Anticoagulants and Antiplatelet Agents PDF

Anticoagulants and Antiplatelet Agents 1  Thrombosis Thrombosis is the formation of unwanted clot within a blood vessel Thrombotic disorders: § MI § Deep venous thrombosis (DVT) § Pulmonary embolism (PE) § Acute ischem...

Anticoagulants and Antiplatelet Agents 1  Thrombosis Thrombosis is the formation of unwanted clot within a blood vessel Thrombotic disorders: § MI § Deep venous thrombosis (DVT) § Pulmonary embolism (PE) § Acute ischemic stroke 2  Thrombus vs. Embolus Thrombus: a clot that adheres to a vessel wall Embolus: a thrombus that detaches from a vessel wall and float in the blood § Both are dangerous and can occlude blood vessels  Arterial vs. Venous thrombosis Arterial thrombosis Venous thrombosis: Ø Formed usually at Ø It is rich in fibrin with fewer atherosclerotic plaques in platelets medium-sized vessels. Ø triggered by v blood stasis or v inappropriate activation of the Ø It consists of a platelet-rich coagulation cascade. clot 4  Chemical mediators synthesized by endothelial cells Intact endothelial cells secret inhibitors of platelet aggregation: Ø Prostacyclin (Prostaglandin I2) Ø Nitric oxide (NO) Damaged endothelium secret less, resulting in platelet aggregation 5  Platelet activation Injury exposes reactive subendothelial matrix proteins such as collagen and von Willebrand factor, which results in: § Platelet adherence and activation § Secretion and synthesis of vasoconstrictors § Secretion of platelet-recruiting and activating molecules. 6 Products secreted from platelet granules include: Adenosine diphosphate (ADP): a powerful inducer of platelet aggregation Serotonin (5-HT): stimulates aggregation and vasoconstriction Thromboxane A2 (TXA2): synthesized from arachadonic acid within platelets and is a platelet activator and potent vasoconstrictor. Platelets activating factor (PAF) 7  Platelet aggregation Activation of platelets by ADP and TXA2 results in: Ø A conformational change in glycoprotein (GP)IIb/IIIa receptors, Ø enabling them to bind fibrinogen Ø Binding to fibrinogen cross-links adjacent platelets, resulting in aggregation and formation of a platelet plug. Simultaneously, the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot 8 Platelet Activation 9 Platelet aggregation 10  Anti-Clotting Thrombolytics Anti-Platelet Aggregation Anti-Blood Coagulation (Antiplatelets) (Anticoagulants) 11  Platelet activation inhibitors COX-1 Blockade of Blockade of PDE III inhibition ADP receptors GP IIb/IIIa inhibitors Aspirin Ticlopidine Abciximab Dipyridamo Clopidogrel Eptifibatide Prasugrel Tirofiban Ticagrelor 12 COX-1 inhibition 13  Aspirin (Acetylsalicylic acid) Mechanism of action: irreversibly inhibit COX-1 enzyme in the platelets, thus prevents TXA2 synthesis, thereby preventing platelets aggregation. Platelets do not have nuclei, thus cannot produce new COX-1 Inhibition of platelet aggregation lasts for the life of the platelets (7-10 days) Complete inactivation of platelets occurs with daily 75 mg Aspirin. The recommended daily dose: 50-325 mg 14 Therapeutic use of Aspirin (Acetylsalicylic acid) Prophylactic treatment of: § Transient cerebral ischemia § Prevention of MI 15 Pharmacokinetics of Aspirin (Acetylsalicylic acid) Aspirin is absorbed passively and quickly metabolized into Salicylic acid Salicylic acid is further metabolized by the liver or excreted renally unchanged Aspirin half life: 15-20 min Salicylic acid half life: 3-12 hr 16 Adverse effects of Aspirin (Acetylsalicylic acid) It increases bleeding time: increase risk of hemorrhagic stroke and GI bleeding (especially at high doses) Note: Ø other COX-1 inhibitors like Ibuprofen inhibit the enzyme reversibly Ø They can compete with Aspirin for the same binding site on the enzyme Ø Thus prevents the irreversible inhibition of COX-1 17 Blockade of ADP receptors 18  Ticlopidine, Clopidogrel, Prasugrel & Ticagrelor Mechanism of action: Block the P2Y ADP receptors on platelets, thus prevent GP IIb/IIIa receptors activation, which is necessary for fibrinogen-mediated platelet-platelet interaction All are irreversible blockers except Ticagrelor Ticagrelor and Prasugrel require 1-4 hr for max efficacy Ticlopidine and Clopidogrel require 3-5 days for max efficacy 19 Therapeutic uses: Clopidogrel: Prevention of thrombosis associated with: Atherosclerotic events with recent MI or stroke Acute coronary syndrome (unstable angina or non-ST elevation MI) Percutaneous coronary intervention (PCI), with/without coronary stenting PCI 20 Therapeutic uses: Ticlopidine: Reserved for patients intolerant to other therapies due to life- threatening hematologic reactions Prevention of transient ischemic attacks (TIA) and strokes in patients with prior cerebral thrombotic events 21 Therapeutic uses: Prasugrel: Acute coronary syndrome: unstable angina, non-ST-elevation MI and ST-elevation MI Ticagrelor: Prevention of arterial thrombosis in unstable angina, acute MI including those undergoing PCI 22  Pharmacokinetics Clopidogrel is a prodrug The therapeutic efficacy is entirely dependent on its active metabolite (generated by CYP2C19) Susceptible to genetic polymorphism Poor metabolizers should receive another antiplatelet drug 23  Side effects These agents can prolong the bleeding time Ø No antidote available Ø More pronounced with Prasugrel & Ticagrelor Ticlopidine is associated with severe hematologic reactions: Ø Agranulocytosis Ø Aplastic anemia Ø Thrombotic thrombocytopenic purpura (TTP) 24  Side effects TTP can also be caused by Clopidogrel & Prasugrel (but not Ticagrelor Clopidogrel can rarely cause neutropenia Prasugrel is contraindicated for patients with history of TIA or stroke (can increase the risk of bleeding) Concomitant administration of Aspirin reduces the efficacy of Ticagrelor 25 Blockade of GP IIb/IIIa 26  Abciximab, Eptifibatide and Tirofiban Mechanism of action: they block GP IIb/IIIa receptors on the platelets, thus prevent the binding of fibrinogen and von Willebrand factor. 27  Abciximab, Eptifibatide and Tirofiban Ø Abciximab is a monoclonal antibody Ø Eptifibatide is a cyclic peptide Ø Tirofiban is chemical compound 28  Therapeutic uses of GP IIb/IIIa receptor blockers Given IV with Heparin & Aspirin as adjunct to PCI to prevent cardiac ischemic complications. Abciximab is approved for unstable angina not responding to conventional therapy when PCI is planned within 24 hr Adverse effects: Bleeding especially if used with anticoagulants 29 Phosphodiesterase III (PDE III) inhibitors 30  Dipyridamole Mechanism of action: Ø inhibit PDE III thereby elevate cytopalsmic cAMP in both vascular tissue and platelets, Ø resulting in decreased TXA2 synthesis, causing vasodilation and reduced platelets aggregation Ø Dipyridamole is used for stroke prevention, and usually given with Aspirin 31 Blood coagulation 32  Blood coagulation Intrinsic pathway Extrensic pathway Vascular injury Expose collagen Vascular injury to blood XII XIIa Expose tissue factor XI XIa (Thromboplastin) IX IXa VIIa VII X Xa X Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin  Endogenous inhibitors of coagulation Protein C Protein S Tissue factor pathway inhibitor Antithrombin III (ATIII) These inhibitors naturally restrict the coagulation to the site of vascular injury. 34  Anticoagulants They work by two mechanisms: I. inhibit the action of the coagulation factors (e.g. Heparin) or II. inhibit the synthesis of these factors (e.g. Warfarin). 35  Heparin Large sulfated polysaccharide polymer obtained commercially from porcine intestinal mucosa Molecular weight: 15,000-20,000 Highly acidic, can be neutralized by Protamin (basic molecule) that function as an antidote. 36  Heparin Half life: 1.5 hr Administration: SC or IV bolus (loading dose) followed by slow IV infusion. It causes hematoma when given IM 37  Low-Molecular Weight Heparins (LMWHs) Drugs: Enoxaparin, Deltaparin, Tinzaparin Molecular weight: 2000-6000 Have greater bioavailability Longer duration of action, 3-12 hr (given less frequently, once or twice daily) Administration: SC 38  Mechanism of action of Heparin & Low-Molecular Weight Heparins (LMWHs) Heparin + ATIII Heparin-ATIII complex irreversibly inactivate Thrombin (IIa) and factor Xa Prevents the conversion of Fibrinogen into Fibrin LMWH-ATIII complex inactivate factor Xa only but not Thrombin 39  Therapeutic uses of Heparin & Low-Molecular Weight Heparins (LMWHs) Provides an immediate anticoagulant activity Given in the following cases: - Acute venous thrombosis (DVT & PE) - Prophylaxis of post-operative thrombosis - Acute MI - In combination with thrombolytics for revascularization - In combination with GP IIb/IIIa blockers during angioplasty and placement of coronary stents 40  Therapeutic uses of Heparin & Low-Molecular Weight Heparins (LMWHs) Safe in pregnancy (do not cross the placenta) LMWHs do not require monitoring, thus given for inpatient & outpatient. The anticoagulant activity of Heparin is monitored by “activated partial thromboplastin time” test (aPTT), should be 1.5 – 2.5 fold of the normal control. LMWHs can be monitored by factor Xa activity, when required (renal dysfunction, pregnancy, obesity) 41  Adverse effects of Heparin & Low-Molecular Weight Heparins (LMWHs) Bleeding: - May result in hemorrhagic stroke Ø Discontinue Heparin and give slow IV infusion Protamine sulfate. Ø Protamine sulfate dose should be titrated since it has a week anticoagulant activity, Ø thus excess protamine sulfate can worsen bleeding 42  Adverse effects of Heparin & Low-Molecular Weight Heparins (LMWHs) Hypersensitivity reactions: because it comes from Porcine - Chills - Fever - Urticaria - Anaphylaxis 43  Adverse effects of Heparin & Low-Molecular Weight Heparins (LMWHs) Heparin-induced thrombocytopenia (HIT): - Serious condition - Immune-mediated - Risk of venous & arterial embolism Osteoporosis (with prolonged use) 44  Contraindications of Heparin & Low-Molecular Weight Heparins (LMWHs) Bleeding disorders (e.g. hemophilia) Alcoholism Recent surgery in the brain, eye or spinal cord History of HIT 45  FondaparinuX Small synthetic drug Structure-activity relation ship similar to LMWHs Selectively binds ATIII and increase neutralization of factor Xa by ATIII Indication: treatment and prevention of DVT & PE 46  Fondaparinux Half life: 17- 21 hr Elimination: renally unchanged Contraindicated in severe renal impairment Side effect: bleeding (NO antidote available) 47  Direct thrombin (IIa) inhibitors Drugs: - Argatroban - Bivalirudin - Desirudin - Dabigatran etexilate Mechanism of a action: Directly inhibit thrombin (IIa) thereby inhibit fibrin generation 48  Pharmacokinetics of direct thrombin (IIa) inhibitors Given only parenterally, except Dabigatran etexilate that can be given orally All are eliminated renally except Argatroban (hepatic metabolism) Half-life is relatively short (25-50 min) except Dabigatran etexilate (8-14 hr) 49  Clinical use of direct thrombin (IIa) inhibitors Alternative to heparin in patients with history of HIT: Patients undergoing PCI Patients with unstable angina undergoing angioplasty Prevention of DVT in patients undergoing hip replacement surgery Dabigatran etexilate: prevention of stroke and embolism in patients with atrial fibrillation aPTT for monitoring effect 50  Side effects of direct thrombin (IIa) inhibitors Bleeding (antidote available for Dabigatran: idarucizumab) aPTT for monitoring the effect of these drugs except for Dabigatran etexilate Abrupt discontinuation of Dabigatran etexilate increase risk of thrombosis Dabigatran etexilate causes GI side effects: dyspepsia, esophagitis, GI bleeding 51  Inhibitors of factor Xa Drugs: - Rivaroxaban - Apixaban Mechanism of a action: Directly inhibit factor Xa thereby inhibit thrombin generation Administered orally Eliminated renally Therapeutic uses: Prevention of DVT, PE and stroke Side effects: Bleeding (antidote: coagulation factor Xa [recombinant] 52  Coumarin anticoagulants (Warfarin) This family of drugs is used as rudenticide Warfarin is the only one used clinically Warfarin has narrow therapeutic window Requires continuous monitoring by INR test (target range 2 – 3, for some patients {e.g. with prosthetic valves} 2.5 – 3.5). * INR: international normalized ratio 53  Mechanism of action of Warfarin Nonfunctional Functional Factors Factors II, VII, IX, X II, VII, IX, X Reduced Vit K Oxidized Vit K NADP+ NADPH Warfarin 54  Therapeutic uses of Warfarin Prophylaxis and treatment of DVT & PE Prevention of thromboembolism during surgery Thromboembolic disorders: Ø Atrial fibrillation Ø Patients with prosthetic valves Ø Following MI 55  Pharmacokinetics of Warfarin Oral bioavailabilty:100% Extensively binds plasma albumin (around 97%) Elimination by hepatic metabolism Half life: 2.5 days Half life of the clotting factor 6-80 hr; Ø latency period of 36-48 hr before the effects are seen Does not affect established thrombi 56  Major drug interactions of Warfarin CYP-450 inhibitors e.g. Amiodarone, SSRI increase anticoagulant effect CYP-450 inducers e.g. Phenytoin, Carbamazapine, Barbiturates decrease anticoagulant activity 57  Major drug interactions of Warfarin Aspirin: - Displace warfarin from plasma protein→ ↑ warfarin free fraction & ↑ anticoagulant activity - Inhibition of platelet function Antibiotics eradicate intestinal normal flora bacteria → ↓ Vit. K production → ↑ anticoagulant activity 58  Side effects of Warfarin Bleeding: requires monitoring by INR test, also called prothrombin time (PT) test Teratogenic 59  Management of Warfarin toxicity Minor bleeding: slow reverse of action is initiated: Drug withdrawal or Administration of Vit K Takes time until coagulation factors can be activated by reduced Vit K 60  Management of Warfarin toxicity Severe bleeding: rapid reverse of action is required: High doses of parenteral Vit K Infusion of: whole blood, frozen plasma or plasma concentrates of blood factors 61  New Anti-platelets Medication: Vorapaxar Mechanism of Action: The first in a new drug class. A protease-activated receptor-1 (PAR-1) antagonist. Blocks thrombin-mediated platelet activation without interfering with thrombin-mediated cleavage of fibrinogen. Decreases the tendency of platelets to clump together to form a clot. 62  Indications: Recent MI, or established peripheral artery disease Pharmacokinetics: Orally effective, high bioavailability t1/2 ≈ 20 hrs, providing consistent antiplatelet effects eliminated mainly in feces  Adverse effects: Increased risk of bleeding, including life- threatening & fatal bleeding Bruising more easily than normal. Blood in urine or stool.  Thrombolytic Drugs Streptokinase Alteplase Retaplase Tenectaplase Urokinase 65  Thrombolytic Drugs Mechanism of action: They facilitate the conversion of Plasminogen to Plasmin (a protease that hydrolyzes fibrin meshwork) thus dissolve clots and tissue reperfusion occurs. Normally administered with antiplatelet or anticoagulant drugs All are given IV Thrombolytics 66  Clinical uses of thrombolytic drugs Treatment of acute thrombosis: Acute MI Acute ischemic stroke (hemorrhagic stroke must be excluded before) DVT & PE Ø Effective within the first 2 - 6 hr only Ø Their tendency to cause bleeding limited their use 67  Contraindications of thrombolytic drugs Pregnancy Patients with healing wounds Intracranial bleeding Brain tumor Head trauma Metastatic cancer 68 Drugs Used to Treat Bleeding 69  Causes of inadequate blood clotting Vit K deficiency Genetic mutation of clotting factors - Factor VIII: hemophilia A - Factor IX hemophilia B Drug induced Thrombocytopenia 70  Vit K deficiency Most common causes: Elderly with impaired absorption of fat Newborns Dietary deficiency Antimicrobial therapy 71  Treatment of Vit K deficiency Oral or parenteral administration of Phytonadione (vit. K) It is recommended that all newborns should receive an injection of Phytonadione at birth 72  Clotting factors & Desmopressin Clotting factors are obtained by recombinant DNA technology Desmopressin (used for diabetes insipidus) - Vasopressin V2 receptor agonist - Can increase plasma conc. of von Willebrand factor & factor VIII - Used to prepare patients with von Wilebrand disease or mild hemophelia A for elective surgery 73  Antiplasmin Agents Drugs: Aminocaproic acid, Tranexamic acid, Aprotinin MOA: Inhibit plasminogen activation, thus inhibit fibrinolysis Clinical indication: Prevention and management of acute bleeding episodes in patients with hemophilia or other bleeding disorders Risk: MI, stroke, renal damage Antiplasmin Agents 74