University:
West Coast University
Course:
PHAR 740 | IPC Cardiopulmonary and Renal III
Academic year:

2024
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419

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49
Author:

Asal A.

factor's't platatte inactive Thrombosis formsintreblood Antiplatelet-Anticoagulant Pharmacology Use the Handout and the Presentation as a guidance to study the book chapter Required Reading: Basic & Clinical Pharmacology 15th edition, Katzung, Chapter 34 (Access Pharmacy) Parto Khansari Ph.D. 1/24/2024 Thrombosis Pharmacology Learning Outcomes              Differentiate between the primary and secondary hemostasis based on its role in thrombosis Describe the structure, and function of platelets in thrombosis Describe the events in platelet adhesion, activation, and aggregation List the pharmacological classes and drugs of antiplatelets Describe the mechanism of action, site of action, and adverse effects of COX inhibitors, Phosphodiesterase inhibitors, ADP receptor inhibitors, GPII-IIIa antagonist Describe the events in coagulation cascade Compare and contrast the intrinsic and extrinsic pathways Explain the role and components of the common pathway List the endogenous anticoagulants and review their mechanisms Describe the mechanism of action, effects on coagulating cascade, and adverse effects of Warfarin, Heparin, Direct Thrombin Inhibitors, Factor Xa inhibitors Evaluate and differentiate between International Normalized Ratio and activated partial thromboplastin time laboratory tests Describe the physiological process of endogenous fibrinolytics List and describe the mechanism of action and major side effects of fibrinolytic agents Thrombosis Hemostasis: Cessation of Bleeding, set of physiological process Which blocks the site of bleeding (localized), and simultaneously maintain the blood in fluid state Thrombosis: Pathological State, occurs when endothelial cells are damaged (e.g. atherosclerosis) results in inappropriate activation of hemostatic process. Clot Formation Etfknow whichore and incoaglating whichone isantiloglat Endothelial Injury Exposure of Collagen Exposure of Tissue Factors Platelet Activation Activation of Common Pathway Platelet Recruitment Thrombin Formation Platelet Aggregation t Insoluble soluby Fibrin Formation Glaststep Fibrin Clot firstfirstinsole Pharmacology of Thrombosis  Antiplatelet Agents:      Platelet COX inhibitor Phosphodiesterase Inhibitor ADP Receptor Inhibitor GPIIb/IIIa Receptor antagonist Thrombin Receptor Antagonist  Anticoagulant Agent  Heparin  Unfractionated  Low Molecular Weight  Direct Thrombin Inhibitors  Factor Xa inhibitor  Warfarin (Coumadin) bodydoes as Mimis exactlywhat  Thrombolytic Agent  Recombinant Tissue Plasminogen Activator (r-tPA) Overview of Sequence of Events in Hemostasis A. Transient localized vasoconstriction first stg (e.g. endothelin, reflex neurogenic endothelial to mechanism) endothelial B. Primary Hemostasis Exposure to subendothelial matrix Platelet adhesion-activation-aggregation C. Secondary Hemostasis Exposure to tissue factor Activation of coagulating cascade Stable clot formation D. Limiting the hemostatic process to the site of vascular injury. Primary Hemostasis Primary Hemostasis: To form a platelet plug to stabilizes vascular injury.  