Syed (Clotting mechanisms - anti-thrombotic agents) Flashcards
Anti-thrombotic drugs
Designed to prevent formation and progression. Not designed to dissolve clots already formed.
Inhibitors of clotting mechanism
Antithrombin- inhibits factors IIA, IXa and Xa
Protein S- co-factor for activation of protein C
Protein C- inactivate factors Va and VIIIa
Tissue factor pathway inhibitor (starts extrinsic pathway)- inhibits activity of factor VIIa
Plasminogen- converted to plasmin via tissue pathway activator (t-PA) which causes lysis of fibrin to fibrin degradation products
Selection of agents
3 classes.
The anticoagulants heparin (UFH- unfractionated heparin), low molecular weight heparin (LMWH), warfarin, and others are used in the treatment and prevention of both arterial and venous thrombi.
Platelet aggregation inhibitors (e.g. aspirin and clopidogrel), alone or in combination with anticoagulants, are used in the prevention of arterial thrombi.
Fibrinolytic agents (e.g. Streptokinase) are used in the rapid dissolution of thromboembolism, notable during myocardial infarction.
Anti-platelet agents
Inhibit platelet aggregation.
They are used in the management of arterial thrombosis (not venous).
The main types of anti platelet drugs include:
- Thienopyridines- clopidogrel, prasugrel, ticlopidine
- Glycoprotein IIb/IIIa inhibitors- abciximab, eptifibatide
- Others- aspirin, dipyridamole, ticagrelor
Thromboxane TXA2 promotes platelet aggregation whilst prostacyclin PGI2 inhibits it. Both are produced by cyclooxygenase enzyme and balance is important.
Aspirin inhibits cyclooxygenase irreversibly resulting in altering balance between TXA2 and PGI2. Mainly used for arterial thrombosis.
Clopidogrel and ticlopidine inhibit ADP dependant aggregation of platelets.
Antagonists of glycoprotein receptors (abciximab, tirofiban) inhibits diverse agonists because different pathways of activation converge on GP IIb/IIIa receptors.
Aspirin
Mode of action- irreversibly inhibits cyclooxygenase reducing synthesis of thromboxane A2 for the life of the platelet.
Low dose aspirin recommended for the prevention of serious vascular events in high risk patients.
In patients with no previous cardiovascular disease benefits in terms of CV prevention should be weighed against risks
Common side effects:
- GI irritation
- increased bleeding time
- allergy
- bronchospasm
- GI and intracranial bleed (rare)
Category C in pregnancy, low doses considered safe but should be avoided where possible in 3rd trimester.
Clopidogrel and Prasugrel
Used as a substitute if patient can’t take aspirin.
Block the platelet ADP receptor which prevents activation of the platelet glycoprotein IIb/IIIA complex preventing platelet aggregation and thrombus formation.
Platelets are affected for their whole lifespan by these drugs.
They prolong bleeding time therefore used with caution in patient with bleeding disorders.
Clopidogrel is used in patients for whom aspiring is contraindicated or in combination with aspirin in patients who either have a CV event on aspirin or after stunting.
Diarrhoea is a common side effect.
Prasugrel
Newer agent.
Used for:
- Prevention of atherothrombotic events (with aspirin) in ACS (acute coronary syndrome) to be managed with PCI (percutaneous coronary intervention- surgery to treat blockages)
- Comparison of Prasugrel and Clopidogrel in ACS after PCI
- Prasugrel was superior in primary and secondary outcomes but had an increased risk of major bleeding
Dipyridamole
Inhibits platelet function by inhibiting phosphodiesterase thereby increasing platelet cAMP which blocks platelet response to ADP.
Uses:
- Combination with warfarin in patients with prosthetic heart valves
- Combination with aspirin for the secondary prevention of stroke
Side effects:
- Causes vasodilation so may cause headaches, hot flushes, hypotension, and tachycardia
- Can cause allergic reactions
Ticagrelor
New drug
Binds reversibly to the P2Y12 receptor, inhibiting platelet aggregation.
Indicated for use in ACS (with aspirin).
Study showed that Ticagrelor with aspirin was more effective than Clopidogrel with aspirin in preventing CV events in patients with ACS.
Significant reduction in MI and vascular death
Side effects:
- Bleeding
- Nausea/diarrhoea
- Headache
- Non-cardiac chest pain
Glycoprotein Ib/IIIa receptor inhibitors
Abciximab, Eptifibatide, Tirofiban.
Prevent binding of fibrinogen to platelets by occupying platelet glycoprotein -> reduced platelet aggregation.
Used with heparin and low dose aspirin for prevention of ischaemic cardiac complications following coronary interventions.
Given IV
Anticoagulants
Can be divided into
- Indirect Parenteral Anticoagulants
- Heparin
- LMWH and Danaparoid
- Direct thrombin inhibitors
- Dabigatran
- Bivalirudin
- Vitamin K antagonists
- Warfarin
- Phenindione
- Factor Xa inhibitors
- Apixaban
- Fondaparinux
- Rivaroxaban
Previously classified as
1. Injectable anticoagulants
2. Oral anticoagulants
Indirect Parenteral Anticoagulants (IPAs)- Heparin
Unfractionated heparin (UFH)
- A mixture of sulphated glycosaminoglycans
- Rapidly acting, parenteral anticoagulant
Adverse effects of Heparin
Haemorrhage
Bruising
Pain at injection site
Thrombocytopenia
Osteoporosis (especially in females long term)
Hyperkalemia
Hypersensitivity
IPAs- LMWHs and Danaparoid
Comparison of LMWHs and Danaparoid with UFH
