anticoagulants Flashcards
calcium chelators
. citrate and ethylenediamine tetra-acetic acid (EDTA)
Ca2+ is required for activation of multiple factors e.g. factors V, IX, X, XIa, XIII and prothrombin (factor II)
Chelating Ca2+ makes it unavailable to participate in coagulation cascade
heparin
A naturally occurring sulphated glycosaminoglycan (i.e. a negatively-charged linear polysaccharide)
Comes as different salts: sodium-, lithium-, ammonium- heparin
Mechanism: heparin binds to antithrombin to inhibit multiple coagulation factors
unfractionated heparin: mechanism
Heparin binds to and greatly enhances the action of the endogenous anticoagulant antithrombin III which circulates in plasma
The heparin-antithrombin III complex binds to and inhibits the action of clotting factors IIa, IXa, Xa, XIa, XIIa
Immediate inhibition of clotting
low molecular weight heparin
Any heparin chain can inhibit factor Xa by binding to antithrombin
But, to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin
Unfractionated heparin is long enough, but the shorter strands of LMWH are not
uses of heparin
Intravenous administration for treatment of: -
Deep vein thrombosis
Pulmonary embolism
Unstable angina
Peripheral artery occlusion
side effects: skin reactions, hyperkalaemia
oral anticoagulation
e.g. warfarin
Structural analogue of vitamin K
Blocks synthesis of coagulation factors (in the liver)
mechanism of warfarin
Referred to as a “Vitamin K antagonist”
The liver requires vitamin K to complete synthesis of prothrombin and factors VII, IX, and X
Warfarin blocks vitamin K epoxide reductase – an enzyme that reduces vitamin K to its active form (K1)
Lack of K1 prevents γ-carboxylation of glutamic acid residues thereby reducing the availability of clotting factors
No carboxylation => no Ca2+ binding => no coagulation
warfarin metabolism
Warfarin occurs as a pair of enantiomers that are differentially metabolized by multiple cytochrome P450 enzymes
Potential interactions occur with drugs that are metabolized by the same enzymes (BNF lists 245 interactions with warfarin)
Most interactions change warfarin plasma concentrations and therefore bleeding risk
reversal of anticoagulant effect
Idarucizumab is a humanised monoclonal antibody fragment
Non-competitive binding specifically to dabigatran and its metabolites
Reverses anticoagulant effect within 5 min
Uses: to treat serious bleeds or prior to emergency surgery)
reversal of facto X inhibitors
Andexanet alfa is a specific reversal agent for apixaban, rivaroxaban, and edoxaban
It is a recombinant truncated form of human factor Xa – acts as decoy to prevent interaction with real Factor Xa complex
Catalytically inactive since can’t adhere to platelets due to missing membrane-binding domain
antiplatelet drugs
Platelets not normally active, but activated by:
Collagen
Thrombin
Thromboxane A2, ADP and 5-HT from adjacent activated platelets
Platelet activation is suppressed by endothelium-derived: -
Prostaclyclin (PGI2)working via cAMP
Nitric Oxide (NO) working via cGMP
dipyridamole
Inhibits cyclic nucleotide phosphodiesterases, enzymes which break down intracellular cAMP and cGMP —>
increase in cAMP and increase in cGMP (potentiates effects of prostacyclin and NO)
Therefore inhibits platelet activation
Uses: Secondary prevention of ischaemic stroke; prophylaxis of thromboembolism associated with prosthetic heart valves
fibrinolytic (thrombolytic) agents
Infused intravenous or intra-arterial to dissolve blood clots
Life-threatening pulmonary embolism
Myocardial infarction or ischaemic stroke - to re-open occluded coronary or cerebral arteries
