Drugs affecting clotting and hemopoiesis /-\ Hemostasis Hemostasis is the arrest of blood loss from / damaged vessels and is essential to life mechanisms playing part in hemostasis are - vasoconstriction - blood coagulation (coagulation factors) - thrombocytes adhesion and activation hemostasis is consisting of 3 phases: vascular platelet coagulation —► continuing with fibrinolysis (to prevent V coagulation which is not necessary in \. following parts of the vessel) Required for the proper functioning of HAEMOSTASIS processes CORRECT BLOOD FLOW (no stagnation of blood) INTACT BLOOD-VESSEL WALL (preserved endothelium and sufficient production of all its mediators) BALANCED REGULATION of coag. and anticoag. processes DYSFUNCTION PATHOLOGY Bleeding conditions Hypercoagulation states Congenital disorders Acguired disorders PHI I MED Primary haemostasis defect Secondary haemostasis defect Decreased activity ■=> Increased activity ■=> Fibrinolysis defect Lack of anticoagulant factors • Coagulation facforsT Anticoagulation ^factors KOAGULOPATHY TROMBOPHILIA

is recommended to monitor its level during prolonged treatment. Direct anticoagulants HEPARIN • in vitro elongation of APTT - activated parcial thromboplastin time - 25-39s, —> therapy control decreasing adhesivity and count of thrombocytes H PGF-I), anticoagulant, antithrombotic, antifibrinolytic, antiinflammatory, antilipidemic activity efficient in vitro and in vivo in contrast with peroral anticoagulants Direct anticoagulants _HEPARIN_ • It is administered intravenously, in bolus 3 times a day or by Continuous infusion (non-standard bioavailability after i.m. and s.c. administration - still sometimes given s.c. as part of miniheparinization) • It remains in circulation for a short time (it binds to endothelial cells and macrophages and acute phase proteins) • It does not cross the placenta or into breast milk • Biotransformation occurs in the liver O inactive product • Renal excretion • Elimination half-life is proportional to the dose administered ...... PHI - r Direct anticoagulants HEPARIN Indication: •Deep vein thrombosis (DVT) and pulmonary embolism (PE): treatment and prophylaxis •Acute coronary syndromes •Percutaneous coronary intervention (PCI) •Thromboembolic disorders •Arterial embolization: treatment and prophylaxis (atrial fibrillation) •Vascular and cardiac surgery •Extracorporeal circulation (hemodialysis, hemofiltration, and cardiopulmonary bypass during cardiac surgery) •Arterial and venous catheters, pulmonary artery catheters (heparin flushes) •Diagnostic and therapeutic interventional radiologic procedures Direct anticoagulants ,_HEPARIN_ /Kl: bleeding / condition after big surgery malign hypertension trombocytopenia abortus imminens Protamine sulfate = specific antagonist - basic protein with afinity to negative charged heparin —► complex - overdose treatment 1mg/100u of heparin AE: bleeding - GIT, urinary system and adrenal glands •trombocytopenia \ •hypersensitivity r Direct anticoagulants Low-molecular-weight heparins eparin fragments Nadroparin (Fraxiparin), enoxaparin (Clexane), dalteparin (Fragmin), parnaparin, reviparin, certoparin... • mol. weight cca 2-9 kDa (heparin 15 - 20) • s.c. application • lower risk of adverse effects, less frequent dosing • patients are able to give injections themselves at me Direct anticoagulants Low-molecular-weight heparins • increase ATI 11 activity against I la and Xa (early phase of coagulation) • halflife is doubled when compared to heparin (cca 200 mins), much better bioavailability • they do not prolong APTT, however monitoring is not required, because they are eliminated by 1st. order kinetics eliminated by liver, monitoring of thrombocytes FOR COMPLEMENTARY ANTICOAGULANT THERAPY sulodexide (soft capsules, inj.sol.) Mixture of 80 % - „medium" molecular weight heparin 20 % - glykosaminoglykan dermatan 1. Antithrombine activators MoA is complex, due to the effect of both components • Anticoagulant, antiplatelet, mild fibrinolytic • Lipolytic effect due to activation of lipoprotein lipase • Protective and reparatory effects on endothelium • Improving the rheological properties of blood I: DVT, ischaemic heart disease, critical limb ischaemia (CLI), microcirculatory disorders in diabetic, scerebral artery occlusion. U HI I ED Direct anticoagulants Heparinoids polysulphur esters of sacharids e.g. Heparansulfate^ dermatansulphate or mixture danaparoid • obtained from animal intestinal mucous membrane • they are mostly used locally on skin (thrombophlebitis, injuries) we can use them to substitute heparin in HIT_ -N Direct anticoagulants Sulphonated pentasacharid _s .