Drug used in disorders of coagulation Vladimír Moravec, M.D.

Mechanisms of blood coagulation Trombogenesis: the platelet - white trombus - red trombus Hemostasis: 1.adhesion and activation of platelets 2.fibrin formation 3.vascular contraction

Blood coagulation 1.Intrinsic system 2.Extrinsic system Two pathways: Viz.Figure

Monitoring of coagulation 1. Extrinsic koagulo-pathways - components presents in plasma – aPTT 2. Intrinsic koagulo-pathways – with participation of tishue components – Prothrombin time (Quick test), INR (International normalized ratio)

Bleeding therapy Haemostatics - local vasoconstriction Antifibrinolytics - inhibit fibrinolysis Antiaggregants – against platelets agregation Fibrinolytics – rapidly lyse thrombus Anticoagulants -blood coagulation

1. Haemostatic drugs Somatostatin Antithrombin III Protamine sulfate, vitamin K - antidotum Ethamsylate - facility of platelets agregation Desmopressin, Terlipressin Vasopresin, alfamimetics – vasoconstriction Global efficacy : plasma, coagul. factors Local efficacy: gelatin, collagen Deficience of factors F. VIII., F. IX.

Somatostatin naturally occurring tetradecapeptide that produces numerous physiologic effects. rapidly inactivated by peptidase enzymes; its plasma half-life is 1 to 3 minutes.

Clinical applications efficacy in a variety of clinical conditions, including carcinoid syndrome, enterocutaneous and pancreatic fistulas, the dumping syndrome, VIPomas, glucagonomas, diabetes mellitus, insulin excess in neonates, psoriasis, and short-bowel syndrome its efficacy in upper gastrointestinal bleeding is controversial

ANTITHROMBIN III purified preparations of antithrombin III derived from human plasma. Antithrombin III concentrate is primarily used for the prophylaxis and treatment of patients with congenital antithrombin III deficiency and disseminative intravascular coagulopathy.

PROTAMINE SULFAT strongly basic protein that is capable of neutralizing the effects of HEPARIN. dose is 1 mg IV for every 100 units of HEPARIN remaining in the patient; doses of 50 mg should not be exceeded within a 10-minute period to decrease the risk of adverse effects; the dose is usually administered by intravenous bolus over 1 to 3 minutes, but a constant infusion over 30 minutes may also be given.

2. Pharmacology of the anticoagulant drugs 1.- Heparin X Protamin sulfat, Antitrombin III., LMWH, Fraxiparin 2. - Warfarin X Vit K, Pelentan Dicumarol, Phenprocoumon (6days)

ANTICOAGULANTS 1. direct - Heparin (antidotum-Protamin sulfat), Antithrombin III., Low-molecula-weight-heparin(LMWH) , Heparinoids – (local)

2. indirect - Warfarin (antidotum Vit K), Pelentan ANTICOAGULANTS 2. indirect - Warfarin (antidotum Vit K), Pelentan

Heparin aktivation Antithrombin III. Inhibition of thrombocyt agregation Aktivation of lipoprotein lipase (hypolipidemic effect) bolus 5-10 tis. m.j., 1 tis. J/hod, aPTT Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin.

Generic name: antiXa/IIa t 1/2 (hod) LMWH Generic name: antiXa/IIa t 1/2 (hod) Dalteparin 2 : 1 119-139 sodium Nadroparin 3,2 : 1 132-162 calcium Enoxaparin 2,7 : 1 129-180 Tinzaparin 1,9 : 1 111

Hirudin In nature - Hirudo medicinalis Specific thrombin inhibitor from the leech. Now is prepared by recombinant DNA technology – lepirudin selective inhibitor of thrombinu, action is independent of ATIII. Hirudin has litle effect on platelets or the bleeding time. APTT monitoring antidotum is not available

Cumarine anticoagulants Oral anticoagulants. Block the carboxylation of several glutamate residues in prothrombin and factors VII, IX, X., and protein C.(endogenous anticoagulans) antagonists of Vitamin K - f. VII, IX, X, dicumarol - Etylbiskumacetate (Pelentan) monocumarin - Warfarin , 1xd

3. Fibrinolytic drugs Rapidly lyse thrombi by catalyzing plasmin protease from its precursor plasminogen. Fibrin degradation Administered by intravenous infusion (250 000 units, followed by 100 000 units/h Indication: multiple pulmonary emboli, central deep venous thrombosis, acute myocardial infarction Viz figure

Fibrinolytics drugs trombolytics 1. generation : streptokinase, urokinase – not selective, systemic fybrinolysis trombolytics 2. generation: tissue plasminogen activators (tPA) with recombinant types: rt-PA Alteplase - is unmodified human t-PA. Antistreplase (ASPAC)- anisolated plasminogen streptokinase activator complex.

Fibrinolytics drugs Streptokinase is a protein synthetised by streptococci that combines with the plasminogen. This complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synth. By the kidney that directly converts to plasmin. Antistreplase consists of a complex plasminogen and streptokinase that has been acylated to protect.

FIBRINOLYTICS FIBRINOLYTICS Plasminogen Inhibition Activation Various stimuli + Blood proactivator Blood activator + - Antiactivators urokinase + - Streptokinase Activator + Proactivator Plasmin t-PA Anistreplase + + Thrombin Degradation products Fibrin split products Fibrinogen Fibrin

Antifibrinolytics Antidotum: Aprothinin, PAMBA, Etha aminokapronic acid.

4. Antitrombotic drugs: Drug that antagonize pathway interfere with platelet agregation in vitro and prolong the bleeding time in vivo.

Platelet function is regulated Platelet function is regulated by three categories of substances: Contains agents generated within the platelet that interact with membrane receptors: Catecholamines, collagen, thrombin, prostacyclin ADP, prostaglandinD2, E2, serotonin Paltelets within platelet: cAMP a cGMP, TxA2

Antitrombotic - antiplatelet drugs Representants: Aspirin – inhibition of prostaglandine meetabolisme Ticlopidin, Clopidogrel – inhibition of ADP-induced platelet aggregation Dipyridamol Abciximab – parenteral – blockade of GP 2b/3a

Aspirin, ASA Aspirin inhibits the synthesis of TxA by irreversible acetylation of the enzyme cyclooxygenase 2. The platelet canot manufacture new enzyme during its 10-day lifetime. Prolong the bleeding time. Studies were conducted to ëwaluate the use of aspirin for 4-5 years in the primary profylaxis of cardiovascular mortality. Dosses?? 100-325 mg/day

Ticlopidine Reduce platelet aggregation by inhibiting the ADP pathways of platelets. Adverse effects include nausea, dyspepsia, hemorage, leukopenia. Dosage is 250 mg/twice day Its useful in patients who cannot tolerate aspirin.

Ticlopidin a Clopidogrel

Ticlopidin - negatives?? Adverse ractions: Granulocytopenie ( 2,4% cases). Ticlopidin is more Expensive against aspirin.

Abciximab New class of platelet-inhibiting drug that blocks platelet receptors. Is a mouse/human chimeric monoclonal antibody that blocks IIb/ IIIa receptors.

5. Drugs used in bleeding disorders Vitamin K Fibrinogen Deficience of f. VIII., f. IX. Fibrinolytic inhibitors: Aminocapronic acid, PAMBA, Aprothinin

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