Antiplatelet and fibrinolytic drugs Flashcards
Give an overview of thromboembolic diseases
- Thromboembolic diseases are common
- E.g. deep vein thrombosis and pulmonary embolism
- Consequence of AF
- Can result in TIAs, ischaemic stroke, MI
What is the difference between a thrombus and an embolus?
- A thrombus is a clot adhered to a vessel wall
- An embolus is an intravascular clot distal to the site of origin
What is venous thrombosis associated with?
- Stasis of blood
- Damage to veins
- Less likely to see endothelial damage
- High red blood cell and fibrin content
- Low platelet content, evenly distributed
Outline arterial thrombosis
- Usually forms at site of atherosclerosis following plaque rupture
- Lower fibrin content and much higher platelet content
What is Virchow’s triad?
- Reduced blood flow
- Increased coagulability
- Blood vessel injury
What can cause reduced blood flow?
- Atrial fibrillation
- Long distance travel
- Varicose veins
- Venous obstruction
- Immobility
- Ventricular/venous insufficiency
What can cause blood vessel injury?
- Trauma
- Orthopaedic or major surgery
- Hypertension
- Invasive procedures
What can cause increased coagulability?
- Sepsis
- Smoking
- Coagulation disorders
- Malignancy
Outline platelet activity in healthy endothelium
- Prostacyclin (PGI2) produced and released by endothelial cells
- Inhibits platelet aggregation
- PGI2 binds to platelet receptors
- Increases cAMP concentration in platelets
- Causes decreased Ca2+
- Prevents platelet aggregatory agents
- Stabilises inactive GP IIb/IIIa receptors
What is the average lifespan of a platelet?
- 8-10 days
- 10% replaced each day
Outline how a thrombus is formed
- Atherogenic pathway
- Fibrous cap
- Plaque rupture
- Thrombus formation
- Platelet adhesion at damaged endothelium
- Extensive cascade of signalling molecules
- Recruitment of more platelets
How are platelets activated?
- Release of platelet granules
- GPIIb/IIIa receptors and fibrinogen
- Increases Ca2+ and decreases cAMP in platelets
- Cascade and amplification from platelet to platelet
What are some examples of platelet granules?
- ADP
- Thromboxane A2
- Serotonin
- Platelet activation factor
- Thrombin
What drugs do we use to target platelet-rich, white arterial thrombi?
- Antiplatelet
- Fibrinolytic drugs
What drugs do we use to target red venous thrombi?
- Parenteral anticoagulants
- Oral anticoagulants
Give examples of cyclo-oxygenase inhibitors
- Aspirin
Outline thromboxane A2
- Potent platelet aggregating agent
- Formed from arachidonic acid by COX 1
What is the mechanism of action of cyclo-oxygenase inhibitors such as aspirin?
- Inhibits COX-1 mediated production of thromboxane A2
- Reduces platelet aggregation
- Irreversible
Why does aspirin not completely inhibit platelet aggregation?
- Other aggravating factors
- Doesn’t irreversibly inhibit COX 1 in every patient
What is the low non-analgesic dose of aspirin?
- 75 mg
What is the loading dose of aspirin used in acute coronary syndromes?
- 300 mg
Which other part of clotting is affected by higher doses of aspirin?
- Inhibits endothelial prostacyclin
How is aspirin absorbed into the body?
- Absorbed by passive diffusion
- Hepatic hydrolysis to salicylic acid
What are the adverse side effects of aspirin?
- Gastrointestinal irritation
- GI bleeding (peptic ulcer)
- Haemorrhage (stroke)
- Hypersensitivity
What are the contraindications of aspirin?
- Reye’s syndrome - avoid until <16 years
- Hypersensitivity
- 3rd trimester (leads to premature closure of ductus arteriosus)
- Caution with other antiplatelets/anticoagulants
What causes a lack of efficacy of aspirin in some people?
- COX-1 polymorphisms
- People produce different quantities of COX-1
Why does the antiplatelet effect of aspirin only last 7-10 days?
- 7-10 days is lifespan of a platelet
- Platelets don’t have nuclei
- So they can’t make more COX-1 to replace the COX-1 that is irreversible bound to aspirin
What are some aspirin indications?
- Some AF patients after stroke
- Secondary prevention of stroke and TIA
- Secondary prevention of acute coronary syndromes
- NSTEMI/STEMI - initial 300 mg loading dose (chewable)
- Often co-prescribed with other anti-platelet agents
What else needs to be prescribed for patients using aspirin in the long term?
