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Clinical Pharmacology > 11.2 Anticoagulants > Flashcards

11.2 Anticoagulants Flashcards

1
Q

How does haemostasis limit bleeding following injury?

A

adhesion and activation of platelets and fibrin formation

haemostatic plug + fibrin mesh → stable bleeding control

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2
Q

What is thrombosis?

A

pathological haemostasis – blood clot formation in the absence of bleeding

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3
Q

What are some common thromboembolic diseases?

A
  • deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • transient ischaemic attacks (TIA), ischaemic stroke
  • myocardial infarction (MI)
  • consequence of atrial fibrillation (AF)
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4
Q

How do venous and intracranial thromboses vary from arterial thromboses?

A

Venous and intracardiac thromboses = red thrombus, driven largely by coagulation cascade and fibrin
Arterial thrombus = white thrombus that is platelet rich

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5
Q

What is the function of anticoagulant drugs?

A

prevent thrombus formation and thrombus growing

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6
Q

What are the 2 pathways within the coagulation cascade?

A

Extrinsic pathway = exposure of tissue factor to blood on the surface of the sub endothelium after vascular injury. Leads to rapid coagulation of blood within a couple minutes.

Intrinsic pathway = triggered when blood comes in contact with a negative charge such as collagen in the subendothelium. Activation takes longer

Both converge on the common pathway on the step from prothrombin II to thrombin IIa

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7
Q

How is the coagulation cascade inhibited?

A

Coagulation factors are present in blood as zymogens

Number of intrinsic inhibitors of this pathway including antithrombin III (AT-III), protein C and protein S

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8
Q

Give examples of genetically determined haemophilias?

A

Classic haemophilia = lack of factor 8
haemophilia B = lack of factor 9
Treated with adding in clotting factors .

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9
Q

How do blue topped blood bottles and purple topped blood bottle differ?

A

Purple top - contains EDTA - a calcium collator, collates the calcium so no longer free to be a cofactors in the clotting cascade so the blood can no longer clot.

Blue top = citrate tube. Citrate also a calcium collator. Difference is that the reaction is reversible, so calcium can be added back so can later test clotting of blood.

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10
Q

How are heparin pharmalogically produced?

A

Extracted for pharmaceutical use from porcine intestinal mucosa (less so now - bovine lung)

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11
Q

Where are heparins naturally produced in the body

A

Mast cells and vascular endothelium

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12
Q

What is the difference between unfractionated heparin and low molecular weight heparin?

A

Unfractionated heparins are very large (45 polysaccharides) and therefore harder to administer
LMWH are much smaller -only 15 polysaccharides

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13
Q

What is the function of heparins?

A

Inhibit coagulation in vitro and in vivo

- Enhance antithrombin III (AT-III) activity - ~ 1000-fold

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14
Q

Where in the coagulation cascade does heparin have its affects?

A

Forms a heparin antithrombin complex which acts on factor Xa and thrombin IIa predominantly
LMWH-antithrombin complex mainly acts on the factor Xa

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15
Q

Why is it important to consider the pharmacokinetics of unfractionated heparin?

A

Does not have 1st order kinetics. Has mixed elimination around the body so the half life is unpredictable.
At low dose the onset of action is fast as the T1/2 is 30 min, at higher doses can be 2hours.

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16
Q

How is unfractionated heparin usually given?

A

Typically by an IV bolus followed by infusion

Can be given s.c. For prophylaxis with low bioavailability

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17
Q

What is the mechanism of action of unfractionated heparin?

A

Binding to antithrombin (ATIII) causing conformational change and increased activity of ATIII
To catalyse inhibition of thrombin (IIa), heparin needs to simultaneously bind ATIII AND IIa.
Xa inhibition only needs ATIII binding

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18
Q

Give examples of low weight molecular heparins?

A

Dalteparin

Enoxaparin

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19
Q

How are LMWH dosed?

A

Dosed in units per kg dosing.

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20
Q

How is LMWHs administered?

A

Subcutaneously

Enoxaparin can be IV in some acute coronary syndrome settings

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21
Q

Why are LMWHs easier to use than unfractionated heparins?

A

As easier to administer, and can be given subcutaneously
absorbed more uniformly as does not bind to endothelial cells, plasma proteins and macrophages as not large enough.
Has a larger bioavailability

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22
Q

What is the mechanism of action of dalteparin?

A
  • Do not inactivate thrombin (IIa) – not long enough

* Inhibition of Xa specifically – by enhancing ATIII activity

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23
Q

What is fondoparinux?

A

synthetic made pentasaccharide that selectively inhibits Xa by binding to ATIII (similar to LMWH action). Given s.c., longer half life of t1/2 18h

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24
Q

Why arent heparins given orally?

