Drugs affecting clotting and hemopoiesis MUDr. Alena Machalová 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 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 Hvpercoaqulation states Congenital disorders Acquired disorders 1,1 UIII IIED Primary haemostasis defect Secondary haemostasis defect Fibrinolysis defect Lack of anticoagulant factors Anticoagulation "ifa'ctors s= Decreased activity venous thrombosis arterial thrombosis 1,1 ü UI U E D Drugs affecting clotting Anticoagulants Thrombolytics Antiplatelet drugs Drugs improving deformability of ery Antifibrinolytics Hemostatics Blood products Coagulation cascade - the coagulation factors except VIII, V a TF are present in blood in the form of inactive precursors (zymogens) - f. V and VIII are not enzymes -TF-high affinity membrane receptor for fVII - cascade must be regulated by inhibitors, AT III -coagulation is working as an amplifier-why? .... evolutionary advantage Coagulation cascade ■ there are two classical pathways of coagulation - - contact activation pathway (formerly known as the intrinsic pathway, because all the components are present in blood), it is activated when blood comes into contact with artificial surface - tissue factor pathway (formerly known as the extrinsic pathway), this is the more important, primary pathway, which is initiated by contact with „tissue factor", it is also much quicker Contact activation (intrinsic) pathway Damaged Tissue factor (extrinsic) pathway Active Protein C Protein C * thrombomodulin Common pathway XIII •1 - fibrinogen •2 - prothrombin •3 - tissue thromboplastin •4 - Ca ions •5 - proakcelerin •7 - Prokonvertin •8 - antihemofilic factor - von Willebrand faktor •9 - Christmas factor •10 - Stuart-Prover factor •11 - PTA •12 - Hageman faktor •13 - fibrin stabilising factor •14 - protein C Coagulation cascade Endothelium - Covered by heparansulphate Active participant of coagulation -synthesis of vWF, tissue factor, PAI (in response to angiotensin IV) Limitation of hemostasis - PGI2, NO, ADP (platelets inhibition), tPA, thrombomodulin Anticoagulants • do not work against old thrombuses • influencing ATM I or synthesis of coag. factors • monitoring of therapy is necessary • Indications: Deep venous thrombosis Lung embolisation Arterial embolisation Prevention of arterial emboli in patients with heart valve failure, atrial fibrilation and acute myocardial infarction Direct - heparin and its derivates, pentasaccharides, gatrans, xabans Indirect - „oral antikoagulants" Přímá antikoagulancia 1. Antithrombine activators (= inhibitors of Ma and Xa) Heparin UFH LMWH (incl. sulodexide) Heparinoids Pentasaccharides 2. Direct thrombin inhibitors (Ma) gatrans 3. Factor Xa inhibitors xabans NOACs = novel oral anticoagulants alias DOACs Direct anticoagulants HEPARIN i.v. ors.c. anticoagulants, used also in vitro to coat inside surface of test tubes, dialysis machines etc. ■ its molecule has the biggest negative charge of all biomolecules ■ it was discovered in 1916 by a second-year medical student, who was attempting to extract some coagulant substances from various tissues during a vacation project, instead he found a powerful anticoagulant ■ interesting fact: it is present even in bodies of invertebratae, who are lacking coagulation system similar to ours Direct anticoagulants HEPARIN physiologic function is not known, maybe antibacterial protection in wound ■ released together with histamin, maybe to prevent forming of thrombus in dilated vessels ■ produced by mastocytes and basophiles and released mostly in liver (hepar), lungs and gut ■ commercial preparates are extracted from beef lung or pig intestine its doses are specified in units of activity, not in mass Direct anticoagulants HEPARIN a its derivates The effect of heparin depends on the presence of antithrombin III is recommended to monitor its level during prolonged treatment. How does it work? anticoagulation activity of heparin depends on presence of AT III, which is irreversible inhibitor of thrombin activity as well as some other coagulation factors (e.g. factorXa) heparin cca 1000x accelerates and helps interactions of ATI 11 (exposing its active site for quick interaction with proteases)__ Direct anticoagulants HEPARIN • in vitro elongation ofAPTT- activated parcial thromboplastin time - 25-39s, —> therapy control •decreasing adhesivity and count of thrombocytes (I 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 ■=> inactive product Renal excretion Elimination half-life is proportional to the dose administered 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 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 V • p Nun patients are able to give injections themselves at me_ Direct anticoagulants Low-molecular-weight heparins increase ATI 11 activity against lla 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 Theological properties of blood I: DVT, ischaemic heart disease, critical limb ischaemia (CLI), microcirculatory disorders in diabetic, scerebral artery occlusion. 