--- • fondaparinux (Arixtra), indraparinux - (named for Asterix a Obelix) indirectly anti-Xa, deep venous thrombosis, pulmonal embolisation, s.c. admin. r Direct anticoagulants Thrombin inhibitors Antithrombin III - congenital deficiency Hirudin • polypeptide present in leech saliva (Hirudo medicinalis) • reacts directly with thrombin without ATI 11 lepirudin, desirudin, bivalirudin - parenteral administration Argatroban - hepatic metabolism, suitable in kidney failure, HIT Direct anticoagulants Thrombin inhibitors - GATRANS Gatrany - dabigatran (RMP Pradaxa), ximelagatran (prodrug) —► melagatran (withdrawn) • oral anticoagulant therapy without monitoring (high correlation between plasmatic levels and effect) • MoA - They inhibit not only fibrin-bound thrombin but also free thrombin O inhibit thrombin-induced platelet aggregation • P-gp Substrate O DDI (careful with verapamil) • CAVE - gastritis, oesofagitis, GER - GFR 30-50ml/min - over 75 let ■ Beedinn complications (enterorrhagia, hematuria, melena) ■ GIT bleeding O USE GASTROPROTECTIVES Direct anticoagulants Thrombin inhibitors - GATRANS _z ANTIDOTE • idarucizumab Praxbind® 10ml/2,5g = humanized monoclonal antibody fragment that binds specifically to dabigatran with very high affinity and immediately neutralizes its anticoagulant effect. •The binding affinity of idarucizumab for dabigatran is approximately 300 times higher than the affinity of dabigatran for thrombin. ■ Withdrawal of the anticoagulant effect of dabigatran during life-threatening or uncontrolled bleeding or during urgent surgery ■ Intravenous administration (two consecutive infusions or bolus injections, giving a total of 5 g of idarucizumab)_ The use of RMP is limited by its price r Direct anticoagulants Xa inhibitors Xabans • direct Xa inhibition (both pathways) • no effect on platelets or thrombin • oral administration (once a day), rapid onset of action Rivaroxaban (RMP Xarelto) Apixaban Betrixaban For parenteral admin, otamixaban, in CR not registered Direct anticoagulants Xa inhibitors CI: liver insuff. (esp. rivaroxaban) AE ■ bleeding ■ dizziness, headache, stomach pain, elevated bilirubin ■ Rare - serious skin reactions SJS/TEN*, icterus • Interactions with strong CYP3A4 and P-glp inhibitors ANTIDOTE andexanet alfa AndexXa® •Higher affinity for the FXa inhibitor than natural FXa (decoy receptor) * Stevens-Johnson syndrome / toxic epidermal necrolysis aripazine / ciraparantag/PER977 (Perosphere, USA) A small, synthetic, water-soluble molecule that binds by non-covalent hydrogen bonding to FXa inhibitors as well as Flla. In phase 11 of the clinical trial GATRANS or XABANS ?? • ... state of the patient vs expected effects ... _xz_ An increased incidence of GIT bleeding has been reported Hepatal insufficiency is a contraindication for xabans (especially rivaroxaban^ Renal insuficience rivaroxaban is not recommended in patients with clearance of creatinine < 15 ml/min dabigatran is not recommended in patients with clearance of creatinine < 30 ml/min lirtllll ED ADVANTAGES OF NOACs/DOACs Rapid onset of action Absence of interactions with food Only few potent drug interactions Wide therapeutic window, fixed dose in adults No need of monitoring Patient comfort (oral administration) DISADVANTAGES OF NOACs/DOACs Dose reduction in renal insufficiency Limited availability of laboratory tests to check the effectiveness of therapy Potential for overuse (patients with VTE are treated for a long time, even at low risk of relapse) They have a short half-life, so there is a risk of a rapid decrease in the anticoagulant effect