Drugs for thromboembolic disorders (Konorev) Flashcards
All clots involve both
platelets and fibrin but thee degree of involvement of platelet/fibrin in thrombus formation depends on the vascular location
White thrombus
- platelet rich
- Forms in high pressure arteries and is a result of platelet binding to the damaged endothelium and aggregation with little involvement of fibrin
Pathologic condition associated with white thrombi
-local ischemia due to arterial occlusion
in coronary arteries: myocardial infarction/unstable angina
Red thrombus
- fibrin rich with trapped RBC
- Forms in low-pressure veins and in the heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which RBCs become enmeshed
Pathologic conditions associated with red thrombus
-pain and severe swelling, embolism and distal pathology (embolic stroke)
Drugs used in thromboembolic disorders
- Anticoagulants
- Antiplatelet drugs
- Thrombolytics
Anticoagulants
regulate the function and synthesis of clotting factors
Antiplatelet drugs
inhibit platelet function
-Primarily used to prevent clots from forming in the arteries (white thrombi)
Thrombolytics
- destroy blood clots after they are formed
- Re-establish blood flow through vessels once clots have formed
Thrombin
- converts soluble fibrinogen into fibrin; it also interconnects the blood coagulation cascade with platelet aggregation
- so thrombin also involved in platelet activation and aggregation
- on the other hand it can accelerate the clotting cascade by inducing proteolytic cleavage of upstream of thrombin (Xa)
- this is why thrombin and Factor Xa are major drug targets
Which organ will be affected by an embolism as a result of the primary thrombus formation in veins of lower extremities or pelvis
-Lung
Parenteral anticoagulants
Indirect thrombin and factor Xa (FXa) inhibitors:
- Unfractionated heparin (UFH or HMW)
- Low molecular weight heparins (LMW)
- Synthetic pentasaccharide
Direct thrombin inhibitors: Lipirudin, Bivalirudin, Argatroban
UFH (HMW)
Heparin sodium
LMW Heparin
Enoxaprin
Tinzaparin
Dalteparin
Synthetic pentasaccharide
Fondaparinux
Direct thrombin inhibitors
Lepirudin
Bivalirudin
Argatroban
Indirect thrombin and FXa inhibitors MOA
- Indirect thrombin FXa inhibitors–bind plasma serine protease inhibitor ANTITHROMBIN III
- Antithrombin III inhibits several clotting factor proteases, especially IIa, IXa and Xa
- In the absence of heparin, these reactions are slow; heparin increases the antithrombin III activity by 1000 fold
HMW heparin inhibits
- the activity of both thrombin and factor Xa
- provides scaffold for both antithrombin as an inhibitor and thrombin itself
- binds to antithrombin III and thrombin (inactivates thrombin)
- binds via pentasaccharide (sufficient to inactivate Xa)
LMW heparin inhibits
- factor Xa with little effect on thrombin
- shorter chains so cant effect thrombin but inhibits Xa because scaffolding is not required
- Binds to antithrombin III via pentasaccharide but NOT to thrombin (poorly inactivates thrombin)
Fondaparinux inhibits
factor Xa activity with NO effect on thrombin
-Binds to antithrombin III via pentasaccharide (sufficient to inactivate Xa)
Direct thrombin inhibitors MOA (parenteral)
-Direct inhibition of the protease activity of thrombin
-Bivalent direct thrombin inhibitors (direct thrombin inhibitors)
bind at both active site and substrate recognition site
- Lepirudin
- Bivalirudin
- -found in saliva of leeches??
