DRUGS USED IN DISORDERS OF HEMOSTASIS

DRUGS USED IN DISORDERS OF HEMOSTASIS

Coagulation disorders: Thrombosis
pathological development of blood clots resulting from inappropriate activation of hemostatic mechanisms (without the damaged vascular wall) it can occur in either arterial or venous circulation

Low cell concentration High cell concentration
Coagulation disorders: Thrombosis Arterial thrombosis thrombosis secondary to disrupted atherosclerotic plaque coused by platelet contact with subendothelial structures leads to a local occlusive ischaemia, myocardial infarction and strokes „white thrombus“ formation, rich of platelets and fibrin atrial fibrilation → left atrial thrombosis → stroke Low cell concentration High cell concentration

Coagulation disorders: Thrombosis
Venous thromboembolism: deep vein thrombosis + pulmonary embolism (distant embolism) low blood flow, stasis endothelial cell activation hypercoagulability red thrombus rich of RBC and fibrin, few platelets usually originates in the veins in the calf

Drug therapy to treat or prevent thrombosis is extensively used because such diseases are common as well as serious

Thrombosis: Drugs reducing processes of hemostasis: ANTIPLATELET AGENTS Antithrombotics ANTICOAGULANT DRUGS FIBRINOLYTICS (thrombolytics): less important in therapy nowadays Bleeding: Drugs increasing processes of hemostasis: HEMOSTATICS (antihemorrhagic drug)

Pharmacotherapy of thromboembolic diseases: Antithrombotic therapy
Drugs used to prevent and treat red thrombus (VTE): ANTICOAGULANTS Drugs sed for prevention and treatment of platelet-rich „white“ thrombi (ATE): ANTIPLATELET DRUGS Anticoagulants are also effective but not widely used (benefit vs risk of AE) Occlusive thrombi: Mechanical extraction (percutaneous CI, open surgery) FIBRINOLYTIC DRUGS

Anticoagulants Classification is based on the mechanism of action (practically important !!!): Group 1: Rapid inhibition of coagulation factors which occurs also in vitro (in a test tube). Drugs are effective in urgent situations Activators of antithrombin = indirect inhibitors of thrombin, FXa and of other factors: heparins Direct inhibitors of thrombin (FII) or Fxa Group 2. Delayed effect through inhibition of formation of active coagulation factors in the liver. Drugs are active only in the organism (in vivo) warfarin and other coumarins = vitamin K antagonists

Heparins: injectable anticoagulants with immediate effects
Heparins inhibit haemocoagulation both in vitro (in a test tube) and in vivo

Unfractionated = High-MW Heparin
heparin is a heterogenous mixture of sulfated mucopolysaccharides (long unbranched polysaccharides consisting of a repeating disaccharide units) with a high negative charge density the polymeric chain is composed of repeating disaccharide units of D-glucosamine and uronic acid linked by 1-4 inter-glycosidic bond. The uronic acid residue could be either D-glucuronic acid or L-iduronic acid molecular weight ranges from 6,000 to 40,000 Da. The average MW of commercial heparins is between 12, ,000.

Heparins Pentasaccharides UFH unfractionated LMWH Low-molecular weight

Heparin: mechanism of action
Antithrombin (ATIII) is a member of the serine protease inhibitor (serpins) family which regulates coagulation by inactivating activated clotting factors through formation of irreversible complexes with thrombin (FIIa), FXa, FIXa, FXIa and FXIIa. Heparin forms a high-affinity complex with antithrombin. The formation of antithrombin - heparin complex increases by 1000-fold the rate of inhibition of two principle procoagulant proteases, thrombin (factor IIa) and factor Xa. Heparin is an indirect thrombin and FXa inhibitor with a fast onset of action (it requires antithrombin for its effect) inhibition of thrombin leads to inhibition of platelet`s activity = inhibition of platelet aggregation, as well as to a decreased activation of factors V and VIII

Inactivation of coagulation factors is heparin chain-length dependent
Inactivation of thrombin requires the formation of a ternary heparin–antithrombin–thrombin complex. This complex can be formed only by heparin chains at least 18 saccharide units long. In contrast, for factor Xa inhibition only the pentasaccharide unit or short-chain (fractionated) heparins are sufficient lenthtough

Low-molecular weight heparins (LMWH) and pentasaccharides
Anti-FXa / anti-FIIa (thrombin) activity UFH = 1 : 1 LMWH = 2,5-7,5 : 1 Pentasaccharides = 50:1 Inhibition of FXa, unlike thrombin, does not require its binding to heparin but only to antithrombin.

