Anticoagulants

Anticoagulants

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  Department of Pharmacology IGMC,Shimla ANTI PLATELETS
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  WHAT ARE PLATELETS? White, discoid Smallest element of flowing blood 1 - 2 microns diameter Lipid bilayer membrane Normal range 150000 – 450000 microlitre blood Formed from cytoplasm of megakaryocytes No nucleus
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  Normal Function ofPlatelets Haemo stasis Preventing bleeding from wounds Integrity and repair of the vessel wall
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  Thrombogenesis  Platelet aggregatesbound together by fibrin strands (white clots)  Consist mainly of fibrin and RBCs (red clots) Arterial thrombus
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  Platelets and Thromboemolism Occludes artery / disintegrates into emboli occluding distal vessels resulting in ischemic necrosis of tissue supplied by the artery.(AMI)  Veins low pressure : Reduced blood flow (stasis)  Especially in valve pockets  Causes tissue drained by the vein to be edematous and inflamed (DVT)
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  Platelets adhesion andaggregation 9
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  Targets for anti-platelettherapy Aspirin NSAIDs ADP receptor COX-1 TXA2 GPIIb - IIIa Signalling pathways ADP receptor antagonists Clopidogrel THROMBIN receptor Thrombin inhibitors II Phosphodiesterase inhibitors dipyridamole Fibrinogen Receptor Antagonists AA
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  CLASSIFICATION OF ANTIPLATELET AGENT- 1.PGI 2 2. TXA2 inhibitors- 3. ADP antagonists- • Ticlopidine, Clopidogrel 4. Phospodiesterase inhibitor- • Dipyridamole, Pentoxifylline 5. Glycoprotein IIB/IIIA receptors antagonists- Abciximab, Eptifibatide, Tirofiban
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  PGI 2- (Prostacyclins) Naturallyoccurring potent vasodilator and inhibitor of platelet aggregation. Produced by vessel walls, also present in brain ,gut and kidney. Formed from PG endperoxidase by the action of COX Inhibit platelet aggregation by stimulating adenylcyclase increasing cyclic AMP levels in platelets. Prostacyclins causes hypotension , tachycardia ,headache. intense facial flushing Very unstable ,1/2 life of 3 mins. Prostacyclins (Epoprostananol)-used during haemodialysis.
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  ASPIRIN- • MOA- In plateletsmajor COX product is TXA2 , a labile inducer of platelet aggregation and potent vasoconstrictor. Aspirin blocks production of TXA2 by covalently acetylating serine residue near the active site of COX, this enzyme produces cyclic endperoxidase precursor of TXA2. Since platelets do not synthesize new proteins hence the action of aspirin on platelets is permanent (7-10 days).
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  For complete inactivationof platelet COX dose of aspirin req. is 160 mg daily. Reason— Higher doses decrease efficacy of aspirin as they inhibit production of prostacyclins which is spared at low doses. (75-150mg) Higher doses also increase toxicity esp.. Bleeding.
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  USES OF ASPIRIN Preventionof AMI in pts. Of unstable angina Prevention of reinfarction in pts. Of AMI and IHD Prevention of stroke in pts. Of cerbrovascular accidents and h/o TIA For improving prognosis in patients with atherosclerotic peripheral vascular diseases Percutaneous angioplasty for coronary thrombosis , Primary prophylaxis of thromboembolism in pts with prosthetic heart valves
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  ADP Antagonist: Ticlopedine 1.Ticlopidine blocks Gi coupled ADP receptors. 2. It is a prodrug requires conversion to active form by CYP450. 3. Rapid absorption, high bioavailability 4.Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy. 5.Dose-loading 500mg for rapid onset of action. Usual dose 250mgBD AE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic Thrombocytopenia Uses- Prevention cerebrovascular events, in secondary prevention of stroke angina Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting 16
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  Clopidogrel Less toxic thenticlopedine less incidence of leucopenia, thrombocytopenia. Less used than Ticlopidine MOA, PK profile same as Ticlopidine Dose 75mg/day Rest same as Ticlopidine.
