List: Anticoagulants and Thrombolytic Drugs Flashcards
Hemostasis:
Hemostasis: process that maintains the integrity of the circulatory systems after vascular damage
Primary hemostasis:
Primary hemostasis: platelet plug formation (platelets adhere to damaged endothelium to form plug)
Secondary hemostasis:
Secondary hemostasis: blood coagulation (clot forms upon the conversion of fibrinogen to fibrin, and its addition to the platelet plug) –> Formation of a thrombus
Thrombus Formation:
Thrombus Formation: extrinsic and intrinsic pathways merge into common pathway, leading to factor X activation
Factor X to fibrin:
Factor X cleaves prothrombin –> thrombin
Thrombin cleaves fibronigen –> fibrin
Fibrin incorporated into thrombus
Thrombolysis/Fibronolysis:
In response to injury, endothelial cells synthesize and release:
t-PA converts plasminogen:
Plasmin cleaves:
Thrombolysis/Fibronolysis: process of fibrin digestion by plasmin (protease)
- In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA)
- t-PA converts plasminogen plasmin
- Plasmin cleaves fibrin and dissolves the clot
Endogenous Inhibitors of this Process
PAI-1/PAI-2:
α2-antiplasmin:
PAI-1/PAI-2: inhibit t-PA
α2-antiplasmin: inhibitor of plasmin
3 Major Classes of Anticoagulant Drugs:
Indirect Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
Oral Anticoagulants
Indirect Thrombin Inhibitors:
Parenteral Direct Thrombin Inhibitors:
Oral Anticoagulants:
Indirect Thrombin Inhibitors: Heparin, Fodaparinux
Parenteral Direct Thrombin Inhibitors: Hirudin, Bivalirudin, Argatroban
Oral Anticoagulants: Warfarin, next generation drugs (Apixaban, Pradaxa, Rivaroxaban)
Indirect Thrombin Activators
General MOA:
General MOA: antithrombotic effect due to interaction with antithrombin III (ATIII) and factor Xa
Indirect Thrombin Activators
Preparations: (3)
o Unfractionated heparin
o Low-molecular weight heparin
o Fondaparinux (synthetic polysaccharide)
Heparin
General:
General: heterogeneous mixture of sulfated mucopolysaccharides
Heparin Targets: (3)
- Thrombin
- Factor Xa
- Factor IXa
.
Heparin
MOA:
MOA: activated ATIII binds heparin and efficiently degrades thrombin and factor X
Heparin
Therapeutic Use: (6)
- Venous thrombosis (initial treatment)
- Pulmonary embolism (initial treatment)
- Acute MI (initial treatment)
- Surgery requiring cardiopulmonary bypass
- Patients with DIC
- Unstable angina
Heparin
Pharmacokinetics:
LMW can be given ____ and without ______
Pharmacokinetics: LMW heparin preparations have more predictable pharmacokinetics than HMW heparin
- LMW can be given subQ and without laboratory monitoring
Management of Heparin Treatment
Full-dose heparin therapy:
subQ heparin:
Full-dose heparin therapy by continuous IV infusion needs to be monitored by activated partial thromboplastin time (aPTT)
Can give subQ heparin for long-term anticoagulant therapy in patients with contraindications for warfarin use (ie. pregnancy)
Heparin
Toxicity
Bleeding:
Protamine Sulfate:
Heparin-induced thrombocytopenia:
Bleeding: incidence somewhat less in patients treated with LMW form
- Protamine Sulfate: can be given in cases of life-threatening hemorrhage to reverse the effects of heparin (binds tightly and neutralizes it)
Heparin-induced thrombocytopenia: decreased platelet count; lower incidence with LMW form
Fondaparinux
Use:
Use: approved for thromboprophylaxis of patients undergoing hip or knee surgery
- To prevent pulmonary embolism and deep vein thrombosis
Fondaparinux
Management:
Management: similar to LMW heparin
- Can be used with daily subQ administration
- Does not require monitoring
Parenteral Direct Thrombin Inhibitors
Drugs in this Class: (3)
Hirduin
Bivalirudin
Argatroban