UFH Pharmacokinetics and pharmacodynamics:
UFH is a highly charged molecule - it is poorly transported across biological membranes and degraded by gastric acid administration i.v. (immediated effect) s.c. (effect in 1-2 h), maximum effect in 3 h, duration h heparin should not be given intramuscularly because of the danger of hematoma formation t1/ min UFH does not cross the placenta, does not appear in breast milk

UFH Parenteral administration precludes its long-term use.
It is generally given to postoperative patients and to those with acute infarction requiring immediate anticoagulant action Heparin overdose or hypersensitivity may result in excessive bleeding. Protamine sulphate, highly positively charged low-molecular-weight proteins, are used as an anti-dote for excessive bleeding complications.

UFH Dosing of UFH: Monitoring heparin therapy:
i.v. bolus 5000 IU + continuous i.v. infusion 1000 IU/kg/day (individualized according to aPTT) Monitoring heparin therapy: aPTT (activated partial thromboplastin time) i.v. therapy: 6 h after therapy initiation, thereafter once daily target INR: 2 to 2.5-fold prolongation in most situations other possibilities: laboratory test for anti-FXa activity other tests for adverse effect monitoring: trombocyte count (due to the risk of trombocytopenia induced by heparin)

UFH Adverse effects: Bleeding: protamin sulfate: 1 mg i.v. for every 100 IU of heparin The incidence of major bleeding in patients on UFH is 1% to 3%. Thrombocytopenia heparin-induced (HIT) transient non-immune form in 10-25% severe immune-mediated form in 1 to 4% (mortality 30%) antibody-mediated reaction that is associated with thrombosis. The heparin-induced antibody is directed against the heparin-platelet factor 4 complex. These complexes bind to receptors on adjacent platelets, causing aggregation and paradoxical thromboembolism. In case of HIT: alternative drugs like lepirudin, bivalirudin, new oral thrombin and FXa inhibitors, fondaparinux, NO LMWH!!!) Osteoporosis (duration of therapy with heparin > 6 months), Hyperkalaemia injection site reactions hypersensitivity

UFH Contraindications
hypersensitivity to UFH patients actively bleeding hemophilia, thrombocytopenia severe hypertension intracranial hemorrhage ulcerative lesions of the GIT visceral carcinoma advanced hepatic or renal disease despite of the apparent lack of placental transfer, heparin should be used in pregnant women only when clearly indicated

UFH and low-molecular weight heparins comparison
UFH: anticoagulant effect differs between preparations, activity expressed in biological units (IU), the effect varies largely between patients and is less predictable: frequent aPTT monitoring LMWH: the effect is correlated with the dose per kg of body weight, no need for therapy monitoring except for patients with a decreased renal function and morbidly obese individuals (monitoring using the test of anti-FXa activity) LMWH: less risk of adverse effects, only partial neutralization with i.v. protamine sulphate is possible less bleeding less thrombocytopenia

LMWH LMWHs in current use include e.g. enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin, reviparin, and bemiparin.

Antithrombotic management: Venous thromboembolism
VTE Prevention in Surgical Patients The standard of care, as reflected in current guidelines, is to use low-molecular-weight heparin, fondaparinux, or warfarin for thromboprophylaxis after surgery for hip or knee replacement and hip fracture. For abdominal surgery, where the risk of VTE is generally lower than in major orthopaedic surgery, low-dose UFH or LMWH can be used. Because of the convenience of less-frequent dosing, LMWH has generally replaced low-dose UH.

Antithrombotic management: Venous thromboembolism
VTE Prevention in Medical Patients Deep vein thrombosis (DVT) is often asymptomatic. The first sign of thrombosis may be pulmonary embolism (PE) = a potentially fatal cardiovascular event, responsible for between 5% and 10% of deaths in the hospital. Therefore, waiting for the signs and symptoms of VTE to appear before instituting anticoagulant treatment increases the risk of morbidity and mortality. The effect of prophylaxis is a reduction of about 40-60%. Both early ambulation and foot extension exercises help minimise venous stasis and should be encouraged.

Antithrombotic management
Treatment of Established DVT and pulmonary embolism The goals of treatment are symptom relief, prevention of PE, and prevention of DVT recurrence. Initial treatment is either unfractionated heparin by continuous intravenous infusion, low-molecular-weight heparin (LMWH) by subcutaneous injection (once or twice daily), or fondaparinux by once-daily injections followed by treatment with warfarin.

Vitamin K antagonists: warfarin
active only IN -VIVO blocks activation of prothrombin (FII) and factors VII, IX and X. The γ-carboxylation of glutamate residues of the factors does not work BUT! It affects the activation of the endogenous anticoagulant proteins C and S as well ! the effects of warfarin can be reversed with vitamin K (w. acts as an inhibitor of synthesis rather than pharmacological antagonist!!!) or, when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate (contains only the factors inhibited by warfarin) or fresh frozen plasma (depending upon the clinical indication) in addition to intravenous vitamin K

Mechanism of action: prevention of active coagulation factors formation in the liver
Warfarin Vitamin K active inactive active Vit K is consumed during synthesis of active coagulation factors active Vit K is consumed during active coagulation factors formation inhibition of enzymes necessary for active Vit K recycling

Warfarin Pharmacokinetics well absorbed,
binds to plasma proteins( >90%) eliminated via CYP2C9 as 7-hydroxymetabolite (80%) and kidney, crosses the placenta (pregnancy!) does not appear in breast milk

Warfarin Pharmacodynamics: Racemate: the more active form = S-warfarin
Onset of action depends on: absorption: Cmax in 1 h while the maximum effect is reached in 2-3 days a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K-dependent clotting factors: t ½: f VIIa = 6 h, f IXa, Xa, IIa 24, 40 and 60 h there is an 8 to 12-hour delay in the action of warfarin After therapy discont., the effect lasts for 4-5 days.

Warfarin Pharmacodynamics:
w. activates endogenous anticoagulant proteins C and S (having the shortest t1/2) Initially, a pro-thrombotic states develops Therefore, warfarin therapy has to be initiated with heparin INR is monitored and heparin gradually discontinued

Limitations of vitamin K antagonists
A narrow therapeutic index (range between effective and toxic doses). Non-linear pharmacokinetics. Small changes in dose can result in considerable changes in the anticoagulant response.

Interindividual and intraindividual variability in response to warfarin (genetic and nongenetic factors ) Nongenetic factors modifying the effects of warfarin: impairment of hepatic function (decrease in biosynthesis of clotting factors) inhibition of w. elimination due to CYP2C9 blockade (amiodarone, clarithromycin) competition for binding sites of plasma proteins (NSAID) decrease in production of vit K (antibiotics with a broad spectrum) intake of vit. K (incl. food - broccoli) enzymatic induction of CYP2C9 (carbamazepine, barbiturates)

Interindividual and intraindividual variability in response to warfarin (genetic and nongenetic factors ) Genetic factors modifying the effects of warfarin: Genetic polymorphism in the cytochrome P450 2C9: Carriers of two CYP2C9*1 alleles (the wild type) are extensive metabolizers of warfarin. CYP2C9*2 alleles and CYP2C9*3 alleles are associated with significantly decreased CYP2C9 activity, poor metabolizers of warfarin are homozygous carriers of mutated alleles (1/10 of the CL observed in CYP2C9*1 homozygotes): increased effect in poor metabolizers (about fold lower doses) Homozygosity of the vitamin K epoxide reductase complex subunit 1 (VKORC1) variant C1173T (*2) allele was related to increased risk of bleeding after warfarin, therefore 2.4-fold, 1.6-fold and 1.9-fold lower dose requirements compared with the wild-type.

