4.3 Anticoagulant drugs Flashcards
ANTIPLATELET DRUGS
The activation of platelets involves the release of ADP and production of thromboxane A2:
• Release of ADP: from _________________ which stimulates platelet aggregation
• Production of thromboxane A2: conversion of arachidonic acid to _________________ by COX) then thromboxane A2 which induces platelet aggregation •
Antiplatelets are typically used in ___________________
- Clopidogrel: Specifically and irreversibly inhibits an ADP receptor (__________) required for platelet activation
- Aspirin: Inhibits platelet COX thus preventing formation of thromboxane A2
dense granules;
cyclic endoperoxidases ;
arterial thromboembolism (ATEs);
P2Y12 subtype
ANTIFIBRINOLYTIC DRUGS
The most commonly used anti-fibrinolytic drug is _______________ in the following settings (used in bleeding disorders):
• Trauma to reduce blood loss
• Heavy periods (menorrhagia)
• Coagulation factor deficiencies (e.g. Factor XI deficiency)
• Mouth washes in patients with bleeding tendency
TXA is a synthetic derivative of ___________ which binds to both plasminogen and plasmin to competitively inhibit the activation of plasminogen to plasmin
tranexamic acid (TXA);
lysine
Warfarin
Inhibits vitamin K epoxide reductase to prevent vitamin K recycling (required for factor ______________ synthesis):
• Vitamin K is required for the carboxylation of the N-terminal glutamate residue of these facto
II, VII, IX, X
Heparin (UFH/LMWH) Potentiates antithrombins (act on thrombin, factors \_\_\_\_\_\_\_\_\_\_\_\_ ): • UFH: short half-life, administered IV (anti-\_\_\_\_\_\_\_\_) • LMWH (e.g. enoxaparin, dalteparin): longer half-life, administer SC (anti-Xa, weaker anti-IIa)
Xa, IXa, XIa;
IIa
Rivaroxaban/ apixaban
Oral inhibitors of factor Xa:
• _____________: used in treatment of DVT/PE
• ___________: not used in treatment of DVT/PE
Rivaroxaban;
Apixaban
Fondaparinux
Subcutaneous selective inhibitor of factor Xa
Dabigatran
Oral direct thrombin inhibitor used for prophylaxis against thrombosis and stroke prevention in non-valvular atrial fibrillation
Bivalirudin
Parenteral direct thrombin inhibitor used as an adjunct
WARFARIN
Factors II, VII, IX, X require post-translational modification to become activated:
• Modification: carboxylation of _____________ to form Gla domains (require reduced form of vitamin K) → enables them to bind calcium (which then enables them to bind to platelets)
• As the protein is converted to gamma-carboxylated protein, the reduced form of vitamin K becomes oxidised
• Oxidised vitamin K needs to be reduced again (via __________) for reuse in the pathway → warfarin interferes with the function of this enzyme
o Interferes with the production of II, VII, IX, X, causing their levels to fall and thus an anticoagulant effect
The full effect of warfarin may take several days to appear, reflecting the different half-lives of the various coagulation factors:
• _________ has the shortest half-life, so its levels fall the most quickly
• __________________ have longer half-lives, so their levels take longer to fall;
Monitoring warfarin is always essential because it affects a large proportion of the coagulation factors in the extrinsic pathway (largest effect seen on prothrombin time):
• Difficult to manage due to numerous interactions with other substances:
o Dietary interactions due to vitamin K in the diet
o Variable absorption of vitamin K
o Interactions with other drugs (due to protein binding and competition/induction of cytochromes)
• Best monitored using _______________ due to the greater effects of factor II, VII, IX, X on PT
N-terminal glutamic acid residues;
vitamin K epoxide reductase;
Factor VII;
Factors II, IX, X;
prothrombin time (PT) compared to activated partial thromboplastin time (APTT
The PT is a clotting time which is compared to a local normal range:
• Degree of anticoagulation should be comparable in different laboratories regardless of the reagents used and in-house normal ranges:
o INR done in Singapore is comparable to that done anywhere in the world (but PT taken in isolation may not be)
• Converted to a number relating the degree of anticoagulation to an international standard (international normalised ratio/INR) that considers the reagents used to derive the PT:
- INR= ________________