Hirduin:
Bivalirudin:
Argatroban:
Hirduin: bivalent specific, irreversible thrombin inhibitor (leech saliva)
Bivalirudin: bivalent inhibitor of thrombin
Argatroban: small molecule thrombin inhibitor
Parenteral Direct Thrombin Inhibitors
Drug Targets:
Thrombin
Therapeutic Use/Management
Hirudin
Treatment of patients with:
Administered by:
Dose adjusted to maintain:
- Treatment of patients with heparin-induced thrombocytopenia
- Administered by IV
- Dose adjusted to maintain aPTT at 1.5-2
Therapeutic Use/Management
Bivalirudin
Alternative to:
Administered by:
- Alternative to heparin in patients undergoing coronary angioplasty
- Administered by IV
Therapeutic Use/Management
Argatroban
Alternative to:
Alternative to hirudin for prophylaxis treatment of patients with or at risk of developing heparin-induced thrombocytopenia
Parenteral Direct Thrombin Inhibitors
Toxicity
Use with caution in renal failure:
Development of anti-hirudin Abs:
Use with caution in renal failure: can accumulate and cause bleeding
Development of anti-hirudin Abs: can cause paradoxical increase in aPTT (daily monitoring of aPTT recommended)
Warfarin
General:
General: synthetic derivative of coumarin
Warfarin
Administered as:
bioavailability:
T½:
vs heparin:
- Administered as a sodium salt
- Has 100% bioavailability
- Long T½ in plasma (36 hours)
- Slower acting than heparin (for long term management, NOT for an acute event)
Warfarin
MOA:
Blocks ______ of glutamate residues in coagulation factors
MOA: inhibits the vitamin-K dependent synthesis of biologically active forms of the Ca++-dependent clotting factors (prothrombin, VII, IX, X) and protein C (regulatory factor)
- Blocks gamma-carboxylation of glutamate residues in coagulation factors
Warfarin
Therapeutic Use
Prevent progression or recurrence of:
Prevention of ____________ in patients undergoing orthopedic or gynecological surgery
Prevent progression or recurrence of acute DVTs or pulmonary embolism (follows initial course of heparin)
Prevention of venous thromboembolism in patients undergoing orthopedic or gynecological surgery
Warfarin
Preventing systemic emboli in patients with: (3)
Preventing systemic emboli in patients with:
- Acute MI
- Prosthetic heart valves
- Chronic atrial fibrillation
Warfarin
International Normalized Ration (INR)
Therapeutic range for:
Defined as:
Prothrombin time determined from:
International Normalized Ration (INR): therapeutic range for oral anticoagulant therapy
Defined as patient prothombin time/mean of normal prothrombin time for the lab
Prothrombin time determined from a fasting blood sample obtained 8-14 hours after the last dose of an oral anticoagulant
Warfarin
Use with caution in patients with: (3)
Patients with congenital coagulation deficiency
Patients with thrombocytopenia
Patients with hepatic or renal insufficiency
Warfarin
Never use:
Patients who are pregnant (readily crosses the placenta and causes hemorrhagic disorder in the fetus/serious birth defects)
Warfarin resistance:
Difficult to manage because:
Warfarin resistance: can develop in some patients (most common in those with advanced cancer); progression/recurrence of the thrombotic event
- Difficult to manage because raising INR in these patients also increases risk of bleeding
Warfarin
DDIs
Decrease anticoagulant effect:
Decrease anticoagulant effect: barbiturates and rifampin
Warfarin
DDIs
Increase anticoagulant effect:
Increased anticoagulant effect: aspirin and cephalosporins
Oral Direct Thrombin Inhibitors
Main advantage to these new ones is:
New Drugs: (3)
New Drugs: main advantage to these new ones is that they do not require drug monitoring
o Pradaxa: targets thrombin only (already FDA approved)