Monitoring warfarin therapy: Prothrombin time…INR (International Normalized Ratio) Current guidelines recommend INR level of Excessive effect: INR >3 – bleeding, requires hospitalization (45% GIT) INR >4 - risk of intracerebral hemorrhage (mortality 68%) Insuficient effect: thrombo-embolic episodes Dosage: how much? how long? Treatment with warfarin should be initiated with daily doses of mg. The initial adjustment of the prothrombin time results in a dose of 3 -7 mg/day. Duration of w. therapy depends on whether risk factors continue (i.e. inherited disorders, prolonged immobilization) If no continuing factors are identified, a 3-month course of w. therapy can be appropriate.

Unwanted effects bleeding - can be reversed by stopping the drug, administering large doses of vitamin K1 (i.v.), in emergency, fresh-frozen plasma or clotting factor´s concentrates skin necrosis - hemorrhagic infarction - after the start of therapy with warfarin usually in patients with deficiency of protein C teratogenic action - during pregnancy warfarin can cause a serious defect characterized by abnormal bone formation, central nervous system abnormalities, a hemorrhagic disorder in the fetus

Warfarin-induced skin necrosis

Contraindications of vitamin K antagonists
warfarin is teratogenic and is contraindicated during pregnancy bleeding severe hypertension danger of bleeding (cancer, ulcers in the GIT, surgery) severe hepatic and/or renal impairment

Direct thrombin inhibitors
DTI bind directly to the active site of thrombin (do not require endogenous anticoagulant protein antithrombin for their effect)

Direct thrombin inhibitors I
hirudin from leach saliva and lepirudin (its recombinant form) bivalent irrevesrible inhibitors, large molecules administered i.v. suitable for patients with HIT risk of antibody formation (short-term use, no repeated use) monitoring with aPTT no antidote exists bivalirudin: synthetic polypeptide, reversible inhibitor, administered i.v., low risk of antibody formation

Direct thrombin inhibitors II: small molecules
bind only to the active site of thrombin reversible inhibitors argatroban administered i.v. dabigatran administerd orally once daily (and other -gatrans)

Novel anticoagulants: Oral direct thrombin inhibitors: „gatrans“
Dabigatran etexilate is a potent, non-peptidic small molecule that specifically and reversibly inhibits both free and clot-bound thrombin by binding to the active site of thrombin molecule It has been already licensed in the European Union and in Canada for the prevention of VTE in patients undergoing hip- and knee-replacement surgery. Oral drug aministered once daily. Clinical trials are evaluating its efficacy and safety for the treatment of deep venous thrombosis and pulmonary embolism, primary and secondary prevention of VTE, prevention of systemic embolism in patients with atrial fibrillation, and prevention of cardiac events in patients with acute coronary syndromes.

Novel anticoagulants: oral direct FXa inhibitors
Xabans: rivaroxaban, apixaban, betrixaban, These drugs have minimal protein binding and predictable pharmacokinetics that allow fixed (same dose for all) dosing p.o. without laboratory monitoring They are being compared with vitamin K antagonists or aspirin in phase III clinical trials. Rivaroxaban has been already licensed in the European Union and in Canada for the prevention of VTE in patients undergoing hip- and knee-replacement surgery.

Pharmacotherapy of thromboembolic diseases: Antithrombotic therapy
The main drugs used for prevention and treatment of platelet-rich „white“ thrombi (ATE): ANTIPLATELET DRUGS Anticoagulants are also effective but not widely used (benefit / risk of AE) Occlusive thrombi: Mechanical extraction, FIBRINOLYTIC DRUGS

Antiplatelet drugs Classification based on the mechanism of action:
1/ Inhibitors of platelet activation: aspirin, clopidogrel, dipyridamole, cilostazole + several new drugs 2/ Inhibitors of platelets aggregation: GPIIb/IIIa inhibitors Inhibitors of platelet adhesion: inhibitors of platelet-colagen interaction development was so far unsuccesfull Inhibitors of platelet-mediated links to inflammation: investigational drugs.