While anticoagulants are effective in preventing thrombosis, they also increase the risk of bleeding (with several factors affecting):
• Risk of major haemorrhage from warfarin is about 1.1%/year; risk of fatal haemorrhage is 0.25%/year
o Risk of bleeding increases with age
o Risk increases further if the patient has an ______________
• INR also affects the risk of bleeding (INR > 4 has a substantially increased risk), so target INR is not close to 4 (increases risk of becoming severely anticoagulated)
𝐈𝐍𝐑= (𝐏𝐓/ 𝐏𝐓𝐜)𝐈𝐒𝐈;
arterial disease
There are several things that can be done if the bleeding patient is on warfarin/has high INR:
- Stop warfarin
- Give vitamin K
- Give source of coagulation factors (FFP or PCC) Reversal of warfarin effects using vitamin K (give 1 – 5mg of oral vitamin K) is done in the following groups of patients:
Patient with INR > 8: Severe risk of bleeding
Patient with INR 5 – 8 High risk of bleeding if following criteria met: • Age > 70 years • \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ • Arterial disease • \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ • Previous bleeding - Scheduled for surgery in >24 hours
In the management of an emergency/life-threatening bleeding, warfarin is stopped:
• Give IV vitamin K 5mg and _______________; in preference to FFP as it works more quickly and effects last longer)
• Important to consider the risk from bleeding and the underlying thrombotic risk
Hypertensive;
Cerebrovascular disease;
PCC (contains clotting factors
Heparin acts by potentiating the effects of antithrombin with immediate effects (unlike warfarin) → useful for treating emergency acute thromboses:
• Binding to antithrombin causes conformational change which increases the interactions of antithrombin on its protease targets
• Antithrombin works on _______________ , and this effect is accelerated by heparin → used for immediate anticoagulation in VTE and PE
There are several different heparin preparations (UFH, LMWH):
• Unfractionated heparin (UFH) represents a group of polymers with heterogeneous sequences, where the anticoagulant activity depends on a ___________ with a high affinity for ______________:
o Consists predominantly of a ______________ (not all heparin molecules in a preparation will have same pentasaccharide sequence)
• Low molecular weight heparin (LMWH) can be made by ________________ (main method) or fractionation of UFH:
o Average molecular weight of LMWH is less than half of UFH (60% of molecules must have a molecular weight of <8000. Antithrombin activity also depends on the chain length being sufficiently long to bind to both antithrombin and thrombin
• LMWH has a shorter chain length, so it is less effective at inhibiting thrombin compared to UFH, but has very effective anti-Xa activity
thrombin, factor Xa, IXa, XIa;
pentasaccharide sequence;
antithrombin;
sulphated disaccharide repeating unit;
depolymerisation
Unfractionated Heparin
- Primary effects
- Molecular weight
- Chain length
- Half life
- Administration
- Monitoring
- Reversal: Check APTT first, then give 1mg _________ per 100u heparin, maximum dose 50mg
- Anti IIa
- High
- Longer
- <1 hour
- IV continous infusion
- APTT
- protamine
Low Molecular Weight Heparin
- Primary effects
- Molecular weight
- Chain length
- Half life
- Administration
- Monitoring
- Reversal: check anti Xa level firs then give ___________
- Anti Xa (weaker anti- IIa)
- Low (60% <8000)
- shorter
- 4-5 hours
- SC injection (once/ twice daily)
- not routinely monitored (anti factor Xa level if necessary)
- protamine sulphate
The APTT and thrombin time (TT) are prolonged in a patient on UFH, but the PT, APTT, TT may be normal even at therapeutic levels of LMWH:
• Possible for therapeutic levels of LMWH to be associated with prolonged APTT and TT
•LMWH has reliable pharmacokinetics, so monitoring is not usually required, except in the following conditions:
- Renal failure: ______________ < 50; may develop easily in elderly patients who are acutely unwell, causing accumulation of LMWH to potentially dangerous levels
- Later stages of pregnancy: Increased _____________- affects the pharmacokinetics of LMWH
- Unusual conditions/procedures
- *If required, anti-factor Xa levels are measured directly to monitor LMWH as APTT is not an effective measure
Creatinine clearance (CrCl);
plasma volume and GFR
