Pharmacology Lecture 4: Anticoagulant and Fibrinolytic Drugs Flashcards
Purpose of anticoagulants and fibrinolytic drugs
Treat or prevent thromboembolism
Behavior of blood in normal individual in terms of clotting
Blood remains fluid in vessels
Clot when vascular injury occurs
If intravascular thromus is formed, prompt dissolution by a fibrinolytic system
Hemostasis in damaged vessels if bleeding occurs
5 anticoagulant drugs of interest
Heparin
Low molecular weight heparing
Oral antiagulants (dabigatran, rivaroxaban, warfarin)
2 fibrinolytic drugs of interest
Streptokinase
Alteplase (recombinant tissue plasminogen activator)
Define heparin
Mixture of sulphated mucopolysaccharides from mast cells
Heparin function
Acts as a cofactor for antithrombin (III) = increase rate of thrombin-antithrombin reaction at least a thousand fold
Location of antithrombin production
Liver
Antithrombin function
Inhibit activated coagulation factors of the intrinsic and common pathways, most importantly thrombin and factor Xa. Acts as a suicide substrate for these proteases.
How unfractionated heparin is obtained
From mast-cell rich tissues in animals (endogenous)
How are doses of unfractionated heparin expressed and why?
Units of activity (USP units) because biological activity is similar across commercial preparations despite differences in composition
How to administer heparin
Must be injected (given parenterally) because cannot be absorbed through the gastrointestinal mucosa. Usually by continuous vascular infusion
Speed of onset if heparin is given by I.V.
Immediate
Speed of onset if heparin is given subcutaneously and consequence
Delayed by 1-2 hours
Considerable variation in bioavailability due to macrophage destruction
Define how the pharmacokinetics of heparin is saturatable
Most of it is cleared and degraded by the reticulo-endothelial system (fixed amount of macrophages), with a small amount unaltered in the urine
Define continuous vascular infusion
Bolus injection followed by maintenance dose delivered by infusion pump
How to monitor heparin in patient who had continuous vascular infusion
Activate partial thromboplastin time (aPTT)
How to monitor subcutaneously administrated heparin
Once a stable value of aPTT is obtained, can stop lab monitoring
When is unfractionated intravenous heparin used?
In hospitalized patients for initial management of pulmonary embolism following DVT and of DVT above knee joint.
Unstable angina and MI
When is unfractionated subcutaneous heparin sometimes used?
Bed-ridden or hospitalized patients not receiving intravenous heparin for prevention of DVT
5 side effects of unfractionated heparing (toxicity)
Bleeding Thrombocytopenia Allergies Increased loss of hair (reversible) Risk of osteoporosis with prolonged therapy
How to prevent bleeding due to unfractionate heparin
Adequate patient selection
Careful control of dosage
Close monitoring of aPTT
How common is early transient and harmless thrombocytopenia in unfractionated heparin patients? What is the cause?
25% due to platelet aggregation
Potential effect in up to 5% of patients on unfractionated heparin following 5 - 15 days of treatment. What is the significance of this?
Development of heparin-induced anti-platelet antibodies (HIT), which can lead to serious bleeding and paradoxical clotting (medical emergency; important to perform frequent platelet counts)
Contraindications for heparin use
Thrombocytopenia, bleeding disorders, active peptic ulcer disease, severe hypertension, etc.
Does not cross placenta, but still try to avoid in pregnancy unless necessary
Heparin antagonist
Protamine sulfate
When are heparin antagonists required?
Only if bleeding is significant (not for minor bleeding since effects will disappear in a few hours after last injection)
How does protamine sulfate inactivate heparin?
By binding tightly to it
What is replaced unfractionated heparin in many applications
Low molecular weight (LMW) heparin
LMW heparin function
Main effect through a catalytic effect on the inhibition of factor Xa (not thrombin) by antithrombin
Less effect on coagulation in general, but comparable to unfractionated heparin in most cases
2 examples of LMW heparin preparations
Enoxaparin
Dalteparin
How to administer LMW heparin
Given subcutaneously in fixed or weight adjusted dosage once or twice daily
Risk of HIT in LMW heparin
Significantly lower than with unfractionated heparin so monitoring not usually required since pharmacokinetics more predictable
Novelty heparin replacement
Synthetic selective inhibitors of factor Xa (i.e. fondaparinux)
How to administer fondaparinux
Subcutaneously once a day without monitorinf
Problem with fondaparinux
Expensive and no antagonist available yet
How was warfarin synthesized/discovered?
1924: Hemorrhagic disorder found in cattle that had ingested spoiled sweet clover silage
1939: Agent identified as dicoumarol
1948: warfarin synthesized
What was warfarin’s initial use?
Rat poison
What coagulation factors and anticoagulant proteins are produced mainly in the liver?
Factors II, VII, IX, X
Anticoagulant proteins C and S
What do the coagulation factors and anticoagulant proteins produced in the liver require and why?
Reduced vitamin K for the carboxylation of certain glutamate residues
What is the consequence of vitamin K absence on coagulation factors?
Abnormal coagulation factors of formed = do not work
What is the speed of full onset of warfarin effect? Why?