Antiplatelet drugs Established antiplatelet agents:
Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of cyclooxygenase COX-1. Clopidogrel, ticlopidine + other newer drugs are P2Y12 receptor antagonists: block the receptor for adenosine diphosphate (ADP) Tirofiban, abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb/IIIa receptor for fibrinogen which is activated at the surface of platelets preceding the final step of their aggregation. Dipyridamole: the inhibition of adenosine uptake and of phosphodiesterase 5 (a cGMP specific one phosphodiesterase).

Acetylsalicylic acid Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase (COX-1) after low doses of 30 mg/day mg/day (once daily) and both COX-1 and COX-2 after high doses ( mg/day, up to four doses/day). The effects last for 7-10 days (consider the risk of bleeding!)

Acetylsalicylic acid The endothelial production of prostacyclin PGI2, which has the reverse effect to TXA2 (antiaggregation and vasodilatation), is dependent on the co-operation of COX-1 and COX-2. However, PGI2 production is affected only by intermediate (160–500 mg) and high (500–1500 mg) doses of ASA due to the different ASA selectivity to COX-1 and COX-2 and also due to the fact that PGI2 is produced by nuclear endothelial cells with the capacity to produce new COX.

Acetylsalicylic acid Pharmacokinetics: Indications:

Acetylsalicylic acid Drawbacks:

New drugs: prasugrel, cangrelor, ticagrerol
Inhibitors of P2Y12 receptor for ADP (Thienopyridines- clopidogrel, ticlopidine) New drugs: prasugrel, cangrelor, ticagrerol

Thienopyridines Pharmacokinetics: Indications: Drawbacks:

Dipyridamol: the inhibitor of phosphodiesterase 5 and of adenosine uptake

Dipyridamol: increases adenosine and cAMP by several mechanisms
- inhibits the phosphodiesterase which breaks down cAMP increasing cellular cAMP levels and blocking the platelet response to ADP and/or cGMP - blocks the thromboxane synthase as well as the thromboxane receptor inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine inhibits the enzyme adenosine deaminase, which normally breaks down adenosine

Dipyridamol Pharmacokinetics: Indications: Drawbacks:

Cilostazol a selective inhibitor of phosphodiesterase type III (PDE3) in both platelets and vascular smooth muscle cells causing an increased concentration of cAMP vasodilation and inhibition of platelet activation used in the treatment of peripheral arterial disease.

Glycoprotein IIb/IIIa antagonists

abciximab (chimeric antibody) eptifibatid (heptapeptide) tirofiban (nonpeptide tyrosine analog) indication: percutaneous coronary angioplasty in patients with acute coronary symptoms all administered i.v.

Pharmacokinetics: Indications: Drawbacks:

Antiplatelet drugs Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases. 60

Antithrombotic management: antiplatelet drugs
Secondary arterial thrombosis prevention In patients with established atherothrombotic disease, there is a high risk of recurrence of potentially fatal vascular events (MI, stroke) and vascular death. The risk is greater in patients who have previously had acute thrombotic events, particularly if the event occurred < 12 months ago. As time elapses, the risk declines somewhat but will remain higher than for patients without established disease. There is a strong evidence to support the benefit of antiplatelet therapy in this setting

Secondary arterial thrombosis prevention antiplatelet therapy (in fact, mostly aspirin in these studies) reduced the risk of MI and death by approximately a quarter (25%) aspirin in the secondary prevention of stroke decreases its risk by 12% clopidogrel or the combination of aspirin+dipyridamol exert slightly better protective effect against recurrent stroke

Secondary arterial thrombosis prevention: non aspirin drugs clopidogrel and ticlopidine Because the onset of clopidogrel action is slow, a loading dose is used when rapid antithromboitc effects are needed, as in acute coronary syndrome. Repeated daily doses produce a steady state after four to seven days, and platelet function returns to normal a week after the last dose of clopidogrel. Ticlopidine, the older of the two agents, causes neutropenia in 2% of patients, while clopidogrel does not. For this reason, clopidogrel is the preferred drug in this class (non-ASA antiplatelet drugs). The major side effect of clopidogrel, like aspirin, is GI bleeding.

