Anticoagulant, Antiplatelet and Thrombolytic Drugs Flashcards
describe haemostasis - step 1
arrest of blood loss from damaged vessel;
1. vascular wall damage exposing collagen and tissue factor (TF, thromboplastin)
describe haemostasis - step 2
- primary haemostasis;
local vasoconstriction
platelet adhesion to collagen, activation and aggregation (by fibrogen) => soft plug
activated platelets then extend pseudopodia, synthesis and release thromboxane A2 (TXA2)
TXA2 binds to;
platelet GPCR TXA2 receptors causing mediator release and ADP
vascular smooth muscle TXA2 receptor causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors
describe haemostasis - step 3
- activation of blood clotting (coagulation) and the formation of a stable clot (by fibrin enmeshing platelets) => solid clot
this is done via;
ADP binds to platelet GPCR purine receptors that;
act locally to activate further platelets
aggregate platelets into a soft plug act on site of injury, TXA2 acts similarly
expose acidic phospholipids on the platelet surface that initiate coagulation of blood and solid clot formation
describe events occurring at the platelet membrane late in the coagulation cascade important in drug action
production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
inactive factor X is converted by tenase to active factor Xa
inactive factor II (prothrombin) is converted by prothrombinase to active factor IIa (thrombin)
fibrinogen is converted by thrombin to fibrin yielding a solid clot
describe thrombosis
pathological haemostasis => blood clot Virchow's triad; injury to vessel wall abnormal blood flow increased coagulability of blood
describe arterial thrombus
white thrombus - mainly platelets in fibrin mesh
forms an embolus if detached from its site of origin, often lodges in an artery in the brain (stroke), or ther organ
primarily treated with antiplatelet drugs
describe venous thrombus
red thrombus - white head, jelly like red tail, fibrin rich
if detached, forms an embolus that usually lodges in the lung (PE)
primarily treated with anticoagulants
explain the role of vitamin K and warfarin in embolus
Clotting factors II (prothrombin), VII, IX and X are glycoprotein precursors of the active factors IIa (thrombin), VIIa, IXa and Xa that act as serine proteases
Precursors are post-translationally modified to produce the active factors
The carboxylase enzyme that mediates this reaction requires vitamin K in its reduced form as an essential cofactor
warfarin blocks vitamin K reductase
describe cautions of warfarin
very difficult to strike balance between anticoagulant effect and haemorrhage - low therapeutic index
use complicated by delay to maximal effect and several medical and environmental influences
effect must be monitored on regular basis
overdose regulated by administration of vitamin K or concentrate of plasma clotting factors
describe factors that potentiate warfarin action (hemorrhage increase)
liver disease – decreased clotting factors
high metabolic rate – increased clearance of clotting factors
drug interactions;
agents that inhibit hepatic metabolism of warfarin by CYP2C9 (consult BNF)
drugs that inhibit platelet function (e.g. aspirin, other NSAIDs)
drugs that inhibit reduction, or decrease availability, of vitamin K
describe factors that lessen warfarin action (risk of thrombosis increased)
physiological state – pregnancy (increased clotting factor synthesis) – hypothyroidism (decreased degradation of clotting factors)
vitamin K consumption
drug interactions - agents that increase hepatic metabolism of warfarin (consult BNF)
describe the role of antithrombin III
inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site in a 1:1
heparin binds to antithrombin III, increasing its affinity for serine protease clotting factors to increase their rate of their inactivation
describe heparin and low molecular weight heparin
LMWH inhibit factor Xa but not thrombin (Ila)
heparin administered IV or SC
LMWH SC
heparin - in vitor clotting test is required to determine optimum dosage
elimination of heparin is zero order, whereas high MWH is first order
elimination of LMWH is via renal excretion, hence heparin is preferred in renal failure
describe adverse effects of heparin and LMWH
haemorrhage rare; osteoporosis hypoaldosteronism hypersensitivity reactions
describe orally active inhibotrs
direct inhibitors of thrombin or factor Xa
advantages of;
convenience of administration
predictable degree of anticoagulation, but no specific agent tis available to reduce haemorrhage in overdose which is a major disadvantage
prevents venous thrombosis in patients undergoing hp and knee replacement
both agents can predictably cause bleeding but drugs of this type may be very significant advance upon warfarin which they could eventually replace
describe anti-platelet drus
treatment of arterial thrombosis
e. g. aspirin
e. g clopidogrel
e. g. tirofiban
describe aspirin
main anti-platelet agent
irreversibly blocks cyclooxygenase in platelets
prevents TXA2 synthesis
blocks cycloxygenase in endothelial cells inhibiting production of anti-thrombotic prostaglandin I2;
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)
Used orally, mainly for thromboprophylaxis in patients at high cardiovascular risk
Main adverse effect is gastrointestinal bleeding and ulceration
describe clopidogrel
links to P2Y12 receptor by disulphide bond producing irreversible inhibition
used in patients in tolerant to aspirin
oral administration
describe tirofiban
Given IV in short term treatment to prevent myocardial infarction in high risk patients with unstable angina (with aspirin and heparin)
describe the role of plasminogen and fibrinolytic drugs
fibrinolytic cascade exists endogenously which opposes the coagulation cascade (PP)
Fibrinolytics are used principally to reopen occluded arteries in acute myocardial infarction (M.I.), or stroke – less frequently life-threatening venous thrombosis or pulmonary embolism
Administered IV within as short a period as possible of the event
Percutaneous coronary intervention (PCI) is superior if available promptly
Have an additive beneficial effect with aspirin
describe streoptokinase
Not an enzyme, but a protein extracted from cultures of streptococci
Reduces mortality in acute M.I. (given IV, or intracoronary) but action blocked after 4 days by the generation of antibodies. Further doses not to be given after this time
May cause allergic reactions (not be given to patients with recent streptococcal infections)
describe alteplase and duteplase
Are recombinant tissue plasminogen activator (rt-PA)
Are more effective on fibrin bound plasminogen than plasma plasminogen and show selectivity for clots
Do not cause allergic reactions
Short half life, hence given by IV infusion
The major adverse effect of fibrinolytics is haemorrhage that may be controlled by oral tranexamic acid which inhibits plasminogen activation