Platelet Adhesion  Platelet Activation  Platelet Aggregation Platelet Adhesion • Exposure of subendothelial von Willebrand factor and collagen. • Von Willebrand (vWF): • protein secreted by both activated platelets and injured endothelium • Binds to collagen and GPIb on platelets (bridging action to mediate adhesion) • GPVI binds directly Platelet Activation • Conformational changes • Activates protein phosphorylation cascade • Synthesis and release of: • • • • • • Thromboxane (TxA2), Serotonin (5-HT), Adenosine diphosphate (ADP), Calcium, vWF, Platelet factor IV. Platelet Activation 183 Bindsto endothelium recur Asprin Bindstocot FDPracticats no Platelet Activation by Thromboxane A2 otherpatients Platelet Activation by ADP and Thrombin drugsthateffectonADP Antagonist clopidogrel Platelet Aggregation Npp Anages Site of Action for Antiplatelet Agents knowthis picture Antiplatelet Agents Antiplatelets  Aspirin: Irreversible COX inhibitor t  Thienopyridins: Irreversible of ADP receptor antagonist (P2Y12)  Clopidogrel  Ticlopidine  Prasugrel (Effient)  Dipyridamole: Phosphodiesterase Inhibitor, increases cAMP, Block ADP uptake  GPIIb/IIIa Receptor antagonist:  Abciximab (Humanized murine monoclonal Ab)  Etifibatide (small molecule)  Tirofiban (small molecule) Arachidonic Acid COX inhibitor (Aspirin) AA COX-1 Imp Platelet aggregation TXA2 Smooth Muscle Vasoconstriction Inhibits COX irreversibly Inhibits COX-1 and COX-2 non-selectively in platelets, prevents conversion of AA to thromboxane A2 (TXA2), Indicated to prevent arterial thrombosis leading to stroke, TIA, MI, Side effects: bleeding increases dose dependently Aspirin resistance Reye’s Syndrome Phosphodiesterase Inhibitor (Dipyridamole)  Increase in cAMP causes decrease in Cai2+ necessary for platelet aggregation increased level of cAMP and cGMP causes vasodilation Phosphodiesterase (PDE) is an enzyme which breaks downs cAMP cAMP PDE Cai2+ cAMP Dipyridamole prevents platelet aggregation Cai2+ inhibits PDE Promote platelet aggregation cAMP Cai2+ prevents platelet aggregation Stroke, TIA, An adjunct therapy in cardiac valve replacement Vasodilation: cautious in pt with hypotension and coronary diseases Weak antiplatelet agent transient attach Blocks Dipyridamole ADP uptake ministry ADP Receptor Inhibitors affect of proteinkinases Inhibit ADP dependent platelet activation pathway Ticlopidine Clopidogrel Prasugrel Ticagrelor (not a prodrug), competitive antagonist of Press Irreversibly inhibit P2Y ADP receptors needtobe activatedfirst Pro-drugs converted to active form by hepatic P450 requiresenzyme Between subjects variability due to polymorphism in CYP450 (CYP2C19) Interact with other drugs metabolized by P450 (e.g. statins, PPI) PAD, ACS, Secondary prevention of MI, Stroke, Prasugrel: Contraindicated in TIA and stroke Side effects: GI bleeding, leukopenia, Hematologic (neutropenia (more with ticopidine) thrombocytopenia, thrombotic thrombocytopenic purpura) Require Blood Monitoring Glycoprotein IIb/IIIa receptor Antagonist  Eptifibatide: Small molecule  Abciximab: chimeric mouse-human monoclonal antibody  Tirofiban: tyrosine analogue Bind to platelet receptor GPIIb-IIIa prevent platelet aggregation Recommended in pt with ACS, undergoing PCI  Dose adjustment in Pt with renal insufficiency Can be used in combination with aspirin and heparin All cause bleeding Abciximab is irreversible, eptifibatide and tirofiban are reversible Site of Action for Antiplatelet Agents Summary of Antiplatelet Pharmacology Katzung & Trevor's Pharmacology: Examination & Board Review, 12e Antiplatelet drugs COX inhibitor Aspirin Nonselective, irreversible COX Prevention and treatment of inhibitor • reduces platelet arterial thrombosis production of thromboxane A2, a potent stimulator of platelet aggregation Dose required for antithrombotic effect is lower than anti-inflammatory dose (see Chapter 36) • duration of activity is longer than pharmacokinetic half-life due to irreversible action Glycoprotein IIb/IIIa inhibitor (GP IIb/IIIa) Abciximab Inhibits platelet aggregation by Used during PCI to prevent Parenteral administration interfering with GPIIb/IIIa restenosis • acute coronary binding to fibrinogen and other syndrome ligands Eptifibatide, tirofiban: reversible GP IIb/IIIa inhibitors of smaller size