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PNS > Anticoagulants and fibrinolytics > Flashcards

Anticoagulants and fibrinolytics Flashcards

1
Q

What are the common therapeutic applications of anti-coagulants?

A

Alonside aspirin and antiplatelets = used to treat unstable angina and prevent STEMi.

Used prophylactically to reduce risk of stroke, TIA and Deep vein thrombosis + Pulmonary embolism…. (Risk with Atrial fibrillation)

Thromboprophylaxis = before, during and after surgeries as well as broken/fractured bones….
= AFter a hip/knee replacement or during a heart surgery..

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2
Q

What are common adverse reactions to anti-coagulants?

A

Subcutaneous haemorrhages.

Bleeding.

Immune thrombocytopenia = reduced platelets with heparins/LMWHs (complexed with Platelet factor 4)…
(Less common with Fondaparinux)!!!

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3
Q

Adverse reactions to warfarin?

A

Teratogenicity = DONT GIVE TO PREGNANT WOMEN!!!

As well as subcutaneous haemorrhage and bleeding.

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4
Q

Adverse reactions to heparin?
+ Fondaparinux?

A

Heparin and LMWHs can cause:
Bleeding + Subcutaneous haemorrhage.

Immune thrombocytopenia = reduced platelets = NOT with Fondaparinux
With long term use lead to Osteoporosis…

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5
Q

Adverse reactions to Protamine sulfate?

A

HYPERSENSITIVITY + ANAPHYLAXIS.
Antidote to UFH unfractionated heparin./.

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6
Q

What is the MoA of fibrinolytics?
What are the fibrinolytics?

A

Ateplase, Streptokinase and Urokinase = recombinant tPA.
= Clot busters.

Plasminogen is precursor of plasmin.
tPA and uPA are endogenous plasminogen activators.. convert plasminogen to plasmin.

Plasmin converts insoluble fibrin into soluble fibrin and dissolves the clot.

Endothelial cell injury inhibits plasminogen activation by releasing PAI-1, which inhibits uPA/tPA….

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7
Q

What are the therapeutic uses of fibrinolytics?

A

In acute myocardial infarction = dissolve thrombus and reduce further ischaemic damage.

Acute thrombotic stroke!!! = recombinant tPA
Thrombembolisms = Streptokinase

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8
Q

What is the antidote to fibrinolytics?

A

Tranexamic acid = Competitive inhibitor of plasminogen activation by blocking the binding sites for tPA and uPa,
which are endogenous plasminogen activators.

= Promoting clot formation…

High doses block plasmin itself - but dose-dependence side effects….

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9
Q

What are the therapeutic uses of Tranexamic acid?

A

Haemorrhage complications in thrombolytic surgery.

Heavy menstrual bleeding.

Prophylaxis in patients with high risk of haemorrhages… haemophiliacs, biopsies…

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10
Q

ADverse effects of Tranexamic acid?

A

Nausea, vomiting + diarrhoea which is dose dependent….

High doses of Tranexamic acid also inhibit plasmin itself..

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11
Q

What are the main steps in extrinsic coagulation cascade?

A

Endothelial layer damage e.g. atheromatous plaque rupture, exposure of subendothelial layer..
= triggers TF release from leukocytes.

TF binds Factor VII = forming active TF:Factor VIIa complex.
TF:Factor VIIa complex cleaves and activates Factor X.

Factor Xa cleaves prothrombin (Factor II) and forms Thrombin (Factor IIa)…
Thrombin (IIa) converts fibrinogen to Fibrin - Fibrinogen bound on GPIIb/IIIa of activated platetets.

Thrombin converts Factor XIII into Factor IIIa = which cross-links soluble fibrin into a stabilising matrix…

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12
Q

Where do the Extrinsic and Intrinsic pathways converge?

A

TF:VIIa complex of extrinsic cascade activates Factor X.

Intrinsic pathway IXa activates Factor X.

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13
Q

What are the bodies endogenous anti-coagulants?

A

ATIII = Anti-thrombin III.
Heparins!
= which inhibit thrombin, Xa, IXa formations…

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14
Q

What is UFH?

A

UFH is a mixture of naturally occurring heparins - mucopolysaccharides = highly negatively charged.

Heparins between 5k-40kDa…

Extracted from blood with the heparins released from Mast cells and basophils!!!

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15
Q

Where are endogenous heparins released from?

A

Endogenous heparins (inhibit Xa and thrombin formation)….
Released by Mast Cells and Basohpils…

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16
Q

What are LMWHs?

A

Low molecular weight heparins:

Fractionated heparins less than 8kDa.

Enoxaparin = 4.5kDa.
Dalteparin = 6kDa.
Tinzaparin = 6.5kDa.

17
Q

What are the MoA’s of UFH and LMWH?

A

UFH and LMWHs bind to ATIII (Anti-thrombin III) to enhance bnding activity to Factor Xa….
= Inhibit the formation of thrombin.

