Zdravila , ki vplivajo na nastajanje trombov

Lovro Stanovnik

Možnosti vpliva na nastajanje trombusa

• Vpliv na koagulacijo krvi (tvorba fibrina)

• Vpliv na delovanje trombocitov

• Odstranjevanje fibrina (fibrinoliza).

The main events in the formation of an arterial thrombus. Exposure of acidic phospholipids during platelet activation provides a surface on which factors IXa and VIIa interact with factor X; factor Xa then interacts with factor II, Activation of factor XII also initiates the fibrinolytic pathway. (A similar series of

events occurs when there is vascular damage, leading to haemostasis.) PAF, platelet-activating factor; TXA2, thromboxane A2. © 2005 Elsevier

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Major reactions of blood coagulation. Shown are interactions among proteins of the "extrinsic" (tissue factor and factor VII), "intrinsic" (factors IX and VIII), and "common" (factors X, V, and II) coagulation pathways that are important in vivo. Boxes enclose the coagulation factor zymogens (indicated by Roman numerals); the rounded boxes represent the active proteases. TF, tissue factor. Activated coagulation factors are followed by the letter "a": II, prothrombin; IIa, thrombin.

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Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.

The coagulation cascade: sites of action of anticoagulant drugs. Oral anticoagulants interfere with post-translational γ-carboxylation of factors II, VII, IX and X (shown in blue boxes) . Heparins activate antithrombin III. ATIII, antithrombin III; LMWHs, low-molecular-weight heparins; PL, negatively charged phospholipid supplied by activated platelets.

© 2005 Elsevier

The antithrombin-binding pentasaccharide structure of heparin. Sulfate groups required for binding to antithrombin are indicated in red.

Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux, a synthetic pentasaccharide.

Action of heparins. The schematic shows interactions of heparins, antithrombin III

(AT III) and clotting factors. To increase the inactivation of

thrombin (IIa) by AT III, heparin needs to interact with both

substances (top), but to speed up its effect on factor Xa it

need only interact with AT III (middle). Low-molecular-

weight heparins (LMW Hep) increase the action of AT III on factor Xa (bottom), but cannot increase the action of AT III on thrombin because they cannot

bind both simultaneously. (Modified from Hirsh J, Levine

M 1992 Blood 79: 1-17.)

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Comparison of the Features of Heparin, LMWH, and Fondaparinux

FEATURES HEPARIN LMWH FONDAPARINUX

Source Biological Biological Synthetic

Molecular weight (Da) 15,000 5000 1500

Target Xa and IIa Xa and IIa Xa

Bioavailability (%) 30 90 100

t1/2 (h) 1 4 17

Renal excretion No Yes Yes

Antidote effect Complete Partial None

Thrombocytopenia <5% <1% <1%

Varfarin • Oralni antikumarinski derivat • Inhibira podenoto C1 vitamin K epoksidne reduktaze

(VKORC1) • Prepreči sintezo koagulacijskih faktorjev, ki so odvisni od

vitamina K (faktorji II, VII, IX in X) in sintezo antikoagulantnih proteinov C in S.

• V visokem deležu se veže na plazemske beljakovine (cca 97%) – interakcije!

• Stereoselektivno se metabolizira s citohromi P-450 (CYP) v inaktivne hidroksilirane metabolite

• Pri metabolizmu varfarina so udeleženi naslednji CYP: 2C9, 2C19, 2C8, 2C18, 1A2 in 3A4.

• Ti izoencimi kažejo veliko genetsko variabilnost (teže predvidljiv učinek varfarina)

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Presentation Notes

Structural formulas of the vitamin K antagonists. 4-Hydroxycoumarin and indan-1,3-dione are the parent molecules from which the vitamin K antagonists are derived. The asymmetrical carbon atoms in the coumarins are shown in red.

Mechanism of vitamin K and of warfarin. After the peptide chains in clotting factors II, VII, IX and X have been synthesised, reduced vitamin K (the hydroquinone) acts as a co-factor in the conversion of glutamic acid to &gamma;-carboxyglutamic acid. During this reaction, the reduced form of vitamin K is converted to the epoxide, which in turn is reduced to the quinone and then the hydroquinone by vitamin K epoxide reductase component 1 (VKORC1), the site of action of warfarin.

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Warfarin, a vitamin K antagonist, is an oral anticoagulant. It competes with vitamin K (note the similarity in their structures) for the reductase enzyme

(VKORC1) that activates vitamin K and is the site of its action. Downloaded from: StudentConsult (on 7 December 2011 01:10 PM)

© 2005 Elsevier

Klopidogrel • Antagonist adenozin difosfata(ADP) na trombocitnih

receptorjih P2Y12 ⇒ preprečena aktivacija glikoproteina GPIIb/IIIa

• Predzdravilo – aktivacija s CYP2C19, CYP3A4, CYP2B6 in CYP1A2

Indikacije • profilaksa arterijskih trombembolij • stabilna koronarna bolezen, pešanje srca, ateroskleroza

z dokazano kapjo • svež miokardni infarkt • akutni koronarni sindrom • miokardni infarkt z dvignjenim ST-segmentom • po operacijah na srcu

Structures of ticlopidine, clopidogrel, and prasugrel.

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Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin. Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA; α2-antiplasmin (α2-AP) inactivates plasmin

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Sites of action of antiplatelet drugs. Aspirin inhibits thromboxane A2(TxA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TxA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) from binding to activated glycoprotein (GP) IIb/IIIa. SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets.

Fibrinolytic system. The schematic shows interactions with coagulation and platelet pathways and sites of action of drugs that modify these systems. LMHs, low-molecular-weight heparins. For more details of platelet

activation and the coagulation cascade, refer to Figures 24.1, 24.2 and 24.7. Downloaded from: StudentConsult (on 7 December 2011 01:10 PM)

© 2005 Elsevier

Indikacije za uporabo fibrinolitikov

Indications Alteplase Reteplase (Recombinant) Tenecteplase Urokinase

acute myocardial infarction Yes Yes Yes Yes (Off Label) arterial thromboembolism Yes (Off Label) Yes (Off Label) Yes (Off Label) coronary artery thrombosis Yes Yes Yes Yes (Off Label) deep venous thrombosis (DVT) Yes (Off Label) Yes (Off Label) Yes (Off Label) intravascular catheter occlusion prophylaxis Yes (Off Label)

ischemic stroke Yes occluded arteriovenous (AV) cannula Yes (Off Label)

occluded IV catheter Yes Yes (Off Label) Yes (Off Label) percutaneous coronary intervention (PCI) Yes (Off Label) Yes (Off Label)

pulmonary embolism Yes Yes

Efficacy of aspirin and streptokinase for myocardial infarction. The curves show cumulative vascular mortality in patients treated with placebo, aspirin alone, streptokinase alone or a combined aspirin-streptokinase regimen. (ISIS-2 trial 1988 Lancet ii: 350-360.)

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Effect of adding clopidogrel to aspirin. The curves show cumulative hazard rates for major vascular events in patients with acute coronary syndromes treated either with placebo + aspirin or clopidogrel + aspirin. (Modified from CURE Investigators 2001 N Engl J Med 345: 494-502.) Downloaded from: StudentConsult (on 7 December 2011 01:10 PM)

© 2005 Elsevier