Antiplatelets, Anticoagulants And Thrombolysis Flashcards
Give examples of thromboembolic diseases
DVT PE TIA Ischaemic stroke MI AF
What is a thrombus?
A clot adhered to a vessel wall
What in an embolus?
Intravascular clot distal to site of origin
What is a venous thrombosis?
Venous thrombosis associated with stasis of blood or damage to the veins - less likely to see endothelial damage.
High red blood cell and fibrin content, low platelet content evenly distributed.
What is an arterial thrombus?
Usually forms at site of atherosclerosis following plaque rupture.
Lower fibrin content and much higher platelet content.
How does the dug given vary depending on the type and composition of the thrombus?
Platelet rich “white” arterial thrombi - antiplatelet and fibrinolytic drugs.
Lower platelet content “red” venous thrombi -parenteral anticoagulants (heparins..)and oral anticoagulants (warfarin)
A combination of both may be used in some patients often in secondary prevention.
What is particularly important in platelet aggregation?
GPIIB/IIIa surface receptors
How do antiplatelet agents work?
Inhibit platelet aggregation.
Damaged endothelium leads to recruitment of platelets, activation and aggregation at site of injury.
What type of drug is aspirin?
Cyclo-oxygenase inhibitor
How do cyclo-oxygenate inhibitors work?
Potent platelet aggregating agent thromboxane A2 is formed from arachadonic acid by COX-1
Aspirin inhibits COX-1. It reduces TXA2 and inhibits platelet aggregation - irreversible. This only works at a very low (75mg) non-analgesic dose.
How does aspirin work at a higher dose?
Inhibit endothelial prostacyclin (PGI2)- this has a counter effect.
What is the half life of aspirin?
20mins
ADRs of aspirin?
Bleeding time prolonged - haemorrhagic stroke, GI bleeding (peptic ulcer)
What are the indications of aspirin?
Secondary prevention of stroke and TIA if other agents are 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)
Give examples of ADP receptor antagonists
Clopidogrel
Prasugrel
Ticagrelor
How do ADP receptor antagonists work?
Inhibit binding of ADP to P2Y12 receptor which inhibits activation of GPIIb/IIIIa receptors (calcium mediated)
Describe the characteristics of Clopidogrel
Prodrug - hepatic metabolite with a half life of 7-8 hours.
Irreversible inhibitor
Slow onset of action without loading dose - it can be unpredictable in antiplatelet action
Reduces morbidity and mortality post thromboembolic stoke
Reduces secondary events post MI (with aspirin)
Useful for prophylaxis in patients intolerant to aspirin.
Ticagrelor
Is active and has active metabolites
But , more expensive than clopidogrel
Give examples of glycoproteins IIb / IIIa inhibitors
Abiciximab
Tirofiban
Epitifibatide
All given as IV infusion
How do glycoproteins iiB/IIIa inhibitors work?
Predominant platelet integrin culminating in binding of fibrinogen and VWF.
They target the final common pathway - more complete platelet aggregation.
They are all given IV with a bolus.
How does abciximab work?
Antibody irreversibly blocks GPIIb/IIIa receptors preventing fibrinogen from binding.
Results in an 80% reduction in aggregation.
But there is a higher bleeding risk.
What type of drug is epifibatide?
It is a synthetic peptide that binds reversibly.
What type of drug is titofiban?
It is a non-peptide reversible antagonist.
ADRs of Glycorotein iiB?
Thrombocytopenia - need to get the platelet count after several hours.
Give an example of a phosphodiestrase inhibitor
Dipyridamole
How does dipyridamole work?
It inhibits reuptake of adenosine - Increase plasma adenosine - inhibits platelet aggregation via A2 receptors.
Also act as phosphodiesterase inhibitor which prevents cAMP and cGMP degradation. It inhibits expression go GPIIb/IIIa.
It is typically given as modified release with a half life of 12 hours.
.
ADRS of dipyridamole?
Flushing and headache, hypersensitive
When dipyridamole used?
Secondary prevention fo ischaemic strokes and TIAs .
Adjunct to oral anticoagulants for prophylaxis of thromboembolism following valve replacement.
Give examples of fibrinolytic agents
Streptokinase (can only be given once)
Alteplase
Reteplase
Tenecteplase
Tranexamic acid
How do fibrinolytics work?
They dissolve the fibrin meshwork of thrombus
Why does streptokinase only work once?
Only works once because of antigenic effects
Usually
Give an example of a vitamin K antagonists
Warfarin
How does warfarin work?
Inhibits production of vitamin K dependant clotting factors
Stops conversion of vitamin K to active reduced form (inhibits reductase)
Hepatic synthesis of clotting factors II, VII, IX, X all require vitamin K as a cofactors (Ca2+ also a cofactor).
Why is here a delay in action of warfarin?
Delay in onset of action as circulating active clotting factors present for several days.
Must be cleared and replaced with noncarboxylated forms - inactivated clotting factors.
So, give heparin for few days at start
Why is warfarin highly persons pecific?
Racemic mixture and way it is metabolised.
Also functional 2C9 polymorphisms
So, need to measure INR all the time.
When is warfarin used?
DVT prophylaxis PE prophylaxis and treatment AF with high risk of stoke Protein S and C deficiency Following orthopaedic surgery (stasis)
Describe the PK of warfarin
Functional 2C9 polymorphisms contribute to significant individual variability.
Plasma conc. does not correlate directly with clinical effects.
crosses placenta - avoided in 1st (teratogenic) and 3rd (brain haemorrhagic) trimesters.
Response governed by CYP2C9, other drugs, vitamin K intake, coagulation proteins.
Why monitor warfarin?
Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma.
Called International Normalised Ratio (INR).
This allows for standard corrected value comparable across labs.
What is the main ADRs of warfarin? How do you manage it?
BLEEDING!
Most effective antidote is vitamin K1
Prothrombin complex concentrate i.v.
Fresh frozen plasma
And stop warfarin.
Consider the side and severity of the bleeding
What drug-drug interactions are there with warfarin?
Huge number! May potentiate anticoagulation but some decrease effects.
What should INR be?
In healthy people an INR of 1.1 or below is considered normal. An INR range of 2.0 to 3.0 is generally an effective therapeutic range for people taking warfarin for disorders such as atrial fibrillation or a blood clot in the leg or lung.
- 5 - DVT, PE, AF
- 0 - Recurrent DVT or PE in patients currently receiving anticoagulation, mechanical prosthetic valves
How do parenteral anticoagulants work?
(Heparin)
Inhibits the action of coagulation factors by binding to antithrombin III and activating it by causing a conformational change.
How does unfractionated heparin work?
Binding of antithrombin (ATIII) causing conformational change and increase activity,
ATIII inactivates thrombi, factor Xa and others.
It catalyse the inhibition of IIa, heparin needs to simultaneously bind ATIII and IIa.
Xa inhibition only needs ATIII binding.
LMWHs examples
Bempiparin Dalteparin Enoxaparin Reviparin Tinzaparin
LMWHs
Easier to dose than UFH
Made from UFH
Consistent half life
More predictable in response as does not bind to endothelial cells, plasma proteins and macrophages.
Shorter chain
Less monitoring required
Less likely to cause thrombocytopenia
Does not activate thrombin
Targets Xa specifically - less monitoring required.
Compare UFH vs LMWH
Dose response Bioavailability Metabolism Monitoring Administration Initiation Half life Action
Dose response: non linear vs predictable
Bioavailability: Variable vs predictable
Metabolism: Plasma protein binding, depolymerisation, desulphation vs Rapid liver or slower renal excretion
Monitoring: Unpredictable (use PTT) vs no monitoring (mg/kg dosing)
Administration: I.V. vs S.C.
Initiation: I.V. bolus then I.V.I vs OD / BD s.c.
Half life: 30mins low dose / 2hrs high dose vs 2hrs
Action: I.V. infusion fast anticoagulation vs s.c. slower onset.
When are heparin used?
DVT, PE, AF - administered prior to warfarin loading
LMWH typically used
ACS - reducing recurrence or extension of coronary artery thrombosis post MI and NSTEMI.
During pregnancy (not cross placenta)
Prevent venous thromboembolism - perioperative prophylaxis with LMWHs for several days (more convenient).
Describe the ADRs of heparin
Bruising and bleeding
Heparin induced thrombocytopenia (HIT)
Osteoporosis
Hypersensitivity (like warfarin) is rare
How do you reverse heparin?
Protamine sulphate dissociates heparin from ATIII, irreversible binding, lots of positive charges neutralise sulphate i.v. or i.v.i.
Greater effect with UFH than LMWH.
Can be used as antidote to heparin following surgery.
What is fondaparinux?
Syntetic pentasaccharide selectively inhibits Xa by binding to ATIII.
What is apixaban?
DOACs / NOACs
Direct Xa
Inhibits both free Xa and that bound with ATIII, do not effect thrombin (IIa) - hepatic metabolism and excreted partly by the kidneys.
What is arrgatroban?
Direct thrombin inhibitors
Selective direct competitive thrombin inhibitors, both circulating and thrombus bound IIa.
Active metabolites have relatively short half life (30-60mins)