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  Dipyridmole- • MOA Inhibition ofPDE (phospodiesterase enzyme) and/ or by blockade of adenosine which act at A2 receptor to stimulate adenylcyclase thus increase CAMP causing platelet inhibition. Current recommended use- Along with Warfarin in primary prophylaxis of thromboemboli in patients with prosthetic heart valves
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  Xanthine analogue Increases deformabilityof RBCs thus increases microcirculation, reduce fibrinogen levels, inhibit pl. aggregation. Uses- CVAs esp.TIA(transient ischemic attacks) , Ischemic ulcers of legs Dose 400mg tds Pentoxifyllines
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  Glycoprotein IIB/IIIA receptorsantagonists Platelet surface receptor, receptor for fibrinogen and von willebrand factor,which anchors platelets to foreign surface and each other thereby mediating aggregation. Receptor is activated by TXA2, Collagen, and thrombin to developbinding sites for its ligands. Inhibition of binding to this receptor blocks platelet aggregation induced by the agonist.
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  Abciximab Monoclonal antibody causeplatelet receptor blockade. Given IV max. effect seen with in 2hrs, DOA 10-12 hrs. Use- percutaneous angioplasty for coronary thrombosis Prevents restenosis, recurrent and death when used in conjugation with aspirin and heparin. Dose-0.25mg bolus---0.125microgm/kg/min for 12hrs IV AE-bleeding Contraindication same as fibrinolytics
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  Coagulation Phase Two majorpathways Biosynthesis of these factors are dependent on Vitamin K1 and K2 Most of these factors are proteases Normally inactive and sequentially activated Hereditary lack of clotting factors lead to hemophilia -A Intrinsic pathway Extrinsic pathway
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  Clotting factors 23
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  Intrinsic Pathway  Allclotting factors are within the blood vessels  Clotting slower  Activated partial thromboplastin test (aPTT)  Blood sample + calcium  Mix with negatively charged phospholipid  Kaoline (aluminum silicate)  Determine clotting time  Generally clotting occurs in 26 to 33 seconds  Used to detect defects in the intrinsic pathway Extrinsic Pathway  Initiating factor outside the blood vessels - tissue factor  Clotting - faster - in Seconds  Prothrombin test (PT)  Tissue Thromboplastin factor III  Mix with phospholipid extract  Add calcium and blood sample  Determine clotting time  Generally 12 - 14 seconds  Used to detect defects in extrinsic pathway
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  Diagnosis of coagulationdefects Prolonged APTT No change in PT • Defective Intrinsic Pathway No change in APTT Prolonged PT • Defective Extrinsic Pathway Prolonged APTT Prolonged PT • Defective in Common pathway
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  Blood Vessel Injury IXIXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin II Thrombin IIa Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants
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  Activation Inactive XI ActiveXIa XIIa +
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  ANTICOAGULANTS  These arethe drugs used to reduce coagulability of blood.  Classification In vitro anticoagulants In vivo anticoagulants Heparin A) -Heparin Sodium citrate -Low molecular weight Heparin Sodium oxalate -Danaparoid Sodium edetate -Lepirudin -Heparan sulfate B) Oral anticoagulants
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  B) Oral anticoagulants Warfarin sodium  Bishydroxycoumarin (dicumarol)  Acenocoumarol  Phenindione
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  Chemistry & Occurence Straightchain mucopolysaccharide, glycosaminoglycans MW 10000-20000. Average=15,000 d (~45monosaccharide chains) Strongest organic acid in the body. Heparin is present in all tissues containing mast cells, richest source are liver, lung (bovine) and intestinal mucosa (porcine) LMWH isolated from standard heparin by gel filtration chromatography or partial depolymerization. (1000- 10000 daltons). H e p a r i n
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  MOA  Heparin bindsto antithrombin III -----complex  Increases thrombin –AT reaction 1000folds.  Heparin induces conformational change in ATIII to expose its interactive sites.  Long heparin molecule provides scaffolding for clotting factors ( Xa & IIa) aswellas ATIII.  At low conc. interferes with intrinsic pathway while at high common pathway.  ATIII inhibits activated clotting factors of intrinsic and common pathway including thrombin, Xa, IXa and thus acts as Succide substrate
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  ATIII-SUCCIDE SUBSTRATE
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  Thrombin inhibition catalysedby heparin AT R H AT H AT H AT H R P P P P R R
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  FXa inhibition catalysedby heparin AT R H AT H AT H AT H R P P P P R R
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  Anticoagulant Properties ofHeparin 1. Inhibits the thrombin-mediated conversion of fibrinogen to fibrin 2. Inhibits the aggregation of platelets by thrombin 3. Inhibits activation of fibrin stabilizing enzyme 4. Inhibits activated factors XII, XI, IX, X and II
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  Pharmacokinetics  Not effectiveorally  Sc/ iv administration  Onset immediate, peak in 5-10mins  Metabolized in liver  Excretion through kidney.