if the dose is left out LIU '11 En Iniciace Propagace New anticoagulants Koagulační kaskáda Trombinová aktivita TF/Vlla Fibrinogen I IIa I Villa fondaparinux idraparinux apixaban Va : rivaroxaban desirudin blvalirudin argatroban dabigatran Rbrin "Hold it, I wonder if I might try the warfarin again?" Indirect anticoagulants Indirect anticoagulants structural similarity with vitamin K kompetitive antagonists of vitamin K - vit K is essencial for posttranslational carboxylation in clotting factors II (prothrombin), VII, IX, X, protein C and protein S - inducing synthesis of structuraly incomplete coag. factors j only in vivo delayed effect ___ I Food sources of vitamin K include cabbage, cauliflower, spinach and other green, leafy vegetables, as well as cereals Indirect anticoagulants v J_ binding to plasma protein (up to 99%) • metabolised in liver (CYP450), excretion - bile, urine • monitoring by measuring the INR - (international normalised ratio) healthy preson INR 0.8-1.2 with warfarin INR 2-3 AE: - haemorrhage in skin, GIT, kidneys, brain - rarely necrose of small intestine or skin or soft parts of the body Warfarin embryopathy: nasal hypoplasia chondrodysplasia punctata CNS abnormity mikrocephalia blindness Kl: - gastrointestinal ulceration - trombocytopenia - malign hypertension - pregnancy (teratogenic, bleeding), breast-feedina_ Indirect anticoagulants V_J • I: prevention of trombembolic diseases deep venous trombosis lung embolism • anticoagulant effect can be supressed by administering dose of vit K 20-40mg iv Warfarin • p.o. or i.v. aplikation • D: starting doses 5-15mg long-term doses 5-7 mg Dikumarol Etylbiskumacetat Fenprokumon Indirect anticoagulants v_) High variability in dosing • according to some published papers 0,5 - 50 mg/day! • genetic influences • CYP 2C9 activity (need to reduce doses down to 60%) -in Caucasian population 10 - 20% of people • mutation of C1 subunit epoxid-reductase (enzyme directly influenced by warfarin) - need to reduce dosing - in Caucasian population 14 - 37% of people • the therapy must be often customized according to diet, comorbidities • there are tables to help physicians Indirect anticoagulants V_J Warfarin - many interactions (plasma binding, CYP metabolisation) - mostly | risk of bleeding (sometimes induction of biotransformation - St. John's wort, phenobarbital, rifampicin) - alcohol !!!, allopurinol, anabolic steroids, several ATB and chemotherapeutics, disulfiram, thyroid hormones... - Cardiology drugs - ASA, heparin, chinidin, amiodaron... PHARMACOGENETICS of WARFARIN _THERAPY_ Gene CYP2C9 encodes an enzyme by which warfarin is metabolised. Polymorphism affects the pharmacokinetics and the amount of DRD Gene VKORC1 encodes the Ci subunit of the transmembrane protein "vitamin K epoxide reductase system" = VKOR. Patients with variant alleles need lower doses of WARFARIN to maintain the same INR (2-3 times) Up to 20% of the population belong to the high-risk group of carriers of the VKORC1 AA or VKORC1 GA polymorphism and at the same time at least one CYP2C9 mutation (2 *. 3 *)_ muni i MED CPIC - Clinical Pharmacogenetics Implementation Consortium recommends using the pharmacogenetic algorithm at http://www.warfarindosing.org - a dosing /table predicting the optimal dose of warfarin with r68pS(*t©o(f)MWlFfeOt©Ce5rding to CYP2C9 and VK0RC1 genotypes, recommended by CPIC and modified from FDA materials VK0RC1 CYP2C9 *l/*2 *l/*3 *2T2 *2T3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg • The ranges are derived from many published clinical (pharmacogenetic) studies Warfarin - drug interactions Tabulka 2. Klinicky signifikantní interakce jednotlivých lékových skupin s warfarinem (upraveno dl Míra interakce Antibiotika Kardiovaskulární léky Analgetika CNSI Potenciace Vysoká Ciprofloxacin Kotrimoxazol Erytromycin Flukonazol Isoniazid Metronidazol Mikonazol Amiodaron Klofibrát Fenofibrat Propafenon Phenylbutazone Pirox i kam Alkoh Citalc Sertri Pravděpodobná Amoxicillin/klavulanát Azithromycin Klarithromycin Levofloxacin Ritonavir Tetracyklín Acetylsalicylová kyselina Fluvastatin Simvastatin Acetaminophen Tramadol Celecoxib Disulf P hen; Fluvo Inhibice Vysoká Griseofulvin Nafcillin Ribavirin Rifampin Cholestyramin Barbil Karba Pravděpodobná Ritonavir Bosentan Azathioprin Interní medicína pro praxi | 2011; 13(11) | www.internimedicina.cz Adapted from Moravec, Terapie warfarinem a režimová opatření - mýty a fakta. Interní medicína pro praxi. 