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Pharmacology > Anticoagulants > Flashcards

Anticoagulants Flashcards

Inc. antiplatelets, TXA and thrombolytics.

1
Q

Define thrombus…

A

A mass of clotted blood within the lumen of a blood vessel, adhered to the wall of the vessel.

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2
Q

Define embolus…

A

An entity within a blood vessel which has migrated from its site of origin to a distal site.

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3
Q

Venous Thrombus

A

Lots of RBC’s and fibrin. Fewer platelets but those present are well distributed.

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4
Q

Arterial Thrombus

A

Typically a result of atherosclerotic plaque rupture. Many platelets but these are not evenly distributed, instead existing in the white areas of the Lines of Zahn. Little fibrin.

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5
Q

Which anticoagulant would be most suited to an arterial thrombus?

A

Anti-platelet agents + Fibrinolytics. Crossover with other drug classes possible.

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6
Q

Which anticoagulant would be most suited to a venous thrombus?

A

Parenteral anticoagulants (heparins) and oral agents (Warfarin/ DOACs/ NOACs). Crossover with other drug classes possible.

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7
Q

What is the most important site at which platelets bind to each other in aggregation.

A

Glycoprotein IIb/IIIa. These join together to allow platelets to aggregate forming the initial platelet plug.

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8
Q

Name some agents which serve to activate or up-regulate GPIIb/IIIa receptors on platelets:

A
  • ADP
  • TXA2 (Thromboxane)
  • Thrombin
  • (Fibrin)
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9
Q

Exposure to what substances in the vessel wall activates platelets/ the clotting cascade?

A
  • Collagen
  • vWF (Von Willebrand Factor)
  • Tissue factor
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10
Q

What effect does the prostaglandin PGI2 have on platelet aggregation?

A

It down regulates receptors and inhibits GPIIb/IIIa activation. Coagulability influenced by its level relative to that of Thromboxane.

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11
Q

Name a COX inhibitor anticoagulant…
What process does it inhibit?
At what does does it have these prophylactic anticoagulant effects?

A

Aspirin!
Inhibits COX1 preferentially preventing the conversion of Arachidonic Acid to Thromboxane A2 (TXA2). This provides irreversible inhibition of platelet aggregation.
This works over the long term at a dose of 75mg which is lower than the 300mg used for analgesia or in acute MI.

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12
Q

What are some important side effects of Aspirin?

A

Higher doses can inhibit the formation of PGI2 having a functional antagonistic effect. It prolongs bleeding time so may lead to haemorrhagic stroke / peptic bleeding.

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13
Q

Half life and metabolism of Aspirin…

A

Metabolised into Salicylic Acid in the liver. Polymorphisms in COX1 in some people can decrease efficacy.

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14
Q

How long will the effect of Aspirin last, making reference to the lifetime of a platelet.

A

Platelet lasts 7-10 days so Aspirin also lasts this long. It is important that this is considered in anaesthetic pre assessment clinics before surgery.

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15
Q

Clinical indications for Aspirin.

A
  • Second line in preventing strokes if other agents contraindicated.
  • Part of the picture in preventing ACS, esp. in stable angina and peripheral vascular disease.
  • Part of dual antiplatelet therapy post PCI/stenting.
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16
Q

Give some examples of drugs in the P2Y12 class?

A

Clopidogrel, Prasugrel, Ticagrelor.

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17
Q

What is the MOA of Clopidogrel?

A

Inhibits binding of the platelet activator ADP to P2Y12 receptors, preventing the subsequent activation of GPIIb/IIIa receptors.

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18
Q

Important pharmacokinetics of Clopidogrel.

A

These are pro-drugs, metabolised in the liver, giving a 7-8hr half life. Onset of action is slow so a loading dose is given to allow for a more predictable onset of action. Useful post thromboembolic stroke/post MI.

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19
Q

How does Ticagrelor differ from Clopidogrel?

A

More expensive, large study suggests small (stat sig) increase in efficacy. It is an active drug as packaged, not a prodrug.

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20
Q

Glycoprotein IIb/IIIa inhibitors

A

Abciximab, Tirofiban, Eptifibatide.

All target the final step in the aggregation pathway ( GPIIb/IIIa).

21
Q

Abciximab MOA

A

A mAb that binds to Glycoprotein IIb/IIIa irreversibly preventing platelet aggregation. IV INFUSION w loading bolus

22
Q

Tirofiban MOA

A

A synthetic peptide which binds to Glycoprotein IIb/IIIa reversibly. IV INFUSION w/ loading bolus

23
Q

Eptifibatide

A

Non peptide reversible antagonist of Glycoprotein IIb/IIIa. IV infusion w/ loading bolus.

24
Q

What are the advantages of the direct GPIIb/IIIa inhibitors over drugs such as Clopidogrel/Aspirin?

A

With the exception of Abciximab these are reversible and so platelets recover their ability to aggregate quicker.

25
Q

What is the main side effect of the direct GPIIb/IIIa inhibitors?

A

THROMBOCYTOPENIA, check platelet counts after a few hours on infusion.

26
Q

What is Dipyridamole?

A

This is a phosphodiesterase inhibitor which acts as an anticoagulant in the prevention of strokes/TIA and as an adjunct to warfarin after valve replacements. It prevents cellular reuptake of adenosine, keeping levels outside the cells high so that it acts on A2 receptors preventing platelet aggregation. Also prevents breakdown of cAMP/cGMP inhibiting the expression of GPIIb/IIIa.