o Rivaroxiban: targets factor Xa
o Apixaban: targets factor Xa
Oral Direct Thrombin Inhibitors (apart from warfarin)
Pradaxa:
Rivaroxiban:
Apixaban:
Pradaxa: targets thrombin only (already FDA approved)
Rivaroxiban: targets factor Xa
Apixaban: targets factor Xa
Fibrinolytic Drugs
General MOA:
General MOA: cause rapid lysis of thrombi by catalyzing the activation of plasmin
Fibrinolytic Drugs
Tissue Plasminogen Activator (tPA)
General:
General: endogenous serine protease that is a poor plasminogen activator in the absence of fibrin
Fibrinolytic Drugs
Tissue Plasminogen Activator (tPA)
MOA:
Presence of fibrin _____ the speed of activation
Clearance:
Half Life:
MOA: binds to fibrin via lysine binding sites at amino terminus and activates bound plasminogen
- Presence of fibrin increases the speed of activation several hundredfold
Clearance: occurs by hepatic metabolism
- Half Life: 5-10 minutes
Fibrinolytic Drugs
Tissue Plasminogen Activator (tPA)
Use: (3)
Use: lyses thrombi during the treatment of
- Acute MI
- Pulmonary embolism
- Severe DVT
Recombinant tPA: (2)
Effect on half lives:
Recombinant tPA: Reteplase and Tenecteplase
Increased half lives (allow for convenient bolus dosing)
Fibrinolytic Drugs
Streptokinase
General:
General: produced by beta-hemolytic streptococci
Fibrinolytic Drugs
Streptokinase
MOA:
MOA: no intrinsic enzymatic activity, but forms a stable complex with plasminogen, producing a conformational change that exposes the active site on plasminogen –> plasmin
Fibrinolytic Drugs
Streptokinase
Use:
Use: decreased due to advent of newer agents
Fibrinolytic Drugs
Recent Studies:
Recent Studies: suggest that angioplasty without stent placement is superior to thrombolytic therapy, when it is feasible
Fibrinolytic Drugs
Hemorrhage:
_____ at sites of vascular injury
Hemorrhage: major toxicity of all thrombolytic agents; results from 2 factors
Lysis of fibrin in physiological thrombi at sites of vascular injury
Fibrinolytic Drugs
Hemorrhage
A systemic lytic state that results from systemic formation of plasmin, causing: (2)
- Fibrinogenolysis
- Destruction of other coagulation factors (V and VIII especially)
Fibrinolytic Drugs
Toxicity
Aminocaproic acid:
Aminocaproic acid: potent inhibitor of fibrinolysis (blocks interaction of fibrin and plasmi) and can reverse excessive fibrinolysis
Contraindications to Thrombolytic Therapy
Any of the following within 10 days: (4)
- Surgery (including organ biopsy)
- Puncture of noncompressible vessels
- Serious trauma
- Cardiopulmonary resuscitation
Contraindications to Thrombolytic Therapy
Within 3 months:
History of :
Active ____ or _____ disorder
o Within 3 months: serious GI bleeding
o History of HTN (diastolic >110 mmHg)
o Active bleeding or hemorrhagic disorder
Contraindications to Thrombolytic Therapy
CV:
Aorta;
Pericardium:
o Previous cerebrovascular accident or active intracranial process
o Aortic dissection
o Acute pericarditis
Antiplatelet Drugs: (4)
- Aspirin
- Dipyridamole
- Clopidogrel (Plavix)
- Ticlopidine
Aspirin
MOA:
Acetylates ______ near the active site of ______
Effects last for:
MOA: blocks platelet aggregation and vasoconstriction by inhibiting synthesis of thromboxane A2
Acetylates a serine residue near the active site of COX-1 (responsible for production of precursor of TXA2)
Effects last for the life of the platelet (7-10 days)
Aspirin
Low dose immediately after a heart attack to :
Low dose long-term for prevention of: (3)
Low dose immediately after a heart attack to reduce the risk of another or to prevent the death of cardiac tissue
Low dose long-term for prevention of:
- Heart attacks
- Strokes
- Blood clot formation
Aspirin
Toxicity
