Anticoagulants Flashcards
What are the major dangers of anticoagulants?
- Major adverse effect is bleeding, which is frequently life-threatening or fatal
- Account for the highest number of adverse events of all drug classes
How does arterial thrombosis occur?
- Occurs in association with pre-existing vascular disease
- Occurs under conditions of high flow
- Predominantly platelet aggregates bound by fibrin strands
- Cause tissue ischemia by obstructing flow or embolizing to distal circulation
How does venous thrombosis occur?
- Generally lower limbs; other sites especially with associated thrombophilia
- Occurs under conditions of low flow, stasis
- Composed of red cells and fibrin with relatively fewer platelets
- Obstruct venous return; venous inflammation; pulmonary emboli
What are common causes of venous thrombosis?
Hospitalization
Surgery
Immobilization
Cancer
What are common causes of arterial thrombosis?
Stroke in atrial fibrillation
Myocardial infarction
Mechanical heart valves
Peripheral arterial occlusion
Which type of thrombosis causes vascular damage?
Arterial thrombosis causes vascular damage.
What is the mechanism of arterial and venous thrombosis?
Arterial => Shear stress
Venous =>Stasis and activated coagulation
What are arterial and venous thrombi composed of?
Arterial => Platelets, fibrin (white thrombi)
Venous => RBC, fibrin (red thrombi)
What is the antithrombotic treatment or arterial and venous thrombi?
Arterial => antiplatelet agents
Venous => anticoagulants
How do anti-platelet agents work?
Prolong bleeding time/PFA-100
How does aspirin act?
Aspirin inhibits platelet aggregation by irreversible
acetylation of platelet cyclo-oxygenase (COX)
Describe the mechanism of aspirin.
1) Arachadonic acid is liberated from platelet membranes by phospholipases that are activated by various stimuli
2) Arachidonic acid is ultimately converted to thromboxane A2
3) Thromboxane A2 mediates platelet aggregation via specific platelet receptors
4) Aspirin prevents formation of thromboxane A2 and therefore inhibits TXA2 mediated platelet aggregation
Describe the kinetics of aspirin.
- Rapid absorption, peak platelet effect at 1 hour (3-4 hours for enteric coated)
- Oral bioavailability 40-50%
- Half-life is 15-20 minutes BUT effect on platelets is irreversible
How long should aspirin be discontinued before an invasive procedure?
Must discontinue aspirin 10 days in advance of invasive procedures for complete restoration of normal platelet function
What are the adverse effects of aspirin?
- GI upset, ulcer, bleed (dose dependent)
- Bleeding is increased with concurrent use of anticoagulants, some supplements
- Exacerbates bleeding tendency in patient with bleeding disorders
- Elderly are more susceptible
Name two reversible COX inhibitors.
1) Ibuprofen
2) Naproxen
What is the main difference in action on platelet function between reversible/irreversible COX inhibitors?
Platelet function is restored with reversible COX inhibitors when the drug is cleared
Describe the kinetics of ibuprofen.
- Rapid absorption of oral dose; peak effect 1-2 hours
- Half-life is ~2 hours
- Essentially all of the drug is excreted (urine) 24 hours after the last dose
- Holding the drug for 1-2 days preoperatively is sufficient
Describe the kinetics of naproxen.
- Half life is 12-17 hours
- Must discontinue several days before surgery
What are the antithrombotic indications for aspirin (3)?
- Primary and secondary prevention of arterial thrombosis
- Reduces disorders associated with placental insufficiency (e.g., preeclampsia)
- Efficacious for prevention of venous thromboembolism in limited situations (e.g., hip fracture surgery)
How do P2Y12 receptor antagonists act?
Inhibit ADP-induced platelet aggregation via irreversible (but partial) alterations of ADP receptor P2Y12
- Defects in platelet P2Y12 receptor are associated with bleeding disorders
What are prominent examples of P2Y12 receptor antagonists?
1) Thienopyridines
- Clopidogrel
- Prasugrel
2) Ticagrelor
Describe the metabolism of clopidogrel.