Oral anticoagulants
- coumarin anticoagulants: warfarin
- NOAC (novel oral anticoagulants): Factor Xa inhibitors and direct thrombin inhibitors
NOAC (novel oral anticoagulants)
- Factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban
- Direct thrombin inhibitors: Dabigatran
Coumarin anticoagulants
- Warfarin
- Most commonly prescribed anticoagulant in US
MOA of warfarin (coumarin anticoagulant)
- Inhibits reactivation of vitamin K, by inhibiting enzyme vit K epoxide reductase
- Inhibits carboxylation of glutamate residues by GGCX (gamma-glutamyl carboxylase) in prothrombin and factors VII, IX and X making them inactive
Warfarin dosing
- High individual variability in the optimal Warfarin dose based on:
- Genetics, disease states, drug-drug interaction, diet
Drug therapeutic window for warfarin is
narrow
Warfarin dose is titrated based on
Laboratory testing: prothrombin time (INR)
- 2.0-3.0 range for patients on warfarin
- INR is monitored as patients visit the clinic regularly
Oral anticoagulants that inhibit factor Xa
- Rivaroxaban
- Apixaban
- Edoxaban
Parenteral anticoagulants that inhibit factor Xa
- Fondaparinux
- LMWH
Oral anticoagulants that target factor IIa
-Dabigatran
Parenteral anticoagulants that target factor IIa
Argatroban
Bivalirudin
Clinical use of parenteral anticoagulants
-Administer to patients with deep vein thrombosis, atria arrhythmias and other CONDITIONS THAT PREDISPOSE TOWARDS RED THROMBI
Parenteral anticoagulants are used in the treatment/prevention of
- embolic stroke
- pulmonary embolism
- used for prevention of emboli during surgery or in hospitalized patients (reduces risk of emboli)
Parenteral anticoagulants: heparin locks used to
prevent clots from forming in catheters
Clinical uses of oral anticoagulants
- used to prevent thrombosis or prevent/treat thromboembolism
- Atrial fibrillation
- Prosthetic heart valves
Antidotes for HMW and LMW heparins
Protamine sulfate
When are antidotes for anticoagulants used
-used in situations of bleeding complication or traumatic injury causing bleeding or surgery–need to stop the action of anticoagulants to prevent excessive bleeding
Antidotes for Foxaparinux and DTI (parenteral drugs)
- Not available
- DTIs are generally very short acting drugs so antidote usually not necessary but need to be careful about Foxaparinux because no antidote but long lasting
Antidote to warfarin (oral)
- Vitamin K
- Prothrombin complex concentrate
Antidote to NOAC–DTI
Idarucizumab
Antidote to NOAC FXa inhibitors
-not out yet but most likely Andexanet alfa will get approved soon
Blood coagulation test used to monitor patients on heparins
aPTT
anti Xa
-measures intrinsic and common pathway
Blood coagulation test used to monitor patients on warfarin
PT-based (INR)
-measures activity of extrinsic and common pathway
Blood coagulation test used to monitor patients on NOAC–FXa inhibitors
Anti-Xa
-measures common pathway
Blood coagulation test used to monitor patients on NOAC–DTI
Diluted thrombin time (TT)
-measures activity of common pathway
Categories of antiplatelet drugs
- Inhibitors of thromboxane A2 synthesis
- ADP receptor blockers
- Platelet glycoprotein receptor blockers
- Inhibitors of phosphodiesterases
Antiplatelet drugs: Inhibitors of thromboxane A2 synthesis
-Aspirin (acetylsalicylic acid)
Antiplatelet drugs: ADP receptor blockers
- Clopidogrel
- Prasugrel
- Ticlopidine
- Ticagrelor
Antiplatelet drugs: Platelet glycoprotein receptor blockers
Abciximab
Eptifibatide
Tirofiban
Antiplatelet drugs: Inhibitors of phosphodiesterases
Dipyridamole
Cilostazol
Platelet aggregation/activation–many different molecules but all eventually converge on what pathway?
