Antithrombotic and Thrombolytic drugs Flashcards
Warfarin - MoA
Vit. K antagonist
Inhibit the synthesis of coagulation factors whose formation is dependent on vit K, factor II (Prothrombin), VII, IX and X.
Also it inhibits the synthesis of proteins C and S, which are endogenous anticoagulants that inactivates factor V and VIII and promote fibrinolysis.
Warfarin - Indication and goal of treatment
Long term treatment: Deep vein thrombosis, prevention of thrombosis in pt with atrial fibrillation or an artificial heart valve.
Pulmonary embolism
Used with heparin type anticoagulant for treatment of MI
Goal of treatment: prevent thrombus formation or expansion and to prevent embolization and other potentially fatal consequences of thrombosis.
Warfarin - Adverse Effects and Contraindication
Bleeding (mild nose bleed to life threatening hemorrhage)
Fetal warfarin syndrome(bone deformities and bleeding. Malformations are partly a result of antagonism of vit K-dependent maturation of bone proteins during a process in which these proteins are carboxylated. Vit K antagonists and Warfarin block this process –> birth defects
Contraindication: Pregnancy (Crosses the placenta and can cause fetal hemorrhage + fetal warfarin syndrome), Hypertension –> Increased risk of stroke
Warfarin - Interactions and special considerations
Special considerations:
Delayed onset of action, max effect is observed 3-5 days after started therapy –>
Pt with acute thromboembolic disorders can be treated with low molecular weight heparin plus warfarin, LMWH can be withdrawn once warfarin acts.
Prothrombin time should be monitored when adding/discontinuing drugs that interact with warfarin
Interactions:
Interacts with drugs that induce or inhibit cyt P450.
Most serious interactions are with drugs that increase the anticoagulant effect and place the patients at risk of hemorrhage, ex: Salicylates (by reducing prothrombin), cephalosporins
Decrease anticoagulant effect by inducing CYP enzymes that metabolize warfarin: rifampin, barbiturates
Cholestyramine inhibit absorption of warfarin from gut.
Amiodarone, cimetidine, erythromycin, fluconazole, gemifibrozil, isoniazid, metronidazole, sulfinpyrazone inhibit metabolism of warfarin increase the risk of bleeding.
Phytonadione (vit K1) directly antagonize the effect of warfarin, used to treat hemorrhage caused by anticoagulant activity.
Heparin - MoA
Inactivates clotting factors by potentiating the activity of an endogenous anticoagulant called antithrombin III (most powerful endogenous inhibitor of thrombin (factor II) ) and active factor X
Heparin - Indication
Acute thromboembolic disorders, peripheral and pulmonary embolism, venous thrombosis, disseminated intravascular coagulation.
Prevent clotting in arterial and heart surgery, during blood transfusions, renal dialysis and blood sample collection
Prevent embolization of thrombi that might cause cerebrovascular events in patients with acute atrial fibrillation.
Low doses (subc): prevent DVT and pulmonary embolism in high risk patients.
Heparin - Special consideration and interactions
Treatment of bleedings by heparin and LMWHs consist of adm protamine sulfate (positively charged protein that binds to negatively charged heparin and inactivates it) given IV. Severe bleeding may req adm of fresh plasma or clotting factors.
Risk of bleeding increased by salicylate
Heparin - Adverse effects
Bleeding caused by excessive anticoagulation
Hyperkalemia (because of suppression of aldosterone secretion).
Heparin induced thrombocytopenia(HIT)
Type 1 HIT: in 25% of pat treated with heparin. Caused by direct interaction between heparin and platelets –> platelet aggregation. It is usually mild and reversible within 4 days despite continued heparin treatment.
Type 2 HIT: less common, caused after 2-14 days, caused by immunoglobulin (IgM or IgG) mediated platelet inactivation –> high risk of thrombotic complications and mortality. In this case heparin must be stopped.
