Anticoagulants Flashcards
What ca thromboembolic diseaseds she a result of
Thromboembolic diseases are common
- deep vein thrombosis (DVT) and pulmonary embolism (PE) - transient ischaemic attacks (TIA), ischaemic stroke
- myocardial infarction (MI)
- consequence of atrial fibrillation (AF)
What are venous and arterial thrombosis associated with
• Venous thrombosis associated with stasis of blood and or damage to the veins – less likely to see endothelial damage
High red blood cell and fibrin content, low platelet content evenly distributed
• Arterial thrombosis – usually forms at site of atherosclerosis following plaque rupture
Lower fibrin content and much higher platelet content
Describe the composition of different thrombi
- Platelet rich “white” arterial thrombi – antiplatelet and fibrinolytic drugs
- Lower platelet content, “red” venous thrombi – parenteral anticoagulants (heparins etc.) and oral anticoagulants (warfarin etc.)
- A combination of both may be used in some patients often in secondary prevention
Descrbe atiplately abets
Inhibit platelet aggregation which is a critical component of arterial thrombus formation
GPIIb/IIIa surface receptors play a central role
• Damaged endothelium leads to recruitment of platelets, activation and aggregation at site of injury
What are cycle-oxygenate inhibitors
G aspirin
• Potent platelet aggregating agent thromboxane A2 formed from arachidonic acid by COX-1
• Aspirin - inhibition of COX-1 reduces TXA2 and inhibits platelet aggregation – irreversible
• Action at very low non-analgesic doses (~75 mg)
• Higher doses inhibits endothelial prostacyclin (PGI2) (lecture 17) - counter
effect
• t1/2 ~20 min, hydrolysed in liver to salicylic acid - 3-12h
• Bleeding time prolonged – haemorrhagic stroke, GI bleeding (peptic ulcer)
• COX-1 polymorphisms result in lack of efficacy in some
-
- Secondary prevention of stroke and TIA if other agents contraindicated
- Secondary prevention of ACS in combination with others
- Post PPCI and stent to reduce ischaemic complications
- Secondary prevention of MI in stable angina or peripheral vascular disease
- Inhibition lasts for lifespan of platelet as non-nuclear (7-10 days)
What are p2y12/adp redecptantagonists
Clopidogrel, prasugrel, ticargrelor
• Inhibit binding of ADP to P2Y12 receptor → inhibit activation of GPIIb/IIIa receptors (calcium mediated)
• Clopidogrel and prasugrel are irreverisible inhibitors – (p.o.)
• Prodrugs – hepatic metabolites t1/2 - 7-8h (clopidogrel), ~ 8 days (prasugrel)
• Clopidogrel has slow onset of action without loading dose – can be unpredictable in antiplatelet action
reduces morbidity and mortality post thromboembolic stroke reduces secondary events post MI (combination with aspirin)
useful for prophylaxis in patients intolerant to aspirin
• Used typically for up to 12 months post MI (secondary prevention)
• Ticagrelor (p.o.) is active and has active metabolites – more expensive than clopidogrel
• Acute treatment dictates what secondary combination used
Describe glycoproteins iib/iiia inhibitors
Eh abciximab, Tirol always, eptiibatie • Predominant platelet integrin culminating in binding of fibrinogen and von Willebrand factor (VWF)
• Target final common pathway – more complete platelet aggregation
• Abciximab – antibody irreversibly blocks GPIIb/IIIa receptors preventing fibrinogen binding, >80% reduction in aggregation – bleeding risk (potentially more so than other agents)
• Eptifibatide synthetic peptide that binds reversibly
• Tirofiban is a non peptide reversible antagonist
• All given i.v.i. with bolus
• Slow dissociation of abciximab (relative to t1/2 - ~30min) gives longer than predicted action – 12-36h post infusion
Aggregation recovery more quickly with others
• Thrombocytopenia – platelet count needed after several hours
Descrive ohosphodiesterase inhibitors
Eg dipyridamole.
• Dipyridamole (p.o.) inhibits cellular reuptake of adenosine → increased plasma adenosine → inhibits platelet aggregation via A2 receptors
• Also acts as phosphodiesterase inhibitor which prevents cAMP and cGMP degradation → inhibit expression of GPIIb/IIIa
• Hepatic metabolism – typically modified release t1/2 12h
• Flushing and headache, hypersensitivity
• Secondary prevention of ischaemic stroke and TIAs
• Adjunct to oral anticoagulants for prophylaxis of thromboembolism following valve replacement
Gove an overview of fibrinolytic
Ss
Streptokinase alteplase
• Clinically used agents are naturally occurring or recombinantly produced plasminogen activators
• i.v. or i.a.
• Streptokinase usually given as short infusion for CAO – antigenic so can
not be given repeatedly – less commonly used than the others
• PPCI vs. thrombolysis, how long since symptoms, how long until PPCI
could be performed
tranexamic acid
Give an overview of anticoagulant agents
S
Anticoagulant drugs – prevent thrombus formation and thrombus growing
Describe vitamin k antagonists
Vitamin K antagonists
• Inhibits production of vitamin K dependant clotting factors (koagulation vitamin – Scandinavian sp.)
• Stops conversion of vitamin K to active reduced form (inhibits reductase)
• Hepatic synthesis of clotting factors II (prothrombin), VII, IX and X require active vitamin K as cofactor
• Ca2+ also a cofactor
• Delay in onset of action as circulating active clotting factors present for several days
-Must be cleared and replaced with noncarboxylated forms – inactive clotting factors
• t1/2 36 -48h - racemic mixture – highly person specific
What are the therapeutic uses of warfarin
DVT prophylaxis and treatment
PE prophylaxis and treatment
AF with high risk of stroke
protein S and C deficiency following orthopaedic surgery (stasis)
• Slow onset of action likely to require heparin cover (see later slides) if anticoagulation needed immediately
• Good GI absorption and taken orally ~100% bioavailability – most common first choice for long term AC – but tide is changing
• Time to synthesise new clotting factors needs considering - pre surgery
• Highly protein bound – remember displacement PK issues
• Activity highly variable in individuals – monitoring required (INR)
Describe pk ad warfarin monitoring
• Functional 2C9 polymorphisms contribute to significant inter individual variability
• Plasma conc. does not correlate directly with clinical effect – blood coagulation ~ 48h later
• Crosses placenta – avoided in 1st (teratogenic) and 3rd (brain haemorrhage) trimesters
• Response governed by CYP2C9, other drugs, vitamin K intake, coagulation proteins
Monitoring
• Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma
• Referred to as international normalised ratio – INR
• Allows for standard corrected value comparable across laboratories
What are the adrs of warfai
• Principle ADR is bleeding – a patient taking warfarin is always of clinical interest
• Most effective antidote is vitamin K1 prothrombin complex concentrate i.v. fresh frozen plasma
of course stop warfarin!
• Consideration of site and severity of bleeding – planning in elective surgery patients at risk (AF, valve replacement)
• Anticoagulation can be difficult to manage for several weeks after
• Alternatives may need to be used in high risk patients with monitoring
