1. Vascular Pharmacology
Phil Copeman and Alex Hammant

2. Haemostasis drugs Fibrinolytics Antiplatelets Anticoagulants Aspirin
Alteplase
Clopidogrel
Abciximab, tirofiban and eptifibatide
Streptokinase activator complex / anistreplase
Anticoagulants
Heparin
Unfractionated
LMWH
Fondaparinux
Warfarin
Rivaroxaban
Dabigatran
Bivalirudin

3. What are the two main stages of clotting?
Primary Haemostasis – haemostatic plug formation (Platelet aggregation)
Secondary Haemostasis - clot formation (Fibrin cleavage)

4. Primary Haemostatsis - Explain how the haemostatic plug forms? (6)
Endothelial damage exposes collagen
vWF binds to collagen.
Platelets bind to vWF
Platelets are activated: they change shape and secrete granules
Thromboxane A2 causes vasoconstriction and aids platelet aggregation (MoA of aspirin)
ADP (MoA of clopidogrel)
ADP causes conformational change in GPIIb/IIIa platelet receptors, inducing binding to fibrinogen. Fibrinogen joins the platelets together, causing platelet aggregation.
The coagulation cascade causes an eruption of thrombin, which converts fibrinogen to fibrin, consolidating the haemostatic plug.
Platelets adhere to the damaged vascular endothelium via linkage of glycoprotein (GP) Ia receptors with exposed collagen and via linkage of Ib receptors with von Willebrand’s factor, a circulating factor that is similar to clotting factor VIII. The adherence of platelets to vascular endothelium activates the platelets and leads to the synthesis and release (degranulation) of various mediators of platelet aggregation, including thromboxane A2 (TXA2), adenosine diphosphate (ADP), and 5-hydroxytryptamine (serotonin). These mediators increase the expression of GP IIb/IIIa receptors that bind to fibrinogen and thereby cause platelet aggregation. Aspirin and clopidogrel inhibit the synthesis or activity of specific mediators of platelet aggregation, whereas abciximab, tirofiban, and eptifibatide block GP IIb/IIIa receptors.
Thromboxane A2 is produced from arachidonic acid by the COX-1 enzyme and aids platelet aggregation. Aspirin irreversibly inhibits COX-1 enzyme, preventing formation of TXA2 and aggregation of platelets.
Binding of ADP to P2Y12 receptors causes the conformational change of GPIIb/IIIa, allowing them to bind fibrinogen and cause platelet aggregation. Clopidogrel irreversibly inhibits the P2Y12 receptor.

5. Antiplatelet drugs
All antiplatelet drugs prevent platelet aggregation

6. Aspirin
Thromboxane A2 is produced from arachidonic acid by the COX-1 enzyme and aids platelet aggregation.
Aspirin irreversibly inhibits COX-1 enzyme, preventing formation of TXA2 and aggregation of platelets.

7. Aspirin
Thromboxane A2 is produced from arachidonic acid by the COX-1 enzyme and aids platelet aggregation.
Aspirin irreversibly inhibits COX-1 enzyme, preventing formation of TXA2 and aggregation of platelets.

8. Clopidogrel
Normally - Binding of ADP to P2Y12 receptors causes the conformational change of GPIIb/IIIa receptors, allowing them to bind fibrinogen and cause platelet aggregation.
Clopidogrel irreversibly inhibits the P2Y12 receptor, inhibiting the effects of ADP and thereby preventing platelet aggregation.
Basically – “Clopidogrel reduces platelet aggregation by irreversibly blocking the effects of ADP on platelets”
Medical Pharmacology At A Glance, M.J. Neal
It is often used by patients in whom aspirin is contraindicated.

9. Clopidogrel

10. Should probably call it
Vitamin K Epoxide Reductase
Found in liver
The importance of the conversion of fibrinogen to fibrin is that:
Fibrinogen is soluble
Fibrin is insoluble

11. So…which pathway does warfarin effect?
Extrinsic pathway of coagulation

12. What are the contraindications of warfarin therapy?
Haemorrhagic stroke
Significant bleeding
48 hrs post partum
First trimester of pregnancy
Severe hepatic and renal impairment

13. Which cytochrome P450 isoform is responsible for the reduction (and thus deactivation) of warfarin?
CYP2A6

14. What are the side effects of warfarin?
Nausea
Pyrexia
Vomiting
Alopecia
Haemorrhage
Purpura
Diarrhoea
Rash
Jaundice
Hepatic dysfunction
Pancreatitis

15. If warfarin affects the extrinsic pathway, how would you measure its effect on coagulation?
Prothrombin Time OR
INR

16. What is the target INR for most patients taking warfarin?
2.5
Can you think of any conditions where the target INR might be 3.5?
Recurrence of venous thromboembolism whilst on warfarin therapy
Antiphospholipid syndrome
Mechanical prosthetic heart valve
Cornary artery graft thrombosis

17. How long does it take for warfarin to take its therapeutic effect? Why?
2-4 days
Because it takes time for the clotting factors in the blood to be metabolised/depleted

18. Anticoagulant drugs - Heparin
Inhibits coagulation by activating antithrombin III
Antithrombin III inhibits thrombin, Xa and other coagulation factors
Acts on the intrinsic pathway
Increases aPTT time
Reversed with protamine sulphate
Other factors inhibited by heparin include VIIa, IXa, XIa and XIIa; its actions on thrombin and Xa seem to be the most important
Acts on intrinsic pathway: PET A PITBULL

19. Types of heparin Low-molecular weight heparin (LMWH)
Administered subcutaneously
More predictable – can be given to outpatients
Fewer side effects
Increase the effect of antithrombin III on Factor Xa
Less reversible with protamine sulphate than unfractionated
Unfractionated heparin
Inhibits thrombin and Factor Xa
Administered I.V.
Unpredictable anticoagulant activity so can only be given in hospital because its effects need to be monitored
Can cause heparin-induced thrombocytopenia

20.
The importance of the conversion of fibrinogen to fibrin is that:
Fibrinogen is soluble
Fibrin is insoluble

21. Fibrinolytic drugs
MoA: Activate plasminogen to form plasmin, which breaks down clots
Types of recombinant t-PA:
Alteplase, Reteplase, Urokinase
Streptokinase activator complex / anistreplase
Streptokinase bound to plasminogen in a complex
Slowly activated in plasma
Not clot-selective
Can only be used once because the body forms antibodies against it

22. What stops clots forming normally?
Endothelium is normally antithrombotic
Antiplatelet
Even if the platelets are activated, there’s nothing for them to bind to on the endothelial surface
Platelets also produce NO, and Prostacyclin (PGI2) which stop platelet adhesion
Anticoagulant
Antithrombins (e.g. antithrombin III), a type of endogenous anticoagulants, inhibit the activity of thrombin and other coagulation factors
Heparin-like molecules activate antithrombin III
Proteins C and S
Tissue Factor Pathway Inhibitor
Fibrinolysis
Endothelial cells synthesise t-PA, which degrades thrombi
Proteins C and S, which are activated by thrombomodulin, act in a complex to inhibit clotting by inactivating factors Va and VIIIa
Tissue Factor Pathway Inhibitor, an endothelial cell surface protein, inhibits the tissue factor-factor VIIa and factor Xa