Heparin related drugs/ LMWH + Adverse effects
Fondaparinux
Enoxaparin
Dalteparin
Bleeding caused by excessive anticoagulation
Fondaparinux - MoA
Most selective active factor X inhibitor
Fondaparinux - Indications
Prophylaxis of DVT in pat having hip fracture or hip replacement surgery or knee-replacement surgery.
Enoxaparin and Dalteparin - MoA
Inactivate factor X because the LMWH-AT-III complex has less afifnity for thrombin than does the heparin-AT-III complex
Enoxaparin and Dalteparin - Indications
Prevent venous thromboembolism associated with abdominal surgery or knee or hip replacement.
Prevent ischemic complications of unstable angina or non-ST segment elevation (non Q wave) MI, used in acute coronary syndrome and angioplasty
Enoxaparin: DVT and prevent thromboembolism caused by severely restricted mobility during acute illness
Bivalirudin and Argatroban - MoA
Directly inhibit thrombin without needing AT-III as a cofactor
Bivalirudin - Indication
Prevent Thrombosis in pt with unstable angina and acute MI, including those undergoing coronary angioplasty and stent insertion.
Argatroban - Indication
Prophylaxis and treatment thrombosis in pat with HIT, including persons undergoing percutaneous coronary interventions for MI
Dabigatran - MoA
Potent, competitive, reversible inhibitor of thrombin, a protease enzyme that converts fibrinogen to fibrin in the final step of blood coagulation.
Inhibits both fibrin-bound and unbound (free) thrombin.
Dabigatran - Indication
Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (–> lower rate of stroke and intracranial bleeding in these pat then with warfarin)
Treatment and prevention of DVT and PE in pt who have been treated with a parenteral anticoagulant for 5-10 days
Prevention of DVT in those undergoing hip-replacement sugery.
Alternative to warfarin for pt who have been poorly controlled or not well monitored
Dabigatran - Special consideration
Prodrug (dabigatran etexilate) –> converted to dabigatran by esterases in gut, blood and liver)
Reduce dose in pt with renal impairment –> prolongation of half-life.
Dabigatran - Adverse effects
Increased risk of bleeding (including GI) there is no antidote–> give plasma or RBC.
GI complains, dyspepsia, gastritis like symptoms. (taking drug with food or H2 blocker may prevent symp)
Dabigatran - Interactions
Idarucizumab: reverse dabigatran’s anticoagulant effect in cases of life-threatening or uncontrolled bleeding or emergency surgery
Rifampin and P-glycoprotein
Pgp inhibitors (verapamil, amiodarone, quinidine, clarithromycin): can be given, but 2 or more hours before/after dabigatran.
Direct thrombin inhibitors
Bivalirudin
Argatroban
Dabigatran
Active factor X inhibitors (Xa inhibitors)
Apixaban
Rivaroxaban
Edroxaban
Active factor X inhibitors - Indication
Decrease risk of stroke and systemic embolization in persons with nonvalvular atrial fibrillation + prevention of DVT and PE in persons undergoing knee- or hip-replacement surgery.
DVT and PE to decrease risk of recurrences of DVT and PE in persons with previous episodes.
Arterial fibrillation where warfarin has not been effective
Apixaban - Contraindication and Adverse effects
Potent inh of CYP3A4 and P-glycoprotein –> increased plasma concentrations
Bleeding and thrombocytopenia
Rivaroxaban - Interaction
Metabolized by P450, 3A4 –> OBS pat taking 3A4 inhibitors.
Antiplatelet drugs
Aspirin
Dipyridamole
Cilostazol
Aspirin - MoA
Inhibit the synthesis of prostaglandins (the most important prostaglandin affecting platelet aggregation is prostacycline and TXA2).
Prostacycline: synthesized by vascular endothelial cells and inh platelet aggregation and thrombosis
TXA2: synthesized by platelets and promotes platelet aggregation.