BUT
UFH also inhibit Thrombin itself.

LMWHs and UFH can bind to ATIII to enhance Factor Xa inhibition.

Only UFH are large enough to also bind to ATIII and bind to exosite 2 of thrombin to inhibit thrombin itself too!!

18
Q

What is the anti-thrombin activity of LMWHs?

A

LMWH’s bind to ATIII to enhance binding activity of Factor Xa = inhibiting formation of thrombin from prothrombin….

However, The larger the MW of LMWHs, the more they can also inhibit the activity of Thrombin itself.

Need to occupy ATIII and exosite 2 of thrombin.

19
Q

What is the antidote of UFH?

A

Protamine Sulfate!

Protamine Sulfate is highly positively charged protein, forming inactive ion pair with -ve charge UFH.

= Reversing bleeding + anti-coagulant activity of UFH.

20
Q

What are the cons of Protamine Sulfate?

A

Can cause hyper sensitivity and anaphylactic reaction.

Protamine Sulfate is antidote to UFH, and less effective against LMWHs.

21
Q

What is Fondaparinux?

A

A synthetic anti-coagulant.

Mimics binding site of heparin on ATIII.

Enhance activity of ATIII inhibition of factor Xa

NO ANTIDOTE!!!!
and does not cause thrombocytopenia!

22
Q

What are NOACs?

A

XABAN

Apixaban
Rivaroxaban

Selective, direct inhibitors of Factor Xa (as opposed to enhancing ATIII inhibition of Xa)…

Block formation of thrombin.

= Long lasting anticoagulants.
With an antidote!!! Andexanet alfa (recombinant Factor Xa)

Aswell as Dabigatran

23
Q

What are the Direct Thrombin Inhibitors?

A

Lepirudin and Bivalirudin

RUDIN!!!
= Hirudin analogues/recombinant

Hirudin analogues/recombinants bind to active thrombin (Factor IIa).

Bind to active, free thrombin BUT NOT TO FIBRIN BOUND THROMBIN

24
Q

What is Lepirudin?
Bivalirudin?

A

Lepirudin is irreversible thrombin inhibitor.

But Bivalirudin is a competitive inhibitor with fribrinogen (once bivalirudin is cleaved)…

= BUT ONLY TO FREE ACTIVE THROMBIN!!!

25
Q

What is Dabigatran?

A

A pro-drug NOAC!

Dabigatrin is a rapid, reversible thrombin inhibitor which can inhibit both free and fibrin-bound forms of active thrombin.

To inhibit thrombin induced platelet aggregation.

PLUS HAS ANTIDOTE =Idarucizumab

26
Q

What is the antidote to dabigatran

A

Humanise mAB for Dabigatran NOAC reversible both form of thrombin inhibitor.

27
Q

What is warfarin?

A

Oral anticoagulant, pills indicate dose.

Racemix mixture and S-warfarin is much more potent than R-warfarin.

Metabolised by CYP P450 - particulary S-warfarin = interactions + complex pharmacokinetic interactions…

28
Q

What is the antidote to Warfarin?

A

Vitamin K! (quinone).

The substrate for VKORC1…. needed to form hydroquinone for carboxylation of glutamate residues in prothrombin and Factor X and Factor VII!!1

29
Q

What is the MoA of warfarin?

A

Hydroquinone is a substrate for Glutamyl carboxylase…
Glutamyl carboxylase converts Glutamate residues to Carboxyglutamate in:
ProThrombin, Factor VII, and Factor X!!!

Warfarin competitively inhibits VKORC1 which is innvolved in recylcing reduced Vitamin K into Quinone/Vitamin K and back into Hydroquinone….

= Reduced carboxylation of these residues… interferes with activation of prothrombin by Factor Xa…
Interaction with acidic phospholipids…

30
Q

What are the pros and cons of Warfarin?

A

Antidote = Cheap Vitamin K.
= V. cost effective.

Cons:
Narrow therapeutic window - need to balance risk of haemorrhaging with clotting…

Metabolised by CYP 450…
= polymorphisms aswell as drug interactions.
VKORC1 and CYP2C9 polymorphisms…
= Complex pharmacokinetics.

31
Q

What can affect Warfarin pharmacokinetics?

A

Asian americans are more sensitive to warfarin whilst african americans are more resistant! = VKORC1 polymorphisms
Caucasians = more sensitive due to CYP2C9 polymorphisms.
= Ethnic differenes…

CYP2C9 = fluoxetine, ibuprofen, celecoxib
AMIODARONE!!!! inhibits CYPC29!

32
Q

How can plasma warfarin be increased or decreased?

A

Excess alcohol, albumin displacing drugs like ASPIRIN!!!!!!!, Liver disease.

P450 activators…. excess green food (Vit K), crhonic acloholism = reduced GI absorption..

PNS (14 decks)

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