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CVR 2 > Anticoagulants, Antithrombotics and Thrombolytics > Flashcards

Anticoagulants, Antithrombotics and Thrombolytics Flashcards

1
Q

what are some in vitro anticoagulants?

A

heparin
polyanionic

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2
Q

what is heparin?

A

sulphated glycosaminoglycans (mucopolysaccharides) of variable chain length (unfractionated; 5,000-40,000 Daltons)

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3
Q

what is pilyanionic?

A

Calcium chelators, e.g. citrate and ethylenediamine tetra-acetic acid (EDTA)

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4
Q

what are some in vivo anticoagulants?

A
  1. Heparin or low molecular weight heparin (LMWH) - more consistent effects
    - given as an injection and for atrial fibrillation
  2. Oral anticoagulants- vitamin K antagonists and newer agents (thrombin inhibitors and factor Xa inhibitors)
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5
Q

what is the mechanism of action of heparin?

A
  • Heparin binds to and enhances the action of the endogenous anticoagulant, antithrombin III
  • The heparin-antithrombin III complex binds to and inhibits the action of clotting factors IIa, IXa, Xa, XIa, XIIa
  • Immediate inhibition of clotting - unlike warfarin
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6
Q

what does LMWH target/inhibit?

A

low MW heparins inhibit factor 10a predominantly

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7
Q

what is the difference between heparin and LMWH?

A

-any heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT)
-but, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin
-half the chains of LMWH are long enough

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8
Q

what are the disadvantages of LMWH?

A

-requires dosage adjustment in renal insufficiency. renal function monitoring is required
-cannot be used in patients with HIT once it develops
-longer half-life may prolong risk of bleeding
-only partially (60%) reversed with protamine
-expensive
-bruising at injection site, patient education is required

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8
Q

describe the advantages of LMWH?

A

-high bioavailability of subcutaneous route
-lower incidence of HIT
-no need to monitor PTT
-ideal agent during pregnancy (SC route)

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9
Q

what is the process of administration of heparin and LMWH?

A
  • Not orally active (absorption prevented by high MW and charge) - wont be absorbed in the gut.
  • Given intravenously or sub-cutaneously
  • Does not cross placenta or blood-brain barrier
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10
Q

what can heparin and LMWH be used for?

A
  • Deep venous thrombosis (DVT)
  • Can be used safely in pre-eclampsia of pregnancy (foetus unaffected)
  • in vitro anticoagulant
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11
Q

what are the side effects of heparin?

A
  • Allergic reactions
  • Haemorrhage
  • Heparin-Induced Thrombocytopaenia (HIT)
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12
Q

how would you reverse these side effects?

A
  • Heparin antagonist: protamine
  • (a polycationic protein- binds and inactivates heparin) (cationic would target the anionic negatively charged part of heparin)
  • This is less effective against LMWH
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13
Q

as heparin is administered through injections, what is an example of an oral anticoagulant?

A
  • e.g. warfarin
  • Structural analogue of vitamin K (as seen below)
  • Blocks synthesis of coagulation factors (in the liver)
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14
Q

what is the mechanism of action of warfarin?

A
  • Reduced vit. K is essential for post-ribosomal g-carboxylation of glutamic acid residues at N-terminals of factors II, VII, IX and X
  • Warfarin blocks vit. K reductase, so blocking carboxylation
  • no g-carboxyglutamate residues
    • so no Ca2+ binding
    • so no coagulation
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15
Q

what is warfarin?

A
  • Warfarin is a vitamin K antagonist (antagonists bind to the active site of the enzyme where the normal substare would bind, but does not activate the enzyme and instead blocks it).
  • Warfarin interferes with the post translational gamma carboxylation of glutamic acid residues which results in the factors 2,7,9 and 10.
16
Q

how does warfarin interfere with post translational gamma carboxylation of glutamic acid residues?

A

Since Warfarins structure is similar to Vitamin K, it can competitvely bind to the active site and here inhibits the enzymic reduction reaction of vitamin K to its active Hydroquinone form.

17
Q

what are the uses of warfarin?

A
  • Venous thrombosis
  • To prevent pulmonary embolism
  • To prevent embolism in patients with atrial fibrillation
  • Prophylaxis of thrombosis after insertion of prosthetic heart valves etc.
18
Q

what is the activity of warfarin?

A
  • Active in vivo but not in vitro
  • Effect delayed 1 - 3 days (time for existing pool of functional clotting factors to be replaced by dysfunctional factors)
  • This is because warfarin acts only on new factors and not ones which are previously made so they need to be used first before warfarin can come into play (hence the 1-3 day delay)
  • For this reason, heparin shuld be used for immediate requirement.
19
Q

how is warfarin administered?

A
  • Orally active (more convenient than heparin)
  • 99 % bound to plasma albumin (very little is free)
  • Aspirin displaces warfarin from binding sites on albumin, increasing plasma [warfarin]; aspirin also inhibits platelet function leading to major danger of haemorrhage
20
Q

what are the side effects of warfarin?

A

Haemorrhage

Crosses placenta and blood-brain barrier (should not be used in pre-eclampsia of pregnancy - haemorrhage in foetus)

21
Q

how could the side effects of warfarin be reversed?

A

Transfuse with plasma or coagulation factor concentrates

Oral vitamin K - but reversal is slow - require carboxylation to resume (1-3 days)

22
Q

why do we need new orally active improved coagulants?

A
  • The need for new orally active and improved anticoagulants.
  • Difficulties in getting warfarin dose right due to complex pharmacokinetics resulting from plasma protein binding and accumulation in adipose tissue
  • High incidence of haemorrhage requires careful monitoring of patient’s clotting time (INR)
  • The INR is derived from the ratio of a patient’s prothrombin time to a normal (control) sample
  • INR target range on warfarin 2.0-3.0
  • Higher INR increases risk of haemorrhage
  • Lower INR increases risk of thrombosis
  • Monitoring is inconvenient and expensive
23
Q

what are some newly introduced oral anticoagulants?

A
  • potential to replace warfarin, but high cost presently restricts use
  • no need to monitor patients
  • dabigatran exilate - direct thrombin (factor IIa) inhibitor
  • rivaroxaban – direct factor Xa inhibitor
  • no involvement of AT III
  • active immediately – no 2-3 day wait
24
Q

how can platelets not normally active be activated?

A
  • Collagen
  • Thrombin
  • Thromboxane A2, ADP and 5-HT synthesised by adjacent activated platelets
25
Q

how is Platelet activation is normally suppressed?

A

by endothelium-derived prostacyclin and nitric oxide?- Prostacyclin increases CAMP
- Nitric Oxide increase CGMP

26
Q

what are anti-thrombotic agents?

A
  • Low dose aspirin (75 vs 300 mg tablets)
  • Irreversibly inhibits cyclooxygenase (COX) - acetylation of terminal serine 530
  • Inhibits synthesis of platelet TXA2 - this cannot recover since platelets have no nucleus
  • Also inhibits endothelial production of prostacyclin - but this recovers through synthesis of new COX
  • Low dose aspirin prevents re-infarction – risk ¯ by 20 %
  • Very widely used
  • Not used in individuals with irritation of gastric muscosa and gastric bleeding
27
Q

what is dipyridamole?

A
  • Inhibits cyclic nucleotide phosphodiesterases ®
  • ­ cAMP and ­ cGMP (potentiates prostacyclin and NO - which make CAMP and CGMP which inhibits platelet activation)
  • So inhibits platelet activation
28
Q

what is Epoprostenol (stabilised prostacyclin)?

A
  • Must be given (i.v.)
  • Short duration of action (t½ ~ 3 min)
  • Used during haemodialysis
  • Prevents agregation of platelets
29
Q

what is clopidogrel?

A
  • Blocks platelet ADP (P2Y) receptors, preventing GPIIb/IIIa receptor exposure
    12
  • Widely used to prevent re-infarction – risk ¯ by 20%
  • Used in combination with aspirin (benefit additive)
30
Q

what is Abciximab (monoclonal antibody to GPIIb/IIIa)

A
  • Blocks GPIIb/IIIa receptors exposed by pathway any
  • Used during surgical exploration/clearing of intravascular blockage, e.g. coronary artery thrombosis
  • Antigenic – can be used once only
31
Q

what are some fibronolytics (throbolytic) agents?

A

tissue plasminogen activator
streptokinase

32
Q

what is tissue plasminogen activator (t-PA)?

A
  • enzyme produced by vascular endothelium
  • activates only plasminogen bound to fibrin (clot selective)
  • human recombinant t-PA now available (alteplase); non-antigenic (no gen anticoagulant effect)
33
Q

what is streptokinase?

A
  • isolated from group C haemolytic streptococci
  • activates plasminogen systemically - high incidence of haemorrhage (not clot selective)
  • not an enzyme - binds to plasminogen and activates it by inducing a conformational change
  • antigenic \ ineffective after recent streptococcal infection (antibodies present
34
Q

what are some uses of fibrinolytic?

A
  • Infused i.v. or i.a.
  • venous thrombosis
  • myocardial infarction or thrombotic stroke - to re-open occluded coronary or cerebral arteries (given together with aspirin to inhibit platelets)
  • But never used in haemorrhagic stroke
  • Side effects: allergy (streptokinase) and haemorrhage
  • Haemorrhage treated with tranexamic acid an inhibitor of plasminogen activation

CVR 2 (9 decks)

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