Anticoagulants, Antiplatelets And Thrombolysis Flashcards
Name some indications for Warfarin
PrEvention and treatment of:
DVT (taken for 3-6 months)
PE (taken for 6 months)
After having prosthetic heart valve fitted
Thrombophilia
AF
What are the contraindications for Warfarin?
Pregnancy (1st semester teratogenic and 3rd trimester risk of brain haemorrhage)
Peri-op
Haemorrhagic stroke
48 hours post partum
Outline the pharmacokinetics for Warfarin
Oral, half life 48 hours, gradual onset (turn over of clotting factors), CYP450 metabolism, variation in dose, action persists after cessation
Describe the mechanism of action for Warfarin
Vitamin K is required for the synthesis of clotting factors II (prothrombin), XII, IV, X. In this process vitamin K becomes oxidised and needs to be reduced to be used again. Warfarin competitively inhibits this step reducing the synthesis of vitamin k dependent factors
What are the main ADRs of Warfarin?
Haemorrhage, bruising, purpura, teratogenic
When might the action of Warfarin be potentiated?
CYP450 inhibitors, antiplatelets, cephalosporin (reduced vitamin k from gut bacteria), protein displacers e.g. NSAIDs
When can the action of Warfarin be inhibited?
CYP450 inducers
What monitoring is required for Warfarin treatment?
INR, prothrombin time (determines INR), LFT, FBC, give anticoagulant card
How would your reverse the action of Warfarin?
Stop Warfarin, antagonism of therapy with IV vitamin K (slow), fresh frozen plasma (fast)
What are some indications for heparin?
Prevention of thrombo-embolism e.g. Peri-operative (LMWH) when Warfarin has to be stopped, immobile patients
Treatment of DVT, PE, AF prior to Warfarin (LMWH)
Treatment of MI, angina
Pregnancy when Warfarin can not be used
What are some contraindications for heparin?
Haemorrhagic disorder, thrombocytopenia, recent cerebral haemorrhage, severe hypertension, peptic ulcer, trauma
What are the differences in pharmacokinetics between unfractionated heparin and low molecular weight heparin?
Unfractionated - IV, non linear, variable bioavailability (binds to cells), requires monitoring, loading dose needed, half life 1-2 hours
Low molecular weight - SC, high bioavailability, more linear, longer half life
What is the mechanism for heparin and what is the difference I’m action between unfractionated and low molecular weight?
Heparin binds to antithrombin III and causes a conformational change increasing its activity to increase the inhibition of factors II and Xa
To catalyse Xa inhibition, only antithrombin III has to be bound (achieved by unfractionated and low molecular weight) but to inhibit II heparin needs to bind II and antithrombin III and only unfractionated heparin can do this
What are the main ADRs for heparin?
Bleeding - intracranial, injection sites, GI, epistaxis
Bruising
Thrombocytopenia - binds to platelet factor and causes an autoimmune response (less likely with LMW)
Osteoporosis (long term use)
What monitoring is required for unfractionated heparin?
Activated partial thromboplastim time (measures the efficacy of the clotting cascade)
What is the reversal therapy for heparin?
Protamine sulphate - dissociation of heparin and antithrombin III (irreversibly binds to heparin)
When would you use antiplatelets?
Prophylaxis of disorders resulting from intravascular clotting
Name 2 antiplatelets that inhibit thromboxane A2 and describe the mechanism for each
Aspirin - inhibits COX enzyme
Dipyridamole - inhibits platelet phosphodiesterase which usually breaks down cAMP, high levels of cAMP inhibits platelet aggregation
Thromboxane A2 is released from activated platelets which causes platelet aggregation and vasoconstriction
Name 2 antiplatelets that are ADP receptor antagonists and explain how they work
Clopidogrel, ticlopidine - inhibits ADP dependent aggregation by binding to the P2Y12 receptor where ADP usually binds to a Gi protein to inhibit cAMP thus increased cAMP reduces platelet aggregation.
What are GpIIb/III inhibitors and how do they work?
These are antiplatelets used during PCI by inhibiting the receptors on platelets where fibrinogen usually binds to cause aggregation
Describe the normal thrombi clearance pathway
Plasminogen binds to fibrin strands within the thrombus and is converted to plasmin by tPA and uPA which cleaves fibrin. This is regulated by circulating factors such as PAI-1
What are the indications for thrombolytic therapy?
Acute MI <12 hours - history and ECG
PE
Major venous thrombosis
Ischaemic stroke - if haemorrhage has been ruled out (not recommended due to increased risk of induced cerebral haemorrhage)
What are the contraindications for thrombolysis?
Active peptic ulcer, bleeding, recent trauma/surgery, history of cerebral haemorrhage, uncontrolled hypertension, coagulation defect, previously had streptokinase (for streptokinase)
What are the two main thrombolytic drugs and how do they work?
Streptokinase - derived from b haemolytic streptococci binds to plasminogen and induces a conformational change to plasmin
Alteplase (recombinant tPA) - acts like the endogenous tPA and works mainly in the presence of fibrin so is clot specific
What are they windows of opportunity when treating coronary occlusion, VTE and ischaemic stroke with thrombolysis?
Coronary occlusion - <12 hours
VTE - longer
Ischaemic stroke - <3 hours
What are the main ADRs for thrombolytics?
Risk of inducing haemorrhage
Streptokinase - allergic reaction, hypotension, can only be used once (generates antibodies)
How would you encourage BP to rise I hypotension induced by thrombolytics?
Slow the IV
How would you treat bleeding following thrombolytic therapy?
Blood transfusion, volume expanders, inhibition of fibrinolysis (tranexamic acid, apoprotin, specific recombinant factors, pooled clotting factors)
What studies looked at the efficacy of thrombolytics in MI and what did they conclude?
ISIS-3 and GISSI - streptokinase and Alteplase have the same efficacy
What study looked at mortality and the use of thrombolytics and what did they conclude?
GUSTO - alteplase achieved slightly greater mortality reduction but increased risk of haemorrhagic stroke
Within the first 1-2 hours being treated with thrombolytics for MI, how many deaths per 1000 treated are prevented?
60
