Lecture 9 Prevention of Thrombosis Flashcards
what happens when arthrosclerotic plaque forms in an artery?
blood coagulation:
Thrombin, fibrinogen and fibrin form
Platelet reactions:
Adhesion , activation and aggregation of platelets
Leads to further aggregation of platelets
what does the rupture of an atherosclerotic plaque in an artery lead to?
A thrombus
What are the three classes of drugs that have been developed to prevent and/or reverse thrombus formation?
anticoagulant
Antiplatelet agents
Fibrinolytic agents
What is an example of an anticoagulant?
Factor XA inhibitors, antithrombin, heparin and vitamin K antagonists
They modify blood clotting mechanisms
What is an example of antiplatelet agents?
aspirin
Inhibit COX-1 activity to inhibit platelet aggregation
what is an example of a fibrinolytic agent?
Alteplase
They breakdown fibrin
What are the classes of anticoagulant drugs?
selective factor Xa inhibitors
Direct thrombin inhibitors
Heparin and Low molecular weight heparins
vitamin K antagonists
What are the targets of anticoagulants?
They target various factors in the coagulation cascade preventing stable fibrin framework
what are direct acting oral anticoagulants?
reversible inhibitors of thrombin
Idarucizumab reversal agent
Reversible inhibitors of activated factor X (thrombin)
Prevents thrombin generation
Prevents thrombus development
what are the first line treatments for Venous thromboembolisms?
Apixaban or rivaroxaban
- Confirmed proximal DVT or PE
which drugs are given if first line treatment of Venous thromboembolism is contraindicated?
Low molecular weight heparin - followed by etexilate or edoxaban
OR
LMWH given with a vitamin K antagonist (at least 5 days) - followed by a vitamin K antagonist on its own
what type of patients would need treatment for venous thromboembolisms?
patients undergoing surgery
Which drugs are direct acting oral anticoagulant?
Apixaban, dabigatran, etexilate, edoxaban and rivaroxaban
What are the indications of apixaban, dabigatran, etexilate, edoxaban, rivaroxaban?
prevention of stroke
Secondary prevention of DVT and/or PE
What are the indications of Apixaban, dabigatran, etexilate, rivaroxaban?
Prevention of venous thromboembolism following surgery
what are the indications of rivaroxaban?
prevention of atherothrombotic events in patients with coronary or peripheral artery disease following an acute myocardial infarction
What are the contraindications of Apixaban?
avoid in conditions with significant risk of bleeding:
Gastrointestinal ulceration
Malignant neoplasms with high risk of bleeding (erosion of blood vessels)
Oesophageal varices (veins - dilated and distended)
what are the side-effects of Apixaban?
Anaemia
haemorrhage
what are the pharmacodynamics of heparins?
They are a family of sulfa mucopolysaccharides found in the secretary granules of muscle cells
Commercial preparations vary in molecular weight 3000-30000Da
Inhibit coagulation by activating antithrombin III
what is the action of antithrombin III in the presence of heparin?
it is a naturally occurring inhibitor of thrombin and clotting factors IX, Xa, XI and XII
In the presence of heparin it becomes 1000 times more active and inhibition of clotting factors is instantaneous
What are the differences between heparin and low molecular weight heparins?
They have more consistent activity
what are examples of low molecular weight heparins?
daltrparin sodium, enoxaparin sodium and tinzaparin sodium
What are the advantages of heparins?
they are more synthetic so have more consistent effects
They are predictable so easier to figure the dose
What are the pharmacokinetics of heparin and LMWH pharmacokinetics?
inactive given orally
Administered via IV or subcutaneously
Heparin has a short half life
LMWH have longer duration of action
Eliminated by renal excretion
Side effects include bleeding and hypersensitivity (thrombocytopenia - too little platelets)
overdose treated by IV protamine
What is the mechanism of action of vitamin K antagonists?
inhibition of the activation of vitamin K1 dependent clotting factors: II, VII, IX AND X
48 to 72 hours for the anticoagulant effect to develop
what are the side-effects of vitamin K antagonists?
haemorrhage
Skin necrosis
what are the vitamin K antagonists?
warfarin
acenocoumarol
phenindione
Why is warfarin main target INR?
because there is a variability of effect so dose has to be built up
Which enzyme does warfarin have a direct effect on?
vitamin K reductase (VCORC1)
what are the pharmacokinetics of warfarin?
Absorption - rapidly and almost totally absorbed from the GI, peak after 0.5-4h after administration
Distribution - lower volume of distribution, mainly plasma protein bound
Metabolism - action is terminated by me metabolism in the l liver using CYP450 enzymes
excretion - metabolites are conjugated to glucuronide and excreted in urine and faeces
Half life - 15 to 80 hours
Dose is highly variable
How are antiplatelet drugs useful?
it is a useful prophylactic and therapeutic strategy against myocardial infarction and stroke caused by thrombosis
what is an example of an anti-platelet drug?
Aspirin
what are the clinical uses of anti-platelet drugs?
Used to prophylactically prevent arterial thrombosis leading to:
Transient ischaemic heart attack
Stroke
Myocardial infarction
how do antiplatelets work?
Aspirin irreversibly inhibits COX-1, therefore inhibiting the synthesis of TXA2
No new COX -1 is synthesised
So the inhibition is irreversible and effective for the life of the circulating platelet
when are ticlopidine and clopidogrel used?
in transient ischaemic heart attack (ticlopidine)
Post myocardial infarction or stroke (clopidogrel)
what are examples of fibrinolytic drugs?
Streptokinase and alteplase
what is the mechanism of fibrinolytic (thrombolytic) drugs?
they potentiate the effects of the fibrinolytic system by stopping the balance between the breakdown and formation of thrombosis
They activate conversion of plasma to plasma which breaks down fibrin, thus dissolving clots
How are fibrinolytic drugs administered?
Using IV
what are the half lives of fibrinolytic drugs?
They are short (<10-90 mins)
what are the main uses of fibrinolytic drugs now?
Restoring catheter and shunt function, by clots causing occlusions
To dissolve clots that result in strokes
What is INR?
It is the coagguabilty effect of the blood
low = clot quickly
high = clot slowly