At higher doses:
Use in combination with _______ increases risk of upper GI bleeding
Increased at higher doses (especially bleeding)
Use in combination with clopidogrel or warfarin increases risk of upper GI bleeding
Dipyridamole
MOA:
MOA: vasodilator
Dipyridamole
Use:
Use: only recommended for postoperative prophylaxis of thromboemboli in patients with prosthetic heart valves, in combination with warfarin
Dipyridamole
Toxicity
most common:
most severe:
N/V/D most common
Leukopenia is most severe
Clopidogrel (Plavix)
MOA:
MOA: platelet ADP receptor antagonist (inhibits platelet activation)
Clopidogrel (Plavix)
Use: (4)
Used with aspiring after angioplasty (continued for at least 1 year)
Reduce stroke and MI in patients with recent strokes and MIs
Treatment of peripheral arterial disease
Treatment of acute coronary syndrome
Clopidogrel (Plavix)
Toxicity
Vs dipyridamole and ticlopidine:
Less frequent cases of:
Toxicity: more favorable side effect profile that dipyridamole and ticlopidine
Less frequent cases of thrombocytopenia and leukopenia
Ticlopidine
MOA:
MOA: platelet ADP receptor antagonist (inhibits platelet activation)
Ticlopidine
Use:
Reduce the risk of thrombotic stroke in patients who have experience stroke precursors and/or in patients who have had a completed thrombotic stroke
Ticlopidine
Toxicity
most common:
most severe:
N/V/D most common
Leukopenia is most severe
Glycoprotein IIb/IIIa Inhibitors
Inhibit platelet aggregation by blocking: (2)
Glycoprotein IIb/IIIa Inhibitors: inhibit platelet aggregation by blocking the binding of these platelet-surface integrins to fibrinogen and von Willebrand factor (block cross-linking of platelets)
Glycoprotein IIb/IIIa Inhibitors: (3)
o Abciximab
o Eptifibatide
o Tirofiban
Abciximab
MOA:
MOA: Fab fragment of a humanized mAb against the AlphaIIbBeta3 receptor
Abciximab
Use
In conjunction with ______ for coronary thromboses
Use along with aspirin and heparin effective in preventing: (3)
In conjunction with percutaneous angioplasty for coronary thromboses
Use along with aspirin and heparin effective in preventing restenosis, recurrent MI and death
Abciximab
Major side effect:
If severe:
Toxicity: major side effect is bleeding
If severe: platelet transfusions can reverse aggregation defect
Eptifibatide
MOA:
MOA: cyclic peptide inhibitor of the fibrongen binding site on AlphaIIbBeta3 integrin
Eptifibatide
Use
Treatment of:
What have reduced MI and death by ~20%?
Treatment of acute coronary syndrome (IV)
Angioplastic coronary interventions (IV)- have reduced MI and death by ~20%
Eptifibatide
Major side effect:
If severe:
Toxicity: major side effect is bleeding
If severe: platelet transfusions can reverse aggregation defect
Tirofiban
MOA:
MOA: nonpeptide, small-molecule inhibitor of AlphaIIbBeta3 integrin
Tirofiban
Use in conjunction with:
For: (2)
Use: in conjunction with heparin
- Non-Q wave MI
- Unstable angina
Tirofiban
Toxicity:
What is possible?
Transfusions required to:
Toxicity: bleeding on local sites of clinical intervention and systemically
Major bleeding possible
Transfusions required to terminate bleeding
Example of Treatment Regimen for Acute MI
Prehospital: (4)
o Aspirin
o Oxygen (CPR if necessary)
o Analgesia/ECG/Antiarryhtmics
o Defibrillation
Example of Treatment Regimen for Acute MI
Hospital: (5)
o Antiarrhythmics an same supportive care as above
o Fibrinolytic therapy (up to 12 hours after onset), OR
o Coronary angioplasty, OR
o Coronary artery bypass graft surgery
o Anticoagulant (aspirin, heparin, start on warfarin)
Example of Treatment Regimen for Acute MI
Outpatient: (3)
o Antiarrhythmics as necessary
o Anticoagulant (aspirin or warfarin)
o Antiplatelet drug