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  Unfractionated Heparin  HighDose  Treatment of venous/arterial thrombi  Requires monitoring  IV- 5,000 Units bolus, then 30,000-35,000 units/24 hrs  80 Units/kg bolus, then 18 Units/kg/hr to maintain aPTT in therapeutic range  therapeutic goal – 2-2.5 times normal control value (- 30 sec)
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  Low Dose UnfractionatedHeparin  Surgical Prophylaxis  5,000 Units SC 2 hr preop  5,000 Units SC every 12 hours  Medical Prophylaxis  5,000 Units SC every 12 hours  No monitoring required
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  ADVANTAGES OF LMWH 1.Less anti IIa activity than anti Xa activity 2. Good pk profile 3. More predictable dose response 4. Can be given by subcutaneous route 5. No monitoring required, can be given OPD basis 6. Less anti-platelet effects 7. Longer t1/2’s 8. Decreased hospital stay 9. More favorable benefit – risk ratio
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  LMWH  1mg/ kgS.C BD for DVT  30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery  1mg/ kg S.C BD for DVT  30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery
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  Adverse effects  Allergicand anaphylactic manifestations  Bleeding (1-33%)-antidote- Protamine sulphate  Heparin induced thromocytopenia. (more than 25%)  Alopecia  Osteoporosis  Hyperkalemia
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  Mechanisms of HIT Type 1 (Non immune):  Fall in platelet count occurs within the first two days after heparin initiation, and returns to normal with continued heparin administration, and is of no clinical consequence.  Direct effect of heparin on platelet activation.  Type 2 (Immune):  Approx 0.3 to 3 percent of patients receiving heparin  Mediated by antibodies to a heparin-platelet factor 4 complex.  Seen with unfractionated heparin but in not with LMWH
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  Warfarin Warfarin, a coumarinderivative, is the most commonly used oral anticoagulant (OAC) . Warfarin is a vitamin K antagonist - Impairs the generation of active vitamin K, decreasing the amounts of vitamin K dependent coagulation factors • (FII, FVII, FIX, FX) Depending on factors such as age, risk factors, recurrence, etc., warfarin may be continued for anywhere from 1 month to lifelong
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  Oral anticoagulants :warfarin, dicumarol  Coumarins - warfarin, dicumarol  Isolated from clover leaves  Structurally related to vitamin K  Inhibits production of active clotting factors  Absorption rapid –high plasma protein binding binds to albumin  Clearance is slow - 36 hrs  Delayed onset 8 - 12 hrs  Overdose - reversed by vitamin K infusion  Can cross placenta - do not use during late pregnancies
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  Mechanism of action DescarboxyProthrombin Prothrombin Reduced Vitamin K Oxidized Vitamin K NADHNAD Warfarin
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  Warfarin Monitoring Warfarin Monitoring •Why monitor? Need to balance proper anticoagulation without bleeding risk. • Monitored with PT, expressed as INR: INR = [Patient PT / Mean Normal PT]ISI • Where ISI = International Sensitivity Index, assigned by each thromboplastin manufacturer
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  INR : InternationalNormalized Ratio.  Different thromboplastins vary in sensitivity  To give PT values a consistent basis of comparison from lab to lab, WHO instituted the INR:  A uniform value in which the PT is expressed as a ratio.  Many manufacturers aim for an ISI of 1.0.  INR is affected by diet (because of the vitamin K dependent mechanism of action), other medications,  Monitored routinely, every 2 to 4 weeks
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  Drug interaction- PrototypeWarfarin Category Mechanisms Examples of drugs Drugs that Increase Warfarin Activity Decrease binding to Albumin Aspirin, Sulfonamides Inhibit Degradation Cimetidine, Decrease synthesis of Clotting Factors Antibiotics (oral) Drugs that promote bleeding Inhibition of platelets Aspirin Inhibition of clotting Factors Heparin Antimetabolites Drugs decrease Warfarin activity Induction of metabolizing Enzymes Barbiturates Increases synthesis of Clotting Factors Vitamin K