2011; 13(11) Warfarin - drug interactions i lékových skupin s warfarinem (upraveno dle 13) askulární léky Analgetika CNS léky GIT léky Jiné on St ion Phenylbutazone Pi roxi kam Alkohol Citalopram Sertralin Cimetidine Omeprazol Anabolické steroidy icylová kyselina in tin Acetaminophen Tramadol Celecoxib Disulfiram Phenytoin Fluvoxamine Fluorouracil Tamoxifen Levamisole Paclitaxel ramin Barbituráty Karbamazepin Merkaptopurin i Azathioprin Vakcína chřipky ernimedicina.cz Adapted from Moravec, Terapie warfarinem a režimová opatření - mýty a fakta. Interní medicína pro praxi. 2011; 13(11) OTHER FACTORS AFFECTING INR Decrease of INR Reduced metabolism Uremia Higher intake of food containing a lot of vitamin RISK of treatment ineffectiveness and thrombus formation RISK of bleeding Increase of INR ■ Increased metabolism (thyrotoxicosis, fever, infection) ■ Malaabsorption states with vitamin K deficiency ■ Hepatal insuficiency ATB therapy and suppression of intestinal microflora Normal Situation Prothrombin (Plasma) Prothrombinase Thrombin Antithrombin Bathtub kinetics Inactive Thrombin (Serum) The dynamics of thrombin appearance and disappearance are like the filling of a bathtub without a stopper from a large bucket (the bucket size Is the amount of prothrombin, prothrombinase activity determines how fast It Is poured In, and the drain size Is the action of antlthrombln) Heparin Prothrombin —► Prothrombinase Nonnal In T f Thrombin Antithrombin >r I nactiveThrombi n r--- Bathtub Kinetics Heparin makes antithrombin a much more potent thrombin inhibitor, it works on the drain side. Thrombin comes in normally but goes out much faster. The result is less thrombin. Hirudin Prothrombin —► Prothrombinase Nctaafln irudin binds Thrombin Inactive Thrombin Hirudin binds directly to thrombin, so the IN- and OUT velocities remain unchanged but thrombin itself is inhibited. Oral Anticoagulation Prothrombin Prattmombinase Lfess In Thrombin a Antithrombin Noi^naJ)Out ^-r Inactive Thrombin r '- Bathtub Kinetics Lack of vitamin K or drugs that prevent its functioning (vitamin K antagonists) make that several clotting factors including prothrombin, are not formed normally. However, thrombin decay remains normal, or: less in and normal out Fibrinolysis • via FXII, at the same time with coagulation steps leading to removal of the thrombus - fibrinolysis are taken • the most important factor is plasmin, it is found in inactive form in plasma and it is incorporated into thrombus bound to fibrin • to prevent early thrombus dissolution it contains also a2- antiplasmin, which is inhibitor of plasmin, and is nearly completely inhibiting it • plasmin activation is possible via two main plasmin activators - t-PA (tissue PA) produced by endotelium and u-PA (urokinase like PA) produced by fibroblasts, epitelium, pneumocytes, placent cells etc.) Fibrinolysis t-PA-PAI-1 complex Plasminogen activation t-PA Plasminogen Fibrinooen — --.Cross-I.nked fibrin Formation of insoluble fibrin Factor XIII Thrombin Factor XIII Fibrin-degradation products the main role of t-PA is regulation of iv thrombi, u-PA participates in proteolytic processes like tissue remodelation, tumor invasion, fertilisation or embryogenesis urokinase is u-PA metabolit - enzym found in urine with preservated aktivation ability fibrinolysis aktivation is under controle of plasminogen activator inhibitor PAI 1-3 and protein nexin /-\ Fibrinolysis • fibrinolysis is influenced by fibrin - on its surface complex t-PA + plasminogen + fibrin is formed, activated plasmin is immediately inhibited by a2-antiplasmin • lysis occurs when t-PA is released from endotelium upwards from wound (reaction to slowing-down of the blood flow) • this release of t-PA activates small amount of plasmin, which alterates