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
What are the dis of warfarin
Huge number of DDIs
majority potentiate anticoagulation action but some decrease effects
• Inhibition of hepatic metabolism especially CYP 2C9 Amiodarone, clopidogrel, intoxicating dose of EtOH, quinolone, metronidazole
• Inhibit platelet function Aspirin
• Reduce vitamin K by eliminating gut bacteria cephalosporin antibiotics
• Displacement of warfarin from plasma albumin
NSAIDs and drugs that decrease GI absorption of vitamin K -Addition of these agents will increase INR
• Acceleration of warfarin metabolism barbiturates, phenytoin, rifampicin, St Johns Wort -Addition of these agents will decrease INR
Descirb warfarin use and inr
This is not an exhaustive list
INR 2.5 (+/-0.5)
• DVT PE
AF (risk>benefit) INR 3.5 (+/-0.5)
• Recurrent DVT or PE in patients currently receiving anticoagulation
Mechanical prosthetic valves – valve type and location dependant
• Odds Ratio of bleeding – particularly subdural haemorrhage relatively constant up to INR ~ 3
beyond this odds ratio increases dramatically
• Before initiation consider: PMH, bleeding risk, DDIs, age, mobility, blood tests, base INR, loading dose, heparin cover
What are pareteral anticoagulants
Unlike warfarin heparins inhibit the action of coagulation factors
• Heparin produced naturally in mast cells and vascular endothelium
• Extracted for commercial use from porcine intestinal mucosa
• Unfractionated heparins are typically large 5-30 kDa
• Low molecular weight heparins (LMWH) prepared from unfractionated heparin by chromatography 1-5 kDa
• Interaction with antithrombin ~1000 times slower without heparins
Desribe ufh
Typically ~ 45 polysaccharide units mixture, t1/2 30min low dose, 2h higher doses
• Binding of antithrombin (ATIII) causing conformational change and increased activity
• ATIII inactivates thrombin IIa and factor Xa but also IXa, XIa and XIIa
• To catalyse inhibition of IIa, heparin needs to simultaneously bind ATIII
AND IIa.
• Xa inhibition only needs ATIII binding
• Typically i.v. infusion, s.c. for prophylaxis with much lower bioavailability
heparin
What are lmwhs
Eg bempiparin dalteparn
Typically ~ 15 polysaccharides which are absorbed more uniformly (mg/kg dosing)
• Bioavailability > 90%, longer t1/2 ~ 2h
• More predictable dose response as does not bind to
endothelial cells, plasma proteins and macrophages
• Do not inactivate thrombin (IIa) – not long enough
• Target Xa specifically - less monitoring is usually required
• Less likely than UFH to cause thrombocytopenia
• s.c. administration
• Cleared by kidneys
Descrbe the pl of heparins
Ss
Describe eh use of heparins
DVT, PE and AF
Administered prior to warfarin – quicker onset prior to warfarin loading LMWH typically used unless particularly fine control required
Evidence supports outpatient unmonitored bodyweight adjusted LMWH use c.f inpatient i.v. UFH
• ACS
reducing recurrence or extension of coronary artery thrombosis
post MI and NSTEMI – unstable angina – typically with long term oral tx
• During pregnancy used as do not cross placenta – monitored with caution
• Prevention of venous thromboembolism
perioperative prophylaxis with LMWHs for several days – convenience over UFH
What are the adrs of heparins
Bruising and bleeding
Intracranial, at site of injection, GI, epistaxis
hepatic and renal compromise, elderly or those with carcinoma at higher risk
• Heparin induce thrombocytopenia (HIT)
Autoimmune response typically 5-14 days after initiation antibodies to heparin platelet factor 4 complex
depletion of platelets
paradoxically can lead to thrombosis as more platelets activated alternative anticoagulation initiated and reversal of heparin
lab assay will confirm HIT
• Osteoporosis is rare long-term ADR, higher risk with UFH and more prevalent in pregnancy
• Hypersensitivity (like warfarin) rare
Decsribe heparin reversal
Protamine sulphate dissociates heparin from ATIII, irreversible binding, Lots of positive charges neutralises sulphate
i.v. or i.v.i.
• Greater effect with UFH than LMWH, no affect on fondaparinux (next slide)
• Monitor partial prothomboplastin time (PTT) if using UFH
• Protamine sulphate can be used as antidote to heparin following surgery where large doses may be used – typically cardiac patients
What are other iia and da inhibitors
Ss Fondaparinux – syntetic pentasaccahide selectively inhibits Xa by binding to ATIII – s.c., t1/2 18h, less monitoring than UFH
• Direct acting oral anticoagulants (DOACs) OR NOACs
Direct Xa
Inhibit both free Xa and that bound with ATIII, do not effect thrombin (IIa) - hepatic metabolism and excreted partly by kidneys, t1/2 ~10h - p.o.
Direct thrombin inhibitors
Selective direct competitive thrombin inhibitors, both circulating and thrombus bound IIa
active metabolites have relatively short t1/2s ~ 30-60min – p.o.
