Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 22- Anticoagulants > Flashcards

Lecture 22- Anticoagulants Flashcards

1
Q

Haemostasis

A
  • Limits bleeding following injury- adhesion and activation of platelets and fibrin formation
    • Haemostatic plug + fibrin mesh= stable bleeding control
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Thrombosis=

A

pathological haemostasis – in the absence of bleeding (things have gone wrong)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Thromboembolic disease is common

A
  • deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • transient ischaemic attacks (TIA), ischaemic stroke - myocardial infarction (MI)
  • consequence of atrial fibrillation (AF)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Venous and intracardiac thrombosis driven largely by

A

coagulation cascade and fibrin compared to arterial thrombus - mainly platelet rich

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

the coagulation cascade

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Anticoagulant drugs

A

prevent thrombus formation and thrombus growing

  • by regulating the coagulation cascade preventing solidification of all blood
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Coagulation factors are present in blood as

A

zymogens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

name an intrinsic inhibitor of the coagulation cascade

A

antithrombin III (AT-III)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

key contributors tot he regulation of the coagulation cascade

A
  • Number of intrinsic inhibitors of this pathway including antithrombin III (AT-III)
  • Vascular endothelium and its regulation of many mediators also critical for balance in coagulation cascade (and platelet activation)
  • Calcium is an important cofactor in many of the coagulation cascade steps (think of chelators used in blood tubes)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

name some anticoagulants

A
  • Heparins
  • Warfarin
  • Direct oral anticoagulants (DOACS)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

heparins are produced naturally in

A

mast cells and vascular endothelium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

production of heparins

A
  • Extracted for pharmaceutical use from porcine intestinal mucosa (less so now - bovine lung)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

types of heparin

A
  • Unfractionated heparins (UFH) are large ~7-30 kDa
  • Low molecular weight heparins (LMWH) ~1-6 kDa produced in 1980’s
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

basic MOA of heparins

A
  • Enhance antithrombin III (AT-III) activity - ~ 1000-fold
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Indications for use of heparins

A
  • Prevention of venous thromboembolism
    • perioperative prophylaxis with LMWH - duration and dose is dependant on risk
  • During pregnancy used as do not cross placenta – monitored with caution
  • Venous Thromboembolism (VTE)–DVT and PE
    • initial treatment prior to oral agents (see later slides)
    • Long term in some patient group
    • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Unfractionated heparin (UFH) pharmacokinetics

A
  • ~ 45 polysaccharide unit mixture
    • fast onset of action t1/2 30min low dose
    • 2h at higher doses – mixed elimination so is unpredictable
  • Typically i.v. bolus and infusion, s.c. for prophylaxis with low bioavailability
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Unfractionated heparin (UFH) Mode of action

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

name some low molecular weight heparins (LMWH)

A
  • dalteparin, enoxaparin, fondaparinux
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Low molecular weight heparins (LMWH) Pharmacokinetics

A
  • Typically ~ 15 polysaccharides which are absorbed more uniformly (units/kg dosing)
  • Almost always s.c. (enoxaparin i.v. in ACS)
  • Bioavailability > 90%, longer t1/2 ~ 2+h
  • More predictable dose response as does not bind to endothelial cells, plasma proteins and macrophages – it isn’t long enough
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

LMWH MOA

A
  • Do not inactivate thrombin (IIa) – not long enough
  • Inhibition of Xa specifically – by enhancing ATIII activity
  • Fondaparinux – synthetic pentasaccharide selectively inhibits Xa by binding to ATIII – s.c., t1/2 18h
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

unfractionated heparin vs LMWH

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

when are UFH used

A

moderate renal impairment and v.fine control

23
Q

when are LMWH used

A

most situations

24
Q

Adverse drug reaction

A
  • Bruising and bleeding (most common)
    • Intracranial
    • Site of injection
    • GI
    • Epistaxis
  • Heparin induce thrombocytopenia (HIT)
    • Autoimmune response 2-14 days after initiation of heparin
      • Antibodies to heparin platelet factor 4 complex produced
      • Depletion of platelets
      • but paradoxically can lead to thrombosis as more platelets activated by damaged endothelium
  • Hyperkalaemia- inhibition of aldosterone secretion
  • Osteoporosis- rare long-term use, higher risk with UFH and more prevalent in pregnancy (least common)
25
Q

heparin Contraindications

A
  • Clotting disorder
  • Renal impairment (LMWH and fondaparinux)
26
Q

heparin drug-drug interactions

A
  • Antithrombotic drugs
  • ACEi/ARB
  • Spironolactone
27
Q

Heparin monitoring and reversal

A
  • (activated) partial thomboplastin time (aPTT) when using therapeutic i.v. doses of UFH required – dose titrated/adjusted against this value
  • LMWH much more predictable in its action so normally requires little monitoring
28
Q

heparin reversal agents:

A
  • Protamine sulphate forms inactive complex with heparin – given i.v. dissociates heparin from ATIII, irreversible binding amount given guided by heparin dose
    • Paradoxically can cause bleeding!?
    • Much greater effect with UFH than LMWH, no affect on fondaparinux
29
Q

name the vitamin k antagonist

A

warfarin

30
Q

warfarin uses

A
  • Venous thromboembolism
  • PE
  • DVT (and secondary prevention Superficial vein thrombosis)
  • Atrial fibrillation with high risk of stroke (use CHA2DS2Vasc)
  • Patients who need cardioversion
  • Heart valve replacement bio prosthetic and some mechanical
  • Generally used in longer term anticoagulation compared to heparins
  • Slow onset of action likely to require heparin cover (see later slides) if anticoagulation needed immediately
31
Q

Pharmacokinetics of warfarin

A
  • Good GI absorption and taken orally ~95+% bioavailability
  • 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
32
Q

How is warfarin different to heparin

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)
  • Half life= 36-48h (some variation)
33
Q

MOA

A
  • Inhibit activation of vitamin K dependant clotting factors (coagulation vitamin)
  • Inhibits conversion of vitamin K to active reduced form – competitive inhibition of VKOR
  • Hepatic synthesis of clotting factors II, VII, IX and X requires vitamin K as cofactor for activation
34
Q

warfarin adverse drug reaction

A
  • Bleeding- any pt taking warfarin are of clinical interest
    • Epistaxis and spontaneous retroperitoneal bleeding
35
Q

warfarin antidote

A
  • Most effective antidote is vitamin K1
    • addition of prothrombin complex concentrate i.v. Stop warfarin!
36
Q

warfarin Contraindications

A
  • Pregnancy
    • Crosses the placenta
    • Avoided at least in 1st (teratoegnic) and 3rd (haemorrhage) trimesters
  • Hepatic disease
  • Response affected by CYP2C9
  • Perioperative anticoagulation needs to be considered – need to consider if and when to pause warfarin specific patient group and local guidelines will dictate
    • Bridging therapy with LMWH often required when initiating or temporarily stopping warfarin (surgery, sickness…)
37
Q

drug drug interaction warfarin

A

Drug-drug reaction (huge number- potentiate anticoagulant effect, but some decrease)

  • Vitamin K intake e.g. fluctuating amount of green vegetable e.g. broccoli, cucumber
  • Changes to gut bacteria e.g. cephalosporin antibiotic (reduces vitamin K)
  • Alcohol
  • Inhibition of CYP29C9 e.g. clopidogrel, alcohol, amiodarone
  • Displacement of warfarin from plasma albumin by NSAIDS and drugs that decrease GI absorption of vitamin K
    • Likely increase INR (more anticoagulated)
  • Accelerated warfarin metabolism by inducers e.g. barbiturates, phenytoin, rifampicin, St Johns Wort
    • Decrease INR- less anticoagulation
38
Q

Warfarin use and INR

A
  • Monitoring required due to huge variation in patient response
  • Keeping diet and lifestyle/medications stable is important
  • Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma
  • Referred to as international normalised ratio – INR - clotting time against a standard
    • Allows for standard corrected value comparable across all laboratories
39
Q

which factor is most sensitive to vitamin K deficiency

A
  • Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma
40
Q

aiming for an INR of 2.5

A
  • DVT
  • PE
  • AF (risk
41
Q

aiming for an INR of 3.0 - 3.5

A

Recurrent DVT or PE in patients currently receiving anticoagulation

42
Q

people on warfarin carry

A

Carry Anticoagulant card- risk of internal bleeding e.g. after fall or crash

43
Q

High INR=

A

more anticoagulated

44
Q
A
45
Q

Low INR

A

less anticoagulated

46
Q

INR stands for

A

international normalised ratio

47
Q

DOAC

A
  • Direct acting oral anticoagulants (DOAC)
    • May see described as NOAC but DOAC internationally preferred
48
Q

name some DOACs

A
  • Direct Xa acting drugs
    • Apixaban
    • Edoxaban
    • Rivaroxaban
      • Inhibit both free Xa and that bound with ATIII, do not directly effect thrombin (IIa) - hepatic metabolism and excreted partly by kidneys
  • Direct IIa acting drug
    • Dabigatran
      • Selective direct competitive thrombin inhibitor, both circulating and thrombus bound IIa
49
Q

NOAC adminstration

A
  • Oral administration, standard dosing and little to no direct monitoring required
    • When would monitoring be beneficial? E.g. where adherence isn’t good
50
Q

DOAC indications

A
  • Different DOACs are indicated in many presentations where vitamin K antagonists (warfarin) used to be the only option
  • Antidotes now available
    • Andexanet and idarucizumab
51
Q

ADR DOAC

A

ADR

  • Bleeding (lower intracranial bleed risk compared to warfarin)
  • Caution and dose adjustment separately in GI bleed risk groups
52
Q

DOAC Contraindications

A
  • Metabolism and elimination by several routes
  • X 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
53
Q

Drug drug interaction

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

Clinical Pharmacology, Therapeutics & Intro to Prescribing (39 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions