Fibrinolytic Drugs PDF

Fibrinolytic Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to: List...

Fibrinolytic Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to: List the major drugs used as thrombolytics and procoagulants. Explain the mechanisms of action of coagulants and thrombolytics, their major side effects, their clinical indications, how their activity is monitored, and their antidotes, if any. Recall drug interactions where these drugs are involved, and explain the mechanisms of interactions. 2 2 1 Anticoag antiplatelet cannot break apartan existing dot they can onlyprevent clotformation or if clotformingprevent it from growing in size Thrombolytics (Clot Busters) Why use thrombolytics? - Platelet inhibitors or anticoagulants do not break the thrombus (clot) that is already formed Fibrinolytics are used for disintegrating thrombus Plasmin is the endogenous fibrinolytic Activation of zymogen plasminogen produces plasmin Plasminogen activators  tPA (endogenous)  Recombinant tPAs  Streptokinase  Urokinase Fibrin Plasminogen Plasmin Blood clot 3 3 Thrombolytics : Mechanism of Action 2checksbalancesofthrombolysis Itdaltimisit Gee Paines Edesired 4 4 2  Thrombolytics : Mechanism of Action The Fibrinolytic System. Plasmin is formed by the proteolytic cleavage of plasminogen by tissue-type or urokinase-type plasminogen activator. Plasmin formation can be inhibited by plasminogen activator inhibitor 1 or 2, which binds to and inactivates plasminogen activators. In the fibrinolytic reaction, plasmin cleaves crosslinked fibrin polymers into fibrin degradation products. α2- Antiplasmin, which circulates in the bloodstream, neutralizes free plasmin in the circulation. 5 5 Streptokinase TEE - Plasminogen activator - Protein extracted from cultures of the streptococci bacteria - Administered IV for the treatment of patients with ST elevation myocardial infarction Fibrinolytic therapy for the treatment of ST-segment elevation myocardial infarction reduces mortality when administered within 12 hours of symptom onset. betoo otherwisemight latetobreakupclot 6 6 3  Recombinant tPAs Tissue plasminogen activator (t-PA) is a serine protease produced by human endothelial cells; therefore, t-PA is not antigenic. t-PA binds to so gete to the newly formed (fresh) thrombi with high affinity, causing fibrinolysis at the site of a thrombus. It is inactivated by plasminogen activator inhibitor. clot formed thrombus Recombinant (DNA) tPAs: notantigenic o Alteplase (Activase®) – ‘clot selective’ – selective to fibrin-bound plasminogen o Reteplase (Retavase®) - Longer half-life o Recombinant tPAs are less antigenic peopledon'tdevelop allergiestoit 7 7 Streptokinase - Plasminogen activator - Protein extracted from cultures of the streptococci bacteria - Administered IV for the treatment of patients with ST elevation myocardial infarction Fibrinolytic therapy for the treatment of ST-segment elevation myocardial infarction reduces mortality when administered within 12 hours of symptom onset. - Antibodies produced can reduce effect of further administration (~1 year). Thus, previous administration is a contarindication to its use, because of the risk of anaphylaxis streptokinase isantigenicso usedtotreat oncewill if pt not useagainduetoriskofallergieswhyBecauseantibodiesareformed ADR: thrombolytic actions of streptokinase are relatively nonspecific and can result in systemic fibrinolysis. breaking both up Anddesireddots undesired 8 8 4  Urokinase - Trypsin-like plasminogen activator chemical produced by the kidney, and excreted in the urine collecturinesamples 9 9 Side Effects & CIs of Fibrinolytics  Bleeding, GI and cerebral hemorrhage bleedinginbrain  Contraindicated in invasive procedures, hemorrhagic i cerebrovascular disease, serious GI bleeding, hemorrhagic disorders, severe uncontrolled hypertension. E it ging Reversal of Fibrinolytic Effects α2-antiplasmin: present in plasma and rapidly inactivates plasmin. Aprotinin: naturally occurring polypeptide (inhibits plasmin, tPA and thrombin; increase risk of postoperative acute renal failure)Eating Aminocaproic acid and Tranexamic acid (inhibit plasminogen and plasmin; may not increase the risk of postoperative acute renal failure) Fresh plasma (provides coagulation factors) Coagulation factors 10 10 5  Use of Fibrinolytics in Pregnancy Fibrinolytics usually belong to pregnancy category C. Hence selection of fibrinolytics in pregnant patients is difficult. Factors affecting the crossing of drugs to the placenta are molecular weight, lipid solubility, drug pH, and binding to plasma proteins. Drugs with MW higher than 1,000 Da often poorly cross the placental barrier. So, is it okay to use these drugs in pregnancy? w̅ 11 11 1000Daltons Donotcrossplacentaasmuch SUMMARY 12 12 6  General Drug Interactions  Bone marrow suppressants these productionofplatelets  Anticoagulants - antiplatelet agents - fibrinolytics bleedingrisk  Botanicals – Ginko biloba (anti-platelet) – St. John’s wort (increased the activity of CYP3A4 in the liver, fi and thus the activation of clopidogrel) – Garlic (inhibition of platelet aggregation, and enhancement of fibrinolytic activity) anticoagulant 13 13 Ultimate Goal of Antithrombotic Therapy: Prevention of THROMBOSIS without causing BLEEDING! Thrombotic Bleeding risk risk 14 14 O O O 7 O 8 0 0 Any questions? The End 15 15 8