Drugs affecting blood coagulation Flashcards
Thrombosis
Unwanted formation of clots in arterial or venous circulation
Venous thrombosis
Associated with stasis of the blood and/or damage to the veins
Clot may become dislodges (embolus) and travel, e.g. pulmonary embolism, cerebrovascular accident
High fibrin content, low platelet content
Arterial thrombosis
Thrombus usually forms at site of atherosclerosis, especially after plaque rupture e.g. coronary thrombosis
Low fibrin content, high platelet content (white thrombus)
Classification of agents
Anticoagulants and platelet inhibitors prevent thrombus formation (anti-thrombotics)
Fibrinolytic enzymes cause lysis of thombus
Antifibrinolytic drugs promote haemostasis
Anticoagulants- parenteral
Unfractionated (standard) heparin Low molecular weight heparins Fondaparinux Bivalirudin Argatroban
Anticoagulants- oral
Warfarin, acenocoumarol and phenindione
Apixaban, edoxaban and rivaroxaban
Dabigatran
Heparins
Injectable anticoagulants, active in vivo and in vitro
A family of highly sulphated glycosaminogylcans
Highly negatively charged
Unfractionated (standard) heparins
Medical heparin is of animal origin i.e. bovine lung, bovine, porcine or ovine intestinal mucosae
Biological activity stated in units/mL
Action inhibited naturally by heparinases in blood
Protamine sulphate (highly positively charged) is used to bind and inactivate heparin
Heparin-induced thrombocytopenia is a major adverse effect of prolonged treatment, activation, aggregation, then removal of platelets
>5-7 dyas, immune mediated response
Unfractionated heparins MOA
UFHs activate and potentiate action of anti-thrombin III leading to the inactivation of thrombin (IIa) and other factrs e.g. Xa
Low molecular weight heparins
Obtained by fractionation or depolymerisation of UFHs
LMWHs do not inactivate thrombin but inactivate factor Xa
Dalteparin, enoxaprin, tinzaparin
Fondaparinux is a synthetic pentasaccharide fragment that inactivates factor Xa
Increasingly widely used due to long action (once daily SC injection), less likely than UFHs to induce thrombocytopenia
Alternative injectable anticoagulants
Hirudin is a 65-amino acid anticoagulant peptide originally isolated from leech, thrombin factor IIa inhibitor
Bivalirudin is a synthetic peptide derivative, specifically licensed for coronary care setting (e.g. PCI)
Argatraban is a small molecule direct thrombin inhibitor, useful as an alternative to heparin when heparin-induced thrombocytopenia has developed
Vitamin K antagonists (coumarins)
Active in vivo only
Inhibit gamma carboxylation of factors II, VII, IX and X by blocking reduction (activation) of K vitamins (menadione derivatives)
Examples of coumarins
Warfarin, phenindione, acenocoumarol
Used prophylactically to prevent thrombosis over prolonged periods (including life-long use)
Slow onset, long duration of action
Enormous range of drug interactions which can cause increased or decreased anticoagulant activity
Novel oral anticoagulants (NOACs)
Apixaban, edoxaban and rivaroxaban are orally active small direct inhibitors of factor Xa
Dabigatran is an orally active small molecule ihibitor of thrombin (factor IIa), argatroban for IV use only
No routine INR monitoring required
Potential for drug interactions but fewer than with warfarin
Rapid onset, convenient once or twice daily dosing
Therapeutic use of anticoagulants
Primarily in management of venous thrombo-embolism but also arterial thrombosis, especially post MI
Injectable anti-coagulants: treatment and prevention of DVT e.g. during hospitalisation for orthopaedic surgery, treatment of pulmonary embolism, post thrombolysis in ACS to prevent arterial re-occlusion, to prevent clotting in extracorporeal circulators
Usually short term although LMWHs may be used chronically
Uses of oral anticoagulants
Used for long term (including life-long) prophylactic treatment: prophylaxis against DVT, in atrial fibrillation with stroke risk, prophylaxis after extensive anterior MI
Warfarin requires regular monitoring of INR and dose adjustment (e.g. for change of diet, drugs, alcohol consumption, infection etc.)
NOACs are more convenient, fewer interactions and no INR monitoring but much more expensive
Platelet aggregation inhibitors
Target diverse mechanisms of platelet activation (not the protein clotting factors in blood)
Critical role of GPIIb/IIIa expression on platelet surface
Used to inhibit thrombus formation int he arterial rather than venous circulation
Thromboxane synthesis inhibitors
ADP receptor blockers
Glycoprotein IIb/IIIa inhibitors
Therapeutic fibrinolytic enzymes
Clinically used agents are naturally occuring or recombinantly-produced plasminogen activators
e.g. streptokinase, alteplase, reteplase, tenecteplase, urokinase
Streptokinase and anistreplase are antigenic- antobody production within 4 days, therefore inactive if given again within 1 year of first administration
Major uses of fibrinolytics
Treatment of acute coronary syndromes, especially acute MI
Used as early as possible, some benefit if given up to 12 hours after onset
Heparin and anti-platelet therapy provide additional survival benefit
Percutaneous coronary intervention becoming treatment of choice if available, but not possible in all cases, so fibrinolytics remain a common treatment
Other uses of fibrinolytics and major adverse events
Other uses: massive pulmonary embolism, acute ischaemic stroke, DVT
Major adverse events: intracerebral haemorrhage, allergic reaction and anaphylaxis
Antifibrinolytic agents (pro-clotting factors)
Act by various mechanisms to reduce fibrinolysis and promote clot formation/ stability
Tranexamic acid: synthetic lysine derivative, inhibits plasminogen activation by reversible blockade of lysine binding sites on plasminogen
Used to prevent or control excessive bleeding e.g. after surgery, dental extraction, thrombolytic overdose, menorrhagia, epistaxis
