Cardiovascular and renal pharmacology: Clot lysis

Question 1

Streptokinase

Answer 1

47kDa protein
Formed by haemolytic streptococci
Binds to plasminogen activator, causes generation of plasmin
Leads to degradation of fibrin in clots, & breakdown of clotting factors II, V, VII.

Question 2

Plasmin

Answer 2

Protease
Hydrolyses Arg-Lys bonds
Causes degradation of the fibrin in clots & breakdown of clotting factors II, V, VII

Question 3

Plasminogen

Answer 3

Precursor of plasmin

Question 4

Anistreplase

Answer 4

Combination of plasminogen and anisoylated streptokinase.

Question 5

Anisoylated streptokinase

Answer 5

Streptokinase is inactive until anisoyl group removed in the blood- this happens relatively slowly (t1/2 ~ 2h).
More prolonged activity than streptokinase alone.

Question 6

Alteplase

Answer 6

Recombinant human tissue plasminogen activator
Single chain
Greater activity on plasminogen bound to fibrin- localises action.

Question 7

Duteplase

Answer 7

Recombinant human tissue plasminogen activator
Double chain
Greater activity on plasminogen bound to fibrin- localises action.

Question 8

Aspirin

Answer 8

Oral low dose used alongside other therapies to prevent further thrombosis.
Used prophylactically
Low dose aspirin + clopidogrel can improve morbidity & mortality in patients over a wide range of heart disease

Question 9

Clopidogrel

Answer 9

Inhibits platelet aggregation

Inhibits binding of ADP to its receptos on platelets.

Question 10

Eptifibatide

Answer 10

Inhibitor of glycoprotein IIb/IIIa receptor

Cyclic heptapeptide inhibitor

Question 11

Tirofiban

Uses?

Answer 11

Inhibitor of glycoprotein IIb/IIIa receptor
Non-peptide inhibitor
Can be used like heparin: for prevention of MI in patients with unstable angina/ who have previously suffered certain types of MI (identified by ECG)

Question 12

Abciximab

Uses?

Answer 12

Inhibitor of glycoprotein IIb/IIIa receptor
Monoclonal antibody against the receptor, also binds to vitronectin receptor on platelets, endothelial cells & vascular smooth muscle cells.

Used with coronary angioplasty for coronary artery thrombosis

Question 13

Heparin

Answer 13

Naturally occurring anticoagulant produced by basophils & mast cells.
Binds to enzyme inhibitor antithrombin III (AT-III), causing a conformational change resulting in exposure of its active site.
Activated AT-III then inactivates thrombin & other proteases involved in blood clotting, notably factor Xa

Has to be given by injection
Uses:
- (like tirofiban): unstable angina & after MI
- treatment of DVT
- prophylactic drug to prevent clot formation during & as a result of surgery.

Question 14

Warfarin

Answer 14

Inhibits synthesis of clotting factors II, VII, IX, X, as well as regulatory factors protein C, S and Z.

Uses:

• (similar to heparin): prophylactically to prevent development/ recurrence of thrombosis in at risk individuals
• prevent clot formation on prosthetic heart valves.
• rodenticide (although many rats show resistance due to years of use). Risk of accidental poisoning of other animals.

Can be given orally
Dosing complicated as interacts with many commonly used drugs & chemicals that may be present in various food & drink. Blood levels of drug need to be carefully & continuously monitored if taken over long period.

Question 15

Dabigatran

Answer 15

Thrombin inhibitor

Approved 2012 for use in patients with atrial fibrillation (can lead to clot development) & one additional risk factor for stroke. Evidence that can reduce risk by up to 40% compared to warfarin.
Also administered prophylactically to prevent thromboembolism in patients who have had recent hip/knee replacement surgery.

Question 16

Rivaroxaban

Answer 16

Factor Xa inhibitor

Similar used to dabigatran (given prophylactically to reduce risk of stroke/ thromboembolism)

Question 17

Aminocaproic acid

Answer 17

Chemically similar to lysine
Competitively inhibits plasminogen activation
Used to prevent excessive clot lysis (can lead to severe bleeding)

Question 18

Tranexamic acid

Answer 18

Analogue of aminocaproic acid
Competitively inhibits plasminogen activation.
Used to prevent excessive clot lysis (can lead to severe bleeding)

Question 19

Glycoprotein IIb/ IIIa receptor

Answer 19

Needed for fibrinogen bridging between platelets (& between platelets & foreign surfaces) that causes aggregation.

Question 20

Victronectin

Answer 20

Involved in cell adhesion & haemostasis

Binds to its receptor on platelets, endothelial cells & vascular smooth muscle cells.