- Activation of GP IIb/IIIa
- is an integrin–dimer and has both a cytoplasmic part and EC domain
- EC domain is able to bind to adhesion fibrous proteins (fibronectin, fibrinogen)
- activated as a result of inside out signaling–events happening inside the cell will activate integrin to bind to EC fibrous adhesive protein
Compounds that inhibit platelet aggregation
- NO–inhibits platelets via cGMP
- Prostacyclin–inhibits platelet aggregation by producing cyclic nucleotides–increases cAMP
PDE inhibitors
- prevents the composition of cyclic nucleotides
- cAMP
GPIIb/IIIa inhibitors
- blocks the site at which GPIIb/IIIa interacts with the ligand
- The ligand has the amino acid sequence RGD
- So these drugs block the integrin from interacting with the RGD sequence
COX inhibitors
-Inhibit cyclooxygenase and eventually blocks production of TxA2 (a potent platelet aggregator)
ADP receptor blockers
- Normally, platelets contain vesicles with ADP, serotonin and other compounds in them and are released upon activation of platelets and serotonin and ADP can interact with receptors and induce platelet aggregation
- These drugs block ADP from binding to the receptors irreversibly blocking platelet aggregation
Aspirin MOA
- Inhibition of cyclooxygenase
- Decreased TxA2 production
- TxA2 receptor is a GPCR coupled to Gq protein–>increases Ca conc and platelets and activates protein kinase C which signals and activates integrin to bind to exogenous fibrinogen
- so aspirin blocks this process
Clopidogrel, Ticlopidin, prasugrel MOA
- ADP receptor blockers
- Inhibition of AC by ai
- normally, coupled to Gi which inhibits adenyl cyclase and decreases conc of cAMP and induces platelet aggregation so ADP receptors block this and will increase cAMP and prevent platelet aggregation
Dipyradamole (phosphodiesterase inhibitors)
- Blocks the degradation of cAMP
- Inhibition of cAMP degredation
- Levels of cAMP in platelets are increased
Platelet glycoprotein GP IIb/IIIa is
an integrin binding to EC ligands: fibrinogen, vitronectin, fibronectin, von Willebrand factor
Platelet GP receptor antagonists
- Target Arg-Gly-Asp (RGD) sequence
- Prevent binding of ligands to the GP IIb/IIIa receptor to inhibit platelet aggregation
GPIIb/IIIa antagonists
- Abciximab (monoclonal Ab)
- Tirofiban
- Eptifibatide
- inhibits interaction with fibrinogen (exogenous fibrous proteins)
Clinical use of antiplatelet drugs
- prevention of thrombosis in unstable angina and other acute coronary syndromes
- Prevention of ischemic stroke and arterial thrombosis in peripheral vascular disease
- In patients undergoing percutaneous coronary angioplasty and stenting
-Inhibitors of phosphodiesterase are considered
adjunct antiplatelet agents and used in combination with other antiplatelet agents or anticoagulants
Drug combinations using PDE inhibitors
-Dipyridamole with aspirin to prevent cerebrovascular ischemia
-dipyradamole with warfarin in patients with prosthetic heart valves
Cilostazol is primarily used to treat intermittent claudication
Thrombolytic (fibronolytic) drugs MOA
- induce fibriolysis (lyse fibrin in thrombi after they have formed)
- activate endogenous fibrinolytic system by converting plasminogen into plasmin
tpA: tissue type plasminogen activator drugs (fibrinolytic drug)
- Alteplase: recombinant human protein
- Reteplase: recombinant modified human protein
- Tenecteplase: recombinant mutated human protein
uPA: urokinase type plasminogen activator (fibrinolytic drug)
-Urokinase
Streptokinase preparations (fibrinolytic drug)
-streptokinase–purified from bacteria
Clinical uses of thrombolytic drugs
- Acute embolic/thrombotic stroke (within 3 hours)
- Acute myocardial infarction (within 3-6 hrs)
- Pulmonary embolism
- Deep venous thrombosis
- Ascending thromboplebitis
Treat with tPA to do what? Most effective when? Adverse effects?
- treat with tPA to break down the clot and open up artery
- most effective within 3 hours after embolic and thrombotic stroke
- can exacerbate the damage produced by hemorrhagic stroke