Arterial thrombosis prevention: Three GpIIb/IIIa-inhibiting antiplatelet drugs are currently available for clinical use: abciximab, tirofiban, and eptifibatide. They are used to achieve antithrombotic effect during percutaneous coronary interventions and to treat acute coronary syndrome. The antithrombotic effect of these medications is rapidly reversible.

Arterial thrombosis prevention: Dipyridamole is prescribed in combination with warfarin to prevent cardiac emboli in patients with mechanical heart valves and in combination with aspirin for secondary stroke prevention. Cilostazole is indicated for symptomatic peripheral artery disease.

Stroke prevention in atrial fibrilation AF is associated with a markedly increased long-term risk of thromboembolism. There is a 2-4- fold elevated risk of mortality and 4-7-fold elevated risk of stroke. Data compiled in meta-analyses of stroke prevention in AF provide strong support for the use of vitamin K antagonist warfarin adjusted to maintain the INR in the range of 2.0 to 3.0. Despite a higher risk for AE, the anticoagulant drug warfarin is used in this indication Pooled data from six trials, showed that adjusted-dose warfarin decreased stroke risk by 64%, compared with a 22% decrease in risk in patients taking antiplatelet agents New oral anticoagulants are succesfully tested in these indications

Treatment of MI Platelet-rich thrombi tend to form under conditions of high-shear stress, as occurs in arterial circulation. For this reason, antiplatelet agents are an essential component in the treatment of ACS. Aspirin mg chewed (promotes buccal absorption) - according to a clinical study provides a 23% reduction in mortality.

Treatment of MI Clot lysis is associated with hypercoagulability, as thrombin molecules are exposed during the process. This sets the stage for recurrent thrombosis and possible vessel reocclusion. For this reason, anticoagulant therapy is critical during the acute phase of treatment. The combination of antiplatelet and anticoagulant therapy is more effective than either strategy alone.

Treatment of MI In patients without contraindications, acute care often includes dual antiplatelet therapy with aspirin and clopidogrel. Parenteral glycoprotein IIb/IIIa inhibitors provide additional protection against platelet aggregation, particularly in those undergoing PCI. Unfractionated heparin or low-molecular-weight heparin is generally used for anticoagulation. Other anticoagulant options for use during PCI include the direct thrombin inhibitors bivalirudin and argatroban and new trombin (gatrans) and FXa inhibitors (xabans)

Thrombolytic drugs rapidly dissolve thrombi by catalyzing the formation of the protease plasmin from its precursor plasminogen Indications: pulmonary embolus, MI, stroke, … most effective if administered immediately the advantage of administration is highest within the first sixty minutes, but may extend up to 4-5 hours after the start of symptoms

Fibrinolysis inhibition of fibrinolysis activation of fibrinolysis

Thrombolytic drugs

Thrombolytic drugs recombinant t-PA and analogs of t-PA, urokinase, streptokinase, complex streptokinase -plasminogen Indications: thrombolytic i.v. therapy: acute myocardial infarction, acute thrombotic stroke, deep vein thrombosis, pulmonary embolus, clearing thrombosed shunts and cannulas Contraindications (bleeding or increased risk) active internal bleeding haemorrhagic cerebrovascular disease pregnancy invasive procedures in which hemostasis is important, recent trauma and major surgery peptic ulcer disease patients taking anticoagulants

Thrombolytic drugs Unwanted effects:
bleeding may be treated with antifibrinolytics, fresh plasma or coagulation factors Allergic reactions (Streptokinase)

Thrombolytic drugs 1-st generation:These drugs create a generalized fibrinolytic state when administered i.v.: both protective hemostatic thrombi and target thromboemboli are broken down Streptokinase - a protein synthetized by Streptococci that combines with plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase - a human protein synthetized by the kidney isolated from human urine that directly converts plasminogen to active plasmin.