than abciximab ADP receptor antagonists Clopidogrel Prodrug: active metabolite by Acute coronary syndrome, Oral administration CYP2C9 and CYP2C19 prevention of restenosis after irreversibly inhibits platelet PCI, prevention and treatment ADP receptor of arterial thrombosis Gastrointestinal toxicity, nephrotoxicity • hypersensitivity reaction due to increased leukotrienes; tinnitus, hyperventilation metabolic acidosis, hyperthermia, coma in overdose Bleeding, thrombocytopenia with prolonged use Bleeding, gastrointestinal disturbances, hematologic abnormalities Ticlopidine: older ADP receptor antagonist with more toxicity, particularly leukopenia and thrombotic thrombocytopenic purpura Prasugrel: newer drug, similar to clopidogrel with less variable kinetics, activation primarily by CYP3A4 Ticagrelor: reversible ADP receptor antagonist that does not require activation r PDE and adenosine uptake inhibitor Dipyridamole Inhibits adenosine uptake and Prevention of thromboembolic Oral administration Headache, palpitations, inhibits phosphodiesterase complications of cardiac valve contraindicated in congestive (PDE) enzymes that degrade replacement • combined with heart failure cyclic nucleotides (cAMP, aspirin for secondary cGMP) prevention of ischemic stroke Cilostazol: similar to dipyridamole Anticoagulant Agents Thrombosis Pharmacology Learning Outcomes      Describe the events in coagulation cascade Compare and contrast the intrinsic and extrinsic pathways Explain the role and components of the common pathway List the endogenous anticoagulants and review their mechanisms Describe the mechanism of action, effects on coagulating cascade, and adverse effects of Warfarin, Heparin, Direct Thrombin Inhibitors, Factor Xa inhibitors  Evaluate and differentiate between International Normalized Ratio and activated partial thromboplastin time laboratory tests Pharmacology of Thrombosis  Antiplatelet Agents:      Platelet COX inhibitor Phosphodiesterase Inhibitor ADP Receptor Inhibitor GPIIb/IIIa Receptor antagonist Thrombin Receptor Antagonist  Anticoagulant Agent  Heparin  Unfractionated  Low Molecular Weight  Direct Thrombin Inhibitors  Factor Xa inhibitor  Warfarin (Coumadin)  Thrombolytic Agent  Recombinant Tissue Plasminogen Activator (r-tPA) Coagulating Cascade Sequence of Enzymatic events (activation of a series of proenzymes) Most factors are circulating in the blood in inactive form All factors have roman numerals and the activated forms are signified by “a” (X Xa) Ca2+ is a cofactor in many of the steps Major activation reaction occurs at the membrane surface of endothelial & platelets. The division between intrinsic and extrinsic is arbitrary The intrinsic pathway is activated in vitro The extrinsic pathway is activated in vivo In hemostasis/thrombosis, most likely extrinsic pathway starts at the Site of injury (tissue factor), and amplified by intrinsic pathway  Common pathway is the pivotal step Coagulating Cascade XII Intrinsic Pathway (Surface Contact) XIIa Ca++ XI XIa Ca++ IX IXa VIIIa Ca++ X T Extrinsic Pathway (Tissue Damage) VIIa VII Ca++ Tissue Factors Xa Ca++ Va Thrombin (factor IIa) Prothrombin (factor II) Soluble Common Pathway insoluble protein Fibrin (factor Ia) Fibrinogen (factor I) XIII XIIIato Bindstoglysoprota 253BA wattles Thrombin AEaggÉÉwrevered Its role in coagulation includes: • Amplifies the factor V and VIII activation • Convert soluble fibrinogen to insoluble fibrin • Activate factor XIII to cross link the fibrin polymer • Strongly activate platelet (granule release) • Activate factor V, VII, VIII, XI Its anticoagulation role includes: • Activates protease-activated receptors (PAR)on intact endothelial cell to release NO and PGI2, • t-PA (platelet inhibitors), tissue plasminogen activator (t-PA) • Converting Plasminogen