Lecture 22- Anticoagulants

Question 1

What is thrombosis?

Answer 1

Pathological haemostasis within a blood vessel;

Question 2

What is the difference between arterial and venous thrombi in terms of their platelet content?

Answer 2

Arterial = platelet rich
Venous = Lower platelets more fibrin

Question 3

What is antithrombin III?

Answer 3

Endogenous inactivator of clotting factors

Question 4

How do coagulation factors circulate in the blood?

Answer 4

As zymogens (inactive enzymes)

Question 5

What is an important co facotr of the coagulation cascade?

Answer 5

Calcium (Ca2+)

Question 6

What is the function of calcium in the coagulation cascade?

Answer 6

Needed for clotting to occur

Ca2+ in citrate tubes or EDTA tubes chelate calcium preventing coagulation

Question 7

Where are heparins naturally produced?

Answer 7

Mast cells
Vascular endothelium

Question 8

What are the 2 main types of heparins?

Answer 8

Unfractioned heparin

Low molecular weight heparins

Question 9

What natural substance can we increase the levels of to prevent clotting?

Answer 9

Antithrombin III (AT-III) activity

Question 10

How do heparins act as anticoagulants?

Answer 10

Enhance antithrombin III (AT-III) actiivty preventing clotting

Question 11

What is the purpose of anticoagulant drugs?

Answer 11

Prevent thrombus formation and thrombus growing

Question 12

What is the onset of action of unfractioned heparin?

Answer 12

Fast onset of action

T1/2 = 30min low dose, 2hr at higher doses

It has mixed elimination so is unpredictable

Question 13

How is unfractioned heparin administered?

Answer 13

Normally IV bolus and infusion

Can be given s.c for prophylaxis but low bioavailability

Question 14

How does unfractioned heparin act as an anticoagulant?

Answer 14

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

Question 15

What does unfractioned heparin need to bind to to inhibit factor Xa?

Answer 15

just ATIII

Question 16

How does the absorption of unfractioned heparin and low molecular weight heparin differ?

Answer 16

Unfractioned heparin = unpredictably

Low molecular weight heparin = more uniformly (dosed with certain number of units per kilo)

Question 17

What are some examples of low molecular weight heparins?

Answer 17

Dalteparin
Enoxaparin

Question 18

How are low molecular weight heparins likes Dalteparin and Enoxaparin normally administered?

Answer 18

Subcutaneously

Question 19

How does the half life of low molecular heparins like Dalteparin and Enoxaparin differ to unfractioned heparin?

Answer 19

Low molecular heparins have longer t1/2 at 2hrs +

Question 20

How do low molecular weight heparins like Dalteparin and Enoxaparin act as anticoagulants?

Answer 20

Inhibts Xa by enhancing ATIII

DOESNOT inactivate Thrombin (IIa) its too short

Question 21

What is a synthetic low molecular weight heparin?

Answer 21

Fondaparinux

Question 22

How does the synthetic low molecular weight heparin fondaparinux act as an anticoagulant?

Answer 22

Selectively inhibits Xa be enhancing ATIII

Given s.c

Question 23

What type of molecules are heparins?

Answer 23

Negatively charged molecules

Question 24

What is the difference in speed of action of Unfractioned heparin and low molecular weight heparins?

Answer 24

UF = IV infusion fast Anticoagulation

LMWH. = s.c slower onset

Question 25

What are some indications for using heparins or fondaparinux?

Answer 25

Prevent VTE or preiopereative prophylaxis of VTE During pregnancy since dont cross placenta DVT PE Acute coronary syndromes During Percutaenosu coronary intervention NSTEMI

Question 26

What are some adverse drug reactions to heparins?

Answer 26

Bruising and bleeding = Intracranial, at site of injection, GI and epistaxis Heparin I induced thrombocytopenia autoimmune response Osteoporosis Hyperkalaemia (Inhibts aldosterone secretion)

Question 27

What is heparain induced thrombocytopenia?

Answer 27

Autoantibodies to heparin Platelet factor 4 complex produced, platelets depleted which can paradoxically lead to thrombosis as more platelets activated by damaged endothelium

Question 28

What are the contraindications to heparins?

Answer 28

Clotting disorders GI ulcers Renal impairment (LMWH and fondaparinux)

Question 29

What are the drug-drug interactions of heparins?

Answer 29

Other antithrombotic drugs ACEi, ARBs and other K+ sparring diuretics

Question 30

What value is measured when monitoring a patient who is being dosed with unfractioned doses of heparin?

Answer 30

Activated partial thromboplastin time (aPTT)

Question 31

Why does low molecular weight heparirn require little monitoring when given to patients whereas unfractioned heparin needs lots of monitoring?

