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Cardiovascular > Thrombosis Drugs > Flashcards

Thrombosis Drugs Flashcards

1
Q

What are the 2 things that activated platelets do?

A

Extend pseudopodia and synthesise and release thromboxane A2 (TXA2).

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2
Q

Where does TXA2 bind to on platelets?

A

GPCR TXA2 receptors (TP receptors).

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3
Q

What does TXA2 binding to TP receptors cause the platelets to do?

A

Release mediators (5-hydroytryptamine [5-HT aka serotonin] and ADP).

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4
Q

Other than platelets, where else does TXA2 bind to and what does it cause?

A

Vascular smooth muscle cell TXA2 receptors causing vasoconstriction.

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5
Q

What is the vasoconstriction caused by TXA2 augmented by?

A

Mediator 5-HT binding to smooth muscle GPCR 5-HT receptors.

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6
Q

Where does ADP bind to on platelets?

A

GPCR purine receptors (P2Y12).

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7
Q

What binds fibrinogen on the platelets and what increases the expression of these?

A

Platelet glycoprotein (GPIIb/IIIa).

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8
Q

What 3 things do purine receptors do once ADP binds to them?

A
  1. Act locally to activate further platelets.
  2. Aggregate platelets into a soft plug at site of injury (through increased GP expression).
  3. Expose acidic phospholipids on the platelet surface that initiate coagulation of blood and solid clot formation.
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9
Q

What factors form tenase and what does this enzyme do?

A

IXa and VIIIa. They activate factor X.

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10
Q

What factor does Xa bind to and what does this make?

A

Va, makes prothrombinase.

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11
Q

What enzyme converts prothrombin into thrombin?

A

Prothrombinase.

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12
Q

What does thrombin do?

A

It converts fibrinogen into fibrin which forms a solid clot.

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13
Q

Describe an arterial thrombus.

A

White thrombus, mainly platelets in fibrin mesh, forms an embolus if detaches that can cause stroke.

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14
Q

What are arterial thrombi primarily treated with?

A

Antiplatelet drugs.

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15
Q

Describe a venous thrombus.

A

Red thrombus, white head with jelly-like red tail, fibrin rich, embolus usually lodges in lung.

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16
Q

What are venous thrombi primarily treated with?

A

Anticoagulants.

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17
Q

How do the precursors of factors 2, 7, 9 and 10 become active?

A

Post translationally modified by gamma-carboxylation of glutamate residues.

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18
Q

What kinds of enzymes are 2a, 7a, 9a and 10a?

A

Serine proteases.

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19
Q

What does the carboxylase that mediates gamma-carboxylation require as an essential cofactor?

A

Vitamin K in its reduced form.

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20
Q

What is the enzyme that reduces vitamin K and what drug blocks it?

A

Vitamin K reductase, warfarin.

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21
Q

What is vitamin K, the reduced and the oxidised form of vitamin K called?

A

K - quinone. Reduced - hydroquinone. Oxidised - epoxide.

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22
Q

Does warfarin block coagulation in vivo and in vitro?

A

No, only in vivo.

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23
Q

Why does warfarin have a slow onset of action (2-3 days)?

A

Inactive factors need to replace active ones that are slowly cleared from the plasma.

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24
Q

How long is warfarin’s half life?

A

Usually about 40 hours.

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25
Q

How may and OD of warfarin be treated?

A

Administration of vitamin K1 (as phytomenadione) or a concentrate of plasma clotting factors (IV).

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26
Q

What are the factors that increase the action of warfarin?

A

Liver disease (decreased clotting factors), high metabolic rate (increased clearance of clotting factors), drug interactions e.g. antiplatelets, vitamin K affectors, inhibit hepatic metabolism of warfarin.

27
Q

What are the factors that lessen warfarin action?

A

Pregnancy (increased clotting factor synthesis), hypothyroidism (decreased degradation of clotting factors), vit K consumption, drug interactions.

28
Q

How does antithrombin III inhibit the coagulation cascade?

A

Neutralises all serine protease factors e.g. Xa and IIa by binding to their active site.

29
Q

What does heparin bind to and how does it work?

A

Binds to antithrombin III. It increases its affinity for factors (particularly Xa and IIa) to greatly increase their rate of inactivation.

30
Q

What is the difference between the inactivation of IIa and Xa with the binding of heparin?

A

Heparin must bind to both AT III and IIa to inactivate, only needs to bind to AT III to inactivate Xa.