Rapidly absorbed and metabolized to SR 26334
- Processed by CYP3A4
- Metabolism inhibited by concurrent use of atorvastatin
- Maximum inhibition of platelet aggregation by 4-6 hours after oral dose
- Plasma elimination half-life 8 hours
- Steady state platelet inhibition (50-60% inhibition) achieved by 4-7 days
What are the indications for clopidogrel?
- Secondary prevention of arterial thrombosis
- Prevention of coronary stent thrombosis (with aspirin)
What are the adverse drug effects associated with clopidogrel?
- Similar to aspirin with respect to bleeding
- Increased bleeding complications when both aspirin and clopidogrel are used together
- Thrombotic thrombocytopenic purpura (TTP)
- Rash and diarrhea
Describe the metabolism of the prodrug prasugrel.
- Rapidly absorbed
- Requires activation by enzymatic metabolism (predominantly CYP3A & CYP2B6)
- Peak effect 1-2 hours after oral dose
- Half life ~7 hours
- Steady state platelet inhibition (70% inhibition) achieved by 3-5 days
What are the indications for prasugrel?
- Management of acute coronary syndromes with percutaneous coronary interventions
- Prevention of coronary stent thrombosis (with aspirin)
What adverse side effects are associated with prasugrel?
- Similar to aspirin & clopidogrel with respect to bleeding
- Increased bleeding when aspirin & prasugrel are used together
- Increased risk of stroke (both hemorrhagic and ischemic)
- Contraindicated in patients with history of TIA or stroke
- TTP is class effect
Describe the metabolism of Ticagrelor.
- Rapidly absorbed
- Active metabolite generated by CYP3A4 but parent drug is also active
- Peak effect 2 hours after oral dose
- Half life 7-9 hours
- Steady state platelet inhibition achieved by 3-5 days
What are the indications of Ticagrelor?
- Prevention of thrombotic cardiovascular events in patients with acute coronary syndromes
What are the adverse reactions associated with Ticagrelor?
- Similar to other antiplatelet agents with respect to bleeding
- Dyspnea & bradycardia (similar structurally to adenosine)
- Gynecomastia in men
When should aspirin be used as an oral anti-platelet agent (5)?
1) Coronary artery disease/angina/MI
2) Thrombotic stroke/Transient cerebral ischemia
3) Peripheral arterial disease
4) Added to warfarin in patients with prosthetic heart valves who develop systemic embolism on warfarin alone
5) Atrial fibrillation in patients with contraindication to warfarin, NOACs
When should clopidogrel be used as an oral anti-platelet agent (4)?
1) Transient cerebral ischemia
2) Prevention of arterial thrombosis where aspirin contraindicated
3) With aspirin for coronary stent thromboprophylaxis
4) Recurrent arterial thromboembolism despite treatment with aspirin
When should prasugrel/ticagrelor be used as an oral anti-platelet agent (1)?
1) Acute coronary syndromes
What is the mechanism of action of GP IIb/IIIa receptor antagonists?
- Binds GP IIb/IIIa receptor on platelet membrane
- Blocks binding of fibrinogen to GP IIb/IIIa (the final common pathway of platelet aggregation)
What is the major indication for use of GP IIb/IIIa receptor antagonists?
Major indication is to prevent acute vessel closure following percutaneous coronary intervention
How are GP IIb/IIIa receptor antagonists administered?
IV only
What are the 3 main types of GP IIb/IIIa receptor antagonists?
1) Monoclonal antibody Fab fragment: Abciximab
2) Cyclic heptapeptide: Eptifibatide
3) Small molecule: Tirofiban
What is heparin?
Heparin is a highly sulfated family of glycosaminoglycans found in all animals above the horseshoe crab.
- It is produced by mast cells
- Accelerates inhibition coagulation factors by antithrombin
Describe the IV bioavailability/kinetics of heparin.
- Intravenous: 100% bioavailable
- Anticoagulant effect is immediate
- Binds widely to plasma proteins
- Heparin resistance
Describe the subcutaneous bioavailability/kinetics of heparin.
- Poor bioavailability
- Acceptable anticoagulant effect 1-3 hours after injection
- Must use higher doses than IV
- Less frequent dosing
What is the anticoagulant of choice in pregnancy?