the structure of fibrin and enlarge fibrin surface, thus enabeling the activation of more of plasminogen • this way activation overbalance inhibition and lysis accelerates • e-aminokapronic or tranexamic acid, binds to fibrinogen and prevent its adsorption on fibrin antidote, haemophilic patients • fibrinolysis is depending on PA/PAI ratio, which is under influence of many external factors: • exercise, stress, fear, anger, smoking • It level of PAI is in the morning, at the same time t-PA is a => the highest incidence of AMI f-\ Fibrinolytika (trombolytika) Fibrinolytics (thrombolytics) are plazminogen activators (PA). Ideal thrombolytic drug should be administered i.v. and should cause selective thrombolysis in the thrombus without converting plasminogen into plasmin I. generation Fibrinolytics II. generation I. generation Non-selective —► systemic activation of plasmin • streptokinase • urokinase II. generation Binding to fibrin —► fibrinolysis targeted on the thrombus •t-PA • anistreplase • saruplase Fibrinolytics (thrombolytics) Clinical use: Severe lung embolisation Deep venous thrombosis Arterial oclusion Acute myocardial infartion therapy Unwanted effects Bleeding f-\ Fibrinolytics (thrombolytics) Contraindications Absolute Active bleeding from intracranial or chest trauma Bleeding from tumor or from vascular abnormality Relative Hypertension Other risks of bleeding r Fibrinolytics (thrombolytics) non-selective streptokinase • nonenzymatic protein isolated from (3-hemolytic streptococcus • indirectly causes activation of plasminogen • parenteral administration —► lysis of ACUTE thrombi • it is cheap, but antigenous - prev. bolus hydrocortisoni 100 mg i.v., do not give again in 1 year after the previous usage •I: - very good drug for recanalisation after IM infusion + AcSal - RMP Stroptaso Fibrinolytics (thrombolytics) nonselective _urokinase_ origin is human urine, metabolic product of u-PA direct plasminogen activator not antigenous weaker than streptokinase, j, AE, RMP Rhootromb Fibrinolytics (thrombolytics) selective t-PA (alteplase) • high afinity to fibrin • concentrations used in therapy are 1000x higher than physiologic, short t1/2 = risk of reoclusion • alteplase RMP Actilyse - recombinant, single-chain t-PA • duteplase - double-chain tPA • reteplase - similar but has a longer elimination half- life allowing bolus administration, simpler structure = only peptid domain of tPA • tenecteplase (TMK-tPA), RMP Metalyse - bolus administration, 80x higher selectivity than alteplase Defibrinants ankrod, batroxobin snake toxins, degradating fibrinogen to fibrin —► consumption, thrombolytic action • used more often as anticoagulant than trombolytics • Ankrod (ancrodum) is purificated defibrinant protease from snake Ankistrodon rhodostoma (Calloselasma rhodostoma) - Malayan pit viper, which is used as fibrinogenolytic and anticoagulant. •Batroxobin is serin protease from snake Bothrops atrox-v Common lancehead, which is decreasing plasma level of fibrinogen, Vglasminogen and a2 -antiplasmin. It has similar effects as ankrod. /-\ Antifibrinolytics • inhibit plasmin from binding to fibrin • additive drugs used when substituting loss of coagulation factors to stop bleeding during/after surgery (e.g. tonsilectomy, prostatectomy) • menorrhagia • dental surgery in heamophilic patients (extraction) • AE: nausea, Kl: DIC • £-aminokapronic acid (EACA) • tranexamic acid - renaissance - reduce blood loss during trauma bleeding (accidents, accidents) • p-aminometylbenzoic acid (PAMBA) renal elimination •aprotinin - inhibits proteolytic enzymes (trypsin, chymotrypsin and plasmin) - for fibrinolytic drugs overdose, pancreatitis, patient at risk of major blood loss during heart or liver surgery - platelets adhesion to vasal subendotel via collagen, basal membrane, lb receptors and vWF (which is cast loose from complex with FVIII during coagulation) - start of many complex reactions, shape changes, release of many substances —► support adhesion, lysozym (antibacterial), vasoconstriction, PF4 - binds ATIII - prevents early inhibition of coagulation, atracts leukocytes etc. - aggregation is promoted by various agonists including colagen, thrombin, ADP and TXA acting on specific receptor on the platelet surface, activation leads to expresion of lllb/lla receptors which binds fibrinogen and links platelets together (aggregation) - forming clot is at the same time signal for surrounding tissues to start works on its cleaning away = fibrinolysis (release of t-PA) Procoagulant Activity GP la/lla Activation And Release f-\ Antiplatelet drugs (Antiagregants) ^inhibition of agregation, specific profylaxion of arterial thrombose, secundar prevention of AMI • antiplatelet therapy after AMI needs to be started as soon as possible (for the best results not later than 1 hour after first symptoms) • usually used in combination with heparin to ensure proper perfusion and infarction size reduction • there are other drugs with antiplatelet activity, but these are not used in this indication : hydrochlorochin, klofibrate, indometacin, fenylbutazon, some of prostaglandins and neurotropics f-\ Antiplatelet drugs (Antiagregants) How do they work? . .inhibition of thromboxan A2 syntese - inhibition of COX ASA, indobufen, sulfinpyrazon 2. Inhibition of thromboxan A2 syntese via increasing cAMP level in thrombocyte • inhibition of fosfodiesterase - dipyridamol, pentoxifylin • stimulation of adenylatcyklase - prostacyklin and analogs 3. Inhibition of fibrinogen cross-bridging among thrombocytes • inhibition of ADP P2Y12 receptor in thrombocyte membrane - ticlopidin, Clopidogrel, prasugrel, ticagrelor • inhibition of fibrinogen receptor in thrombocyte membrane V (llb/llla) - tirofiban, lamifiban, monoclonal antibodies - \. abciximab) Antiagreganria: Mechanismus účinku antiagreganrií: Kys. aceíyl-saiicylová Suiflnpyrazon In do buf en Trombocyty Endotciiální buňky Uklopidin C <:[ AGREGACE TB c VAZODILATACE Dipyridamol Kyselina arachidonová kyselna acetylsal cylová /blokáda G P lib lila agrogaco dostičok l tvorba trorrbu vWF - von Willebrandův faktor Obr. 3 Aktivační kaskáda vedoucí ke shlukování destiček. f-\ Antiplatelet drugs (Antiagregants) Indications: ischemic cerebrovaskular diseases ischemic heart disease • periferal arteries disesases • to reduce thrombogenous effect of synthetic materials Antiplatelet drugs acetylsalicylic acid_ • deacetylates and irreversibly inhibits COX • COX: in thrombocytes —► TXA2 (agregation) in endotel cells —► PGI2 (antiagregation and vasodilatation) =^ we want to block TXA2 • Thrombocytes unlike endotel cells are not able to syntetise COX = selective inhibiton of COX in thrombocytes (persistence 7-10 days) • Effect depends on dose (high doses block also endotel COX) Antiplatelet drugs acetylsalicylic Low doses of AcSal can reduce risk of AMI and sudden death in patients with angina pectoris down to 50% Also other NSAID (ibuprofen, naproxen) have antiagregant effect, but this effect is not irreversible • AMI - first-aid treatment immediately administer 500mq ASA Antiplatelet drugs acetylsalicylic acid • D: usually 50-100mg per day • there is no laboratory test to monitore effectivity of therapy - only clinical symptoms • No antidote available, in case of need it is possible to administer hemostyptics, antifibrinolytics or thrombocytes Antiplatelet drugs acetylsalicylic acid • Indication: • AIM, instable AP • Prevention of AIM (also combined with warfarin) • Ischemic brain stroke • After PTCA, by-pass Disadvanatges: • AE - about 20% of pacients • Rezistance to ASA 10-20% of pacients f-\ Antiplatelet drugs (Antiagregants) Other NSAIDs with antiaggregant properties - but reversible Sulfinpyrazon • NSAID, competitive inhibitor of COX • inhibing adhesion of thrombocytes and releasing of several substances • elonging persistance of platelets in circulation • Indobufen - short effect, expensive • Picotamide Antiplatelet drugs - pentoxifylin improves deformability of erythrocytes •decreasing level of fibrinogen and blood viscosity, thus improving microcirculation, antiinflamatory ef._ /- Antiplatelet drugs - dipyridamol coronary vasodilatant, phosphodiesterase inhibitor • decreasing adhesivity of platelets to damaged endotel t cAMP in platelets \ TXA2 used in combination with aspirin, warfarin_ /- Antiagregancia - cilostazol • vasodilatant, phosphodiesterase inhibitor • in limb ischemia, claudication Antiplatelet drugs - tienopyridines V_) • block receptor P2Y12 for ADP (activates receptors on surface of thrombocytes —► this is where fibrinogen binds) • onset is slow (several days) and lasts 7-10 days • NU: hemorrhage, diarrhea and leucopenia 1. Ticlopidin (RMPTicIid) 2. Clopidogrel • better effect, less AE • convenient combination with ASA after PCI with stent implantation RMP Plavix, Clopidogrel... • Fix combination with ASA RMP Duoplavin, Duocover 3. Prasugrel - 3.generation RMP Efient Antiplatelet drugs - non tienopyridines V_J REVERSIBLE Ticagrelor Adm. 2x a day According to clinical studies has a better reduction in CV events than after the combination of Clopidogrel + ASA administration Cangrelor Rapid onset of action in minutes (for continuous infusion only) Biological half-life is only 3 minutes O full platelet function is restored within 1 hour of stopping the infusion f-\ Antiplatelet drugs GP llb/llla Rc antagonists • they are supposed to block all pathways of platelet activation since they all converge on activation of GP llb/llla receptor 1. eptifibatide - small peptide, i.v. adm., short effect 2. tirofiban, lamifiban - similar structure to ligands for GP llb/llla receptor, i.v. adm. effect lasts 2-4 hours 3. abciximab - monoclonal antibody fragment directed against the receptor, only for high-risk patients, immunogenous al active inhibitors - sibrafiban, roxifiban, lefradafiban... - did not pass clinical trials Antagonists llb/llla Rc In clinical practise ve have currently available these intravenous drugs: abciximab (ReoPro), tirofiban (Aggrastat) a eptifibatid (Integrilin) Disadvantage is high price In our conditions we consider llb/llla blockers indicated in: - PCI with thrombus in coronar arthery confirmed by angiography - high-risk patient (with positive troponin, diabetics) - in intervention on degeneratively changed aortocoronar bypass kysel na acetylsal cylová kyselina arachidonová j_ _7jŽL_ / blokáda GP II:) lila agrogaco destiček tvorba trorrbu vWF - von Wllebranduv faktor Obr. 3 Aktivační kaskáda vedoucí ke shlukování destiček. klidové forma trombocytu ruptúra plátu. adheze trombocytu aktivace trombocytu exprese receptoru GP llb/lllo blokáda trombocytu vWF - von Willebrandův faktor Obr. 4 Mechanismus účinku inhibitoru receptoru GP fib/llla. Hemostatics Used to control and stop bleeding in injured patients or after surgery or in diseases causing excessive bleeding. • gelatine • gelatine sponge • colagen • etamsylate • vasopresine derivates • frozen blood plasma, human fibrinogen, thrombin, coagulation factors (Novo VII) Topical hemostatic Commercial name Passive or Mechanical Agents Gelatins Surgifoam , Gel foam , Gclfilm , Gelita-spon-% Geli putty5: Collagen Instate Helitene";, Helistar1 Cellulose-based products: oxidized regenerated cellulose Surgicel Original Surgicel Nu-Knit®, Oxycel , Surgicel Fibrillar , Interavd , Gelitacel® Cellulose-based products: oxidized cellulose ActCel®, Gelitacel'' Polyssacharide hemospheres Arista™AH Adhesives BioGlue® Active Agents Topical thrombin Thrombin-JMI®, Evithromx, Recothrom® Fibrin sealants Tisseel®, Evicels, Crosseal™ Flowable agents Porcine gelatin + thrombin Bovine collagen + thrombin Surgiflo®, Floseal® Hemostatická houbička SKn RUM* OSI HEMOSTATIC GEL Minor Wound Care Bleeding Stop Cel 3ml Syringe ♦ 5 Tips P HOC-0?Jj Hemodenr 40cc Item «9007073 Tachosil matrice pro tkáňové lepidlo c-\ Hemostatics \_) Etamsylate (RMP Dicynon): antihemorrhagic and angioprotective effect no influence on coagulation factors or fibrinolysis stimulates trombopoiesis increase PGI2 synthesis Vasopresine derivates: terlipresin —► lypresin, orniprosin strong vasoconstriction, decrease of blood flow in splanchnic area (decrease in portal pressure) and skin desmopresin is also used in treatment of diabetes insipidus (longer t1/2 than vasopresin) and nykturia in children and adults, it increases activity of fVIII and release of tPA