIB/IIIa inhibitors of smaller size

*ADP RECEPTOR ANTAGONISTS

*CLOPIDROGEL: prodrug; active metabolite irreversibly inhibits PLT ADP receptor

#CLINICAL APPLICATION: ACS, prevention of restenosis after PCI, prevention of treatment of arterial thrombosis

#ADMINISTRATION: ORAL

#TOXICITIES: bleeding, GI disturbances, hematologic abnormalities

*TICLODIPINE: older ADP receptor antagonist with more toxicity, particularly leukopenia and thrombotic thrombocytopenic purpura

*PRASUGREL: newer drug, similar to clopidrogel with less variable kinetics

*DIPYRIDAMOLE: inhibits adenosine uptake and inhibits phosphodiesterase enzymes that degrade cAMP and cGMP

#CLINICAL APPLICATION: prevention of thromboembolic complications of cardiac valve replacement; combined with aspirin in secondary prevention of ischaemic stroke

#ADMINISTRATION: ORAL

#TOXICITIES: headache, palpitations, contradicated in congestive heart failure

DRUGS USED IN BLEEDING DISORDERS

*VITAMIN K: increases supply of reduced vit. K which is required for synthesis of functional vit. K dependent clotting factors ant anticlotting factors

#CLINICAL APPLICATIONS: vit. K def., reversal or excessive warfarin anticlotting activity

#ADMINISTRATION: ORAL?PARENTERAL

#TOXICITIES: severe infusion reaction when given IV or IM

*PROTAMINE