to plasmin Anticoagulant Classification Heparin Unfractionated Low Molecular Weight Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Direct Thrombin Inhibitors: Lepirudin Desirudin Bivalirudin Argatroban Dabigatran (Pradaxa)  Thrombin Receptor Antagonists Vorapaxar Factor Xa inhibitor Fondaparinux (Arixtra) Rivaroxiban (Xarelto) Apixaban (Eliquis) Oral Vitamin K antagonist  Warfarin (Coumadin) At Heparin Antithrombin: a "suicide substrate" for intrinsic and common pathway proteases Heparin Heparin, LMWHs, and fondaparinux have no intrinsic anticoagulant activity; rather, these agents bind to antithrombin and accelerate the rate at which it inhibits various coagulation proteases. Mucopolysaccharide stored in secretory granules of mast cells Unfractionated: MW 5-30 KDa Prepared from bovine lung, porcine intestinal mucosa Serves as a catalytic template to accelerate binding of antithrombin III to activated proteases by 1000 fold High dose interfere platelet aggregation and prolong bleeding Adverse effect: sever bleeding, thrombocytopenia, heparin resistance hyperkalemia osteoporosis and alopecia: Does not cross the epithelial cells of GI track, hence administered subcutaneously (SC) or intravenously (IV). Require monitoring : activated partial thromboplastin time (aPTT) assess intrinsic and common pathway Protamine reverse its effect Heparin Heparin, LMWHs, and fondaparinux have no intrinsic anticoagulant activity; rather, these agents bind to antithrombin and accelerate the rate at which it inhibits various coagulation proteases.  Enoxaparin (Lovenox)  Dalteparin (Fragmin)  Tinzaprin(Innohep) Low Molecular Weight: MW 1-5 KDa Selective toward Xa asInactive Better therapeutic index No effect on platelet aggregation Monitoring is not done routinely Heparin Comparison of Heparin, LMWH, and Fondaparinux FEATURES HEPARIN LMWH FONDAPARINUX Source Biological Biological Synthetic Molecular weight (Da) 15,000 5000 1500 Target Xa and IIa Xa and IIa Xa Bioavailability (%) 30 90 100 t1/2 (h) Renal excretion 1 No 4 Yes 17 Yes Antidote effect Complete Partial None Thrombocytopenia <5% <1% <1% Direct Thrombin Inhibitors Diverse chemical structure (Parenteral anticoagulants) Lepirudin (Refludan) Derived from medicinal leech protein hirudin Inhibit both free and fibrin bound thrombin Approved in pt with Heparin induced Thrombocytopenia (HIT) Desirudin (Iprivask) Another Recombinant formulation of hirudin (lack sulfate group) Prophylaxis against DVT Bivalirudin (Angiomax) Synthetic peptide Approved in pt with HIT Argatroban (Acova), Small molecule Safe in pt with renal insufficiency Approved in pt with HIT Dabigatran (Pradaxa) Prodrug, an oral anticoagulant which reversibly blocks thrombin. Safe in pt with renal insufficiency Approved in pt with HIT Factor Xa Inhibitor     Rivaroxaban (Xarelto) Apixaban (Eliquis) Fondaparinux (Arixtra) Endoxaban (Savaysa) New oral anticoagulant (NOA) Similar efficacy to LWM heparin Fixed oral dose Better safely profile  No need for monitoring Indirect Factor Xa Inhibitor Fondaparinux (Arixtra) Synthetic pentasacharide Indirect and reversible inhibitor of factor Xa Binds to antithrombin III, induces conformational changes to enhance binding of antithrombin III to factor Xa Eliminated through urine, monitoring of renal function No effect on aPTT and INR. Administered subcutaneously into the fatty tissue of the abdominal wall and its Major adverse effect is bleeding. Idraparinux a hypermethylated version of fondaparinux with a t1/2 of 80 h AXimports Vitamin K Dependent Pathway Warfarin inhibits the conversion of oxidized vitamin K epoxide into its reduced form, vitamin K hydroquinone coglatingfactors inliver Reduced Vitamin K Oxidized Vitamin K Vitamin K dependent Factor II, VII, IX, X Protein C and S htt Inactive form in