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Antiplatelets & Thrombolytics (P2Y-12 Receptor Antagonists (Mechanism…
Antiplatelets & Thrombolytics
Aspirin
Mechanism of action:
Irreversibly inhibits COX-1 & COX-2, thereby inhibiting the production of TXA-2
Platelets do not have a nucleus, therefore cannot make new COX-1, resulting in inhibition of TXA-2 synthesis which is required for platelet activation & aggregation
Clinical effects:
Inhibited platelet aggregation & thrombus formation
Clinical use:
Low doses for acute coronary syndrome & prevention of thromboembolism in high-risk patients
A higher dose is not shown to improve clinical effects, only adverse effects
Low doses are shown to be more selective for COX-1
Adverse effects:
Bleeding
GI disturbances (due to direct irritation of GI mucosa & COX-1 inhibition)
Allergic reactions (urticaria, bronchoconstriction)
P2Y-12 Receptor Antagonists
Mechanism of action:
Irreversibly binds the P2Y-12 platelet receptor which usually acts as a chemoreceptor for ADP
This prevents ADP-mediated activation of the GPIIb/IIIa complex thus inhibiting platelet aggregation
Inhibits platelet aggregation for the life of the platelet
Clinical effects:
Inhibited platelet aggregation & thrombus formation
Clinical use:
Prevention of ischaemic stroke, AMI or unstable angina refractory to aspirin treatment
Drugs:
Clopidogrel, Ticagrelor, Ticlodipine
Pharmacokinetics:
Clopidogrel is a pro-drug & activated by P450 enzymes in the liver, therefore some patients (5-45%) do not respond well due to polymorphisms of P450 enzymes
Ticagrelor is an oral, rapid-onset, reversible version of clopidogrel, and not a pro-drug
Adverse effects:
Bleeding
Dipyridamole
Mechanism of action:
Inhibits phosphodiesterase enzymes that normally break down cAMP, thus increasing cAMP
This results in a decreased release of granules by platelets
Also blocks adenosine uptake into RBCs which increases cAMP in platelets
Clinical effect:
Inhibited platelet aggregation & thrombus formation
Clinical use:
Prevention of recurrent ischaemic stroke in combination with aspirin
Adverse effects:
Bleeding
Not very well tolerated
Also causes vasodilation leading to flushing, dizziness & headaches
GPIIb/IIIa Inhibitors
Mechanism of action:
Blocks GPIIb/IIIa receptors thus preventing fibrinogen from binding to the GPIIb/IIIa receptors which prevents platelet linkage
Clinical effects:
Inhibited platelet aggregation & thrombus formation
Clinical use:
Unstable angina & NSTEMI patients
Percutaneous coronary intervention
Drugs:
Abciximab, Eptifibatide, Tirofiban
Adverse effects:
Bleeding
Thrombolytic Drugs
Drugs:
IV alteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase
Mechanism of action:
Converts plasminogen to plasmin which catalyses the breakdown of fibrin
Unlike anticoagulants & antiplatelets, thrombolytic drugs can actually dissolve clots
Clinical effects:
Thrombus degradation
Clinical use:
Acute STEMI (within 12 hours of chest pain)
Ischaemic stroke (within 3 hours of symptom onset)
Massive VTE
Adverse effects:
Bleeding
Streptokinase is extracted from cultures of streptococci and therefore may cause anaphylaxis (Should not be given to those who have used streptokinase >3 days earlier as they may have built up neutralising antibodies)