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  New Anticoagulants Limitations of traditional anticoagulants ,both with Heparin and Warfarin, have prompted the development of new agents
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  New Anticoagulants Parenteral FXaInhibitors
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  FXa Inhibitors Parenteral syntheticpentasaccharide analogs Fondaparinux (Arixtra®) • Synthetic and highly selective inhibitor of FXa • Acts as cofactor to AT • Administered by subcutaneous injection ONCE A DAY • Absolute bioavailability of 100%
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  FXa Inhibitors Parenteral syntheticpentasaccharide analogs Danaparoid • LMW mixture of heparinoids (glycosaminoglycans, GAGs); acts as cofactor to AT • Anticoagulation effect is predominantly mediated by inhibition of FXa • Also has some anti-IIa effects • Fast acting, generally predictable dose response
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  Direct Thrombin Inhibitors Lepirudin(Recombinant hirudin) • Recombinant hirudin, a derivative of the saliva of the medicinal leech Hirudo medicinalis • First direct thrombin inhibitor (DTI) to be approved by the FDA for anticoagulation in patients with (HIT) • Can be monitored with APTT, TT,
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  Direct Thrombin Inhibitors Argatroban •A synthetic anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) • Active against both free and clot-bound thrombin • Argatroban is typically monitored by APTT, but other methods like the chromogenic anti-IIa assay may be more accurate.
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  Direct Thrombin Inhibitors Bivalirudin •Synthetic polypeptide hirudin analog that interacts with the thrombin active site to reversibly inhibit thrombin • Alternative to heparin • Administered parenterally • Short half life • Monitored by Activated Clotting Time (ACT)
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  Direct Thrombin Inhibitors Ximelagatranoral anticoagulant • Studies have shown similar efficacy and bleeding risk to warfarin • Does not need monitoring • Was not FDA approved: more studies needed to assess liver failure risk
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  USES OF ANTICOAGULANTS
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  USES OF ANTICOAGULANTS
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  The Extent ofThrombotic Disease Annually in the U.S. 1.5 million MIs-Mortality of 30% (450,000) 500,000 CVAs - Mortality of 30% (150,000) 2 million DVTs 200,000 deaths from PE
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  Venous Thromboembolism Third mostcommon cardiovascular disease Significant morbidity and mortality VTE includes: • Deep Venous Thrombosis (DVT) • Pulmonary Embolism (PE)
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  Economy Class Syndrome Medicalcondition called Venous Thromboembolism Fibrin thrombi. 3months anticoagulants theraphy is required in DVT and PE For prophylaxis of pts.undergoing surgery--- LMWH—
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  Deep Vein Thrombosis Blood clot of lower leg or thigh  Approximately 1 per 1,000 people affected by DVT  Hospitalization for 5 to 7 days  50% of patients with DVT are asymptomatic
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  Pulmonary Embolism Dislodged bloodclot entering the pulmonary circulation Accounts for 5-10% of all hospital deaths 80% of patients die within the first 2 hours CT Scan of Pulmonary Embolism
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  Deep Vein ThrombosisEmbolusPulmonaryEmbolism
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  AMI AND UNSTABLE ANGINA Arterialthrombi-platelet thrombi Use of anticoagulants??? Beneficial in preventing mural thrombi at infarction site and venous thrombi in leg veins. Can be given for short periods till the Pt. is ambulatory. Heparin iv for 2-8 days followed by oral anticoagulant for 3 months. Short term use in unstable angina.