A few days since some factors have very long half lives (i.e. 50 hour for factor II)
How to administer warfarin
Well absorbed orally
Speed of plasma detection and concentration peaks
Plasma detection = 1 hour
Peak = 2 - 8 hours
What does warfarin bind to?
Plasma proteins
Warfarin and pregnancy
Avoid at all costs since it crosses the placenta easily –> bleeding in fetus and malformations
Where is warfarin metabolized and into what?
Metabolized into inactive metabolites in liver and kidney
Plasma half life of warfarin
Varies from 25 - 60 hours (average 40)
Duration of warfarin action
2 - 5 days
What do we use to monitor warfarin?
INR (international normalized ratio)
Why is it important to maintain a therapeutic INR level?
For effective therapy and to reduced bleeding complications
Clinical uses of warfarin
Long term anti-coagulation
Prevent progression or recurrence of DVT above knee joint (w/ or w/o PE complications) after initial heparin treatment
Indefinitely to prevent strokes in atrial fib. or prosthetic valve patients
How to pharmacologically treat DVT above knee joint complicated or not with pulmonary embolism
Initially LMW heparin for 7-10 days as it overlaps with warfarin for 3 - 5 days (since onset of action is slow)
How long is warfarin treatment kept for?
3 - 6 months
Major toxicity of coumarin anticoagulants such as warfarin
Bleeding
Important cause of bleeding with warfarin
Drug interactions
How to treat patient with bleeding due to warfarin
Give fresh plasma or coagulation factor concentrates and vitamin K1
Conditions or drugs are potentially dangerous in patients taking warfarin is they alter (3)…
Uptake or metabolism of warfarin or vitamin K
Synthesis, function or clearance of clotting factors and other elements involved in hemostasis or fibrinolysis
Integrity of epithelia
New oral anticoagulants
Dabigatran
Rivaroxaban
Apixaban
Purpose of new oral anticoagulants
Improve the ease of use, safety and efficacy of oral anticoagulants
Dabigatran function
Direct thrombin inhibitor
How is dabigatran administered?
As a prodrug (dabigatran etexilate) –> broken down in the body to dabigatran
Lab monitoring not required
Onset and half-life of dabigatran
Rapid onset
Plasma half-life = 12 - 16 hours (in patients with normal renal function)
Current approval for dabigatran
Prevention of stroke in patients with non-valvular atrial fib
Prevent thromboembolism in patients who have undergone hip or knee replacement surgery
Advantage of dabigatran over warfarin
Incidence of bleeding is the same or better
No experience in pregnancy (but doesnt mean no effect)
Disadvantage of dabigatran relative to warfarin
More expensive
No specific antagonist yet (in clinical trials)
Rivaroxaban function
Direct factor Xa inhibitor
Rivaroxaban uses
Prevention/treatment of pulmonary embolism, DVT
Prevention of stroke in patients with atrial fib
Prevention of thromboembolism after knee or hip replacement surgery
What does drug elimination depend on for rivaroxaban?
Renal function
What is the status of the bleeding risk profile of rivaroxaban?
Acceptable
Disadvantage of rivaroxaban
No specific antagonist yet
No experience in pregnancy
Apixaban function
Factor Xa inhibitor (most recently approved)
What has apixaban been approved for?
Prevention of stroke in patients with non-valvular atrial fib
Prevent thromboembolism in patients who have undergone hip or knee replacement surgery
General function of fibrinolytic drugs
Catalyse the formation of plasmin from plasminogen, leading to the lysis of thrombi
Effect of fibrinolytic drugs given intravenously
Generalized lysis of thrombi = BOTH of the protective hemostatic thrombi AND targeted pathological thrombi
Define streptokinase
Protein synthesized by B-hemolytic streptococci
Disadvantage of streptokinase
Risk of serious allergic reaction when given a second time, so rarely used today
Define alteplase
Recombinant tissue plasminogen activator (tPA)
Alteplase function
Preferentially activate plasminogen bound to fibrin
Theoretically limits fibrinolysis to formed thrombi to avoid systemic activation
How to administer alteplase
Intravenous infusion
Define tenecteplase
A mutant form of tPA with a longer half-life
How to administer tenecteplase
Bolus injection (rather than IV infusion since longer half-life)
Clinical uses of fibrinolytic drugs (4)
1) Acute MI with ST elevation (first 6 hours after infarction, particularly if percutaneous coronary intervention not available)
2) Large (or multiple) pulmonary emboli
3) Dissolve clots in blocked central catheters
4) Ischemic stroke (first 3 hours)
Subsequent treatment after administering fibrinolytic drugs
Aspirin and clopidogrel
Major risks of fibrinolytic drugs
Hemorrhage
Conversion of an ischemic stroke into a hemorrhagic stroke
2 mechanisms by which fibrinolytic drugs cause hemorrhage
Lysis of “physiological” thrombi
Induction of a systemic lytic state
Antagonist for fibrinolytic drugs
Aminocaproic acid
Aminocaproic acid
Block the binding of plasmin to fibrin = stop bleeding due to fibrinolytic drugs (not devoid of risks)
Contraindications for fibrinolytic drugs (6)
1) Recent surgery
2) Serious gastro-intestinal bleeding in last 3 months
3) Hypertension
4) Active bleeding or hemorrhagic disorder
5) Previous cerebrovascular event
6) Aortic dissection or acute pericarditis