Heparin => Does not cross the placenta
Describe the two phases of heparin clearance.
Initial - rapid - Binds to receptors on endothelial cells and macrophages where it is internalized and metabolized to smaller forms - Binds to plasma proteins Second - slow - Renal
What is unique about the half life of heparin?
The half life of heparin is dose dependent
Describe the “mini” dose regimen for heparin.
- Subcutaneous
- Generally used for thromboprophylaxis
- 5000 units, two to three times per day
- No lab monitoring
Describe the therapeutic/”full” dose regimen for heparin.
- Intravenous
- Bolus dose followed by
- Continuous infusion
- Dose adjusted according to effect on aPTT (goal 80 – 114 sec)
- Used for treatment of acute thrombosis
- Dose adjustments made after 4 to 6 hours at steady state
What are the major side effects of heparin (4)?
1) Bleeding
2) Osteoporosis
3) Skin lesions
- Urticaria
- Papules and plaques
- Necrosis (immune mediated)
4) Hypoaldosteronism
- Interferes with biosynthesis of aldosterone
How does heparin induced thrombocytopenia occur?
Immune mediated: IgG directed against heparin/PF4 antigen on platelet surface
- Thrombocytopenia generally modest
After how many hours do low molecular weight heparins reach peak effect?
Peak anticoagulant effect 4-6 hours after dose
What are the advantages of low molecular weight heparins over unfractionated heparins?
- Fixed, weight-based dose
- Subcutaneous administration
- Allows for self injection at home
- No routine laboratory monitoring required in majority of cases
- More predictable anticoagulant response
- Less heparin induced thrombocytopenia
What are the disadvantages of low molecular weight heparins?
- Long half life may be a problem in bleeding patients as there is no good antidote
- Renal excretion makes use in renal insufficiency difficult
What are the indications for heparins?
- Primary prevention/treatment of venous and arterial thrombosis
- Heparin prevents thrombus propagation and new clot formation while endogenous fibrinolytic system hydrolyzes established clot
What is used to reverse heparin in severe bleeding?
In severe bleeding, treat with protamine sulfate
- Protamine sulfate is an anticoagulant so overdose will exacerbate bleeding
What is Warfarin/Coumadin?
Warfarin is an anticoagulant that works by antagonizing/inhibiting vitamin K
Describe the mechanism of action of Warfarin.
- Vitamin K is required as a cofactor in the pathway that effects gamma carboxylation on coagulation factors II, VII, IX and X
- Gamma carboxylation is required for coagulation factor binding to phospholipid surfaces
- Gamma carboxylation is also required for activity of the endogenous anticoagulants protein C, protein S and protein Z
How is the action of warfarin different from heparin?
- Heparin inhibits activity of preformed coagulation factors
- Warfarin inhibits the synthesis of active coagulation factors
Describe the kinetics of warfarin.
- Oral dose is rapidly and extensively absorbed from the GI tract
- Peak levels reached in 90 minutes after ingestion
- Food slows absorption, but does not alter bioavailability
- Extensively protein-bound in plasma, especially to albumin
Describe the metabolism of warfarin.
- Crosses the placenta; active form does not enter breast milk
- Metabolized in liver by cytochrome P450 enzyme pathways
- Metabolites excreted in urine (2% excreted unchanged in urine)
- Warfarin clearance declines with age
- Clearance is increased in patients on dialysis
- Genetic polymorphisms affect warfarin metabolism and dosing
What is the half life of warfarin?
Half-life is approxmately 33 hours
- Steady state anticoagulation is reached in 7-10 days
What foods rich in Vit K alter the effect of Warfarin?
- Vegetables, especially leafy greens
- Green tea leaves
What medical conditions alter the effect of warfarin?
- Liver disease
- CHF
- Malnutrition
- Hypermetabolic states
- Fever
- Hyperthyroidism
- Warfarin resistance
- Gastric bypass surgery
- Pharmacogenetics
What is warfarin’s effect on PT and aPTT?
Warfarin prolongs the PT and aPTT
Once INR (international normalized ratio) is achieved how should heparin and warfarin be overlapped?
Important to overlap heparin and warfarin by two days once therapeutic INR achieved
PT/INR effect depends on the clearance of which factor?
PT/INR effect depends on clearance of factor VII, which has the shortest half life
Anticoagulant effect depends on clearance of which factors?
Anticoagulant effect depends on clearance of factors IIa and Xa
What are the indications for warfarin (4)?
1) Primary and secondary prevention of venous thromboembolism
2) Stroke prevention in atrial fibrillation, mechanical heart valves
3) Failure of antiplatelet therapy
4) Adjunctive antiplatelet therapy in high risk patients
What are the side effects of warfarin (3)?
1) Bleeding
2) Skin Necrosis
- Thrombosis of venules & capillaries in subcutaneous fat
- Protein C and protein S deficiencies pre-dispose
3) Teratogenic during early fetal development
How can warfarin be reversed?
1) Vitamin K
- Effect seen within hours
- Reversal of rodenticide effect requires months of treatment
2) Fresh frozen plasma
- Contains coagulation factors
- Used when immediate reversal of anticoagulation is needed (e.g., life-threatening bleeding or immediate surgery)
- Short duration of action due to short half-life of factor VII
- Administer vitamin K concomitantly
3) Prothrombin complex concentrates
- Plasma-derived concentrates containing vitamin K dependent factors
- Used when immediate reversal required
When are parenteral direct thrombin inhibitors used?
Used when heparins are contraindicated (HIT) via IV
- no antidote but sort half lives
What is the mechanism of action of parenteral direct thrombin inhibitors?
Mechanism of action => Bind and inactivate thrombin
What will be prolonged with the use of parenteral direct thrombin inhibitors?
Will prolong both PT and aPTT but anticoagulant effect monitored by aPTT prolongation
What is Dabigatran?
Dabigatran is an oral prodrug rapidly converted to active drug by liver, which inhibits thrombin directly
Describe the kinetics of dabigatran.
- Peak level at ~2 hours after ingestion
- Half-life 14-17 hours after reaching steady state
- Bioavailability ~7%
Describe the metabolism of dabigatran.
- Active drug cleared predominantly by renal excretion
- Dose reduction in moderate renal dysfunction
- Do not use in severe renal dysfunction
What are the drug interactions of dabigatran?
Verapamil, quinidine
What are the major side effects of dabigatran?
Bleeding (Gastrointestinal)
What are the indications for dabigatran?
Approved for stroke prevention in atrial fibrillation, acute VTE
What is the mechanism of action of Rivaroxaban?
Inhibits activated factor X (Xa) directly
Describe the kinetics of Rivaroxaban.
- Peak level at ~3 hours after ingestion
- Half-life 4-9 hours after reaching steady state (longer in elderly)
- Bioavailability 80-100%
Describe the metabolism of Rivaroxaban.
- Active drug metabolized by CYP3A4
- Concurrent use with inhibitors –> increased drug exposure
- Ritonavir, clarithromycin, erythromycin, ketoconazole - Concurrent use with inducers –>decreased drug exposure
- Active drug cleared predominantly by renal excretion
- Dose reduction in moderate renal dysfunction
- Concurrent use with inhibitors –> increased drug exposure
- Do not use in severe renal dysfunction
What is the major side effect of rivaroxaban?
Bleeding
What is the indication for rivaroxaban?
Approved for prevention, treatment of acute VTE & stroke prevention in atrial fibrillation
What are fibrinolytic agents?
Clot buster” drugs
- Anticoagulant and antiplatelet agents prevent thrombus formation and extension
- Fibrinolytic agents break down thrombi
Describe the mechanism of action of fibrinolytic agents.
- Convert plasminogen to plasmin which degrades fibrin
- Recombinant tissue plasminogen activator (rTPA; Alteplase)
- Urokinase plasminogen activator
- Binds to plasminogen and the complex degrades fibrin
- Streptokinase
What are the indications for fibrinolytic agents?
- Acute ischemic stroke, coronary or peripheral arterial occlusion
- Massive pulmonary embolism, extensive iliofemoral DVT
- Clear occluded central venous catheters
What is the major adverse side effect of fibrinolytic agents?
Major adverse event is bleeding