27
Q

How does streptokinase work?

A

Forms a complex with plasminogen, catalysing the conversion of other plasminogens into the active fibrinolytic protein plasmin.

28
Q

What does antigenicity mean in the context of Streptokinase?

A

Exposure to it sensitises the body to the drug so administering a second time will result in a hypersensitivity reaction.

29
Q

Alteplase MOA?

When is it used?

A

It is a direct (tissue) plasminogen activator. It activates plasminogen to plasmin which then breaks down fibrin.
Used in PE when there is haemodynamic instability and in MI when PPCI is not possible in a timely manner.

30
Q

How does Warfarin work?

A

It inhibits the production of of clotting factors 2, 7, 9 and 10 by preventing the conversion of Vitamin K to its active form by the enzyme VK Epoxide Reductase. This effects all of the blood clotting pathways by depleting the body of factors OVER THE TIME COURSE OF DAYS.

31
Q

What are some potential issues with Warfarin?

A

Haemorrhage.
Occurs in a racemic mixture which is highly person specific so we have to monitor INR to ensure that blood clotting is in optimum zone.

32
Q

When would Warfarin be used?

A

Anytime, as long as it is not an acute problem in which case a covering heparin would be needed. Used in PE, DVT and AF as well as after valve replacements and in Protein C and Protein S deficiencies (Proteins C and S are natural anticoagulants).

33
Q

How is Warfarin carried in the blood and what are the clinical implications of this?

A

It is protein bound so other drugs may affect its transport by displacing it etc. This is why we should monitor INR regularly in patients undergoing treatment changes.

34
Q

Warfarin in Pregnancy?

A

No! It is teratogenic in the 1st Trimester and carries a risk of brain haemorrhage in the 3rd.

35
Q

Which CYP is involved in Warfarin metabolism?

A

CYP 2C9.

36
Q

What is the INR?

A

INR = Patient’s Prothrombin Time/Normal Prothrombin Time.
This is used as PT is a measure of the extrinsic pathway and the major factor here (7) is the most sensitive to changes in Vitamin K metabolism.

37
Q

Managing bleeding in a patient on Warfarin!

A

Stop the drug!
Give Vitamin K
Octaplex ( Prothrombin Complex Concentrate)
FFP if situation is an emergency.

38
Q

Warfarin Interactions?

A

There are many, most of which potentiate anticoagulation.

  • Alcohol intoxication, amiodarone and metronidazole decrease CYP 2C9 metabolism, increasing INR.
  • NSAID’s increase INR by displacing Warfarin from albumin.
  • Cephalosporins eliminate gut bacteria that produce Vitamin K, increasing INR.
  • Barbituates and Phenytoin induce CYP 2C9 and thus decrease the activity of Warfarin.
39
Q

Target INR’s

A

DVT, PE and AF: We aim for a target of 2.5 +/- 0.5
For mechanical valves or recurrent thrombotic episodes we aim for 3.5 +/- 0.5.
This higher target significantly increases bleeding risk.

40
Q

How do heparins work?

A

They form a complex with the naturally occurring protein ANTI-THROMBIN III and increases (by 1000 times) the speed at which this inactivates clotting factors, specifically factor X and Thrombin. To inactivate factor Xa only ATIII needs to be bound but to inactivate thrombin both this and ATIII must be bound.

41
Q

Different types of heparin…

A

Unfractionated Heparin: Given IV, shorter half life.

LMWH (-parin): Given SC, can be given by patients at home, longer half life of c.2hrs vs 30 mins.

42
Q

What is the advantage of LMWH?

A

Dose response more predictable (only targets Xa and doesn’t bind to other cells/plasma proteins), not as likely to cause thrombocytopenia as UFH. SC administration is easier.

43
Q

Why would you use UFH?

A

Useful if fast anticoagulation is needed in acutely unwell patients where it is given by IV infusion. Usage increasingly niche as LMWH is widespread nowadays. Does have the advantage, because of its longer length, of also being able to inactivate thrombin.

44
Q

Indications for heparins?

A

Acute PE, DVT, (AF). Quicker onset than Warfarin which is more of a maintenance drug. Heparins are preferred to Warfarin in cancer related hypercoagulability. Used in VTE prophylaxis. Useful in pregnancy as they do not cross placenta.

45
Q

Major Heparin ADR’s

A
  • Bleeding! Elderly people / those with carcinoma at a higher risk.
  • Heparin Induced Thrombocytopenia (an autoimmune response typically 5 - 14 days after initiation). Can lead to paradoxical thrombosis as more platelets become activated.
  • More rarely, you can get osteoporosis and hypersensitivity.
46
Q

What is the ‘antidote’ to Heparin?

A

PROTAMINE SULPHATE. Acts to dissociate hepatin from ATIII. Effect on UFH>LMWH.

47
Q

How does Fondaparinux work?

A

Selectively inhibits Xa by binding to ATIII (just like LMWH) but can’t be reversed by protamine sulphate. Minimal monitoring needed.

48
Q

Direct Xa Inhibitors…

A

Apixaban/Rivaroxaban. Directly inhibit Xa.

49
Q

Direct thrombin inhibitors…

A

Dabigatran. Directly inhibits thrombin.

Pharmacology (10 decks)

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