Lecture 22- Anticoagulants Flashcards
What is thrombosis?
Pathological haemostasis within a blood vessel;
What is the difference between arterial and venous thrombi in terms of their platelet content?
Arterial = platelet rich
Venous = Lower platelets more fibrin
What is antithrombin III?
Endogenous inactivator of clotting factors
How do coagulation factors circulate in the blood?
As zymogens (inactive enzymes)
What is an important co facotr of the coagulation cascade?
Calcium (Ca2+)
What is the function of calcium in the coagulation cascade?
Needed for clotting to occur
Ca2+ in citrate tubes or EDTA tubes chelate calcium preventing coagulation
Where are heparins naturally produced?
Mast cells
Vascular endothelium
What are the 2 main types of heparins?
Unfractioned heparin
Low molecular weight heparins
What natural substance can we increase the levels of to prevent clotting?
Antithrombin III (AT-III) activity
How do heparins act as anticoagulants?
Enhance antithrombin III (AT-III) actiivty preventing clotting
What is the purpose of anticoagulant drugs?
Prevent thrombus formation and thrombus growing
What is the onset of action of unfractioned heparin?
Fast onset of action
T1/2 = 30min low dose, 2hr at higher doses
It has mixed elimination so is unpredictable
How is unfractioned heparin administered?
Normally IV bolus and infusion
Can be given s.c for prophylaxis but low bioavailability
How does unfractioned heparin act as an anticoagulant?
Binds to Antithrombin III causing conformational change and increasing actiivty of ATIII
To inhibit thrombin (IIa) heparin needs to bing to both ATIII and IIa
So inhibts Xa + Thrombin IIa
What does unfractioned heparin need to bind to to inhibit factor Xa?
just ATIII
How does the absorption of unfractioned heparin and low molecular weight heparin differ?
Unfractioned heparin = unpredictably
Low molecular weight heparin = more uniformly (dosed with certain number of units per kilo)
What are some examples of low molecular weight heparins?
Dalteparin
Enoxaparin
How are low molecular weight heparins likes Dalteparin and Enoxaparin normally administered?
Subcutaneously
How does the half life of low molecular heparins like Dalteparin and Enoxaparin differ to unfractioned heparin?
Low molecular heparins have longer t1/2 at 2hrs +
How do low molecular weight heparins like Dalteparin and Enoxaparin act as anticoagulants?
Inhibts Xa by enhancing ATIII
DOESNOT inactivate Thrombin (IIa) its too short
What is a synthetic low molecular weight heparin?
Fondaparinux
How does the synthetic low molecular weight heparin fondaparinux act as an anticoagulant?
Selectively inhibits Xa be enhancing ATIII
Given s.c
What type of molecules are heparins?
Negatively charged molecules
What is the difference in speed of action of Unfractioned heparin and low molecular weight heparins?
UF = IV infusion fast Anticoagulation
LMWH. = s.c slower onset
What are some indications for using heparins or fondaparinux?
Prevent VTE or preiopereative prophylaxis of VTE
During pregnancy since dont cross placenta
DVT
PE
Acute coronary syndromes
During Percutaenosu coronary intervention
NSTEMI
What are some adverse drug reactions to heparins?
Bruising and bleeding = Intracranial, at site of injection, GI and epistaxis
Heparin I induced thrombocytopenia autoimmune response
Osteoporosis
Hyperkalaemia (Inhibts aldosterone secretion)
What is heparain induced thrombocytopenia?
Autoantibodies to heparin Platelet factor 4 complex produced, platelets depleted which can paradoxically lead to thrombosis as more platelets activated by damaged endothelium
What are the contraindications to heparins?
Clotting disorders
GI ulcers
Renal impairment (LMWH and fondaparinux)
What are the drug-drug interactions of heparins?
Other antithrombotic drugs
ACEi, ARBs and other K+ sparring diuretics
What value is measured when monitoring a patient who is being dosed with unfractioned doses of heparin?
Activated partial thromboplastin time (aPTT)
Why does low molecular weight heparirn require little monitoring when given to patients whereas unfractioned heparin needs lots of monitoring?
LMWH much more predictable in its action and elimination
What is a drug that can reverse/inactivate heparin?
Protamine sulphate
How does protamine sulphate work to reverse the Anticoagulation of heparin?