- Gastric protection e.g. PPIs
Give some examples of ADP receptor antagonists
- Clopidogrel
- Prasugrel
- Ticagrelor
What is the mechanism of action of ADP receptor antagonists?
- Inhibit binding of ADP to P2Y12 receptors
- Inhibit activation of GPIIb/IIIa receptors
- Independent of COX pathway
Outline the differences between clopidogrel, prasugrel and ticagrelor
- Clopidogrel and prasugrel are irreversible inhibitors of P2Y12
- Ticagrelor acts reversibly at a different site
- Clopidogrel and prasugrel are pro drugs (have active hepatic metabolites)
- Ticagrelor has active metabolites
- Clopidogrel has slow onset of action without a loading dose
- Ticagrelor and prasugrel have a more rapid onset of action
What are the adverse side effects of the ADP receptor antagonists?
- Bleeding
- GI upset - dyspepsia and diarrhoea
- Thrombocytopenia (rare)
What are the contraindications of ADP receptor antagonists?
- Caution in high bleed risk patients with renal and/or hepatic impairment
What are the DDIs of clopidogrel?
- Requires CYPs for activation
- CYP inhibitors e.g. omeprazole, ciprofloxacin, erythromycin, some SSRIs
What are the DDIs of ticagrelor?
- Can interact with CYP inhibitors and inducers
What do we need to be cautious about when prescribing any of the ADP receptor antagonists?
- When prescribing any of these drugs alongside other antiplatelet and anticoagulant agents or NSAIDs
- Due to increased bleeding risk
- Also need to stop up to 7 days prior to surgery
What are some ADP receptor antagonist indications?
- Second agent in dual antiplatelet therapy
- Ischaemic stroke (when aspirin is contraindicated)
- NSTEMI/STEMI - taken for up to 12 months
What factors dictate which ADP receptor antagonists should be used?
- Pt’s age, coronary anatomy and bleed risk
- Need to consider risk of cardiovascular events vs bleeding risk when prescribing
Give some examples of phosphodiesterase inhibitors
- Dipyridamole
What is the mechanism of action of phosphodiesterase inhibitors?
- Dipyridamole inhibits cellular reuptake of adenosine
- Increased adenosine concentration inhibits platelet aggregation via adenosine (A2) receptors
- Also prevents cAMP degradation
- Inhibits expression of GPIIb/IIIa
What are the adverse side effects of phosphodiesterase inhibitors?
- Vomiting and diarrhoea
- Dizziness
What are some DDIs of phosphodiesterase inhibitors?
- Antiplatelets
- Anticoagulants
- Adenosine
What are some indications of phosphodiesterase inhibitors?
- Secondary prevention of ischaemic strokes and TIAs
- Adjunct for prophylaxis of thromboembolism following valve replacement
- Stroke
Give some examples of glycoprotein IIb/IIIa inhibitors
- Abciximab
What is the mechanism of action of glycoprotein IIb/IIIa inhibitors?
- Blocks binding of fibrinogen and von Willebrand factor
- Target final common pathway
- Abciximab is an antibody that blocks GPIIb/IIIa inhibitors
- Administered IV
What are the adverse side effects of abciximab?
- Bleeding
- Dose adjustment for body weight
What are the DDIs of abciximab?
- Caution with other antiplatelet and anticoagulant agents
What are the indications of abciximab?
- Specialist use in high risk percutaneous transluminal coronary angioplasty patients with other drugs
Give some example of clot busters
- Streptokinase
- Alteplase
Outline the mechanism of action of clot busters
- Fibrinolytics dissolve the fibrin meshwork of a thrombus
- Prevent conversion of plasminogen to plasmin
What are the indications for clot busters?
- Alteplase in acute ischaemic stroke <4.5 hours from symptoms
- Following STEMI diagnosis acutely
- Streptokinase can only be used once as antibodies develop
What are the adverse side effects of clot busters?
- Bleeding
What are the DDIs of clot busters?
- Antiplatelets
- Anticoagulants
When do we give primary PCI (stent)?
- Following acute STEMI
- Reperfusion is essential
- Offer primary PCI injury if indicated (this is the preferred coronary reperfusion strategy)
- Reperfusion injury is a negative consequence of PCI
- NSTEMI patients may also be candidates
What are the criteria for primary PCI?
- Presentation is within 12 hours of onset of symptoms
- Primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given