31
Q

What type of molecule is heparin?

A

A naturally occurring sulphated glycosaminoglycan of variable molecular size.

32
Q

Where is heparin extracted from and how is it classified?

A

From offal, preparations have variable potency that are specified in units of activity.

33
Q

Give 2 examples of low molecular weight heparins?

A

Enoxaparin and dalteparin.

34
Q

When would you use heparin instead of LMWH and why?

A

In renal failure (LMWHs are eliminated via renal excretion).

35
Q

What factor does LMWH inhibit?

A

Factor Xa.

36
Q

How are heparin and LMWH administered?

A

Heparin either IV (immediate onset) or SC (delayed onset by 1 hour). LMWH is SC.

37
Q

What kind of test is required for heparin but not LMWH to determine optimum dosage?

A

An in vitro clotting test.

38
Q

What order of elimination is heparin and LMWHs?

A

Heparin - zero order. LMWH - first order.

39
Q

What are the common and rare adverse effects of heparin/LMWH?

A

Common: haemorrhage.
Rare: osteoporosis (long term treatment), hypoaldosteronism, hypersensitivity reactions.

40
Q

What would you give to inactivate heparin and how is it administered?

A

Protamine sulfate IV.

41
Q

Give 2 examples of direct oral anticoagulants and what factor they inhibit.

A

Dabigatran etexilate - thrombin. Rivaroxaban - Xa.

42
Q

What are the advantages of DOACs?

A
  1. They are convenient to administer.

2. They have a predictable degree of anticoagulation.

43
Q

What is a major disadvantage of DOACs?

A

There is no specific agent available to reduce haemorrhage in overdose.

44
Q

What are DOACs currently used for?

A

To prevent venous thrombosis in patients undergoing hip and knee replacements.

45
Q

What is the antiplatelet mechanism of action of aspirin?

A

Irreversibly blocks cyclo-oxygenase (COX) in platelets preventing TXA2 synthesis.

46
Q

What is the thrombotic mechanism of action of aspirin?

A

Blocks COX in endothelial cells inhibiting production of prostaglandin I2 (PGI2).

47
Q

Why does aspirin have an overall antithrombotic effect?

A

Endothelial cells can synthesis new COX but platelets can’t so TXA2 synthesis doesn’t recover till platelets replaced.

48
Q

What is the main adverse effect of aspirin?

A

GI bleeding and ulceration.

49
Q

What does clopidogrel require to work?

A

Hepatic metabolism (is a prodrug).

50
Q

What is clopidogrel’s mechanism of action?

A

Irreversibly inhibits ADP receptor (P2Y12) by linking to it with a disulphide bond.

51
Q

When would clopidogrel be used?

A

In patients intolerant to aspirin, when combined with aspirin has a synergistic action.

52
Q

When would tirofiban be given?

A

IV in short term treatment to prevent MI in high risk patients with unstable angina (alongside aspirin and heparin).

53
Q

Describe the natural way that clots are broken up in the body.

A

Plasminogen is converted into plasmin by endogenous tissue plasminogen activator (tPA). Fibrin is then broken up by plasmin into fibrin fragments.

54
Q

What are the mechanims of streptokinase, alteplase and duteplase?

A

They activate plasminogen.

55
Q

When are fibrinolytic drugs used often and less often?

A

Often - in acute MI or stroke. Less often - life threatening venous thrombosis or PEs.

56
Q

How are fibrinolytic drugs administered?

A

IV within as short as period as possible of the event.

57
Q

What drug do fibrinolytic drugs have a beneficial effect with?

A

Aspirin.

58
Q

What is streptokinase and where do we get it?

A

A protein (not an enzyme), cultures of streptococci.

59
Q

How long is it before streptokinase is useless?

A

After 4 days (action blocked by generation of antibodies).

60
Q

When should you not give streptokinase and why?

A

Patients with recent streptococcal infections, may cause allergic reactions.

61
Q

What are alteplase and duteplase described as?

A

Recombinant tissue plasminogen activator (rt-PA).

62
Q

What type of plasminogen are alteplase and duteplase more effective on?

A

Fibrin bound plasminogen (as opposed to plasma plasminogen) so show selectivity for clots.

63
Q

Why are alteplase and duteplase given by IV infusion?

A

They have a short half life.

64
Q

How may haemorrhage caused by fibrinolytics be controlled?

A

By oral tranexamic acid (inhibits plasminogen activation).

Cardiovascular (32 decks)

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