Anticoagulant, Antiplatelet and Thrombolytic Drugs Flashcards
what is haemostasis?
arrest of blood loss from a damaged vessel
describe the sequence of haemostasis
vascular wall damage exposing collagen and tissue factor
primary haemostasis
- local vasoconstriction
- platelet adhesion, activation and aggregation
activation of blood clotting and the formation of a stable clot
what do activated platelets do?
extend pseudopodia
synthesise and release thromboxane A2 (TXA2)
what does TXA2 bind to?
platelet GPCR TXA2 receptors causing mediator release
vascular smooth muscle cells TXA2 receptors causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors
what happens when ADP binds to platelet GPCR purine receptors?
they act locally to activate further platelets
aggregate platelets into a ‘soft plug’ at the site of injury
expose acidic phospholipids on the platelet surface that initiate coagulation of blood and solid clot formation
how is inactive factor X converted to the active fator?
by tenase
how is inactive factor II (prothrombin) converted to active factor IIa (thrombin)?
by prothrombinase
how is a solid clot formed?
because fibrinogen is converted by thrombin to fibrin
what is a thrombosis?
pathological haemostasis
a haemotological plug in the absence of bleeding
what are the predisposing factors to thrombosis?
Virchow’s triad
what are the 3 factors of virchow’s triad?
injury to vessel wall
abnormal blood flow
increased coagulability of the blood
what is an arterial thrombus?
a white thrombus
mainly platelets in a fibrin mesh
how does an arterial thrombus form an embolus?
if it detaches from the left heart or carotid artery and lodges in an artery in the brain (or another organ)
how is an arterial thrombus primarily treated?
with antiplatelet drugs
what is a venous thrombus?
a red thrombus
white head, jelly-like red tail, fibrin rich
how does a venous thrombus form an embolus?
if it detaches and lodges in the lung (pulmonary embolism)
how is a venous thrombus primarily treated?
with anticogulants
what do the precursors of the active factors require?
vitamin K in its reduced form
when are anticoagulants used?
in the prevention and treatment of venous thrombosis and embolism DVT prevention of post-operative thrombosis patients with artificial heart valves atrial fibrillation
what is the main risk with anticoagulants?
haemorrhage
what is warfarin?
an anticoagulant
structurally related to vit K with which it competes for binding to hepatic vit K reductase preventing production of the active hydroquinone
what does warfarin do?
renders factors II, VII, IX and X inactive
how is warfarin administered?
orally (slower onset of action than heparin)
how can the overdose of warfarin be treated?
with administration of vit K1 or concentrate of plasma clotting factors (IV)
which factors potentiate warfarin action?
liver disease
high metabolic rate
drug interactions
how does liver disease potentiate warfarin action?
decreased clotting factors
how does a high metabolic rate potentiate warfarin?
increased clearance of clotting factors
which drug interactions can potentiate warfarin?
agents that inhibit metabolism of warfarin
drugs that inhibit platelet function
drugs that inhibit reduction, or decrease availability of vit K
which factors lessen warfarin action?
pregnancy
hypothyroidism
vit K consumption
drug interactions
how does pregnancy lessen warfarin action?
increased clotting factor synthesis
how does hypothyroidism lessen warfarin action?
decreased degradation of clotting factors
which drug interactions lessen warfarin action?
agents that increase hepatic metabolism of warfarin
what is the role of antithrombin III?
an inhibiter of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site
how does heparin act?
it binds to antithrombin III, increasing its affinity for serine protease clotting factors to greatly increase their rate of inactivation
name LMWHs
enoxaparin and dalteparin
what is the exception to when LMWHs are prefered?
renal failure
how do LMWHs act?
they inhibit factor Xa but not thrombin (IIa)
how is heparin administered?
IV or SC
LMWH = SC
what is required for heparin but not for LMWHs?
an in vitro clotting test to determine optimum dosage
what are the adverse effects of heparin and LMWHs?
haemorrhage more rarely osteoporosis hypoaldosteronism hypersensitivity reactions
what is dabigatran etexilate?
a new orally active agent that acts as a direct inhibiter of thrombin
what is rivaroxaban?
a new orally active agent that acts as a direct inhibiter of factor Xa
what are the advantages of the new orally active agents?
convenience of administration
predictable degree of anticoagulation
what is the major disadvantage of new orally active agents>
no specific agent is available to reduce haemorrhage in overdose
describe the use of orally active inhibitors
used to prevent venous thrombosis in patients undergoing hip and knee replacements
what are anti-platelet drugs used for?
in the treatment of arterial thrombosis
what are the main antiplatelet drugs?
aspirin
clopidogrel
tirofiban
describe the mechanism of action of aspirin
irreversibly blocks cycloxygenase (COX) in platelets, preventing TXA2 synthesis, but also COX in endothelial cells inhibiting production of antithrombotic prostaglandin I2 (PGI2)
balance is shifted in favour of an antithrombotic effect because endothelial cells can synthesise new COX enzyme whereas enucleate platelets cannot. TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)
describe the use of aspirin
Used orally, mainly for thromboprophylaxis in patients at high cardiovascular risk
what is the main adverse effect of aspirin?
GI bleeding
ulceration
describe the mechanism of action of clopidogrel
Links to P2Y12 receptor by a disulphide bond producing irreversible inhibition
describe the use of clopidogrel
mainly in patients intolerant to aspirin
cost is an issue
administered orally
when combined with aspirin, has a synergistic action
when is tirofiban given?
IV in short term to prevent MI in high risk patients with unstable angina (with aspirin and heparin)
when are fibrinolytics used?
principally to reopen occluded arteries in acute MI or stroke
less frequently, life threatening venous thrombosis or PE
have an additive beneficial effect with aspirin
how are fibrinolytics administered?
IV within as short a period as possible of the event
PCI is superior if available promptly
describe the use of streptokinase
reduces mortality in acute MI but action blocked after 4 days by the generation of antibodies
may cause allergic reactions- not given to patients with recent streptococcol infections
what are alteplase and duteplase?
recombinant tissue plasminogen activators
more effective on fibrin bound plasminogen than plasma plasminogen and show selectivity for clots
describe the use of alteplase and duteplase
do not cause allergic reactions
given by IV infusion
what is the major adverse effect of fibrinolytics?
haemorrhage that may be controlled by oral tranexamic acid which inhibits plasminogen activation
