Anticoagulants Flashcards

(57 cards)

1
Q

What do all anti-coagulant drugs do?

A
  • Prevent thrombus formation and thrombus from growing
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2
Q

What is an endogenous inactivator of many clotting factors?

A
  • Antithrombin III
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3
Q

Why is regulation of the coagulation cascade essential?

A
  • Prevents solidification of all blood
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4
Q

How is the coagulation cascade regulated?

A
  • 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
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5
Q

What are the different types of heparins?

A
  • Unfractionated heparins (large - 7-30 kDa)
  • Low molecular weight heparins (1-6 kDa)
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6
Q

What do heparins do to prevent coagulation?

A
  • Enhance antithrombin III activity
  • To varying degrees
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7
Q

Which clotting factors does heparin inhibit?

A
  • Xa
  • Thrombin IIa
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8
Q

Outline the pharmacokinetics of unfractionated heparins?

A
  • Fast onset of action
  • Half-life is 30 minutes at low dose or 2 hours at higher doses
  • Mixed elimination (unpredictable)
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9
Q

How is unfractionated heparin administered?

A
  • 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
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10
Q

What is the mechanism of action of unfractionated heparin?

A
  • Binds to ATIII increasing its activity
  • Accelerates interaction of antithrombin with thrombin IIa and factor Xa
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11
Q

Give some examples of low molecular weight heparin

A
  • Dalteparin
  • Enoxaparin
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12
Q

How is low molecular weight heparin administered?

A
  • Almost always subcutaneously
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13
Q

Outline the pharmacokinetics/pharmacodynamics of low molecular weight heparin

A
  • Bioavailability >90%
  • Half life is ~2 hours +
  • Typically ~15 polysaccharides which are absorbed more uniformly
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14
Q

What is the mechanism of action of low molecular weight heparins?

A
  • Enhances ATIII activity
  • Inhibits factor Xa
  • Do not inactivate thrombin (LMWH is too short)
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15
Q

What is fondaparinux?

A
  • Synthetic pentasaccharide
  • Selectively inhibits Xa by enhancing ATIII
  • S.c.
  • Half life is 18 hours
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16
Q

Compare the use of UFH vs LMWH

A
  • UFH is used when pt has moderate renal impairment
  • Or when very fine control is needed
  • LMWH can be used in most situations
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17
Q

Compare the metabolism of UFH vs LMWH

A
  • UFH is dose dependent
  • Protein binding, depolymerisation, desulfation (1st and 0 order)
  • LMWH exhibits rapid or slower renal excretion
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18
Q

Compare the monitoring of UFH vs LMWH

A
  • UFH is unpredictable - monitor with activated partial thromboplastin time (dosed in standard units)
  • LMWH generally doesn’t need monitoring (U/kg dosing)
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19
Q

What are some indications for use of heparins and fondaparinux?

A
  • Prevention of VTE e.g. perioperative prophylaxis with LMWH
  • DVT and PE
  • Acute coronary syndromes with DAPT
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20
Q

Can heparins be given during pregnancy?

A
  • Yes
  • Do not cross placenta
  • Monitor with caution
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21
Q

Outline how heparins are used to treat DVT and PE

A
  • Given as the initial treatment prior to oral agents in some
  • Given long-term in some patient groups
  • Treat cancer related VTE
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22
Q

Outline how heparins are used to treat ACS

A
  • 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
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23
Q

What are some adverse drug reactions of heparins?

A
  • Bruising and bleeding
  • E.g. intracranial, at site of injection, GI, epistaxis
  • Heparin induced thrombocytopenia
  • Hyperkalaemia (inhibition of aldosterone secretion)
  • Osteoporosis (rare)
24
Q

What is heparin induced thrombocytopenia?

A
  • Autoimmune response - normally delayed
  • Antibodies to heparin platelet factor 4 complex
  • Depletion of platelets
  • Results in thrombosis
25
What are some contraindications of heparins?
- Clotting disorders - Renal impairment (LMWH and fondaparinux)
26
What are some DDIs of heparin?
- Other antithrombotic drugs - ACEi/ARB - K+ sparing diuretics
27
How is UFH monitored?
- Activated partial thromboplastin time (aPTT) when using therapeutic i.v. doses of UFH - Dose is titrated/adjusted against this value
28
How is LMWH monitored?
- Much more predictable in its action - Requires little monitoring
29
How do we reverse heparin's action?
- Protamine sulphate
30
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
31
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
32
Which clotting factors require vitamin K for their synthesis?
- II, VII, IX, X
33
Give an example of a vitamin K antagonist
- Warfarin
34
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)
35
What is the half life of warfarin?
- 36-48 hours
36
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
37
How do we compensate for the slow onset of action of warfarin?
- Heparin cover if anticoagulation is needed immediately
38
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
39
What affects a patient's response to warfarin?
- CYP2C9 polymorphisms contribute to significant inter individual variability - Vitamin K intake - Alcohol
40
What are the contraindications of warfarin?
- Crosses placenta - Avoid in early post-partum period and following haemorrhagic stroke
41
What are the adverse side effects of warfarin?
- Bleeding - Epistaxis - Spontaneous retroperitoneal bleeding
42
How do we reverse the action of warfarin?
- Give vitamin K1 - Prothrombin complex concentrate i.v. - Stop warfarin
43
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
44
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
45
What does high INR mean?
- More blood anticoagulated
46
What does low INR mean?
- Less blood anticoagulated
47
Why does Warfarin require monitoring?
- Huge variation in patient response - Keeping diet and lifestyle/medications stable is important
48
What is INR?
- International normalised ratio - Clotting time measured against a standard - Allows for standard corrected value comparable across all laboratories
49
Give some examples of direct Xa DOACs
- Apixaban - Edoxaban - Rivaroxaban
50
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
51
Give an example of a direct IIa DOAC?
- Dabigatran
52
What is the mechanism of action of direct IIa DOACs?
- Selective direct competitive thrombin inhibitor - Affects both circulating and thrombus bound thrombin (IIa)
53
What are the benefits of DOACs?
- Oral administration - Standard dosing - Little direct monitoring required
54
Why might we choose to use warfarin over DOACs?
- Requires patient monitoring - Improves adherence - An excuse to monitor patient and check INR
55
What are the adverse side effects of DOACs?
- Bleeding - Skin reactions - Caution in GI bleed risk groups
56
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
57
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