Aspirin is a nonselective irreversible cox inhibitor. –> inhibits platelet aggregation for the life of the platelet.
Aspirin - Indication
Prevent arterial thrombosis in pat with ischemic heart disease and stroke.
Reduces the risk of second MI and stroke.
Prevent MI in persons with coronary artery disease
Acute MI: to prevent enlargement of a coronary thrombus and reduce the severity of cardiac damage.
In pat with transient ischemic attacks- used to prevent an initial or subsequent stroke.
In pat who have artificial heart valves or undergoing percutaneous coronary angioplasty- used with other drugs to prevent thrombosis.
Also to treat peripheral arterial occlusive disease and chronic limb ischemia.
Aspirin Low VS High dose and Interaction
Low doses of aspirin: selectively inhibits the synthesis of TXA2 without much effect on prostacycline.
Higher doses: inhibit synthesis of both prostaglandins.
Increases hypoglycemic effect pf sulfonylureas. Increases risk of GI bleeding, ulceration ass with methotrexate, valproate. Inhibits uricosuric effect of probenecid
Aspirin - Adverse Effects
GI bleedings(due to inh of synthesis of prostaglandins that promotes secretion of bicarbonates to the mucus)
Hypersensitivity
Tinnitus
High doses: Hypoprothrombinemia –> increased risk of bleeding
Dipyridamole - MoA
Inhibiting platelet adhesion to the vessel wall. It can also inhibit platelet aggregation by increasing the formation of cAMP (due to its action as phosphodiesterase inh) and lowering the level of platelet calcium.
Dipyridamole - Indication
As vasodilator: used during myocardial perfusion imaging (to dilate and evaluate the arteries of pt with coronary artery disease)
In combo with aspirin to prevent ischemic (thrombotic) stroke in persons who prev had strokes.
Cilostazol - MoA and Effect
Inhibits type 3 phosphodiesterase and the breakdown of cAMP, thereby increasing cAMP levels in platelets and blood vessels. This leads to inhibition of platelet aggregation and vasodilation.
Improves blood flow and reduces muscle pain, while increasing walking distance in persons with this condition.
Cilostazol - Indication
Intermittent claudication (peripheral vascular disease- pain, weakness in a limb –> limping & lameness)
Cilostazol - Adverse effect and Interaction
Headache
Metabolized by CYP3A4 –> inhibitors of this enzyme (erythromycin) may increase antiplatelet effect.
ADP inhibitors
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor
Clopidogrel and Prasugrel - MoA
Block ADP P2Y12 receptors which inhibits activation of GP-2b/3a receptors and prevents ADP-induced platelet aggregation –> prevents thrombus formation and prolongs bleeding time
Irriversible antagonists.
Clopidogrel and Prasugrel - Indication
Prevention of thrombosis and MI in persons with ACSs
Clopidogrel: Secondary stroke prevention
Clopidogrel: Prevent thrombosis in pt with intermittent claudication, chronic arterial occlusion, AV shunts or fistulas, open heart surgery, and sickle cell anemia.
Reduce thrombosis and MI in pt with ACS who are undergoing angioplasty and coronary artery stent insertion.
Clopidogrel - Adverse effect
Bleeding and Neutropenia
Prasugrel - Adverse effect
Increased incidence of bleeding GI-pain Increased cholesterol and triglyceride levels Nausea Neutropenia
Dipyridamole - Averse effects
GI distress
Headache
Mild/transient dizziness
Rash
Dipyridamole - Interactions
Decreases metabolism of adenosine
Increases risk of bradycardia ass with beta adrenergic receptor antagonists
Cangrelor and Ticagrelor - MoA
Block ADP P2Y12 receptors which prevent ADP-induced platelet aggregation by inhibiting expression of GP iib/iiia receptors for fibrinogen.
Reversible
Cangrelor - Clinical use and Adverse effects
Adjunct to percutaneous coronary intervention (PCI) to reduce risk of thrombotic events during and after these prosedures.
