2. Fibrinolytic system
• The process of dissolution of clot is called
fibrinolysis
Endothelial cells
t-PA
Plasminogen Plasmin
fibrin Fibrin degraded
products
4. FIBRINOLYTICS
• Used to lyse the thrombi / clot to recanalize the
occluded blood vessel (mainly coronary artery)
• Work by activating the Fibrinolytic system
• STREPTOKINASE
• UROKINASE
• RETEPLASE (analogue of alteplase)
• ALTEPLASE (t- PA )
• TENECTEPLASE
5. Streptokinase
• Obtained from -hemolytic streptococci
• Binds with circulating plasminogen to form
complex that activates plasminogen to plasmin
• t ½ = 30 -80 min
• Antigenic ,Pyrogenic
• Destroyed by circulating antistreptococcal
Antibodies
• Hypotension & arrhythmia can occur
6. Streptokinase
Uses
• Acute myocardial infarction
– 7.5 to 15 lac IU; I.V over 1 hr period
• Deep vein thrombosis , Pulmonary embolism
Adverse effects
• Bleeding, hypotension, allergic reactions, fever,
arrhythmias
Contraindications
• Recent trauma, surgery, abortion, stroke, severe
hypertension, peptic ulcer, bleeding disorders
7. Urokinase
• Enzyme isolated from human urine, now
prepared from cultured human kidney cells
• Direct plasminogen activator
• t ½ of 10 to 15 min
• Non antigenic, Non allergenic
• Fever can occur but hypotension rare
• Indicated in patients in whom streptokinase
has been for an earlier episode
8. Alteplase
• recombinant tissue Plasminogen Activator(rt-PA)
• Selectively activates plasminogen bound to fibrin
• Non antigenic ,not destroyed by antibodies
• Rapid acting, more potent
• Superior in dissolving old clots
• Short half life 4-8 min
• Nausea, mild hypotension, fever may occur
• Expensive
9. Newer recombinant tissue
plasminogen activators
• Reteplase :
– Modified rt-PA
– Longer half life 15 -20 min, but less specific for
fibrin bound plasminogen
• Tenecteplase:
– Genetically engineered mutant form of alteplase
– Higher fibrin selectivity and longer half life – 2 hrs
– Single bolus dose 0.5 mg/kg sufficient
– Very expensive
16. Dipyridamole
• Coronary vasodilator and relatively weak
antiplatelet drug
• Mechanism of action
– Potentiates effect of endogenous prostacycline
– In high conc inhibits Phosphodiesterase, so ↑cAMP
• Dose = 100 mg BD/TDS
• used with aspirin to prevent ischemic stroke in
patients of TIA
17. Ticlodipine & clopidogrel
• ADP antagonists, inhibit binding of ADP to its
receptors irreversibly
• Also Inhibit fibrinogen induced platelet
aggregation with out modifying GPIIb/IIIa
• Synergistic action with aspirin
• Both are prodrugs have long duration of
antiplatelet effect
• Clopidogrel a congener of ticlodipine is safer
and better tolerated
20. Abciximab
• Fab fragment of Chimeric monoclonal antibody
against GP-IIb/IIIa.
• Used to prevent platelet aggregation in patients
having PCI, administered along with aspirin &
heparin or LMW heparin
• Most common A/E is bleeding
• May cause thrombocytopenia, hypotension,
bradycardia
• Non antigenic
• Dose: 0.25 mg/kg IV before PCI followed by 10 g/min for 12
hrs
When a clot is formed , an inactive plasma enzyme present in blood called plasminogen is incorporated in to the clot.Endothelial cells of most tissues then secrete tissue plasminogen activator (t-PA) which is released in to the blood & reaches the site of damage (cLot ) - t-Pa CLOT t- Pa inturn activates plasminogen to plasmin – an active enzyme that digests fibrin in to fibrin degraded products Why we need fibrinolysis: because provides check and balances the clotting process so that it should not go out of hand for minor reasons in day to day life. It dissolves clot at the site of damage once the the damage is repaired. The activity of t-PA is checked by Plasminogen activator inhibitor 1 and 2 so that circulating plasminogen may not get activated (it is needed for incorporation in clot) another enzyme alpha 2 antiplasmin also plays important role in fibrinolytic system some of this is bound to fibrin and thereby protects fibrin from premature lysis by plasmin. Secondly it inhibits plas min which escapes into circulation.
As compared to arterial thrombi, venous thrombi are lysed more easily by fibrinolyticsRecent thrombi are lysed better by fibrinolytics than older ones.
MOA: inactive as such but combines with circulatingplasminogen to form an activator complex which limitedly proteolyses otherplasminogen to plasmin. The antistreptococcal antibodies which may be present due to previous infection may destroy streptokinase so initial loading may be required Antigenic and can cause hypersensitivity reactions and anaphylaxis especially when used for second time. Repeat doses are also less effective due to neutralization by antibodies.
