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
2
Q
Thrombosis=
A
pathological haemostasis – in the absence of bleeding (things have gone wrong)
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)
4
Q
Venous and intracardiac thrombosis driven largely by
A
coagulation cascade and fibrin compared to arterial thrombus - mainly platelet rich
5
Q
the coagulation cascade
A
6
Q
Anticoagulant drugs
A
prevent thrombus formation and thrombus growing
- by regulating the coagulation cascade preventing solidification of all blood
7
Q
Coagulation factors are present in blood as
A
zymogens
8
Q
name an intrinsic inhibitor of the coagulation cascade
A
antithrombin III (AT-III)
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)
10
Q
name some anticoagulants
A
- Heparins
- Warfarin
- Direct oral anticoagulants (DOACS)
11
Q
heparins are produced naturally in
A
mast cells and vascular endothelium
12
Q
production of heparins
A
- Extracted for pharmaceutical use from porcine intestinal mucosa (less so now - bovine lung)
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
14
Q
basic MOA of heparins
A
- Enhance antithrombin III (AT-III) activity - ~ 1000-fold
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
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
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
18
Q
name some low molecular weight heparins (LMWH)
A
- dalteparin, enoxaparin, fondaparinux
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
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
21
Q
unfractionated heparin vs LMWH
A
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
- 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 (least common)
25
**heparin Contraindications**
* Clotting disorder
* Renal impairment (LMWH and fondaparinux)
26
**heparin drug-drug interactions**
* Antithrombotic drugs
* ACEi/ARB
* Spironolactone
27
**Heparin monitoring and reversal**
* (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
**heparin reversal agents:**
* **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
name the vitamin k antagonist
warfarin
30
warfarin uses
* 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
**Pharmacokinetics of warfarin**
* 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
**How is warfarin different to heparin**
* 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
**MOA**
* 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
warfarin a**dverse drug reaction**
* Bleeding- any pt taking warfarin are of clinical interest
* Epistaxis and spontaneous retroperitoneal bleeding
35
**warfarin antidote**
* Most effective antidote is vitamin K1
* addition of prothrombin complex concentrate i.v. Stop warfarin!
36
**warfarin Contraindications**
* 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
drug drug interaction warfarin
**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
**Warfarin use and INR**
* 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
which factor is most sensitive to vitamin K deficiency
* Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma
40
aiming for an INR of 2.5
* DVT
* PE
* AF (risk
41
aiming for an INR of 3.0 - 3.5
Recurrent DVT or PE in patients currently receiving anticoagulation
42
people on warfarin carry
Carry Anticoagulant card- risk of internal bleeding e.g. after fall or crash
43
High INR=
more anticoagulated
44
45
Low INR
less anticoagulated
46
INR stands for
international normalised ratio
47
DOAC
* Direct acting oral anticoagulants (DOAC)
* May see described as NOAC but DOAC internationally preferred
48
name some DOACs
* **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
NOAC adminstration
* Oral administration, standard dosing and little to no direct monitoring required
* When would monitoring be beneficial? E.g. where adherence isn’t good
50
**DOAC indications**
* 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
ADR DOAC
**ADR**
* Bleeding (lower intracranial bleed risk compared to warfarin)
* Caution and dose adjustment separately in GI bleed risk groups
52
DOAC **Contraindications**
* 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
**Drug drug interaction**
* Less frequent interactions than warfarin but affected by CYP inhibitors and inducers
* [plasma] reduced by carbamazepine, phenytoin and barbiturates
* [plasma] increased by macrolides