A

As have very poor bioavailability through the gut. Has poor GI absorption as are large negatively charged molecules. Needs to be given parentally.

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25
Q

Do patients on heparins need to be monitored?

A

Only if on unfractionated heparin. Metabolism is unpredictable – monitor with activated partial thomboplastin time (aPTT). LWMH is more predictable and generally doesn’t need monitoring.

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26
Q

What are the common indications of unfractionated heparins?

A

Moderate renal impairment and v. fine control

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27
Q

What are the common indications of LMWH

A

Most settings -
prevention of venous thromboembolism
perioperative prophylaxis with LMWH - duration and dose is dependant on risk
Used during pregnancy as do not cross the placenta.
VTE – DVT and PE
initial treatment prior to oral agents
Long term in some patient groups
Cancer related VTE
Acute Coronary Syndromes (ACS)
short term - reducing recurrence and or extension of coronary artery thrombosis post STEMI - PCI and non PCI patients
NSTEMI

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28
Q

What are the adverse drug reactions of heparin?

A

Bruising and bleeding
Intracranial, at site of injection, GI, epistaxis
Heparin induce thrombocytopenia (HIT) (~1/100 – UFH vs. ~ 1/1000 LMWH) autoimmune response 2-14 days after initiation of heparin
Hyperkalaemia - inhibition of aldosterone secretion
Osteoporosis - rare long-term use, higher risk with UFH and more prevalent in pregnancy

29
Q

What are the contraindications of heparins?

A

Clotting disorders, renal impairment (LMWH and fondaparinux as renally excreted)

30
Q

What are the drug-drug interactions of heparins?

A

Other antithrombotic drugs, ACEi/ARB + spionolactone

31
Q

As the metabolism and elimination of unfractionated heparin is unpredicatable, how do we guide dosing?

A

By heparin monitoring. Monitor the activated partial thromboplastin time (aPTT) when using therapeutic doses of UFH. This measures the clotting ability of the intrinsic pathway and common pathway. Dose is then titrated/adjusted against the value.

32
Q

If a patient has overdosed on heparin, how do we treat it?

A

Protamine sulphate

33
Q

What is the mechanism of action of protamine sulphate?

A

Protamine sulphate forms inactive complex with heparin – given i .v. dissociates heparin from ATIII, irreversible binding

amount given guided by heparin dose

34
Q

What drug class is warfarin?

A

Vitamin k antagonist

35
Q

What is the mechanism of action of warfarin?

A

Competitively inhibits vitamin K epoxied reductase (VKOR) Inhibits conversion of vitamin K epoxide to active reduced form.
Inhibit activation of vitamin K dependant clotting factors - factors 2,7 9 and 10. (koagulation vitamin)

36
Q

Why does it take several days for anticoagulation to occur when taking warfarin?

A

Delay in onset of action as circulating active clotting factors present for several days
- Must be cleared and replaced with non carboxylated forms (inactive clotting factors)

37
Q

What is the normal half life of warfarin?

A

36 to 48 hours

38
Q

What are the common indications of warfarin?

A

Venous thromboembolism
PE
DVT and secondary prevention
Superficial vein thrombosis
Atrial fibrillation with high risk of stroke
Cardioversion
Heart valve replacement bio prosthetic and some mechanical

39
Q

How do we assess likelihood of stroke in a patient with atrial fibrillation?

A

use CHA2DS2Vasc

  • cardiovascular failure, hypertension, age x 2, diabetes, previous stroke x2, vascular disease
  • scored out of 9. The higher the score the greater likelihood of a future stroke
40
Q

What is meant by cardioversion?

A

When an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm using electricity or drugs.

41
Q

Why might heparin and warfarin be used together?

A

Warfarin is generally used in longer term anticoagulation but has a slower onset of actions than heparins. Therefore LMWH may be used initially if anticoagulation needed immediately before using warfarin.
Bridging therapy with LMWH often required when initiating or temporarily stopping warfarin (surgery/sickness)

42
Q

How is warfarin taken?

A

Taken orally as has very good GI absorption.

43
Q

Why does a patient on warfarin need monitoring?

A

As warfarin has very complicated pharmokinetics

  • Functional CYP2C9 polymorphisms contribute to significant inter individual variability
  • [Plasma] does not correlate directly with clinical effect
  • Warfarin is a racemic mixture of two enantiomers – R and S which have different potency and metabolised differently
  • vitamin K intake fluctuations and chronic alcohol intake affect warfarin effectiveness.
44
Q

Why should warfarin not be taken during pregnancy?

A

As it crosses the placenta

  • in first trimester is teratogenic
  • in third trimester increases the risk of haemorrhage
45
Q

What are the contraindications of warfarin?

A

Pregnancy

Hepatic disease

46
Q

What foods need to be regulated when taking warfarin?

A

Foods high in potassium

- bananas, asparagus, broccoli, cabbage, green beans, cucumber, celery

47
Q

What are the ADR of warfarin?

A

Principle ADR is bleeding – a patient taking warfarin is always of clinical interest. Epistaxis and spontaneous retroperitoneal bleeding
Increased risk of intracranial bleeds than DOAC

48
Q

How is warfarin overdose treated?

A

Most effective antidote is vitamin K1
addition of prothrombin complex concentrate i .v.
Stop warfarin!

49
Q

What is INR?

A

international normalised ratio – INR - clotting time against a standard

50
Q

What are some of the drug-drug interactions of warfarin?

A

High INR
-Inhibition of hepatic metabolism especially CYP2C9 e.g Amiodarone, clopidogrel, intoxicating dose of alcohol
- Reduce vitamin K by eliminating gut bacteria involved in production e.g. cephalosporin antibiotics
- Displacement of warfarin from plasma albumin
NSAIDs and drugs that decrease GI absorption of vitamin K

Low INR
- Acceleration of warfarin metabolism
barbiturates, phenytoin, rifampicin, St Johns Wort

51
Q

What coagulation factors are measured when testing INR?

A

Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma

52
Q

What is the desired INR in patients that have experienced a DVT, PE or AF?

A 
INR = 2.5 
INR = 3 -3.5 in recurrent DVT or PE in patients currently receiving anticoagulation.
53
Q

What drug class is apixaban?

A

A direct acting Xa anticoagulant.

54
Q

What is the mechanism of action of direct acting Xa oral anticoagulants?

A

Inhibit both free Xa and that bound with ATIII, do not directly effect thrombin (IIa)

55
Q

What is the pharmokinetics of direct acting anticoagulants?

A

hepatic metabolism and excreted partly by kidneys

56
Q

What is the mechanism of action of dabigatran?

A

Selective direct competitive thrombin inhibitor, both circulating and thrombin bound IIa

57
Q

What drug class is dabigatran?

A

A direct oral IIa anticoagulant

58
Q

Why is the administration of direct oral anticoagulants easier than other anticoagulants?

A

Taken via oral administration, unlike heparin

Standard dosing and no direct monitoring required, unlike warfarin

59
Q

Why is monitoring patients on DOAC sometimes useful?

A

Although not required for dosing, can be useful for patient heck ups and to ensure adherence to the medication

60
Q

What are the ADRs of direct acting oral anticoagulants?

A

Bleeding

Caution and dose adjustments particularly in GI bleed risk groups

61
Q

What are the contraindications of DOACs?

A

dabigatran contraindicated in low creatinine clearance (<30 mL/min)
others are at very low creatinine clearance (<15 mL/min)
Little information on use in pregnancy and breastfeeding – avoid

62
Q

What are the important drug-drug interactions of DOACs?

A

Less frequent interactions than warfarin but affected by CYP inhibitors and inducers
[plasma] reduced by carbamazepine, phenytoin and barbiturates
[plasma] increased by macrolides

63
Q

Give examples of DOAC antidotes

A 
Adexanet = Xa antidote
Idarucizumab = IIa antidote
64
Q

Describe the difference in route of administration of heparins and associated durations of action

A

Unfractionated = given I.V bolus and infusion. Short T1/2 of 30min to 2hour depending on dosage

LMWH = almost always given subcutaneously. Longer half life of over 2 hours

65
Q

Which coagulation factors do heparins inhibit?

A

Thrombin (IIa)

Factor Xa

66
Q

Why is heparin prescribed along side warfarin?

A

As warfarin takes a long time to act as activated clotting factors are circulating in the blood and must be cleared and replaced with the non-carboxylated forms. Heparin has a fast onset of action as inhibits the activated forms, so may be used until the warfarin can begin to take effect.

67
Q

Why is INR monitoring required for patients taking warfarin?

A

Due to its complicated pharmokinetics.

  1. Warfarin action affected by lifestyle such as vitamin K intake and alcohol consumption
  2. Functional CYP2CP polymorphisms contribute to significant inter individual variability
  3. Warfarin is a racemic mixture of two enantiomers – R and S which have different potency and metabolised differently
68
Q

Which of the DOACs is a direct thrombin inhibitor?

A

Dabigatran

69
Q

When would warfarin be more appropriate than a DOAC?

A

In patients with compromised renal function.

Patients that require regular monitoring

Clinical Pharmacology (26 decks)

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