Vascular Pharmacology Phil Copeman and Alex Hammant.

Vascular PharmacologyPhil Copeman and Alex Hammant

Haemostasis drugs Antiplatelets

Aspirin

Clopidogrel

Abciximab, tirofiban and eptifibatide

Anticoagulants Heparin

Unfractionated

LMWH

Fondaparinux

Warfarin

Rivaroxaban

Dabigatran

Bivalirudin

Fibrinolytics

• Alteplase

• Streptokinase activator complex / anistreplase

What are the two main stages of clotting?

Primary Haemostasis – haemostatic plug formation (Platelet aggregation)

Secondary Haemostasis - clot formation (Fibrin cleavage)

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.

Antiplatelet drugs All antiplatelet drugs

prevent platelet aggregation

Aspirin

Aspirin

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.

Clopidogrel

Should probably call itVitamin K Epoxide Reductase• Found in

liver

So…which pathway does warfarin effect?

Extrinsic pathway of coagulation

What are the contraindications of warfarin therapy?

Haemorrhagic stroke

Significant bleeding

48 hrs post partum

First trimester of pregnancy

Severe hepatic and renal impairment

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

CYP2A6

What are the side effects of warfarin?

Nausea

Vomiting

Haemorrhage

Diarrhoea

Jaundice

Hepatic dysfunction

Pancreatitis

Pyrexia

Alopecia

Purpura

Rash

If warfarin affects the extrinsic pathway, how would you measure its effect on coagulation?

Prothrombin Time

OR

INR

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

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

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

Types of heparin

• 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

• 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

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

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