Protamine sulphate is given intravenously to reverse the effects of heparin by binding to it and forming a stable ion pair without anticoagulant properties:
- Short half-life → no need to reverse effects in most situations
• __________ can be checked to see if UFH is still in the system
• If still present, 1mg of protamine per ________ of heparin is given (with a maximum dose of ________ protamine sulphate)
LMWH
- Less effectively reversed by protamine sulphate (maximally 75% reversal for some LMWH, and much lower for other LMWH)
• ______________ level should be checked to determine the overdose
APTT;
100u;
50mg;
Anti-factor Xa
Heparin VS Warfarin
- Onset: Immediate VS Delayed Action
- Cofactor for antithrombin VS ______________
- Administration: Parenteral VS ______
- Monitoring: UFH: APTT; LMWH: none (or anti-Xa levels) VS ______
- Pregnancy: Does not cross placenta (but risk of ___________) VS Teratogenic
- Half life: 1 – 2 hours VS > 24 hours
- Reversal: UFH: protamine; LMWH: protamine (partial) VS Oral vitamin K; FFP/PCC
Vitamin K epoxide reductase antagonist;
Oral;
INR
osteoporosis
New oral anticoagulants include dabigatran, rivaroxaban and apixaban, which are all oral drugs with immediate action:
• No monitoring is needed due to their reliable dose-response
• Drawbacks: lack of experience (side effects, safety), compliance is less certain, no antidote/reversal, some renal dependence
Rivaroxaban and apixaban are suitable for use in patients with mild renal impairment:
• CrCl < 50: drug information must be checked; reduce dose for _______________
• CrCl < 30: use ____________ with caution; __________ is contraindicated
dabigatran;
rivaroxaban and apixaban;
dabigatran
There are 3 main indications for long-term anticoagulant use (NOACs), including thromboprophylaxis, atrial fibrillation (reducing stroke risk) and venous thrombosis:
• Thromboprophylaxis (preventing blood clots in hospitalised patients): NOACs are as good as _______________ at preventing thrombosis
• Atrial fibrillation: RELY study (____________), ROCKET study (___________), ARISTOTLE study (___________) → primary outcome: stroke and systemic embolism
o __________ was shown to be better than warfarin in reducing the risk of stroke and major bleeding, while _____________ are as good as warfarin Factor
- Renal failure: __________ is preferable for patients with CrCl < 30mL/min
- Previous history of intracranial haemorrhage (ICH): _____ have a lower risk of ICH
- Extracranial bleeding: Warfarin is more readily reversible, and NOACs have an increased bleeding risk - Poor control (non-adherence, time in therapeutic range < 65%): NOACs more effective
- Frequent intermittent variable use: of other drugs NOACs less problematic (warfarin has more drug interactions), though it interacts with ____________ (antibiotic)
- New patients: Discuss the pros and cons and some foreseeable problems
• Venous thrombosis: __________ was as good as the standard treatment (LMWH + warfarin) and did not need to be monitored and without injections (simpler management for uncomplicated patients)
enoxaparin (LMWH);
dabigatran;
rivaroxaban;
apixaban;
Apixaban;
rivaroxaban and dabigatran;
Warfarin;
NOACs;
clarithromycin;
rivaroxaban
Monitoring of patients who are on anticoagulants should be done if the patient is bleeding, thrombosed on treatment, overdose or unconscious and requires surgery:
• NOACs affect coagulation tests (do not affect tests in a predictable or clinically useful way) → _______ may be normal or high in patients on appropriate NOAC dose
• APTT and TT may be abnormal in patients on appropriate NOAC dose
• Different test reagents exhibit different sensitivities to these new agents
o As the concentration of dabigatran used increases, the APTT ratio also increases → APTT is useful in indicating ____________ for most APTT reagents
There are several methods of reversing the effects of dabigatran:
- ____________: If ingested within 2 hours before reversal
- _____________: If ingested more than 2 hours before reversal
- Recombinant factor VIIa: Beware of arterial thrombosis if given
- PCC: Lack of data
With rivaroxaban, there is a high degree of ______________, so haemodialysis is not used:
• Recombinant factor VIIa and PCC are used instead
INR;
dabigatran concentration;
Activated charcoal;
Haemofiltration;
protein binding