Binds to heparin forming an inactive complex leading to heparin dissociating from ATIII
How does protamine sulphate affect Unfractioned heparin, LMWH and fondaparinux respectively?
UFH = much greater effect than LMWH
Fondaparinux = no effect
What is warfarin?
Vitamin K antagonist
What is the mechanism of action of warfarin as an anticoagulant?
Competitively inhibits vitamin K epoxide REDUCTASE preventing vitamin K being recycled back into its active form
Therefore reduces hepatic synthesis of vitamin K dependant clotting factors
What clotting factors require vitamin K for the liver to produce them?
II, VII, IX and X
What is the time of onset of warfarin and why?
Delay in onset of
Since it takes several days for circulating active clotting factors to be cleared and replaced with the inactive clotting factors
What is the rough half life for Vit K antagonists like warfarin?
36 - 48hr
What are some indications for warfarin?
VTE
PE
DVT and seconadry prevention
Superficial vein thrombosis
AF patients where DOAC not suitable
Heart valve replacemtn bio prosthetic
Pre cardio version
Why may you temporarily see warfarin and heparin used alongside each other?
Warfarin has a slow onset of action whereas heparin is much quicker
If Anticoagulation is needed immediately often give heparin as cover while waiting for the warfarin to kick in
How is warfarin usually administered?
Taken orally since has good GI absorption
What are the 2 enantiomers of warfarin?
R and S
What is the major contraindication to warfarin?
Pregnant since crosses placenta so needs to be avoided in at least 1st trimester and early post partum
What affects the response by warfarin?
CYP2C9 polymorphisms
Vit K intake (leafy vegetables)
Alcohol
What is the major adverse drug reaction of warfarin?
Bleeding (epistaxis and spontaneous Retroperitoneal bleeding)
If a patient starts bleeding who is taking warfarin what is the first option step to take?
Then following on from that;
1st = GIVE ACTIVE VITAMIN K
Prothrombin complex concentrate via I
Then stopp the warfarin which is inhibiting the Vit K epoxide REDUCTASE
What is bridging therapy?
When you give LMWH when initiating or temporarily stopping warfarin since it takes some time for the effect of warfarin to kick in
What are the many drug drugs interactions of Warfarin?
Drugs that Inhibit CYP2C9 (Amiodarone, clopidogrel, metronidazole, intoxicating dose of alcohol))
Cephalosporin Abx Elimates gut bacteria producing VItamin K so leads to reduced Vit K
Displacemtn of warfarin from plasma albumin (NSAIDs and drugs that decrease GI absorption of Vit K
Aceleration of WArfarin metabolism by barbiturates, phenytoin, Rifampicin and St John’s wart (decreasing INR)
What is meant by a high INR and a low INR?
High INR = more anti coagulated so higher bleeding risk
Low INR = less anti coagulated so less bleeding I risk
What is INR?
Compares prothrombin clotting time against a standardised control plasma
Which clotting facotr is most sensitve to vitamin K deficiency?
Factor VII
What does DOAC stand for?
Direct acting oral anticoagulant
What are some DOACs?
ApiXAban
EdoXAban
RivaraoXAban
What is the mechanism of action of ApiXAban, edoXAban and rivaroXAban acting as an anticoagulant?
Directly inhibits both free Xa and Xa bound to ATIII but DOES NOT effect thrombin (IIa)
How are DOACs like ApiXAban metabolised and excreted?
Hepatic metbolism
Excreted partly by kidneys
How does dabigatran act as an anticoagulant?
Directly and competitively inhibits Thrombin IIa
What anticoagulant inhibts Thrombini IIa?
Dabigatran
What anticoagulant inhibits factor Xa?
Apixaban (DOAC)
Low molecular weight heparins (Dalteparin)
Fondaparinux
What are the adverse reactions of DOACs like Apixaban?
Bleeding
Skin reactions
Dose adjustments needed for GI bleed risk groups
What are the contraindations to oDOACs?
Dabigatran contraindicated in low creatinine clearance
Avoid use in pregnancy and breast feeding
What are the drug drug interactions of DOACs?
Affected by CYP inhibtors and inducers
Macrolides increase plasma conc of DOACs
Carbamazepine, phenytoin and barbiturates reduce plasma conc of DOACs
What are the antidotes for Apixaban and RivaraoXAban?
Andexanet Alfa
What is the antidote for dabigatran?
Idarucizumab