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) o we can use them to substitute heparin in HIT_ Direct anticoagulants Sulphonated pentasacharid • fondaparinux (Arixtra), indraparinux - (named forAsterixa Obelix) indirectly anti-Xa, deep venous thrombosis, pulmonal embolisation, s.c. admin V_J Direct anticoagulants Thrombin inhibitors Antithrombin III - congenital deficiency iHirudoid® Cream 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 - dabiqatran (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 ■=> inhibit thrombin-induced platelet aggregation ' P-gp Substrate ■=> DDI (careful with verapamil) ■ CAVE - gastritis, oesofagitis, GER - GFR 30-50ml/min - over 75 let Beedinn complications (enterorrhagia, hematuria, melena) GIT bleeding ■=> USE GASTROPROTECTIVES Direct anticoagulants Thrombin inhibitors - GATRANS NTIDOTE 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 forthrombin. I: Withdrawal of the anticoagulant effect of dabigatran during life-threatening or uncontrolled bleeding orduring 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 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) k 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 II of the clinical trial. „Universal" NOAC ANTIDOTE (gatrans, xabans) But also LMWH and UFH 1 II I GATRANS or XABANS ?? n . state of the patient vs expected effects . An increased incidence of GIT bleeding has been reported Hepatal insufficiency is a contraindication for xabans (especially rivaroxabanl 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 -irt HE 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_1,1 -SfF New anticoagulants Iniciace Propagace Trombinová aktivita I ľ: íKxjan Koaguiační kaskáda TF/Vlla -*— Xa TFPI NAPc2 K /M TTP889 Villa fondaparinux idraparinux apixaban rívaroxaban Va desimdin bivalirudin argalroban dabigatran Fibrin 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 only in vivo delayed effect Food sources of vitamin K include cabbage, cauliflower, spinach and other green, leafy vegeta.bl.es, as well as cereals Indirect anticoagulants unding 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 Indirect anticoagulants 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 Etylbiskumacetát Fenprokumon Indirect anticoagulants 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 Warfarin - many interactions (plasma binding, CYP metabolisation) - mostly t risk of bleeding (sometimes induction of biotransformation - St. John's wort, phenobarbital, rifampicin) - alcohol III, 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 AAorVKORCI GA polymorphism and at the same time at least one CYP2C9 mutation (2 *. 3 *)_ u ü u 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 reSpe^tecfitlW^RfetttafSirding to CYP2C9 and VKORC1 genotypes, recommended by CPIC and modified from FDA materia Is J KORCI CYP2C9 Vri 'l/*2 *V2 '2/*i GG 5-7 rag 5-7 nig 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 5-7 mg 3-4 mg 3-t mg 3-4 mg 0 5-2 mg 0 5-2 mg i-\ mg 3-1 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg AG AA • The ranges are derived from many published clinical (pharmacogenetic) studies 1,1 u II i IIED 1 Warfarin - drug interactions J Tabulka 2. Klinicky signifikantní inter akce jednotlivých lékových skupin s warfarinem (upraveno c Míra interakce Antibiotika Kardiovaskulárni léky Analgetika CNS PoTenciace Vysoká Ciprofloxacin Amiodaron Phenylbutazone Alko) Kotrimoxazol Klofibrát Pi roxi kam Črtali Erytromycin Fenofibrat Sertr - jkon^zc Propafenon Isoniazid Metronidazol Mikonazol Pravděpodobná Amoxicillin/klavulanät Acetylsalicylovä kyselina Acetaminophen Disu! Azithromycin Fluvastatin Tramadol Pher Klarithromycin Simvastatin Celecoxib Fluv< Levofloxacin Ritonavir Tetracyklín inhibier Vysoká Griseofulvin Cholestyramin Barb Naŕr MM n Karb Ribavirin -■ f ampin Pravděpodobná Ritonavir Bosen ta n Azathioprin Interní medicína pro praxi | 2011; 13(11J | www.internimedicina.cz Adapted from Morave c, Terapie warfarinem a režime vá opatření - mýty a fakta. Interní medicína pro prax 2011; 13(11) I Warfarin - drug interactions j lákových skupin ;_:.) i skulám i léky Analgetika CNS léky GIT léky Jiné ■ Phenylbutazone Piroxtkam Alkohol Citalopram Cimetidine Omeprazol Anabolickě steroidy t Sertralin on cylová kyselina Acetaminophen Disulfiram Fluorouracil n Tramadol Phenytoin Tamoxifen in Celecoxib Fluvoxamine Levamisole Paclitaxel amin Barbituráty Karbamazepin Merkaptopurin Azathioprin Vakcína chřipky ^rn i med icina.cz Adapted from Moravec, Terapie warfarinem a režimová opatrení - mýty a fakta. Interní medicína pro praxi. 2011; 13(11) OTHER FACTORS AFFECTING INR v J ^Decrease of INR ■ Reduced metabolism ■ Uremia ■ Higher intake of food containing a lot of vitamin ^Increase of INR ■ Increased metabolism (thyrotoxicosis, fever, infection) ■ Malaabsorption states with vitamin K deficiency ■ Hepatal insuficiency ■ ATB therapy and suppression of \ intestinal microflora V RISK of treatment ineffectiveness and thrombus formation RISK of bleeding / In Normal Situation Prothrombin Prothrombinase J Thrombin Antithrombin I Inactive Thrombin (Plasma) (Serum) thtub kinetics 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 antithrombin) Heparin Prothrombin "irombinase ^ Thrombin Antithrombin McíŕeiW InactiveThrombin 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. V_J Hirudin Prothrombin ► Prothrombinase NqSnnaTln y / Hirudin binds Thrombin / I a Antithrombin I NorfQjOut _>r Inactive Thrombin Bathtub Kinetics Hirudin binds directly to thrombin, so the IN- and OUT velocities remain unchanged but thrombin itself is inhibited. V__I Oral Anticoagulation PromnjmDirase Thrombin Antithrombin NorfnaDOut Inactive Thrombin 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 1 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 l1— Plasminogen activation \ act I vi X I Fibrin clot t-PA Plasminogen —*■ ^Cross-linked , fibrin I ■ .CH.lt:..I I - of insoluble fibrin Facto* " XIII Fibrin-degradabon products Fibrinolysis > 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 PA11-3 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-anti plasm in 1 lysis occurs when t-PA is released from endotelium upwards from wound (reaction to slowing-down of the blood flow) 1 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 1 this way activation overbalance inhibition and lysis accelerates Fibrinolysis • 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 • tt level of PAI is in the morning, at the same time t-PA is U => the highest incidence of AMI 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 Fibrinolytics (thrombolytics) Contraindications Absolute Active bleeding from intracranial or chest trauma Bleeding from tumor or from vascular abnormality Relative Hypertension Other risks of bleeding Fibrinolytics (thrombolytics) non-selective streptokinase nonenzymatic protein isolated from p-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 Streptase •23.11.2021 Fibrinolytics (thrombolytics) nonselective urokinase • origin is human urine, metabolic product of u-PA • direct plasminogen activator • not antigenous • weaker than streptokinase, J, AE, RMP Rheotromb - K' ■- I. V. I... I, .k. 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 oftPA tenecteplase (TMK-tPA), RMP Metalyse- bolus dministration, 80x higher selectivity than alteplase Fibrinolytics (thrombolytics) selective anistreplase ASPAC J = acetylated streptokinase - plasminogen activator complex • inactive form, binding to fibrin —> deacetylation —> activation • activated anistreplase is quickly eliminated from circulation by a2- antiplasmin —> J, AE • very good effect in AMI \^ antigenous Fibrinolytics (thrombolytics) selective Saruplase (rscu-PA) ) • similar to urokinase, but high afinity to fibrin \ • possible combination of saruplase with t-PA for reperfusion of coronary arteries / \_Defibrinants ankrod, batroxobin_J 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 -Common lancehead, which is decreasing plasma level of fibrinogen, Vpjasminogen and a2 -antiplasmin. It has similar effects as ankrod. ^/ •16 Alf i me praže enzyme obtained by recombinant technology • it is deriváte of metaloproietinase called fibrolase obtained from malayan pit viper • specific MoA: direct degradation of fibrin • advantage - very short t1/2 in systemic circulation currently in clilnical testing Agregation 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 AT1II - 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) Antifibrinolytics inhibit plasmin from binding to fibrin • additive drugs used when substituting loss of coagulation factors to stop bleeding during/after surgery (e.g. tonsiiectomy, prostatectomy) • menorrhagia • dental surgery in heamophilic patients (extraction) • AE: nausea, Kl: DIC • E-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 GP llb/llla VWF Fibrinogen GP I a/I I a Fibrin Procoagulant **J7 Activity Adhesion Prothrotnbinase Complex Activation And Release Collagen Subendothelial Matrix Proteins 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 : hydrochiorochin, klofibrate, indometacin, fenylbutazon, some of prostaglandins and neurotropics Antiplatelet drugs (Antiagregants) How do they work? 1. Inhibition of thromboxan A2 syntese ASA, indobufen, sulfinpyrazon inhibition of COX . Inhibition of thromboxan A2 syntese via increasing cAMP level in thrombocyte inhibition of fosfodiesterase - dipyridamol, pentoxifylin stimulation of adenylatcyklase - prostacyklin and analogs . 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 (llb/llla) - tirofiban, lamifiban, monoclonal antibodies -abciximab) Antiägregqndq: fys. ocgtyl-sallcylová ■ Mechanismus účinku antlsgrcgandi: Tromoocyry I Endptelifiiní buňky AA AA Sulfinpyrazon Indobufen- PG-cnd TMSopUin ■ AGREGACE TB Dipyridamol ■ VAZODILATACE 3 _ kysel na kyselina arachidonová ]__rc*ybal túlavá , GP llb/llla, / blokáda GPIIb.llla ayrogaco dosticok tvorba trorrbu vWF - von V/íll*brandúv faktor Obr. 3 Aktivační kaskáde vedoucí ke sbiukoYáni deettČek. 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 acid • 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 500mg ASA Antiplatelet drugs acetylsalicylic acid D: usually 50-1 OOmg 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 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 vimproving microcirculation, antiinflamatory ef._ Antiplatelet drugs - dipyridamol f' coronary vasodilatant, phosphodiesterase inhibitor ^ • decreasing adhesivity of platelets to damaged endotel t cAMP in platelets J, TXA2 V used in combination with aspirin, warfarin_y Antiagregancia - cilostazol 1 vasodilatant, phosphodiesterase inhibitor 1 in limb ischemia, claudication Antiplatelet drugs - tienopyridines 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 (RMP Ticlid) 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 •23.11.2021 Antiplatelet drugs - non tienopyridines 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 ■=> full platelet function is restored within 1 hour of stopping the infusion 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 ^[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.naaachidor.ovft ]__«cety'5al cylova .G.'llhillla ' Wokada GP llb'llla agrogaco dast.cek tvorba trorrbu - von Wlebrand&v faktor Obr. 3 Aktivacnikaskada vedoucike sMukovsni desticeh. •21 akttaace trornbocytu blokäda ogregace trombocytö Obr. 4 Mechanismus ucinku inhibitcxu teceptord GP flb/ttfa. 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 Surgi/oam* GeJfoam*, Gelfilm*, Gelita-spon®, Geli putty5 Collagen Instate Helitene1, Helistat* Cellulose-based products: oxidized regenerated cellulose Surgieel Original', Surgicel Nu-Knit*, Oxycel* Surgicel Fibrillar, Interceed3, Gelitacel* Cellulose-based products: oxidized cellulose ActCel* Gelitacel® Pol yssacha ride hemispheres Arista™AH Adhesives EioGlue* Active Agents Topical thrombin Thrnmbin-IMP-, Evithrom'-, RecothronV Fibrin sealants Tisseel3-, Evicel* Crosseal™ Flowable agents Porcine gelatin + thrombin Bovine collagen + thrombin Surgiflo*. Floseal* 4 •23.11.2021 Hemostatics Etamsylate (RMP Dicynon): antihemorrhagic and angioprotective effect no influence on coagulation factors or fibrinolysis stimulates trombopoiesis increase PGI2 synthesis Vasopresine derivates: terlipresin —► lypresin, ornipresin strong vasoconstriction, decrease of blood flow in splanchnic area (decrease in portal pressure) note, desmopresin is used in treatment of diabetes insipidus (longer t1/2 than vasopresin) and nykturia in children and adults •23