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MBBS II HIS > L30 - Anticoagulant therapy > Flashcards

L30 - Anticoagulant therapy Flashcards

1
Q

Mechanism of platelet plug formation?

A

1) Damaged endothelial cells (wall defect) expose collagen for GP Ib on resting platelets to stick to through von Willebrand’s factor (vWF)
2) Activated platelets degranulate (ADP, TXA2, 5-HT)&raquo_space; bind to receptors on platelets&raquo_space; express GP IIb/IIIa (= receptor for fibrinogen)&raquo_space; form fibrin

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2
Q

Which coagulation pathway initiates immediate clotting?

A

Extrinsic pathway

TF/Factor 7a complex form within seconds

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3
Q

List 3 major physiological responses to blood vessel damage?

A

• Vasoconstriction • Platelet plug formation • Coagulation

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4
Q

Compare the activators of intrinsic and extrinsic pathways

A

Intrinsic = response to damage to endothelial cells or phospholipids released by activated platelets

Extrinsic = “tissue factor” leaks into the blood

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5
Q

2 major factors of thrombosis?

A
  1. Endothelial injury, e.g.:
     Hypertension
     Hyperlipidemia, diabetes mellitus (oxidative stress)
     Infection (inflammation of endothelium)
  2. Abnormal/turbulent blood flow, e.g.:
     Atherosclerotic plaques
     Cardiac arrhythmias
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6
Q

Name the 3 classes of anticoagulants and their function?

A

Antiplatelet agents*: inhibit Platelet adhesion, activation and aggregation

Anticoagulants*: inhibit activation of coagulation cascade

Thrombolytic agents: Breakdown formation of thrombus

  • = prevention only
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7
Q

Name 4 antiplatlet agents?

A
  1. Cyclooxygenase (COX) inhibitor (aspirin)
  2. ADP receptor antagonists (clopidogrel, prasugrel)
  3. Glycoprotein (GP) IIb/IIIa receptor inhibitors
  4. Dipyridamole
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8
Q

Indication for low dose aspirin?

A

primary prevention of myocardial infarction (heart attack), ischemic stroke

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9
Q

Indication for Clopidogrel, prasugrel?

A

cannot tolerate aspirin (e.g. stomachache)

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10
Q

Indication for aspirin + clopidogrel?

A

(synergistic): e.g. after coronary angioplasty, stenting = prevent thrombosis

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11
Q

MoA of aspirin?

A

1) Forms covalent bond to irreversibly inhibit cyclooxygenase-1 (COX-1: cannot turn arachidonic acid (from membrane phospholipids) into prostaglandin H2)
2) Block thromboxane A2 (TXA2) synthesis in platelet
3) Decrease platelet aggregation

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12
Q

ADR of aspirin and clopidogrel?

A

Aspirin Increase incidence of gastric irritation, bleeding
= avoid in patients with peptic ulcer

Both increase Risk of prolonged bleeding

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13
Q

MoA of ADP receptor antagonists?

A

block P2Y receptors (= ADP receptor) = inhibit ADP-mediated platelet aggregation (cannot activate GPllb/IIIa receptors)

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14
Q

MoA of Glycoprotein (GP) IIb/IIIa receptor inhibitors? Give 3 examples?

A

1) Abciximab = monoclonal antibody to glycoprotein IIb/IIIa receptors
2) Eptifibitide, tirofiban = reversible blockers of glycoprotein IIb/IIIa receptors

Block GP IIb/IIIa receptors = prevent binding of fibrinogen to platelets = decrease platelet aggregation

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15
Q

Indication for GP IIb/IIIa receptor inhibitors?

A

given IV during coronary angioplasty, stenting

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16
Q

MoA of Dipyridamole? (2)

A

Increase cAMP in plt = prevent aggregation

  1. Inhibits phosphodiesterase&raquo_space; cannot break down cAMP&raquo_space; Increase intracellular cAMP levels in platelet
    » decrease Ca2+
    » inhibit platelet aggregation
  2. Inhibits cellular reuptake of adenosine into platelets&raquo_space; increase extracellular [adenosine]&raquo_space; more can stimulate adenosine (A2) receptor
    » more adenylate cyclase converts ATP to cAMP
    » Decrease Ca2+
    » inhibit platelet activation, aggregation
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17
Q

Preparation of Dipyridamole?

A

Ineffective when used alone

usually given in combination with aspirin / warfarin

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18
Q

Name 4 types of anticoagulants?

A

Heparin

Direct thrombin inhibitors

Direct factor Xa inhibitors

Warfarin

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19
Q

List 3 parental and one oral direct thrombin inhibitor?

A

Oral: dabigatran ***

Parental:
 Hirudin (from leech saliva) ***
 Lepirudin (recombinant/synthetic form of hirudin)
 Argatroban (small molecule)

20
Q

MoA of direct thrombin inhibitor?

A

Inhibit thrombin = cannot catalyze Fibrinogen to fibrin = decrease fibrin formation

21
Q

List 3 Direct factor Xa inhibitors?

A

 Rivaroxaban, apixaban, endoxaban

All orally active

22
Q

MoA of Warfarin?

