Pharmacology Of Haemostasis

Question 1

Definition of anticoagulant

Answer 1

Interferes with process of fibrin plug formation to reduce or prevent coagulation

Question 2

How does warfarin work

Answer 2

Inhibits the reduction of vitamin k which is needed as a cofactor in gamma carboxylation of the glutamate residue of clotting factors II, VII, IX, X
During the gamma carboxylation Vit k is converted to k 2,2 epoxide, warfarin stops its conversion (reduction) back to Vit k due to its structural similarity to Vit k

Question 3

What are the half lives of the Vit k dependant clotting factors

Answer 3

II 60hrs
VII 6 hrs
IX 24hrs
X 40hrs

Question 4

Other types of anticoagulant that act similar to wararin

Answer 4

Nicoumalone (a coumarin)
Phenindione (an inandione)

Question 5

Isomerism of warfarin

Answer 5

L and D forms
Given as an racemic mixture

Question 6

How fast does oral warfarin take to reach peak plasma concentration
Bioavailability

Answer 6

1 hr
Bioavailability 100%

Question 7

Type to peak warfarin effect

Answer 7

36-48hrs

Question 8

Degree of protein binding of warfarin
To what

Answer 8

99%
Albumin

Question 9

Breast feeding and warfarin?

Answer 9

Enters breast milk causing issue as newborn gut flora not yet developed for producing Vit k

Question 10

Methods of interaction with warfarin

Answer 10

Competition for protien binding sites
Increased hepatic binding
Inhbition or induction of hepatic enzymes
Reduced Vit k synthesis
Synergistic anti haemostatic action

Question 11

Which drugs may displace warfarin from proteins

Answer 11

NSAIDs, choral hydrate, oral hypoglycaemics, diuretics, amiodarone

Question 12

Why might abx influence warfarin

Answer 12

Alter gut bacteria reducing Vit k synthesis

Question 13

How does oestrogen effect warfarins action

Answer 13

Increases production of Vit k dependant clotting factors

Question 14

Effect of cholestyramine on wawrfarin

Answer 14

Binds it reducing effect

Question 15

How do heparins work

Answer 15

Binding antithrombin increasing its activity on factors IIa IXa Xa XIa, XIIa by confimational change and binding to both the antithrombin and the clotting factor (all but Xa)
Reduces platelet aggregation (due to reduced thrombin)
Increases vascular permeability
Releases lipoprotein lipase into plasma

Question 16

Structure of heparin

Answer 16

Sulphated acid glycosaminoglycans (mucopolysaccharides)
Chain about 50 sugar residues on a protein Skelton
Molecular weight 3000-40000 daltons
Strong negative charge

Question 17

Where is endogenous heparin found

Answer 17

Lungs, arterial walls, mast cells

Question 18

What are lmwhs
How do they work

Answer 18

Fragments of depolymerised heparin purified to contain the antithrombin specific binding site

All inhibit Xa, much reduced antithrombin activity but do require antithrombin for effect

Question 19

Molecular weight of lmwh

Answer 19

3000-8000 daltons

Question 20

Advantages of lmwh

Answer 20

Minimal alteraltion to platelet function
Better interop haemostasis
Possible better vte prophylaxis
Sc administration
Once daily dosing
More predictable (much less protein bound)

Question 21

What is the issue with acute illness and heparin function

Answer 21

Heparin is bond to acute phase proteins so acute illness increases these levels altering Clincial effect

Question 22

Heparin metabolism
Half life

Answer 22

Hepatic, renal and reticularendothelial system
40-90 mins

Question 23

Time to peak action of lmwh and time to degrade to half action

Answer 23

Peak in 3-4 hrs
Degrades to half in 12 hrs

Question 24

Metabolism of lmwh

Answer 24

Renal elimination

Question 25

Effect of heparin on coagulation studies

Answer 25

Increased APTT
Increased TT
Increased activated clotting time

No effect on bleeding time

Question 26

What is used to neutralise heparin
How does it work

Answer 26

Protamine
Cationic protein that attracts the heparin

Question 27

How do apixaban and rivaroxaban work

Answer 27

Inhibiting Xa

Question 28

Structure and How does fondaparinux work

Answer 28

Pentasaccharide based on heparin
Increases anticoagulant effects of heparin

Question 29

Contraindications to fondaparinux

Answer 29

Bacterial endocarditis

Question 30

How does dabigatran work

Answer 30

Inhibits thrombin directly

Question 31

Why does blood transfusion cause calcium issues

Answer 31

Citrate in blood to stop clotting
Usually broken down in liver but when lots given overwhelms liver thus chlelates calcium particularly if liver metabolism reduced eg hypothermia

Question 32

How do alteplase and streptokinase work

Answer 32

Activate plasminogen increasing conversion to plasmin causing clot degredation

Question 33

How is streptokinase made
Consequence

Answer 33

Isolated from group c haemolytic strep cultures
Allogenic - limited duration of use due to antibodies from prev strep infection and allergy is common

Question 34

How does txa work

Answer 34

Inhibits action of plasmin and pepsin

Question 35

How does aspirin work

Answer 35

Inhibits platelet cox2 irreversibly stopping txa2 production
Platelets can’t regenerate Cox2 thus effect on individual platelet is permanent

Does also effect other cox but this can regenerate and platelet cox more readily inactivated

Question 36

What is the effect of prostacyclin on platelets and vasculature

Answer 36

Inhibits aggregation and dissipates formed aggregates
Potent vasodilator

Question 37

How does clopidogrel work
Other drugs in same class

Answer 37

Prasugrel, ticagrelor

P2Y12 inhbitiors (ADP receptor)

Clopidogrel is a prodrug - active metabolite bind irreversibly to p2y12 receptor
Ticagrelor is reversible

Question 38

What class of drug is tirofiban

Answer 38

Glycoprotein IIb iiia inhibitor

Question 39

Effect of desmopressin on clotting

Answer 39

Increases levels of factor viii