Anticoagulants Flashcards
What do all anti-coagulant drugs do?
- Prevent thrombus formation and thrombus from growing
What is an endogenous inactivator of many clotting factors?
- Antithrombin III
Why is regulation of the coagulation cascade essential?
- Prevents solidification of all blood
How is the coagulation cascade regulated?
- Coagulation factors are present in the blood as zymogens
- Lots of intrinsic inhibitors of this pathway incl. antithrombin III
- Vascular endothelium regulates many mediators critical for balance in coagulation cascade
- Ca2+ is an important co-factor
What are the different types of heparins?
- Unfractionated heparins (large - 7-30 kDa)
- Low molecular weight heparins (1-6 kDa)
What do heparins do to prevent coagulation?
- Enhance antithrombin III activity
- To varying degrees
Which clotting factors does heparin inhibit?
- Xa
- Thrombin IIa
Outline the pharmacokinetics of unfractionated heparins?
- Fast onset of action
- Half-life is 30 minutes at low dose or 2 hours at higher doses
- Mixed elimination (unpredictable)
How is unfractionated heparin administered?
- I.V. bolus and infusion
- Given s.c. for prophylaxis with low bioavailability
- I.V. administration allows us to tightly control administration - can easily stop infusion
What is the mechanism of action of unfractionated heparin?
- Binds to ATIII increasing its activity
- Accelerates interaction of antithrombin with thrombin IIa and factor Xa
Give some examples of low molecular weight heparin
- Dalteparin
- Enoxaparin
How is low molecular weight heparin administered?
- Almost always subcutaneously
Outline the pharmacokinetics/pharmacodynamics of low molecular weight heparin
- Bioavailability >90%
- Half life is ~2 hours +
- Typically ~15 polysaccharides which are absorbed more uniformly
What is the mechanism of action of low molecular weight heparins?
- Enhances ATIII activity
- Inhibits factor Xa
- Do not inactivate thrombin (LMWH is too short)
What is fondaparinux?
- Synthetic pentasaccharide
- Selectively inhibits Xa by enhancing ATIII
- S.c.
- Half life is 18 hours
Compare the use of UFH vs LMWH
- UFH is used when pt has moderate renal impairment
- Or when very fine control is needed
- LMWH can be used in most situations
Compare the metabolism of UFH vs LMWH
- UFH is dose dependent
- Protein binding, depolymerisation, desulfation (1st and 0 order)
- LMWH exhibits rapid or slower renal excretion
Compare the monitoring of UFH vs LMWH
- UFH is unpredictable - monitor with activated partial thromboplastin time (dosed in standard units)
- LMWH generally doesn’t need monitoring (U/kg dosing)
What are some indications for use of heparins and fondaparinux?
- Prevention of VTE e.g. perioperative prophylaxis with LMWH
- DVT and PE
- Acute coronary syndromes with DAPT
Can heparins be given during pregnancy?
- Yes
- Do not cross placenta
- Monitor with caution
Outline how heparins are used to treat DVT and PE
- Given as the initial treatment prior to oral agents in some
- Given long-term in some patient groups
- Treat cancer related VTE
Outline how heparins are used to treat ACS
- Dual antiplatelet therapy
- Given short term
- Reduce recurrence/extension of coronary artery thrombosis post STEMI
- UFH is given during percutaneous coronary intervention
- Fondaparinux given following NSTEMI
What are some adverse drug reactions of heparins?
- Bruising and bleeding
- E.g. intracranial, at site of injection, GI, epistaxis
- Heparin induced thrombocytopenia
- Hyperkalaemia (inhibition of aldosterone secretion)
- Osteoporosis (rare)
What is heparin induced thrombocytopenia?
- Autoimmune response - normally delayed
- Antibodies to heparin platelet factor 4 complex
- Depletion of platelets
- Results in thrombosis
What are some contraindications of heparins?
- Clotting disorders
- Renal impairment (LMWH and fondaparinux)
What are some DDIs of heparin?
- Other antithrombotic drugs
- ACEi/ARB
- K+ sparing diuretics
How is UFH monitored?
- Activated partial thromboplastin time (aPTT) when using therapeutic i.v. doses of UFH
- Dose is titrated/adjusted against this value
How is LMWH monitored?