Answer 31

LMWH much more predictable in its action and elimination

Question 32

What is a drug that can reverse/inactivate heparin?

Answer 32

Protamine sulphate

Question 33

How does protamine sulphate work to reverse the Anticoagulation of heparin?

Answer 33

Binds to heparin forming an inactive complex leading to heparin dissociating from ATIII

Question 34

How does protamine sulphate affect Unfractioned heparin, LMWH and fondaparinux respectively?

Answer 34

UFH = much greater effect than LMWH Fondaparinux = no effect

Question 35

What is warfarin?

Answer 35

Vitamin K antagonist

Question 36

What is the mechanism of action of warfarin as an anticoagulant?

Answer 36

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

Question 37

What clotting factors require vitamin K for the liver to produce them?

Answer 37

II, VII, IX and X

Question 38

What is the time of onset of warfarin and why?

Answer 38

Delay in onset of Since it takes several days for circulating active clotting factors to be cleared and replaced with the inactive clotting factors

Question 39

What is the rough half life for Vit K antagonists like warfarin?

Answer 39

36 - 48hr

Question 40

What are some indications for warfarin?

Answer 40

VTE PE DVT and seconadry prevention Superficial vein thrombosis AF patients where DOAC not suitable Heart valve replacemtn bio prosthetic Pre cardio version

Question 41

Why may you temporarily see warfarin and heparin used alongside each other?

Answer 41

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

Question 42

How is warfarin usually administered?

Answer 42

Taken orally since has good GI absorption

Question 43

What are the 2 enantiomers of warfarin?

Answer 43

R and S

Question 44

What is the major contraindication to warfarin?

Answer 44

Pregnant since crosses placenta so needs to be avoided in at least 1st trimester and early post partum

Question 45

What affects the response by warfarin?

Answer 45

CYP2C9 polymorphisms Vit K intake (leafy vegetables) Alcohol

Question 46

What is the major adverse drug reaction of warfarin?

Answer 46

Bleeding (epistaxis and spontaneous Retroperitoneal bleeding)

Question 47

If a patient starts bleeding who is taking warfarin what is the first option step to take? Then following on from that;

Answer 47

1st = GIVE ACTIVE VITAMIN K Prothrombin complex concentrate via I Then stopp the warfarin which is inhibiting the Vit K epoxide REDUCTASE

Question 48

What is bridging therapy?

Answer 48

When you give LMWH when initiating or temporarily stopping warfarin since it takes some time for the effect of warfarin to kick in

Question 49

What are the many drug drugs interactions of Warfarin?

Answer 49

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)

Question 50

What is meant by a high INR and a low INR?

Answer 50

High INR = more anti coagulated so higher bleeding risk Low INR = less anti coagulated so less bleeding I risk

Question 51

What is INR?

Answer 51

Compares prothrombin clotting time against a standardised control plasma

Question 52

Which clotting facotr is most sensitve to vitamin K deficiency?

Answer 52

Factor VII

Question 53

What does DOAC stand for?

Answer 53

Direct acting oral anticoagulant

Question 54

What are some DOACs?

Answer 54

ApiXAban EdoXAban RivaraoXAban

Question 55

What is the mechanism of action of ApiXAban, edoXAban and rivaroXAban acting as an anticoagulant?

Answer 55

Directly inhibits both free Xa and Xa bound to ATIII but DOES NOT effect thrombin (IIa)

Question 56

How are DOACs like ApiXAban metabolised and excreted?

Answer 56

Hepatic metbolism Excreted partly by kidneys

Question 57

How does dabigatran act as an anticoagulant?

Answer 57

Directly and competitively inhibits Thrombin IIa

Question 58

What anticoagulant inhibts Thrombini IIa?

Answer 58

Dabigatran

Question 59

What anticoagulant inhibits factor Xa?

Answer 59

Apixaban (DOAC) Low molecular weight heparins (Dalteparin) Fondaparinux

Question 60

What are the adverse reactions of DOACs like Apixaban?

Answer 60

Bleeding Skin reactions Dose adjustments needed for GI bleed risk groups

Question 61

What are the contraindations to oDOACs?

Answer 61

Dabigatran contraindicated in low creatinine clearance Avoid use in pregnancy and breast feeding

Question 62

What are the drug drug interactions of DOACs?

Answer 62

Affected by CYP inhibtors and inducers Macrolides increase plasma conc of DOACs Carbamazepine, phenytoin and barbiturates reduce plasma conc of DOACs

Question 63

What are the antidotes for Apixaban and RivaraoXAban?

Answer 63

Andexanet Alfa

Question 64

What is the antidote for dabigatran?

Answer 64

Idarucizumab