10 Haemostasis and thrombosis Flashcards
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - actions
antiplatelet (also analgesic and anti-inflammatory)
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - MOA
irreversibly inactivates cyclo-oxygenase (COX)-1
alters balance between thromboxane A2 (TXA2) and prostacyclin (PGI2) in the platelet/vascular endothelium axis
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - abs/distrib/elim
given orally in small doses
excretion in urine, increased if urine is alkalinised
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - clinical use
acute treatment of ACS and stroke
secondary prevention of arterial thrombosis after cardiovascular and cerebrovascular events, including after arterial stents
prevention of pre-eclampsia in pregnancy
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - adverse effects
GI bleeding because the cytoprotective action of PGs (namely ↓acid secretion, ↑mucus and bicarbonate) is decreased
bronchospasm in some individuals
toxic doses cause respiratory alkalosis followed by acidosis
10.01 IRREVERSIBLE COX-1 INHIBITOR
Aspirin - special points
interactions: effects increased by anticoagulants and thrombolytic drugs
10.02 ADENOSINE (P2Y12) ANTAGONISTS
Clopidogrel, prasugrel, ticagrelor - actions
prevent platelet activation
10.02 ADENOSINE (P2Y12) ANTAGONISTS
Clopidogrel, prasugrel, ticagrelor - MOA
clopidogrel and prasugrel irreversibly inhibit the binding of ADP to the purine receptor on platelets, thus inhibiting ADP-mediated platelet activation and interfering with GPIIb/IIIa-mediated platelet aggregation
ticagrelor is a reversible, non-competitive inhibitor of the P2Y12 receptor
10.02 ADENOSINE (P2Y12) ANTAGONISTS
Clopidogrel, prasugrel, ticagrelor - abs/distrib/elim
given orally, loading dose first then once daily
metabolised to an active compound
irreversible actions of clopidogrel and prasugrel mean the effects last several days until platelets are replaced
10.02 ADENOSINE (P2Y12) ANTAGONISTS
Clopidogrel, prasugrel, ticagrelor - clinical use
to prevent/treat MI and other vascular disorders
often given with aspirin
10.02 ADENOSINE (P2Y12) ANTAGONISTS
Clopidogrel, prasugrel, ticagrelor - adverse effects
bleeding, GIT discomfort, rashes, rarely neutropenia
ticagrelor can cause dyspnoea
10.03 GPIIb/IIIa RECEPTOR ANTAGONISTS
Abciximab, tirofiban, eptifibatide - actions
inhibit platelet activation
10.03 GPIIb/IIIa RECEPTOR ANTAGONISTS
Abciximab, tirofiban, eptifibatide - MOA
abciximab is a monoclonal antibody Fab fragment against the platelet GPIIb/IIIa receptor
it binds and inactivates the receptor to prevent the binding of fibrinogen, thus inhibiting platelet aggregation
tirofiban is a synthetic non-peptide and eptifibatide is a cyclic peptide based on the Arg-Gly-Asp (‘RGD’) sequence that is common to ligands for the GPIIb/IIIa receptors
10.03 GPIIb/IIIa RECEPTOR ANTAGONISTS
Abciximab, tirofiban, eptifibatide - abs/distrib/elim
given by IV injection
half-life 10-30 min
10.03 GPIIIb/IIIa RECEPTOR ANTAGONISTS
Abciximab, tirofiban, eptifibatide - clinical use
used in patients with ACS or undergoing coronary intervention to unblock artery
prevents restenosis and reinfarction
10.03 GPIIIb/IIIa RECEPTOR ANTAGONISTS
Abciximab, tirofiban, eptifibatide - adverse effects
bleeding
thrombocytopaenia
10.04 OTHER ANTIPLATELET DRUGS
Dipyridamole
causes vasodilation and inhibits platelet aggregation
prevents platelet adenosine uptake and cyclic GMP phosphodiesterase action
used in some patients with aspirin for secondary prevention of ischaemic stroke and TIAs (if clopidogrel not tolerated or contraindicated)
10.04 OTHER ANTIPLATELET DRUGS
Epoprostenol
agonist at prostanoid IP receptors
causes vasodilation and inhibits platelet aggregation
added to blood entering the haemodialysis circuit to prevent thrombosis, especially for patients in whom heparin is contraindicated
10.05 PLASMINOGEN ACTIVATORS
Alteplase, duteplase, reteplase, streptokinase - actions and MOA
enzymically activate plasminogen to give plasmin, which digests fibrin and fibrinogen, lysing the clot
10.05 PLASMINOGEN ACTIVATORS
Alteplase, duteplase, reteplase, streptokinase - abs/distrib/elim
given by IV injection or infusion
short half-life (except for reteplase)
10.05 PLASMINOGEN ACTIVATORS
Alteplase, duteplase, reteplase, streptokinase - clinical use
MI, acute ischaemic stroke and other arterial thrombosis
ideally given as soon as possible after the onset of thrombosis
occasionally used in severe cases of DVT and PE
10.05 PLASMINOGEN ACTIVATORS
Alteplase, duteplase, reteplase, streptokinase - adverse effects
bleeding (most important), reperfusion dysrhythmias, nausea and vomiting, hypersensitivity reactions
10.05 PLASMINOGEN ACTIVATORS
Alteplase, duteplase, reteplase, streptokinase - special points
streptokinase is a plasminogen-activating protein extracted from cultures of streptococci
alteplase and duteplase are single- and double-chain recombinant tissue plasminogen activators (tPA)
more active on the fibrin-bound plasminogen than on the plasma plasminogen (‘clot selective’)
action blocked by antibodies which appear about 4 days after initial dose - use of either agents should not be repeated after this time has elapsed
10.06 PLASMINOGEN INHIBITOR
Tranexamic acid - actions and MOA
inhibits plasminogen activation and thus prevents fibrinolysis
10.06 PLASMINOGEN INHIBITOR
Tranexamic acid - abs/distrib/elim
given orally and by IV injection or infusion
10.06 PLASMINOGEN INHIBITOR
Tranexamic acid - clinical use
to reduce haemorrhage following dental extraction, major surgery or trauma
for menorrhagia, epistaxis, hereditary angioedema
10.06 PLASMINOGEN INHIBITOR
Tranexamic acid - adverse effects
GIT disturbances
rare: hypersensitivity skin reactions, disturbed colour vision
10.06 PLASMINOGEN INHIBITOR
Tranexamic acid - special points
do not use in patients with massive haematuria as this may cause ureteric obstruction
10.07 ANTICOAGULANTS
Heparin - actions
inhibit blood coagulation
10.07 ANTICOAGULANTS
Heparin - MOA
accelerates action of antithrombin III (ATIII), increasing its inactivation mainly of factors IIa (thrombin) and Xa
also affects IXa, XIa and XIIa
10.07 ANTICOAGULANTS
Heparin - abs/distrib/elim
given by SC or IV injection
elimination half-life 40-90 min
renal excretion
10.07 ANTICOAGULANTS
Heparin - clinical use
to treat DVT, PE, unstable angina, acute peripheral arterial occlusion
10.07 ANTICOAGULANTS
Heparin - adverse effects
main adverse effect: bleeding
thrombocytopaenia, hypersensitivity reactions, osteoporosis
10.07 ANTICOAGULANTS
Heparin - special points
dosage is adjusted according to the activated partial thromboplastin time
overdose treated with protamine sulfate
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - actions
inhibit blood coagulation
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - MOA
accelerate action of antithrombin III (ATIII), increasing its inactivation of factor Xa
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - abs/distrib/elim
given by SC injection
elimination half-life 130-180 min
renal excretion
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - clinical use
to prevent VTE
to treat DVT, PE, MI, unstable angina
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - adverse effects
main adverse effect: bleeding
less likely than heparin to cause thrombocytopaenia, hypersensitivity reactions, osteoporosis
10.08 ANTICOAGULANTS
Low molecular-weight heparin: enoxaparin, dalteparin, bemiparin - special points
no need to monitor the activated partial thromboplastin time
overdose treated with protamine sulfate
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - actions
inhibit blood coagulation
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - MOA
inhibits the reduction of vitamin K and thus prevents the γ-carboxylation of the glutamate residues in factors II, VII, IX, and X
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - abs/distrib/elim
given orally
slow onset because the circulating γ-carboxylated factors have to be degraded
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - clinical use
to treat DVT/PE
to prevent embolisation in atrial fibrillation
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - adverse effects
bleeding - treated by giving natural vitamin K, fresh plasma or prothrombin complex concentrates
10.09 ANTICOAGULANTS
Vitamin K antagonist: warfarin - special points
prothrombin time must be monitored
action increased (with ↑risk of bleeding) by many drugs, e.g. ciprofloxacin, aspirin
action decreased (with ↑risk of clotting) by many drugs, e.g. rifampicin
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - actions
reduce clot formation
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - MOA
dabigatran is a direct inhibitor of clot-bound and free thrombin (factor IIa)
apixaban and rivaroxaban are direct inhibitors of factor Xa
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - abs/distrib/elim
given orally
half-lives: dabigatran 14-17h, apixaban 8-13h, rivaroxaban 5-9h
dabigatran is a prodrug with low bioavailability
apixaban and rivaroxaban are around 50% renally excreted
dabigatran is 80% renally excreted
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - clinical use
to prevent DVT/PE in orthopaedic surgery
to treat VTE
to prevent stroke in atrial fibrillation
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - adverse effects
bleeding - treated with specific reversal agents: idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors
10.10 DIRECT ORAL ANTICOAGULANTS
Dabigatran, apixaban, rivaroxaban - special points
these drugs are administered in standard doses without monitoring
dabigatran can be removed via haemodialysis
apixaban and rivaroxaban are highly protein bound - limits dialysis