- Much more predictable in its action
- Requires little monitoring
How do we reverse heparin’s action?
- Protamine sulphate
How does protamine sulphate work?
- Forms an inactive complex with heparin
- Given IV
- Dissociates heparin from AT III
- Irreversible binding
- Much greater effect with UFH than LMWH
- No effect on fondaparinux
Outline the mechanism of action of vitamin K antagonists
- Inhibition activation of vitamin K dependant clotting factors
- Inhibits conversion of vitamin K to active reduced form
- Hepatic synthesis of certain clotting factors requires vitamin K as a co-factor for activation
Which clotting factors require vitamin K for their synthesis?
- II, VII, IX, X
Give an example of a vitamin K antagonist
- Warfarin
Why is there a delay in onset of action of warfarin?
- Circulating active clotting factors are present for several days
- Must be cleared and replaced with non-carboxylated forms (inactive clotting factors)
What is the half life of warfarin?
- 36-48 hours
What are some indications for use of warfarin?
- VTE
- PE
- DVT and secondary prevention
- AF patients where DOAC not suitable or already taking warfarin
- Heart valve replacement
How do we compensate for the slow onset of action of warfarin?
- Heparin cover if anticoagulation is needed immediately
What are the pharmacokinetics of warfarin?
- Good GI absorption
- 95% bioavailability when taken orally
- Plasma concentration does not correlate directly with clinical effect
- Mixture of two enantiomers which are metabolised differently
What affects a patient’s response to warfarin?
- CYP2C9 polymorphisms contribute to significant inter individual variability
- Vitamin K intake
- Alcohol
What are the contraindications of warfarin?
- Crosses placenta
- Avoid in early post-partum period and following haemorrhagic stroke
What are the adverse side effects of warfarin?
- Bleeding
- Epistaxis
- Spontaneous retroperitoneal bleeding
How do we reverse the action of warfarin?
- Give vitamin K1
- Prothrombin complex concentrate i.v.
- Stop warfarin
When do we need to stop warfarin?
- Perioperative anticoagulation needs to be considered
- Specific patient group and local guidelines will dictate
- Bridging therapy with LMWH often required when initiating or temporarily stopping warfarin
What are the DDIs of warfarin?
- Drugs that inhibit hepatic metabolism, especially CYP2C9
- E.g. amiodarone, clopidogrel, intoxicating dose of alcohol
- NSAIDs and drugs that decrease GI absorption of vitamin K - displace warfarin from plasma albumin
- Barbiturates, phenytoin, rifampicin, St Johns Wort - accelerate warfarin metabolism
What does high INR mean?
- More blood anticoagulated
What does low INR mean?
- Less blood anticoagulated
Why does Warfarin require monitoring?
- Huge variation in patient response
- Keeping diet and lifestyle/medications stable is important
What is INR?
- International normalised ratio
- Clotting time measured against a standard
- Allows for standard corrected value comparable across all laboratories
Give some examples of direct Xa DOACs
- Apixaban
- Edoxaban
- Rivaroxaban
What is the mechanism of action of direct Xa DOACs?
- Inhibit both free Xa and Xa bound with ATIII
- Do not directly affect thrombin (IIa)
- Metabolised by liver
- Excreted partly by kidneys
Give an example of a direct IIa DOAC?
- Dabigatran
What is the mechanism of action of direct IIa DOACs?
- Selective direct competitive thrombin inhibitor
- Affects both circulating and thrombus bound thrombin (IIa)
What are the benefits of DOACs?
- Oral administration
- Standard dosing
- Little direct monitoring required
Why might we choose to use warfarin over DOACs?
- Requires patient monitoring
- Improves adherence
- An excuse to monitor patient and check INR
What are the adverse side effects of DOACs?
- Bleeding
- Skin reactions
- Caution in GI bleed risk groups
What are the contraindications of DOACs?
- Dabigatran contraindicated in low creatine clearance
- Others are contraindicated at very low creatine clearance
- Avoid in pregnancy and breastfeeding
What are the DDIs of DOACs?
- Less frequent interactions than warfarin but affected by CYP inhibitors and inducers
- Plasma concentrations reduced by carbamazepine, phenytoin and barbiturates
- Plasma concentrations increased by macrolides
