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Block C - Circulation > Pharmacology Lecture 4: Anticoagulant and Fibrinolytic Drugs > Flashcards

Pharmacology Lecture 4: Anticoagulant and Fibrinolytic Drugs Flashcards

1
Q

Purpose of anticoagulants and fibrinolytic drugs

A

Treat or prevent thromboembolism

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2
Q

Behavior of blood in normal individual in terms of clotting

A

Blood remains fluid in vessels
Clot when vascular injury occurs
If intravascular thromus is formed, prompt dissolution by a fibrinolytic system
Hemostasis in damaged vessels if bleeding occurs

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3
Q

5 anticoagulant drugs of interest

A

Heparin
Low molecular weight heparing
Oral antiagulants (dabigatran, rivaroxaban, warfarin)

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4
Q

2 fibrinolytic drugs of interest

A

Streptokinase

Alteplase (recombinant tissue plasminogen activator)

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5
Q

Define heparin

A

Mixture of sulphated mucopolysaccharides from mast cells

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6
Q

Heparin function

A

Acts as a cofactor for antithrombin (III) = increase rate of thrombin-antithrombin reaction at least a thousand fold

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7
Q

Location of antithrombin production

A

Liver

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8
Q

Antithrombin function

A

Inhibit activated coagulation factors of the intrinsic and common pathways, most importantly thrombin and factor Xa. Acts as a suicide substrate for these proteases.

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9
Q

How unfractionated heparin is obtained

A

From mast-cell rich tissues in animals (endogenous)

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10
Q

How are doses of unfractionated heparin expressed and why?

A

Units of activity (USP units) because biological activity is similar across commercial preparations despite differences in composition

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11
Q

How to administer heparin

A

Must be injected (given parenterally) because cannot be absorbed through the gastrointestinal mucosa. Usually by continuous vascular infusion

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12
Q

Speed of onset if heparin is given by I.V.

A

Immediate

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13
Q

Speed of onset if heparin is given subcutaneously and consequence

A

Delayed by 1-2 hours

Considerable variation in bioavailability due to macrophage destruction

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14
Q

Define how the pharmacokinetics of heparin is saturatable

A

Most of it is cleared and degraded by the reticulo-endothelial system (fixed amount of macrophages), with a small amount unaltered in the urine

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15
Q

Define continuous vascular infusion

A

Bolus injection followed by maintenance dose delivered by infusion pump

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16
Q

How to monitor heparin in patient who had continuous vascular infusion

A

Activate partial thromboplastin time (aPTT)

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17
Q

How to monitor subcutaneously administrated heparin

A

Once a stable value of aPTT is obtained, can stop lab monitoring

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18
Q

When is unfractionated intravenous heparin used?

A

In hospitalized patients for initial management of pulmonary embolism following DVT and of DVT above knee joint.
Unstable angina and MI

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19
Q

When is unfractionated subcutaneous heparin sometimes used?

A

Bed-ridden or hospitalized patients not receiving intravenous heparin for prevention of DVT

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20
Q

5 side effects of unfractionated heparing (toxicity)

A 
Bleeding
Thrombocytopenia
Allergies
Increased loss of hair (reversible)
Risk of osteoporosis with prolonged therapy
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21
Q

How to prevent bleeding due to unfractionate heparin

A

Adequate patient selection
Careful control of dosage
Close monitoring of aPTT

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22
Q

How common is early transient and harmless thrombocytopenia in unfractionated heparin patients? What is the cause?

A

25% due to platelet aggregation

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23
Q

Potential effect in up to 5% of patients on unfractionated heparin following 5 - 15 days of treatment. What is the significance of this?

A

Development of heparin-induced anti-platelet antibodies (HIT), which can lead to serious bleeding and paradoxical clotting (medical emergency; important to perform frequent platelet counts)

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24
Q

Contraindications for heparin use

A

Thrombocytopenia, bleeding disorders, active peptic ulcer disease, severe hypertension, etc.

Does not cross placenta, but still try to avoid in pregnancy unless necessary

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25
Q

Heparin antagonist

A

Protamine sulfate

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26
Q

When are heparin antagonists required?

A

Only if bleeding is significant (not for minor bleeding since effects will disappear in a few hours after last injection)

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27
Q

How does protamine sulfate inactivate heparin?

A

By binding tightly to it

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28
Q

What is replaced unfractionated heparin in many applications

A

Low molecular weight (LMW) heparin

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29
Q

LMW heparin function

A

Main effect through a catalytic effect on the inhibition of factor Xa (not thrombin) by antithrombin
Less effect on coagulation in general, but comparable to unfractionated heparin in most cases

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30
Q

2 examples of LMW heparin preparations

A

Enoxaparin

Dalteparin

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31
Q

How to administer LMW heparin

A

Given subcutaneously in fixed or weight adjusted dosage once or twice daily

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32
Q

Risk of HIT in LMW heparin

A

Significantly lower than with unfractionated heparin so monitoring not usually required since pharmacokinetics more predictable

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33
Q

Novelty heparin replacement

A

Synthetic selective inhibitors of factor Xa (i.e. fondaparinux)

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34
Q

How to administer fondaparinux

A

Subcutaneously once a day without monitorinf

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35
Q

Problem with fondaparinux

A

Expensive and no antagonist available yet

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36
Q

How was warfarin synthesized/discovered?

A

1924: Hemorrhagic disorder found in cattle that had ingested spoiled sweet clover silage
1939: Agent identified as dicoumarol
1948: warfarin synthesized

37
Q

What was warfarin’s initial use?

A

Rat poison

38
Q

What coagulation factors and anticoagulant proteins are produced mainly in the liver?

A

Factors II, VII, IX, X

Anticoagulant proteins C and S

39
Q

What do the coagulation factors and anticoagulant proteins produced in the liver require and why?

A

Reduced vitamin K for the carboxylation of certain glutamate residues

40
Q

What is the consequence of vitamin K absence on coagulation factors?

A

Abnormal coagulation factors of formed = do not work

41
Q

What is the speed of full onset of warfarin effect? Why?

A

A few days since some factors have very long half lives (i.e. 50 hour for factor II)

42
Q

How to administer warfarin

A

Well absorbed orally

43
Q

Speed of plasma detection and concentration peaks

A

Plasma detection = 1 hour

Peak = 2 - 8 hours

44
Q

What does warfarin bind to?

A

Plasma proteins

45
Q

Warfarin and pregnancy

A

Avoid at all costs since it crosses the placenta easily –> bleeding in fetus and malformations

46
Q

Where is warfarin metabolized and into what?

A

Metabolized into inactive metabolites in liver and kidney

47
Q

Plasma half life of warfarin

A

Varies from 25 - 60 hours (average 40)

48
Q

Duration of warfarin action

A

2 - 5 days

49
Q

What do we use to monitor warfarin?

A

INR (international normalized ratio)

50
Q

Why is it important to maintain a therapeutic INR level?

A

For effective therapy and to reduced bleeding complications

51
Q

Clinical uses of warfarin

A

Long term anti-coagulation
Prevent progression or recurrence of DVT above knee joint (w/ or w/o PE complications) after initial heparin treatment
Indefinitely to prevent strokes in atrial fib. or prosthetic valve patients

52
Q

How to pharmacologically treat DVT above knee joint complicated or not with pulmonary embolism

A

Initially LMW heparin for 7-10 days as it overlaps with warfarin for 3 - 5 days (since onset of action is slow)

53
Q

How long is warfarin treatment kept for?

A

3 - 6 months

54
Q

Major toxicity of coumarin anticoagulants such as warfarin

A

Bleeding

55
Q

Important cause of bleeding with warfarin

A

Drug interactions

56
Q

How to treat patient with bleeding due to warfarin

A

Give fresh plasma or coagulation factor concentrates and vitamin K1

57
Q

Conditions or drugs are potentially dangerous in patients taking warfarin is they alter (3)…

A

Uptake or metabolism of warfarin or vitamin K
Synthesis, function or clearance of clotting factors and other elements involved in hemostasis or fibrinolysis
Integrity of epithelia

58
Q

New oral anticoagulants

A

Dabigatran
Rivaroxaban
Apixaban

59
Q

Purpose of new oral anticoagulants

A

Improve the ease of use, safety and efficacy of oral anticoagulants

60
Q

Dabigatran function

A

Direct thrombin inhibitor

61
Q

How is dabigatran administered?