Thrombolytic drugs 2-nd generation:
Anistreplase (Plasminogen-Streptokinase Activator Complex- APSAC) - a complex of purified human plasminogen+streptokinase that has been modified to protect the enzyme´s active site. When administered, it is activated by hydrolysis freeing the activated streptokinase-activator complex. This complex allows for rapid i.v. injection, greater clot activity (less activity on free plasminogen in the blood) and more thrombolytic activity.

Thrombolytic drugs tissue plasminogen activator (tPA) and its analogs
These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Alteplase: human t-PA manufactured by means of recombinant DNA technology. Reteplase: modified rt-PA with a shorter chain of aminoacids that is able to penetrate inside the thrombi, enhanced fibrinolytic activity -rapid reperfusion, low incidence of bleeding Tenecteplase: modified rt-PA, more fibrin specific

Treatment of STEMI The standard of care for this medical emergency is treatment with the goal of achieving reperfusion. This can be attempted pharmacologically, with thrombolytic therapy (i.e., fibrinolytic medications, such as tissue plasminogen activator), or mechanically, using percutaneous coronary intervention (PCI) or coronary artery bypass surgery.

Treatment of STEMI: thrombolysis Common Agents: t-PA: 30-50mg IV bolus Reteplase:10U x 2 (each over 2 minutes) IV Alteplase: up to 100mg in 90mins (based on weight) Contraindications: Absolute: Prior intracranial hemorrhage, known cerebral vascular lesion, malignant intracranial neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding, recent closed head injury or facial trauma within 3 months Relative: History of chronic, severe HTN, severe/uncontrolled hypertension at presentation (>180/110), history of ischemic stroke >3 months, recent internal bleeding (2-4 weeks), pregnancy, active peptic ulcer, current anticoagulation

Hemostatics Drugs against excessive bleeding
A hemostatic (= antihemorrhagic) agent is a substance that promotes hemostasis (stops bleeding). Antihemorrhagic agents used in medicine have various mechanisms of action: Systemic drugs work by inhibiting fibrinolysis or promoting coagulation. Locally-acting hemostatic agents work by causing vasoconstriction or promoting platelet aggregation.

Hemostatics Drugs promoting hemocoagulation at vasoconstriction phase:
Desmopresin (1-deamino-8-D arginin vasopresin, analog of vasopresinu=adiuretin) synthetic oligopeptide causing a moderate vasoconstriction and releasing the activity of FVIII and vWillebrand factor indications: prophylaxis of bleeding in hemophilia A and vW disease i.v. infusion, intranasally

Hemostatics Drugs promoting hemocoagulation at vasoconstriction phase:
Terlipresin Syntetic oligopeptide (the active metabolite vasopresin is generated via its hepatic metabolism) Long duration of action: 2-5 h I.v. infusion 82

Hemostatics Drugs promoting hemocoagulation at platelet phase:
Ethamsylate acts by improving platelet adhesiveness and restoring capillary resistance. Ind. prophylaxis of capillary bleeding in surgery, ORL, stomatology… i.v., p.o., i.m. 83

Hemostatics Drugs promoting hemocoagulation
at the phase of coagulation: Fresh plasma, concentrates of coagulation factors, recombinant coagulation factors Vitamin K Protamin sulphate: an antidote of heparin 84

Hemostatics Drugs promoting hemocoagulation Vitamin K
Fat soluble vitamin, requires the bile for its absorption, synthetized by intestinal bacteria Hypovitaminosis: in malabsorption, biliary diseases, after broad-spectrum antibiotics, in newborns Indication: bleeding in the states of vit K deficit, antidote of warfarin, in newborns oral, i.v., i.m. routes of administration 85