Bleeding
Ticagrelor - Clinical use
Prevention of thrombosis and MI in persons with ACSs
Reduce thrombosis and MI in pt with ACS who are undergoing angioplasty and coronary artery stent insertion.
Ticagrelor - Adverse effects
Bleeding
Dyspnea
Neutropenia –> rarely used
Glycoprotein IIb/IIIa antagonists
Abciximab
Tirofiban
Eptifibatide
Abciximab - MoA
Prevents platelet aggregation by binding to platelet GP 2b/3a receptors to prevent fibrinogen from binding and crosslinking with platelets.
Abciximab - Clinical use
Prevent platelet aggregation and thrombosis in pat undergoing coronary interventions(coronary angioplasty, stent placement)
Prevent vessel restenosis, reinfarction and death.
Abciximab - Adverse effects
Bleeding
Thrombocytopenia
Hypotension
bradycardia
Tirofiban and Eptifibatide - MoA
Competitive reversible inhibitor of fibrinogen binding to GP 2b/3a receptors
Prevent platelet aggregation by preventing fibrinogen cross-linking of platelets.
Tirofiban and Eptifibatide - Clinical use
Unstable angina and MI often in combo with LMWH
- Prevent coronary thrombosis in persons with unstable angina or non-ST-segment elevation(non Q-wave) MI
- Prevent thrombosis in persons having coronary angioplasty or stent placement for ST-segment elevation MI
Tirofiban and Eptifibatide - Adverse effects
Bleeding
Vorapaxar - MoA
Protease- activated receptor- 1 (PAR-1) antagonists competitively inhibits thrombin access to its target receptor and prevents thrombin- mediated platelet aggregation.
Vorapaxar - Clinical use
Pt with history of MI or with peripheral arterial disease (PAD)
Reduces thrombotic cardiovascular events and mortality
Thrombolytic (Fibrinolytic) Drugs
Alteplase Reteplase Tenecteplase Streptokinase Anistreplase
Thrombolytic Drugs - MoA
Recombinant forms of human tissue plasminogen activator(t-PA) enzyme, converts plasminogen to plasmin and cause fibrinolysis
Thrombolytic Drugs - Clinical use
Degrade thrombi in pat with MI, thrombotic stroke, pulmonary embolism
Open thrombosed renal dialysis and central venous catheters
Venous thromboembolism, such as in cases of extensive iliofemoral vein thrombosis, where catheter-directed thrombolysis is employed as an adjunct to anticoagulants
For patients with ST-segment elevation MI, thrombolytic drugs are used to restore coronary blood flow when patients are not eligible for angioplasty
Thrombolytic Drugs - Adverse effects and Contraindications
Hemorrhage
Arrhythmias (Bradycardia, Tachycardia)
Contraindications: Hemorrhagic stroke Recent surgery Recent trauma Pregnancy Uncontrolled hypertension Cancer Peptic Ulcer Inflammatory Bowel Disease Hypersensitivity
Thrombolytic Drugs - Interactions
Antidote- aminocaproic acid inhibits fibrinolysis(given orally or iv, it can cause thrombosis, hypotension and arrhythmias)
Aminocaproic acid - Clinical use
Stop bleeding caused by thrombolytic drugs
Prevent bleeding in patients who have hemophilia or are recovering from GI or prostate surgery
Aminocaproic acid - Adverse effects
Thrombosis
Hypotension
Arrhytmias
Tranexamic acid - Clinical use
Cyclic heavy menstrual bleedings
Injection in patients with hemophilia who need short-term treatment to prevent hemorrhage during and after tooth extraction
Tranexamic acid - Adverse effects
Thrombosis, which is increased when hormonal contraceptives are used, especially in women who are obese and smoke cigarettes
Aminocaproic acid and Tranexamic acid - MoA
They prevent degradation of plasmin to fibrin
