Pharmacology Lecture 4: Anticoagulants & Thrombolytics (2024-2025) PDF

Lecture 4 ‫بسم اهلل الرمحن الرحيم‬ Anticoagulants And Thrombolytic Drugs 4TH Year Clinical Lab Medicine Students 2024-2025G (1446H)...

Lecture 4 ‫بسم اهلل الرمحن الرحيم‬ Anticoagulants And Thrombolytic Drugs 4TH Year Clinical Lab Medicine Students 2024-2025G (1446H) Prof. Adel Galal El-Shemi & Dr. Bader Alhazmi  Types of Thrombi Arterial Thrombus Venous Thrombus (White Thrombus) (Red Thrombus) Occurs in arteries which carry Occurs in veins which carry oxygenated blood deoxygenated blood. Occurs due to arteries injury or due to atherosclerosis. Occurs due to vein wall injury Primarily consists of platelets or due to slow blood flow (Stasis) and less fibrin. Primarily consist of fibrin+ RBCs Called white thrombi because of their pale color. which gives it a red appearance.  Anti-Coagulants & Thrombolytic Drugs What are anticoagulants and thrombolytic drugs? They are medications used in the management of thromboembolic disorders & reduce the risk of cardiovascular events. They either prevent the formation of blood clots (e.g., Anticoagulants) or dissolve existing clots (Thrombolytics). How they work ? 1- Anti-coagulants work by inhibiting: Blood coagulation cascade & Formation of fibrin network. 2- Thrombolytic drugs work by destructing the formed thrombus: These drugs dissolve existing blood clots and destructing the formed thrombus by activating the fibrinolytic (thrombolysis system) to breakdown fibrin and lyse thrombus restore blood flow. Classes Of Drugs in This Lecture: 1- Anticoagulants (Heparins & Warfarin Families) to prevent formation of venous thrombus. 2- Anti-platelets (Aspirin & other drugs) to prevent formation of Arterial thrombus. 3- Thrombolytic (fibrinolytic) Drugs to breakdown the formed thrombi.  Classes of Anticoagulation & Thrombolytic Drugs 1- Anti-coagulants: Drugs prevent blood coagulation and subsequent venous thrombi and emboli. They are widely used clinically and include: Heparin & Warfarin families. 2- Anti-platelets: Drugs prevent platelet aggregations and subsequent arterial thrombus formation. They include: (a) Aspirin (in Child dose= Asaphen, Entrophen, Novasen). (b) Other antiplatelet drugs (Clopidogrel (Plavix), Prasugrel, Ticagrelor). 3- Thrombolytics (=Fibrinolytics): Drugs dissolve clots or thrombus. Used to treat acute thromboembolic events (e.g. pulmonary embolism or stroke). Work by breaking down fibrin (protein) that forms blood clots. (a) Old drugs (= 2 enzymes): Streptokinase & Urikinase enzymes. (b) Specific thrombolytic agents: (“tPAs” = tissue plasminogen activators,.eg, Alteplase).  Blood Coagulation & Anticoagulant Agents (Blood Thinners) HOW blood clots form? Factor Xa activation Either: A- Extrinsic Pathway prothrombin Thrombin Occurs by tissue factor (TF) activation due to tissue injury activates thromboplastin Fibrin mesh-like matrix OR: of blood clot B- Intrinsic Pathway Occurs when collagen (from damaged vessel) exposed to factor XII Mechanisms (activations) of Blood Clotting: Coagulation of blood is maintained by: Extrinsic pathway (initiated by activation of tissue factor (TF) that activates thromboplastin, caused by tissue injury). Intrinsic pathway (initiated by activation of clotting factor XII, caused by vascular injury). Both pathways activate enzymatic reactions that produce factor Xa which catalyze the conversion of prothrombin (factor II) to thrombin (II a). Thrombin is responsible for generation of fibrin mesh-like matrix of blood clot.  Intrinsic Pathway Extrinsic Pathway Caused by Blood Vessel Injury Caused by Tissue Injury (Trauma) Activate Tissue Factor (TF) XII XIIa Ca++ Activate is essential in Thromboplastin XI XIa all these steps IX IXa VIIa VII X Xa X Factors affected Prothrombin (Factor II) Thrombin By Heparin Ca++ Vit. K dependent Factors Fibrinogen Fibrin monomer Affected by Oral Anticoagulants (Factor I) Thrombin (Warfarin family) Fibrin polymer Fibers Ca++  Classification of ANTICOAGULANTS: * In vitro Anticoagulants:- Primarily used in laboratory settings NOT in a living organism 1- Precipitation of ca++ by oxalate ions or deionization of ca++ by citrate (blue-toped tube). 2- Collecting blood in tubes containing EDTA (violet-toped tube). Warfarin 3- Collecting blood in tubes containing Xa Heparin (green-toped tube). * In vivo Anticoagulants:- used Clinically Oral Anticoagulants = Heparin Heparin family (Given i.v. & s.c. = but not i.m.). Oral Anticoagulants = Warfarin family (coumarin (Dicumarol) derivatives). Note: Heparin acts as in vitro and in vivo anticoagulant Warfarin family acts only as in vivo anticoagulant  Mechanisms of Anticoagulant effects of Warfarin and Heparin & blood clotting tests that are used to adjust their doses ‫هام جدا‬ Warfarin is a vitamin K antagonist. It prevents vitamin K cycle and synthesis of vitamin K-dependent clotting Vitamin K factors: Prothrombin (clotting factor II) and other clotting factors (e.g., VII, IX and X.). Factor Xa Efficacy & safety of warfarin is critically dependent on value of the Prothrombin Time (PT) and International Normalized Ratio (INR). Heparin binds to and activate endogenous anti-thrombin III (ATIII) forming complex that binds irreversibly and inactivates thrombin, and other clotting factors (e.g. Xa, IXa, Xia).. Efficacy & safety of Heparin is critically dependent on value of the partial thromboplastin time (PTT) Test Abbreviation Normal Ranges What is the normal range Prothrombin time PT 11-14 seconds for PT, INR, and PTT? International normalized ratio INR 0.8 to 1.1 Partial thromboplastin time PTT 25-35 seconds Oral Anticoagulants (= Vitamin K Antagonists ) [= Coumarin Derivatives] [= Warfarin Family] Oral Anticoagulants (Vit. K Antagonists) “WARFARIN” Monitoring with PT and INR Warfarin inhibits Vit. K The effectiveness of warfarin Epoxide Reductase therapy is monitored through prothrombin time (PT) and Warfarin inhibits vitamin K Vitamin K international normalized ratio (INR). epoxide reductase in the liver. Warfarin is a vitamin This enzyme is crucial for the K antagonist. In liver, it prevents vitamin K important activation of vitamin K, which is cycle and vitamin K- Very essential for the synthesis of dependent synthesis of clotting factors II (prothrombin), prothrombin and other clotting factors such as VII, IX, and X. VII, IX, X. Warfarin has Delayed In healthy people an INR of 0.8 Onset and Long Duration. to 1.1 is considered normal. why? An INR range of 2.0 to 3.0 is Delayed action (48-72) hours. long action duration 5-7 days generally an accepted of effect after last dose. therapeutic range for people taking warfarin.  Therapeutic Uses of WARFARIN 3- Prophylaxis in 1- Prevention of deep vein Myocardial Infarction thrombosis (DVT): 1. It prevents the formation of DVT. It is used as prophylactic agent to 2. It also prevents the progression prevent thromboembolism formation of existing DVT and pulmonary in patients with: embolism (PE) after initial 1. acute myocardial infarction (MI). heparin treatment. 2. prosthetic heart valves. 2- Prevention of Thrombo-embolism Preventing thromboembolism during major surgeries, including orthopedic and gynecologic surgery. NB: warfarin family are contraindicated in Pregnancy Why??????????? It can cross placental barrier. Result Teratogenic during 1st pregnancy trimester + severe bleeding during labor  Pharmacogenomics & Anticoagulant Drugs Can genetic factors affect warfarin dosing, efficacy and safety ? Warfarin Therapy and the Genotypes CYP2C9 and VKORC1 Warfarin is an anticoagulant that acts by reducing the activity of vitamin Vitamin K K-dependent clotting factors. Genetic Testing VKORC1 and CYP2C9 genotypes are the most important genetic determinants of warfarin dosing regimen, efficacy and safety. VKORC1 gene encodes Vitamin K epOxide Reductase Complex subunit 1 enzyme (which is the target site of warfarin action). Patients VKORC1 who carry polymorphism in the promoter region of the VKORC1 gene enzyme are more sensitive to warfarin and require lower doses. CYP2C9 gene encodes one of the main enzymes involved in the metabolism of warfarin. Several variant CYP2C9 alleles are associated Synthesis of with reduced enzyme activity and lower metabolism rates of warfarin. (ie, we should decrease dose) Blood x Coagulant Factors Warfarin CYP2C9 enzyme Metabolism of Warfarin  HEPARIN Source of heparin in our bodies: Mast cells & Basophils. Origin of commercial heparin: from porcine intestinal mucosa Mechanism of Action:(= How does Heparin prevent blood coagulation): ✓ Heparin binds to endogenous anti-thrombin III forming complex that binds irreversibly and inactivates (ie, block activity of) thrombin and other coagulant factors such as IXa, Xa, Xia, XIIa). ✓ This mechanism occurs normally in the blood, but heparin accelerates this process by a factor of 1000 fold. ✓ Heparin has a very rapid onset but short duration of action. Administration: it is given IV or deep SC. (not given i.m ? Why ????) Antidote: (= What is the antagonist that is used to treat Heparin toxicity): Heparin is highly acidic and can be neutralized by basic antitodte molecules such as “Protamine sulfate 1%”.  Heparin ….. cont. Heparin action is rapid Heparin action is monitored by activated partial thromboplastin time (a PTT) laboratory test. Types of Heparin: 1- Unfractionated Heparin long chain polysaccharide up to 30,000 Daltons Example: standard heparin. 2- Low Molecular Weight Heparin (LMWH) < 6000 Dalton. effective as standard heparin and more safe. also named direct thrombin inhibitors. Example: Enoxaparin and ARGATROBAN  Clinical Uses of Heparin Prevention of deep venous thrombosis (DVT). Treatment of pulmonary embolism and myocardial infarction. Therapeutic uses to limit expansion of thrombi and prevent fibrin formation. Also used in dialyzing machine to prevent thrombus formation. It can be used in pregnant women who will undergo prosthetic heart valves operation.  Side Effects of Heparin Thrombocytopenia (HIT) Hemorrhage Can cause a decrease in platelet Can cause bleeding so it count should be prevented by: 1. Monitor for bleeding time which can lead to an increased risk (activated partial of clotting !!!!! thromboplastin time (aPTT)) 2. Stop the drug This is known as heparin-induced 3. protamine sulfate (1mg/100 thrombocytopenia (HIT). IU heparin). Osteoporosis Long-term use of heparin can lead Hypersensitivity to osteoporosis and abnormal liver function test (LFTs). Can cause allergic reactions: rash, itching, Because heparin can inhibit the swelling, and formation of new bone. In addition, difficulty breathing. prolonged use can affect liver function tests, resulting in abnormal values.  Compare between Heparin & Warfarin? Parameter Heparin Warfarin from porcine intestinal mucosa from plant source Commercial Source Test yourself Test yourself Route of Administration Test yourself Test yourself Mechanism of Action Test yourself Test yourself Onset of action Test yourself Test yourself Duration of action Test yourself Test yourself Clotting test used to adjust its dose Test yourself Test yourself Specific side effects Test yourself Test yourself Antagonist (= Antidote) Test yourself Test yourself  What are the types of antiplatelet drugs? ‫للعلم فقط‬ Antiplatelets prevent platelets from clumping together to form a clot. The most commonly used antiplatelet is aspirin (in child dose), but other kinds include: Adenosine diphosphate (ADP) receptor inhibitors (clopidogrel, ticagrelor, ticlopidine, prasugrel) make platelets less sticky. Adenosine reuptake inhibitors (dipyridamole) block enzymes involved in clotting. Glycoprotein platelet inhibitors (abciximab, eptifibatide, tirofiban) block substances that help clots stick together. Phosphodiesterase inhibitors (cilostazol) widen blood vessels and stop platelets from sticking together. Protease-activated receptor (PAR-1) antagonist (vorapaxar) blocks a substance on platelets that helps them clot.  THROMBOLYTIC (Fibrinolytic) THERAPY: They convert plasminogen to plasmin, the major enzyme responsible for clot breakdown ALTEPLASE (= tissue plasminogen activator; tPA). STREPTOKINASE. URIKINASE. Mechanism of Action: They catalyze the conversion of plasminogen to plasmin which convert fibrin to fibrin degradation products. When used in combination with anti-platelets can prevent reformation of clot.  THROMBOLYTIC THERAPY by Thrombolytic & Fibrinolytic agents Mechanism: converts plasminogen to plasmin to destruct the thrombus. Uses: It is used in the treatment of (1) deep vascular thrombosis (DVT) and (2) pulmonary embolism. Side effects: Hemorrhage when used IV specially in peptic ulceration. It can not be used with history of cerebro-vascular accidents and pregnancy. N.B. ‫ هام جدا‬the old thrombolytic drugs ( Urokinase & Streptokinase) can not differentiate between normal hemostatic plug and pathogenic embolus & thrombus (ie, Non specific) However, tPA drugs (eg, Alteplase) have selective action on the thrombus. Therefore, the hemorrhagic side effects of tPA are less than those of Urokinase & Streptokinase  Summary of Drugs used to Prevent & Treat THROMBO-EMBOLISM Disorders: Drug Class Prototype Main Action Effect/Use Anticoagulant Prevent venous Heparin Family Anti-thrombin Parenteral Thrombosis Anticoagulant Warfarin Family Decrease synthesis of Prevent venous Oral Clotting factors in the liver Thrombosis by antagonizing Vit. K Prevent arterial Antiplatelet Aspirin & Decrease platelet Thrombosis drugs Other Antiplatelet aggregation Thrombolytic tPAs, Streptokinase Fibrinolysis Breakdown of Drugs & Other thrombi thrombolytic agents ‫هو هللا الذى ال إله إال هو عالم الغيب والشهادة‬ ‫هو الرحمن الرحيم‪.‬‬ ‫صدق هللا العظيم‬