Hemostatics Drugs promoting hemocoagulation Fresh frozen plasma
Fibrinogen Coagulation factors concentrates, freeze-dried Prothrombin, Factor IX, X and VII (Proplex) Recombinant coagulation factors EPTACOG ALFA – rFVIIa (NovoSeven) rFVIII used in haemophilia A rFIX used in haemophilia B 86

Antifibrinolytics aminocaproic acid tranexamic acid aprotinin
Plasminogen Plasmin Degradation products Fibrinogen Fibrin Fibrin split Activation Inhibition Various stimuli + Blood proactivator activator t-PA - Thrombin aminocaproic acid tranexamic acid aprotinin Activator

Antifibrinolytics Lysine analogues
tranexamic acid inhibits plasminogen activation and thus prevents fibrinolysis (i.v. or oral administration) aminocaproic acid resembles tranexamic acid PAMBA- p-aminomethylbenzoic acid Aprotinin inhibits the proteolytic enzyme-plasmin: it was associated with renal failure, IM and stroke - used only for special indications, open heart surgery Indications: overdose of fibrinolytics, the surgical procedures that cause an increase in endogenous fibrinolytic agents (liver transplantation) Unwanted effects: thrombotic complications resulting from inhibition of fibrinolysis, which is a natural mechanism of defense against the formation of thrombus: stroke, MI, coronary-bypass graft occlusion

Mode of Action of Lysine Analogues (Aminocaproic Acid and Tranexamic Acid).
Activation of plasminogen by t-PA results in plasmin, which causes degradation of fibrin. Binding of plasminogen and t-PA to fibrin (a ternary complex) makes this process much more efficient and occurs through lysine residues in fibrin that bind to lysine-binding sites on plasminogen (Panel A). In the presence of lysine analogues, these lysine-binding sites are occupied, resulting in an inhibition of fibrin binding to plasminogen and impairment of fibrinolysis (Panel B).

Local hemostatics Several advanced hemostatic agents are currently available. oxidized cellulose fibrin glue and synthetic adhesives constitute the first-line of local hemostatic agents

Local hemostatics Commonly utilized hemostatic agents are derived from oxidized cellulose, commercially available as Surgicel© and Nu-Knit© This class of agent is intended for use as an adjunct to gauze packing, with their hemostatic properties primarily based on their ability to locally activate the coagulation cascade. While they do not contain any intrinsic coagulation components, they are designed to stimulate clot formation and to provide a favorable three-dimensional structure for clot organization.

Local hemostatics Fibrin adhesives are a group of biological tissue adhesives composed of thrombin and purified human or bovine fibrinogen that mimic the final step of the physiologic coagulation cascade, depositing a fibrin-rich clot at the site of application. Commercially available in many forms (Tisseel™, Floseal™), differing in their source components and physical characteristics, these products have been proposed for use in a wide variety of surgical subspecialty settings, as well as in humans with hemophilia and other bleeding disorders

Local hemostatics Synthetic adhesives vommercially available as Coseal™ or BioGlue® constitute an alternative to fibrin-based glue that can be stored at room temperature and do not require complicated preparation. Bioglue® is a synthetic two-component surgical adhesive composed of purified bovine serum albumin (45%) and glutaraldehyde (10%). Its mechanism of action involves the formation of covalent bonds with albumin and tissue surface proteins to form a mechanical seal at the site of hemorrhage. These products, however, are relatively expensive compared to fibrin-based hemostatics.

Local hemostatics Zeolite is a naturally occurring mineral, which works by absorbing water from the injury site in an exothermic reaction that promotes the concentration of coagulation factors and platelets to augment clot formation Chitosan is a novel local hemostatic that is produced commercially by the deacetylation of Chitin (Poly-N-acetyl glucosamine), a structural element in the exoskeleton of crustaceans.

DRUGS USED IN DISORDERS OF HEMOSTASIS

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DRUGS USED IN DISORDERS OF HEMOSTASIS

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