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  RHD, AF Warfarin /low dose aspirin / LMWH are effective in preventing stroke due to embolism from fibrillating atria. Warfarin the most effective. (3-4week theraphy)
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  Blood Hypercoagulability Increased procoagulants Decreasein inhibitors Impaired fibrinolysis Occurs in obstretic conditions, mallignancies, infections.
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  FIBRINOLYTICS
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  Fibrinolysis • Enhance degradationof clots • Activation of endogenous protease • Plasminogen (inactive form) is converted to Plasmin (active form) • Plasmin breaks down fibrin clots
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  FIBRINOLYTICS CONVENTIONAL NONSELECTIVE AGENTS Fibrin selectiveagents
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  FIBRINOLYTICS • Streptokinase -bacterial product - continuous use - immune reaction • Urokinase - human tissue derived - no immune response • Tissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE Inhibitors of fibrinolysis
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   Streptokinase isa protein (but not an enzyme in itself) synthesized by streptococci that combines with the pro-activator plasminogen.  This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin
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   Urokinase isa human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin.  Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within
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   Plasminogen canalso be activated endogenously by tissue plasminogen activators (t-PAs).  Activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation.  Human t-PA is manufactured as ALTEPLASE by means of recombinant DNA technology.
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   RETEPLASE isless expensive than Alteplase. It lacks the major fibrin-binding domain thus is less fibrin-specific than Alteplase  TENECTEPLASE is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Tenecteplase is slightly more fibrin-specific than Alteplase
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  DOSES Streptokinase • Dose:250000 Uloading dose followed by 100000 U every hr for 24 -72 hrs Urokinase • Loading dose of 300000 U followed by 300000 U/hr for 12 hrs Alteplase (t-PA) • 60mg iv over 1 hr followed by 40mg iv at a rate of 20mg/ hr
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  Contraindications to Antithrombotic Therapy Generalrisk factors • Pre-existing coagulation or platelet defect, thrombocytopenia, or other bleeding abnormality • Inaccessible ulcerative lesion(e.g., gastrointestinal tract lesion) • Central nervous system lesion (e.g., caused by stroke, surgery, trauma) • Malignant hypertension • Advanced retinopathy • Old age (relative) • Aspirin or other antiplatelet drugs • Neoplastic disease
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  Contraindications to Antithrombotic Therapy Specificto thrombolytic agents • Recent thoracic, abdominal, or central nervous system surgery • Recent cerebrovascular accident, trauma, or neoplasm • Bleeding ulcer • Anticipated invasive procedures (arterial punctures, biopsies, central lines) • Concurrent hemostatic dysfunction
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  Indications • AMI • Multiplepulmonary emboli. • Pulmonary embolism with hemodynamic instability • Central DVT • Pheripheral vascular disease
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  Drug preparations :to stop bleeding
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  Fibrinolytic Inhibitors: Aminocaproic Acid Similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis  Competitively inhibits plasminogen activation  Oral dosage of EACA is 6 g four times a day  Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours
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  USES  Adjunctive therapyin hemophilia  Bleeding from fibrinolytic therapy  Prophylaxis for re-bleeding from intracranial aneurysms.  Postsurgical gastrointestinal bleeding ,post prostatectomy bleeding ,bladder hemorrhage secondary to radiation and drug-induced cystitis.  Adverse effects  Intravascular thrombosis from inhibition of plasminogen activator  Hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness
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  Drug preparations: clottingdeficiencies Vitamin K • Oral : 5 mg tablets Plasma fractions - for hemophilia • Antihemophilic factor ( VIII, AHF) • Parenteral Factor IX complex • Parenteral : in vials