Why repeat dose of streptokinase shouls be avoided Antistreplase: anisolyatedplasminogen streptokinase activator complex, the complex consists of purified human plasminogen with
Activates plasminogen directly Dose: 2.5 lac IU, I.V over 10 min followed by by 5 lac IU over next 60 min
Prepared by DNA recombinant technology using human tissue cultureDose: 15 mg iv bolus , 50 mg over 30 min then 35 mg over next hr
But reteplase is less specific for fibrinogen bound plasminogenReteplase dose: 10 mg over 10 min repeated after half hour Clinical efficacy, risk of bleeding same for all 3
Acute myocardial infarction:recanalization in 50 -90% cases alternative first line therapy to PTCA, heparin/aspirin started concurrently or soon after thrombolysis to prevent reocclusion. Alteplase higher efficacy and thrombolytic activity than streptokinase, fibrinolytic therapy may also be given in unstable angina, because such patients have coronary thrombi2. Deep vein thrombosis: leg, pelvis, shoulder etc. upto 60% success full, can reduce pain, swelling and also preserve venous valves main advantage, and may be a reduced risk of pulmonary embolism , comparble results with STK, urokinase, alteplase3. Pulmonary embolism: indicated in large , life threatening, pulmonary embolism. The lung function may be better preserved but reduction in mortality is not established. 4. Peripheral arterial occlusion: recanalize 40% of limbs occlusion especially those treated within 72 hrs how ever indicated only when surgical thrombectomy is not possible regional intraarterial used for limb surgeries peripheral arterial thrombolysis is followed by heparin-short term and aspirin long termfibrinolytics have no role in chronic peripheral vascular diseases Stroke: thrombolytic therapy for ischemic stroke is controversial
Non nucleated disc shaped bodies derived from megakaryocytes in the bone marrow and present in the blood at conc of 1.5 to 4 lac /micro litre of blood CAMP metabolized by PDE to 5-AMP and hence any drug which inhibits this enzyme would increase thecamp levels and inhibit platelet aggregation e.gdipyridamoleIn normal undamaged vessel the endothelium plays active part in prevention of thrombus formation, when the vessel is cut or endothelium is damaged exposes the subendothelial collagen 1-4 types leading to secretion of vWF, platelets have high affinity for the subendothelial cells and vWF, they adhere and activation of platelets occurs and they stick to one another aggregate and release ADP, SEROTONIN THROMBOXANE a2, serotonin they promote further aggregation and platelet plug is formed. In veins due to sluggish blood flow a fibrinous tail is formed which traps RBCs, therefore red clot is formed. In arteries the major constituent of thrombus is platelet so white thrombus is formed. Thus antiplatelet drugs are more useful in arterial thrombosis, while anticoagulants are more effective in venous thrombosis.
Platelets adhere to damaged vascular endothelium via linkage of Glycoprotein 1a receptors with exposed collagen, and via linkage of Gp 1b with Von ville brand factor – a circulatory factor that is similar to clotting factor 8. the adherence of platelet to the vascular endothelium leads to activation of platelets and release of various mediators of platelet aggregation including TXA2, adenosine diphosphate, and serotonin , these mediators increase expression of GpIib/IIIa receptors that bind fibrinogen and cause platelet aggregation
Acetylates and inhibits enzyme cox1 and txsynthetase – inactivating them irreversibly because platelets are exposed to aspirin in portal circulation before it is deacetylated , during first pass in liver and platelets cannot synthesize fresh enzyme as they do not have nuclei, TXA2 is supressed at very low doses and till fresh platelets are formed, thus aspirin induced polongation of bleeding lasts fot 5-7 days. Effect of daily dose cumulates and it has been shown that dose as low as 40 mg/day can have antiplatelet action mximal at 160 mgaspirin /dayAspirin also inhibits COX1 and PGI2 synthesis in vessel wall . But intimal cells can synthesize fresh enzym. Activity returns rapidly. It is possible that low doses 75 -150 mg per day or 300 mg biweekly , supress TXA2 formation selectively, whereas higher doses 900 mg/day may decrease both TXA2 and PGI2 production. Also inhibits release of adp from platelets and their sticking to one another
So alone has little clinical significance but improves the response to warfarin, used with it for TE episodes in in patients with prosthetic heart valves. Dipyridamole alone has little effectbut in combination with warfarin or aspirin is effective As a vasodilator used during myocardial perfusion imaging (Thallium scanning) to dilate and evalutae arteries of patient with CAD DIP is
First thieno pyridine derivative Ticlodipine is well absorbed orally , active metabolite in liver so long acting `half life after single dose is 8 hr and on repeated administration is 8 days
Ticlodipine can cause mild to severe neutropenia, patients who are treated with ticlodipine must have a complete blood count, with white cell differential every 2 weeks from second week to third month of treatment. After 3 months CBC is required only when symptoms of infection
Final common pathway in the platelet aggregation is cross linking of platelets by fibrinogen, which binds to an activated gpiib/iiia complex on platelet surface , gpiib /iiia complex is a integrin, integrins are cell surface tranmembraneglycoproteins that function as adhesion receptors to structurally link cell surface to the cytoskeleton.
Significantly prevent vessel restonosis, reinfarction and death
Prosthetic heart valves and AV shunt: used with warfatin reduce formation of microthrombi on artificial heart valves and incidence of embolism.Dipyridamoledoesnot increase the risk of bleeding but incidence of thromboembolism is reduced , whrn it is combined with an oral anticoagulant . Antiplatelet drugs also increase the patency of chronic AV shunt implanted for hemodialysis and of vascular grafts. Peripheral vascular disease: may produce some improvement in intermittent claudication and reduce the incidence of thromboembolismCoronary artery diseases: Myocardial infarction:low dose aspirin started immediately after AMI diagnosis has been made and continued through out convalscence and after recovery Unstable angina: Aspirin reduces risk of MI and sudden death in patients with unstable angina, for maximum benefit given along with heparin followed by warfarin. Primary and secondary prevention of MI: