Anticoagulants, Antiplatelets, Antithrombotics

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Questions and Answers

Which characteristic distinguishes anticoagulant drugs from antiplatelet drugs?

  • Anticoagulants enhance blood coagulation, while antiplatelets inhibit coagulation factors.
  • Anticoagulants block platelet activation, while antiplatelets degrade thrombi.
  • Anticoagulants degrade thrombi, while antiplatelets prevent the occurrence of a thrombus.
  • Anticoagulants impede blood coagulation, while antiplatelets block platelet activation and aggregation. (correct)

Which of the following drugs inhibits vitamin K reductase?

  • Warfarin (correct)
  • Apixaban
  • Heparin
  • Aspirin

The anticoagulant effect of warfarin is primarily due to its interference with which of the following?

  • Activation of plasminogen.
  • Inhibition of platelet aggregation.
  • Synthesis of vitamin K-dependent clotting factors. (correct)
  • Direct thrombin inhibition.

Why is heparin often used in conjunction with warfarin at the start of anticoagulant therapy?

<p>To counteract the transient hypercoagulable state induced by warfarin. (B)</p>
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Why is warfarin contraindicated during pregnancy?

<p>It can lead to fetal harm. (C)</p>
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What is the primary mechanism of action for unfractionated heparin (UFH)?

<p>Activating antithrombin III, which then inactivates several coagulation factors. (B)</p>
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Why can't heparin be administered orally effectively?

<p>Its absorption through the gastrointestinal mucosa is poor. (B)</p>
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Heparin-induced thrombocytopenia (HIT) is caused by what?

<p>An immunological reaction that leads to platelet activation and clot formation. (B)</p>
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Which of the following adverse effects is specifically associated with long-term use of heparin?

<p>Osteoporosis and spontaneous vertebral fractures (C)</p>
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Argatroban's mechanism of action involves?

<p>Direct thrombin inhibition (B)</p>
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Which statement is true regarding argatroban's elimination from the body?

<p>It is mainly excreted in the feces through biliary secretion. (B)</p>
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What is the primary concern when administering argatroban to a patient?

<p>Excessive bleeding (D)</p>
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What is the mechanism of action of apixaban?

<p>Directly inhibiting factor Xa. (B)</p>
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What percentage of apixaban is typically absorbed after oral administration?

<p>50% (B)</p>
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A patient taking apixaban is also prescribed atorvastatin. What is a potential drug interaction that needs to be monitored?

<p>Increased risk of bleeding (B)</p>
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What is the mechanism of action for aspirin as an antiplatelet drug?

<p>Inhibiting cyclooxygenase (COX-1 and COX-2). (A)</p>
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How long does the antiplatelet effect of aspirin typically last, and why?

<p>7-10 days, because platelets cannot synthesize new proteins, so the effect lasts for the life of the platelet. (A)</p>
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What is a potential interaction between aspirin and warfarin?

<p>Increased risk of bleeding (C)</p>
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Which of the following describes the mechanism of action of abciximab?

<p>Binds to the GPIIb/IIIa receptor on platelets, preventing fibrinogen binding. (B)</p>
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A patient is prescribed abciximab. What other medication should be used with caution due to increased bleeding risk?

<p>Acetylsalicylic acid (D)</p>
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Clopidogrel's antiplatelet effects are a result of what action?

<p>Irreversibly inhibiting the P2Y12 receptor on platelets. (B)</p>
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What is a common adverse effect associated with clopidogrel?

<p>Hemorrhage (C)</p>
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What is the mechanism of action of dipyridamole?

<p>Inhibits both adenosine deaminase and phosphodiesterase (C)</p>
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Dipyridamole is contraindicated with what drug?

<p>Warfarin (C)</p>
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What is the primary mechanism of action of alteplase?

<p>Binds to fibrin in clots and converts plasminogen to plasmin. (B)</p>
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What should be used with caution when using Alteplase due to an increased bleeding risk?

<p>Acetylsalicylic acid (A)</p>
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A patient is on warfarin therapy and has an INR value of 8. Which action should be taken?

<p>Administer vitamin K. (B)</p>
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What is the target of Warfarin?

<p>Vitamin K epoxide reductase complex subunit 1 (A)</p>
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What is the half life of Apixaban?

<p>12 hours (C)</p>
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What is the target of abciximab?

<p>Vitronectin (C)</p>
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Clopidogrel is a direct inhibitor of what?

<p>P2Y12 receptor (C)</p>
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Which drug inhibits both ADP receptor and prevents aggregation of platelets and cross-linking?

<p>Clopidogrel (B)</p>
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P2Y purinoceptor 12 is a target of:

<p>Clopidogrel (A)</p>
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What agents are considered being fibrinolytic drugs?

<p>Alteplase and Reteplase (B)</p>
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What drug target both adenosine deaminase and phosphodiesterase?

<p>Dipyridamole (C)</p>
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What is the most common adverse effect of taking Argatroban?

<p>Excess of bleeding (A)</p>
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What is the half life of Heparin?

<p>1.5 h (D)</p>
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Which of the following drugs is a direct factor Xa inhibitor?

<p>Apixaban (A)</p>
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A patient on warfarin therapy requires an immediate surgical procedure. Which of the following medications would most rapidly reverse the anticoagulant effects of warfarin?

<p>Fresh frozen plasma (C)</p>
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A patient with a history of heparin-induced thrombocytopenia (HIT) requires anticoagulation. Which of the following would be the MOST appropriate choice?

<p>Argatroban (B)</p>
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A patient is prescribed apixaban for atrial fibrillation but also takes atorvastatin for hyperlipidemia. How does atorvastatin affect apixaban?

<p>Decreases the metabolism of Atorvastatin (C)</p>
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A patient on aspirin therapy is scheduled for a minor surgical procedure. Which of the following is the most appropriate approach to manage their aspirin therapy?

<p>Continue aspirin at the same dose. (C)</p>
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A patient receiving alteplase for acute ischemic stroke begins to show signs of bleeding. What is the most appropriate immediate action?

<p>Discontinue the alteplase infusion (C)</p>
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Flashcards

Anticoagulants

Drugs that impede blood coagulation and prevent thrombus formation.

Antiplatelet drugs

Drugs that block platelet activation and aggregation.

Fibrinolytic/Thrombolytic drugs

Drugs that degrade thrombi (blood clots).

Warfarin's Mechanism

Inhibits vitamin K reductase, affecting factors II, VII, IX, X, C, and S.

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Warfarin's target

Vitamin K epoxide reductase complex subunit 1.

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Warfarin Protein Binding

99% bound primarily to albumin.

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Warfarin Adverse Effects

Transient hypercoagulable state due to protein C depletion.

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UFH or LMW Heparin with Warfarin

Used to achieve immediate anticoagulation during initial warfarin therapy.

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Heparin Mechanism of Action

Heparin binds reversibly to ATIII and inactivates factors.

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Heparin Targets

Antithrombin-III potentiator and coagulation factor X inhibitor.

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Heparin Absorption

Is not absorbed through the gastrointestinal mucosa.

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Heparin Adverse Effects

Heparin-induced thrombocytopenia, immunological reaction.

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Argatroban's Mechanism

Inhibits thrombin-catalyzed reactions including fibrin formation.

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Apixaban's Mechanism

Inhibiting, in a reversible manner, free and clot-bound factor Xa to inhibit coagulation.

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Apixaban Metabolism

Hepatic by o-demethylation and hydroxylation.

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Aspirin's Mechanism

Directly and irreversibly inhibits cyclooxygenase (COX-1 and COX-2).

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Aspirin's duration of effect

Approximately 7-10 days

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Abciximab Mechanism

Binds to platelet GPIIb/IIIa receptor.

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Clopidogrel's Mechanism

Specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor.

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Dipyridamole's Mechanism

Inhibits both adenosine deaminase and phosphodiesterase.

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Alteplase's Mechanism

Binds to fibrin rich clots cleaning the Arg/Val bond in plasminogen.

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Anticoagulants

Drugs that impede blood coagulation and prevent the occurrence or expansion of a thrombus.

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Antiplatelet drugs

Drugs that block platelet activation and aggregation.

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Fibrinolytic drugs

Drugs that degrade thrombi.

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Study Notes

Anticoagulants, Antithrombotics and Antiplatelets Agents

  • Anticoagulants prevent blood coagulation and the occurance of thrombus
  • Antiplatelet drugs block platelet activation and aggregation
  • Fibrinolytic or thrombolytic drugs degrade thrombi

Anticoagulant Drugs

  • Vitamin K antagonists include: Warfarin, Acenocoumarol, Phenprocoumaron, Phenindione and Fluindione
  • Heparin and related drugs include: UFH or HMWH, LMWH (Enoxaparin, dalteparin, tinzaparin) and Fondaparinux (synthetic pentasacharide)
  • Direct thrombin inhibitors include: Hirudin and Lepirudin, Bivalirudin, Dabigatran, Argatroban and Melagatran
  • fXa inhibitors includes: Rivaroxaban, Apixaban and Edoxaban

Antiplatelet Drugs

  • Antiplatelet drugs include Aspirin, Prasugrel, Ticagrelor and Ticlopidine
  • GPIIb/IIIa receptor inhibitors include: Abciximab, Eptifibatide and Tirofiban
  • P2Y12 adenosine disphosphate receptor inhibitors includes Clopidogrel
  • Inhibitors of both adenosine deaminase and phosphodiesterase includes Dipyridamole
  • Fibrinolitic drugs include Alteplase and Reteplase
  • Other agents include Aminocaproic acid, Tranexamic acid, Phytonadione and Protamine sulfate

Warfarin

  • Inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2).
  • Limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins.
  • Factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited
  • Targets Vitamin K epoxide reductase complex subunit 1
  • Rapidly absorbed following oral administration, but absorption is also percutaneous
  • 99% bound primarily to albumin
  • Metabolised by hepatic microsomal enzymes
  • Almost entirely removed through metabolism
  • Very little is excreted unchanged in urine
  • Metabolites are principally excreted into the urine, and to a lesser extent into the bile.
  • Half life: R-warfarin 37-89 hours, S-warfarin 21-43 hours
  • Transient hypercoagulable state can occur due to residual activity of the longer half-life procoagulants in the face of protein C depletion, overlapping therapy is generally 5-7 days.
  • UFH or LMW heparin is used to achieve immediate anticoagulation until adequate warfarin-induced depletion of the procoagulant clotting factors is achieved.
  • Should never be administered during pregnancy
  • Can cause cutaneous necrosis

Warfarin Drug Interactions

  • Increased Prothrombin Time drugs include: Amiodarone, Cimetidine, Disulfiram, Fluconazole, Metronidazole, Phenylbutazone, Sulfinpyrazone and Trimethoprim-sulfamethoxazole
  • Decreased Prothrombin Time drugs include: Barbiturates, Cholestyramine and Rifampin

Heparin (UFH)

  • Unfractionated heparin (UH) is a heterogenous preparation of anionic, sulfated glycosaminoglycan polymers with weights ranging from 3000 to 30,000 Da
  • Binds reversibly to ATIII, leading to inactivation of factors lla and Xa; the heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin
  • Action is ATIII-dependent
  • Acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin
  • Targets include: Antithrombin-III potentiator, coagulation factor X inhibitor and P-selectin inhibitor
  • Must be given parenterally as it is not absorbed through the gastrointestinal mucosa, usually given by iv infusion or deep sc injection
  • Onset of action is immediate after iv injection but can be delayed 20 to 60 minutes following sc injection
  • Protein binding: Very high, mostly to low-density lipoproteins
  • Also extensively bound by globulins and fibrinogens
  • Sites of biotransformation includes the liver and reticulo-endothelial system
  • Appears to be removed mainly by the reticuloendothelial system
  • A small fraction excreted in urine and cannot be eliminated by hemodialysis.
  • Half life: 1.5 h

Adverse Effects of Heparin (UFH)

  • Heparin-induced thrombocytopenia (HIT syndrome)
  • Platelet counts usually do not fall until between days 5 and 12 of heparin therapy.
  • HIT is caused by an immunological reaction, platelets form clots within the blood vessels, using up coagulation factors
  • Can progress to thrombotic complications like arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation
  • Therapeutic doses for at least 4 months link to osteoporosis and spontaneous vertebral fractures

Heparin Drug Interactions

  • Aliskiren and amiodarone increases risk or severity of hyperkalemia
  • Omega-3 fatty acids increases the anticoagulant activities
  • NSAIDs increases the risk or severity of hyperkalemia

Argatroban

  • Action: Inhibits thrombin-catalyzed or -induced reactions, including fibrin formation, activation of coagulation factors V, VIII, and XIII, protein C, and platelet aggregation
  • Is a prothrombin inhibitor
  • Absorption is 100% intravenous
  • 54% Protein binding
  • Metabolized by liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring
  • Age and gender do not substantially affect the pharmacodynamic or pharmacokinetic profile
  • Primarily excreted in the feces (65%) through biliary secretion; 22% is eliminated via urine
  • Half life: 39-51 minutes
  • Causes excess of bleeding
  • The risk or severity of bleeding can increase when combined with Acetylsalicylic acid
  • The metabolism can be decreased when combined with Atorvastatin

Apixaban

  • An oral, direct, and highly selective factor Xa (FXa) inhibitor (of both free and prothrombinase-bound FXa independently of antithrombin III)
  • Action: Directly inhibits (in a reversible manner), free and clot-bound factor Xa to inhibit coagulation
  • Targets coagulation factor X
  • Absorbs in the stomach and small intestine, bioavailability is about 50%
  • Oral administration absorption is not affected by food
  • 87% plasma proteins
  • Metabolism: Hepatic by o-demethylation and hydroxylation to metabolites (CYP3A4)
  • 25% of the administered dose is eliminated in the feces and urine
  • Eliminated in the feces, excreted by the intestine and bile
  • Half life: 12 hours
  • Causes major bleeding

Apixaban Drug Interactions

  • The serum concentration of Apixaban can be increased when it is combined with Acetaminophen.
  • Can increase the anticoagulant activities of Acetylsalicylic acid.
  • Atorvastatin metabolism can be decreased
  • The risk or severity of bleeding and hemorrhage can be increased when Sulindac is combined

Aspirin

  • Directly and irreversibly inhibits the activity of both types of cyclooxygenase (COX-1 and COX-2) to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid
  • Irreversible acetylation renders cyclooxygenase inactive, preventing the formation of the aggregating agent thromboxane A2 in platelets
  • Platelets lack the ability to synthesize new proteins, so effects persist for the life of the exposed platelets (7-10 days)
  • Inhibit production of prostacyclin (prostaglandin 12), by blood vessel endothelial cells
  • Targets prostaglandin G/H synthase 1 & 2
  • Absorption is generally rapid and complete following oral administration with varying effects following specific salicylate used, dosage form, and gastric or intraluminal pH
  • 99.5% binds to albumin
  • Hydrolyzed primarily in the liver to salicylic acid, conjugated with glycine, forming salicyluric acid and glucuronic acid and excreted largely in the urine
  • Plasma half-life is approximately 15 minutes, which is lengthened depending on the dose.
  • 300 to 650 mg have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to about 9 hours

Aspirin Adverse Effects and Drug Interactions

  • Adverse Effects include: tinnitus, abdominal pain, hypokalemia, hypoglycemia, pyrexia, hyperventilation, dysrhythmia, hypotension, hallucination, renal failure, confusion, seizure, coma, and death
  • Warfarin: The risk or severity of bleeding can increase when Acetylsalicylic acid is combined with (R)-warfarin
  • Statins: Serum concentration of Acetylsalicylic acid can increase when combined with Atorvastatin
  • Fibrates: The metabolism of Acetylsalicylic acid can be decreased when combined with Gemfibrozil

Abciximab

  • A Fab fragment of the chimeric human-murine monoclonal antibody 7E3.
  • Action: binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. Block access of large molecules to the receptor (but not by direct interaction) with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa.
  • Targets integrin beta-3, integrin alpha-IIb and vitronectin
  • Metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production and is excreted renally.
  • Following intravenous bolus administration, concentrations decrease rapidly half-life of less than 10 minutes
  • Second phase half-life of about 30 minutes, related to rapid binding to the platelet GPIIb/IIIa receptors.
  • The risk or severity of bleeding can be increased when combined with Acetylsalicylic acid or Indometacin
  • Omega-3 fatty acids may increase the antiplatelet activities

Clopidogrel

  • Action: Specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor. Importnat in aggregation of platelets and cross-linking by the protein fibrin. Prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
  • Targets P2Y purinoceptor 12
  • Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites
  • Bioavailability isn't affected by food
  • 98% protein binding
  • Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts for appx 85% of the circulating drug-related compounds.
  • Appx 50% of total radioactivity is excreted in urine and approximately 46% in feces over the 5 days post-dosing.
  • Half life: 11 days
  • Adverse effects include vomiting, breathing difficulty, hemorrhage, and prostration
  • The metabolism of (S)-Warfarin can be decreased when combined
  • Increased risk/severity of adverse effects when combined with Aminosalicylic Acid.
  • Atorvastatin metabolism can be decreased when combined

Dipyridamole

  • A phosphodiesterase inhibitor that blocks uptake and metabolism of adenosine by erythrocytes and vascular endothelial cells.
  • Action: Inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, inhibits platelet function. Elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity.
  • Targets: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A and adenosine deaminase
  • 70% absorption, 99% protein binding, hepatic metabolism
  • Metabolized in the liver to the glucuronic acid conjugate and excreted with the bile, half life 40 min
  • Possible adverse effect of hypotension. Vasopressor drug may be used if necessary
  • The risk/severity of bleeding can increase when Dipyridamole in combined with (R)-warfarin
  • Can increase the bradycardic activities of Metoprolol while also increasing antihypertensive activities of Captopril

Alteplase

  • Binds to fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain.
  • The protease domain then cleaves the Arg/Val bond in plasminogen to form plasmin.
  • Plasmin degrades the fibrin matrix of the thrombus, exerting its thrombolytic action.
  • Targets plasminogen and fibrinogen alpha chain
  • Clopidogrel can increase the anticoagulant activities
  • The risk or severity of bleeding can increase when combined with Acetylsalicylic acid or with Heparin

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