liver Anticog Synthesized in an Post-translational Carboxylation of glutamate residue γ-carboxylated glutamate residue binds to Ca++ The binding of Ca2+ to the γ-carboxylated molecules increases the enzymatic activity of coagulation factors IIa, VIIa, IXa, Xa, and protein Ca by approximately 1,000-fold. Warfarin mot inhibitepoxide reductase Synthetic derivative of Coumarine It inhibits the vitamin K epoxide reductase Drug-drug interactions: 99% albumin-bound in plasma so increases the unbound plasma concentration if administered with other highly albumin-bound drugs Adverse effect: Sever bleeding Inhibiting the synthesis of coagulating factors Thrombus formation in pt with genetic mutation in protein C and S Inhibiting the synthesis of endogenous anticoagulant Monitoring of chronic warfarin therapy International Normalized Ratio (INR)= Standardized Prothrombin Time (PT) International Normalized Ratio (INR) Warfarin has a narrow therapeutic index and cause numerous drug–drug interactions, therefore chronic warfarin therapy must be monitored regularly (every 2–4 weeks). International Normalized Ratio (INR) a worldwide Standardized Prothrombin Time (PT) Patient plasma + crude preparation of tissue factors Measure the time requires for blood clot formation Longer it takes for blood to coagulate Less biological active coagulating factors are available in plasma Summary of Anticoagulant Pharmacology Katzung & Trevor's Pharmacology: Examination & Board Review, 12e Subclass Anticoagulants Heparins Unfractionated heparin Mechanism of Action Clinical Applications Pharmacokinetics Complexes with antithrombin III • irreversibly inactivates the coagulation factors thrombin and factor Xa Venous thrombosis, pulmonary Parenteral administration embolism, myocardial infarction, unstable angina, adjuvant to percutaneous coronary intervention (PCI) and thrombolytics Toxicities, Drug Interactions Bleeding (monitor with aPTT, protamine is reversal agent) • thrombocytopenia • osteoporosis with chronic use LMW heparins (enoxaparin, dalteparin, tinzaparin): more selective anti-factor X activity, more reliable pharmacokinetics with renal elimination, protamine reversal only partially effective, less risk of thrombocytopenia Fondaparinux: effects similar to those of LMW heparins Direct factor X inhibitors Rivaroxaban Binds to the active site of Venous thrombosis, pulmonary Oral administration • fixed Bleeding • no specific reversal factor Xa and inhibits its embolism, prevention of stroke dose, no routine monitoring agent enzymatic action in patients with nonvalvular (factor Xa test) atrial fibrillation Apixaban and edoxaban: similar to rivaroxaban, they differ in half lives and P450 interactions. Direct thrombin inhibitors Bivalirudin, argatroban, and Bind to thrombin’s active site Anticoagulation in patients Bivalirudin and argatroban: IV Both: Bleeding (monitor with dabigatran and inhibit its enzymatic action with heparin-induced administration aPTT) thrombocytopenia (HIT) Dabigatran: oral administration Idarucizumab (Fab fragment binds & reverses effect of dabigatran) Coumadin anticoagulant Warfarin Inhibits vitamin K epoxide Venous thrombosis, pulmonary Oral administration • delayed Bleeding (monitor with PT, reductase and thereby embolism, prevention of onset and offset of vitamin K1 is a reversal agent) • interferes with production of thromboembolic complications anticoagulant activity • many thrombosis early in therapy functional vitamin K-dependent of atrial fibrillation or cardiac drug interactions due to protein C deficiency • clotting and anticlotting factors valve replacement teratogen Anticoagulant Agents Pharmacology of Thrombosis  Antiplatelet Agents:      Platelet COX inhibitor Phosphodiesterase Inhibitor ADP Receptor Inhibitor GPIIb/IIIa Receptor