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
Direct thrombin inhibitors
DTIs bind directly to thrombin and block its effect.
The two most commonly used DTIs are Dabigatran (oral) and bivalirudin (parenteral).
Thrombin is central to the clotting process
- It is involved in the conversion of fibrinogen to fibrin
- It activates factors V, VIII, and XI and activates platelets
They therefore have both antiplatelet and anticoagulant effects
Dabigatran
Factor Xa inhibitors
Selectively inhibit factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin and thrombus development.
Indicated for prevention of venous thromboembolism in high rise orthopaedic surgery- hip fracture, knee or hip replacement.
Oral anticoagulants
Warfarin is an oral anticoagulant with a delayed onset of effect that acts as a vitamin K antagonist.
Vitamin K is essential in the conversion of clotting precursors to clotting factors and for the synthesis of protein.
Concentration of these clotting factors diminished gradually because of their different half lives.
Warfarin absorbed completely from the upper GI (bioavailability is 100%).
Side effects include haemorrhage, skin necrosis, purple toe syndrome
Uses of warfarin
Gold standard therapy for long term oral anticoagulation. Used for:
- Prevention and treatment of DVT
- Prevention and treatment of AF with embolism
- Prevention and treatment of PE
- Part of the treatment for MI
- Prevention of thrombus formation after valve replacement
Initiation of therapy
- Heparin given concurrently until adequate warfarin response is shown (can take 5 days to have an effect)
Maintenance dosin
- Regular monitoring is required, and dosage adjustments are made if required due to drug interactions, coexisting disease, large alterations in intake of Vitamin K
Warfarin contraindications
- Bleeding disorders, previous GI bleed
- Haemorrhage retinopathy (bleeding from blood vessels in retina)
- Severe hypertension
- Bacterial endocarditis
- Alcoholism
- Unsupervised dementia- compliance issue
- Renal and hepatic impairment- increased bleeding risk
- Pregnancy- teratogenicity and petal/placental haemorrhage
Drug interactions of warfarin
Many drugs interact with warfarin caused increased or decreased anticoagulant effect.
Mechanism of drug interactions examples:
- Decreased hepatic synthesis of procoagulant factors
- Inhibition of enzymatic metabolism of warfarin
- Increased receptor affinity for warfarin
- Decreased vitamin K synthesis
- Displacement of warfarin from protein binding sites
If drug interaction is found, change the short term medication. For example if patient is on antibiotics, change the antibiotics not the warfarin. Keep the long term medication.
NOACs vs DOACs
NOACs- Novel/New Oral Anticoagulants
DOACs- Direct-acting Oral Anticoagulants
NOACs are now referred to as DOACs.
Used in many situations like heparin and warfarin.
Not used in valvular AF.
Consider NOAC over warfarin is
- Patient on lots of interacting medicines e.g. frequent antibiotic courses
- High alcohol intake
- Unable to cope with varying warfarin doses
- Time in therapeutic range is more than 65% over 6 months in AF
Potential limitations to the use of NOACs
Lack of validated tests to monitor anticoagulant effect
No established therapeutic range
No antidote
Difficulty in assessment of compliance
Unknown potential for long term adverse effects
Unknown cost effectiveness