A

1) inhibits vitamin K epoxide reductase (exam)
2) less reduced vitamin K available to convert non-functional precursors to functional clotting factors by γ- carboxylation of Gla domain on prothrombin, factor 7,9,10&raquo_space; cannot link with phosphatidylserine on platelet membrane
3) Decrease synthesis of clotting factors = reduce clotting

23
Q

Indication of warfarin?

A

Prevent:

  • Thrombosis with AFib
  • Venous thrombosis and Pulmonary embolism
  • Heart valve causing clot
24
Q

Warfarin is orally active and can achieve maximum effect immediately after taking. T or F?

A

Partially false:

  • Orally active = OK
  • Maximum effect Takes 48-72 hours (2-3 days) due to long half-time of clotting factors
25
Q

C/O and ADR of warfarin?

A

1) Bleeding (bruises, epistaxis, gum bleeding)
2) Interaction with significant number of drugs (displace protein bound and CYP450 metabolized drugs)
3) Cross placenta (should not be used during pregnancy = use heparin instead)

26
Q

How to reverse effects of Warfarin?

A

 Stop using drug  Give vitamin K

27
Q

MoA of Heparin?

A

1) bind to antithrombin via a specific pentasaccharide sequence
2) Cause Conformational change in antithrombin&raquo_space; Increase binding affinity for thrombin and factor 10a&raquo_space; limit coagulation cascade
3) Inhibit thrombin and factor 9a, 10a, 11a, 12a = decrease coagulation affect intrinsic pathway the most = prolonged aPTT

28
Q

Indications for heparin?

A

Immediate / short-term anticoagulation (Warfarin is longer term)

 Prevent deep vein thrombosis, pulmonary thromboembolism
 During and after angioplasty and stenting
 After myocardial infarction

29
Q

Admin of heparin?

A

IV (or deep subcutaneous)

30
Q

Which anticoagulant can be safely used in pregnant women?

A

Heparin

does not cross placenta  suitable for use in pregnancy

31
Q

ADR of heparin?

A
  1. Bleeding (easy bruising, epistaxis, gum bleeding), Haemophilia
  2. Hypersensitivity (allergic to heparin)
  3. Heparin-induced thrombocytopenia
32
Q

Explain the MoA of Heparin-induced thrombocytopenia?

A

1) Develops IgG antibody against PF4 on heparin
2) heparin + IgG + PF4 complex interacts with platelets

3) i) Platelet release procoagulants = thrombosis
ii) Splenic macrophages remove platelet

33
Q

Reversal of heparin action?

A

1) Stop using drug

2) Protamine sulfate: combines with heparin as a stable complex = decrease
anticoagulant activity of heparin

3) Direct thrombin inhibitor

34
Q

Name 2 other variants of heparin and their structure? PK compared to regular heparin?

A
  1. Low-molecular-weight heparin, e.g. enoxaparin: same pentasaccharide sequence as regular heparin
  2. Fondaparinux: pentasaccharide sequence only

Both have much higher bioavailability and longer t1/2

35
Q

MoA of Fondaparinux?

A

 Increases antithrombin binding to factor Xa

 No effect on antithrombin binding to thrombin

36
Q

Which heparin variants are reversible?

A

Heparin and Low molecular weight heparin only by Protamine sulphate

Not Fondaparinux

37
Q

Which heparin variant needs monitoring?

A

Heparin only

Highly variable response, elimination, plasma conc

38
Q

What coagulation test is used to monitor heparin?

A

aPTT (activated partial thromboplastin time) = intrinsic and common pathway

> > Heparin binds to antithrombin&raquo_space; antithrombin/heparin complex binds thrombin and factor Xa (and IX, XI and XII) to increase clotting time

39
Q

What’s mixed together in aPTT test?

A

Kaolin (surface activator)
Ca
Phospholipid (partial thromboplastin)
Citrated plasma

40
Q

What coagulation test is used to monitor warfarin?

A

PT = Evaluates extrinsic pathway

Warfarin decrease synthesis of clotting factors (prothrombin, factors VII, IX and X) = increase clotting time

Target INR value = 2-3

41
Q

What’s mixed together in PT test?

A

Thromplastin (Phospholipid + tissue factor) + Ca + citrated plasma

42
Q

List 4 thrombolytic drugs?

A

 Alteplase (recombinant tissue type plasminogen activator (tPA))

 Streptokinase (from bacteria)

 Anistreplase (streptokinase plasminogen complex)

 Urokinase (endogenous protease obtained from human fetal kidney cells)

43
Q

MoA of thrombolytic drugs?

A

activate the formation of plasmin from plasminogen (precursor)&raquo_space; break down fibrin&raquo_space; lyse thrombi and remove blood clot

44
Q

Indication of thrombolytic drugs?

A

(for emergency use):
 Pulmonary emboli
 Deep venous thrombosis
 Acute myocardial infarction

45
Q

ADR and Reversal of thrombolytic drugs?

A

ADR = bleeding

Tranexamic acid: binds to plasminogen, plasmin = inhibits plasminogen activation

Fresh plasma

Coagulation factors

MBBS II HIS (30 decks)

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