antagonist Thrombin Receptor Antagonist  Anticoagulant Agent  Heparin  Unfractionated  Low Molecular Weight  Direct Thrombin Inhibitors  Factor Xa inhibitor  Warfarin (Coumadin)  Thrombolytic Agent  Recombinant Tissue Plasminogen Activator (r-tPA) Regulation of Hemostasis To limit platelet activity and clot formation only to the site of endothelial injury NO and PGI2 release (platelet inhibitors via increase in cAMP) Protein C and S Release of tissue plasminogen activator (t-PA) Release of plasminogen activator inhibitor (PAI-1) to inhibit the activation of t-PA Antithrombin III: inactivate thrombin, factor IXa, Xa, XIa, XIIa Tissue factor pathway inhibitor (TFPI) Endogenous Anticoagulant  Plasmin is synthesized from plasminogen in the liver  T-PA synthesized and secreted by endothelium  t-PA dissolve the intra-arterial blood clots. Tissue Plasminogen Activator (t-PA) Plasminogen Thrombin Plasmin Fibrin Fibrin Degraded Products The activity of t-PA is further regulated by release of plasminogen activator inhibitor-1 released form endothelial cells (PAI-1) which then inhibits the activation of t-PA. Endogenous Anticoagulant Endogenous Anticoagulant Protein C and S (vitamin K dependent protein) Inactivate factors Va and VIIIa Binds to thrombomodulin (receptor) on protein C VIIIa VIII Protein C-Protein S Va V Tissue factor pathway inhibitor (TFPI) Extrinsic pathway is initiated when factor VIIa complexes with TF at the site of vascular injury VIIa:TF complex is feedback inhibited by TFPI Thrombolytic Agents To Lyse Pre-existing Blood Clot  Alteplase (ACTIVASE)  Reteplase (Retavase)  Tenecteplase (Tnkase) rt-PA (alteplase) Recombinant tissue plasminogen activator, a thrombolytic agent which improves tissue perfusion by dissolving intra-arterial blood clots. Streptokinase bacterial enzyme synthesized by streptococci which also has the fibrinolytic characteristic. It lyses the blood clot by converting plasminogen to plasmin. The major side effect with streptokinase is potential activation of immune response. Summary of Thrombolytic Pharmacology Katzung & Trevor's Pharmacology: Examination & Board Review, 12e Thrombolytic drugs Alteplase, recombinant human tissue plasminogen activator (t-PA) Converts plasminogen to plasmin, which degrades the fibrin in thrombi Coronary artery thrombosis, ischemic stroke, pulmonary embolism Parenteral administration Bleeding, especially cerebral hemorrhage Reteplase, tenecteplase: similar to alteplase but with a longer half-life Streptokinase: bacterial protein that forms a complex with plasminogen that rapidly converts plasminogen to plasmin. Subject to inactivating antibodies and allergic reactions Thrombosis Venous Thrombosis (e.g. PE)  Usually originate in deep vein  Low blood flow, activates endothelial, induce coagulation Predominately rich in fibrin (low shear), red thrombus Treatment: Mainly anticoagulant agents Arterial Thrombosis  Endothelial damage Predominately rich in Platelet (High shear), white thrombus Treatment: Mainly antiplatelet agents Virchow’s Triad Endothelial injury Sheer stress associated with hypertension, hyperlipidemia, elevated glucose level in diabetes, vascular injury, infection Abnormal blood flow (turbulence, stasis) Aneurysm, Arrhythmia (e.g. atrerial fibrillation) Hypercoagulability Genetics (e.g. factor V Leiden, proteins C&S deficiency) Acquired (e.g. surgery, malignancy, oral contraceptive, HIT) Heparin-Induced-Thrombocytopenia (HIT) In some pt, heparin stimulates the immune system to generate Ab against heparin-factor IV complex result in platelet removal and hence thrombocytopenia. Conversely Ab binding can result in abnormal platelet activation hand hence prothrombotic state.

Thrombosis Antiplatelet-Anticoagulant Pharmacology

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