A

As a prodrug (dabigatran etexilate) –> broken down in the body to dabigatran
Lab monitoring not required

62
Q

Onset and half-life of dabigatran

A

Rapid onset

Plasma half-life = 12 - 16 hours (in patients with normal renal function)

63
Q

Current approval for dabigatran

A

Prevention of stroke in patients with non-valvular atrial fib
Prevent thromboembolism in patients who have undergone hip or knee replacement surgery

64
Q

Advantage of dabigatran over warfarin

A

Incidence of bleeding is the same or better

No experience in pregnancy (but doesnt mean no effect)

65
Q

Disadvantage of dabigatran relative to warfarin

A

More expensive

No specific antagonist yet (in clinical trials)

66
Q

Rivaroxaban function

A

Direct factor Xa inhibitor

67
Q

Rivaroxaban uses

A

Prevention/treatment of pulmonary embolism, DVT
Prevention of stroke in patients with atrial fib
Prevention of thromboembolism after knee or hip replacement surgery

68
Q

What does drug elimination depend on for rivaroxaban?

A

Renal function

69
Q

What is the status of the bleeding risk profile of rivaroxaban?

A

Acceptable

70
Q

Disadvantage of rivaroxaban

A

No specific antagonist yet

No experience in pregnancy

71
Q

Apixaban function

A

Factor Xa inhibitor (most recently approved)

72
Q

What has apixaban been approved for?

A

Prevention of stroke in patients with non-valvular atrial fib
Prevent thromboembolism in patients who have undergone hip or knee replacement surgery

73
Q

General function of fibrinolytic drugs

A

Catalyse the formation of plasmin from plasminogen, leading to the lysis of thrombi

74
Q

Effect of fibrinolytic drugs given intravenously

A

Generalized lysis of thrombi = BOTH of the protective hemostatic thrombi AND targeted pathological thrombi

75
Q

Define streptokinase

A

Protein synthesized by B-hemolytic streptococci

76
Q

Disadvantage of streptokinase

A

Risk of serious allergic reaction when given a second time, so rarely used today

77
Q

Define alteplase

A

Recombinant tissue plasminogen activator (tPA)

78
Q

Alteplase function

A

Preferentially activate plasminogen bound to fibrin

Theoretically limits fibrinolysis to formed thrombi to avoid systemic activation

79
Q

How to administer alteplase

A

Intravenous infusion

80
Q

Define tenecteplase

A

A mutant form of tPA with a longer half-life

81
Q

How to administer tenecteplase

A

Bolus injection (rather than IV infusion since longer half-life)

82
Q

Clinical uses of fibrinolytic drugs (4)

A

1) Acute MI with ST elevation (first 6 hours after infarction, particularly if percutaneous coronary intervention not available)
2) Large (or multiple) pulmonary emboli
3) Dissolve clots in blocked central catheters
4) Ischemic stroke (first 3 hours)

83
Q

Subsequent treatment after administering fibrinolytic drugs

A

Aspirin and clopidogrel

84
Q

Major risks of fibrinolytic drugs

A

Hemorrhage

Conversion of an ischemic stroke into a hemorrhagic stroke

85
Q

2 mechanisms by which fibrinolytic drugs cause hemorrhage

A

Lysis of “physiological” thrombi

Induction of a systemic lytic state

86
Q

Antagonist for fibrinolytic drugs

A

Aminocaproic acid

87
Q

Aminocaproic acid

A

Block the binding of plasmin to fibrin = stop bleeding due to fibrinolytic drugs (not devoid of risks)

88
Q

Contraindications for fibrinolytic drugs (6)

A

1) Recent surgery
2) Serious gastro-intestinal bleeding in last 3 months
3) Hypertension
4) Active bleeding or hemorrhagic disorder
5) Previous cerebrovascular event
6) Aortic dissection or acute pericarditis

Block C - Circulation (26 decks)

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