L10 - Antiplatelets Flashcards
Venous thrombosis
- associated with stasis of blood +/- damage to the vein
- high RBC content
- high fibrin content
- low platelet content
- red
- soft and gelatinous
Arterial thrombosis
Forms at site of atherosclerosis following plaque rupture
- low fibrin content
- higher platelet content
- white
- lines of Zahn
Healthy endothelium
- Proastacyclin (PGI2) produced and released by endothelium cells
- PGI2 binds to the platelet receptors and increases cAMP in platelets
- The increased cAMP inhibits the release of sequestration calcium from stores
- Less calcium means less platelet aggregation
- Less release of platelet aggregatory mediators
- Glycoprotein IIb/IIIa receptors remains inactive
Glycoproteins IIb/IIIa
- Integrin receptor complex found on platelets
- binds with fibrinogen and vWF to aid platelet aggregation
Platelet activation and aggregation
- Damage to endothelium e.g. by fibrous cap rupture exposes collagen fibres
- Adhesion and activation of platelets
- Chemical mediators are released by platelets granules e.g. thromboxane A2, ADP, serotonin, thrombin and platelet activation factor
- Further cascade of platelet aggregation as GP IIb/IIIa are activated which binds to fibrinogen and another platelet
- Ca2+ is released from its stores and cAMP decreases in platelets
Drug type for arterial and venous thrombi
Arterial thrombi: platelet rich, white
- anti-platelet drugs
- lesser extent fibrinolysis drugs
Venous thrombi: loser platelet content, red
- parenteral anticoagulants - heparin
- oral anticoagulants - warfarin
Secondary prevention in acute coronary syndrome
Combination of both anticoagulants, antiplatelets and fibrinolytics
Aspirin mechanism of action
Cyclo-oxygenase inhibitor
- inhibits COX-1 mediated production of thromboxane A2 and irreversibly reduces platelet aggregation
Why does aspirin not completely inhibit platelet aggregation
There are other methods that platelets use to aggregate, independent of COX 1
COX 1
Normally converts arachidonic acid into prostaglandin H2
Prostaglandin H2 is converted to thromboxane A2
Where is arachidonic acid produced from
Produced and accumulates around the phospholipid membrane
Dose actions of aspirin
Low dose - inhibits platelet aggregation
High dose
- loading dose
- analgesic
- inhibits prostacyclin
Absorption of aspirin
Passive diffusion - hepatic hydrolysis when metabolised to salicylic acid
Side effects of aspirin
Prolonged bleeding time
- haemorrhagic stroke
- GI bleeding
- peptic ulcers - to lesser extent
- Reye’s syndrome
- hypersensitivity
- early closure of the ductus arteriosus in the 3rd trimester
Reye’s syndrome
Occurs after a viral infection in children given aspirin
Can be fatal
Causes oedema and hepatic issues
Therefore do not give aspirin to children under 16
Cautionary measures with aspirin
Taken with other antiplatelets and and anticoagulants
Why does inhibitory effects of aspirin last the lifespan of a platelet (7-10 days)?
Platelets do not have nuclei therefore cannot reproduce COX - 1
COX 1 polymorphism
Can cause lack of efficacy
May not acetylate COX 1 therefore reduces efficacy
When is aspirin used?
In secondary prevention of:
- stroke - initial 300mg daily for 2 weeks
- TIA
- acute coronary syndrome - initial once only chewable loading dose
- MI in stable angina or peripheral vascular disease
Used in:
- post primary percutaneous coronary intervention (PCI) and stents to reduce ischaemic complications
What is also given with long term aspirin?
PPI e.g. omeprazole form gastric protection
ADP receptor antagonist examples
Clopidogrel
Prasugrel
Ticagrelor
ADP receptor antagonists
Inhibits binding of ADP to P2Y12 receptor on platelets therefore less calcium release from stores, inhibiting the activation of GP IIb/IIIa receptors
(Independent of COX -1)
Clopidogrel and prasugrel
Irreversible inhibitors of P2Y12
Pro drugs - require hepatic metabolites to activate them (CYPS)
Onset speed for ADP receptor antagonists
Clopidogrel - slow onset of action without loading dose
Prasugrel - rapid onset but slower than ticagrelor
Ticagrelor - rapid onset (1-2 hours)
Ticagrelor
Acts reversibly at different sites to clopidogrel
Has active metabolites
Side effects of ADP receptor antagonists
- Bleeding
- GI upset - dyspepsia and diarrhoea
- possible thrombocytopenia
- clopidogrel needs stopping 7days prior to surgery
Cautions with ADP receptor antagonists
Renal and hepatic impairment - due to excretion and activation
Clopidogrel requires CYPs for activation therefore (CYP inhibitors)
- omeprazole
- ciprofloxacin
- erythromycin
- SSRI
Ticagrelor can interact with CYP inhibitors and inducers
Co-prescribed with other antiplatelets and anticoagulant agents or NSAIDS
When are ADP receptor antagonists used?
- clopidogrel is used as monotherapy when aspirin is contraindicated
- NSTEMI patients - up to 12months
- STEMI with stent - up to 12 months
Long term secondary prevention for:
- ischaemic stroke
- TIA
Prasugrel with aspirin in ACS patients undergoing PCI for up to 12 months
Glycoprotein IIb/IIIa inhibitors example
Abciximab - monoclonal antibody
Given as IV with bolus
Glycoprotein IIb/IIIa inhibitor mechanism of action
Blocks the glycoproteins IIb/IIIa receptors therefore blocks the binding of fibrinogen and vWF to GP IIb/IIIa
Therefore inhibits aggregation of platelets at the terminal step - better efficacy
Side effects and cautions of abciximab
- bleeding (highest risk) - dose adjustments with body weight
- thrombocytopenia
- hypotension
- bradycardia
Caution with other antiplatelets and anticoagulants
Specialist use in high risk percutaneous transluminal coronary angioplasty patients
Phosphodiesterase inhibitor example
Dipyridamole
Phosphodiesterase inhibitor mechanism
Inhibits the cellular reuptake of adenosine
Increased plasma adenosine
Inhibits platelet aggregation via A2 receptors
Also:
Prevents cAMP degradation
Less calcium released from stored
Less GP IIb/ IIIa receptor activation
Side effects and cautions of dipyridamole
Flushing
Headache
Hypersensitivity
Caution with:
- antihypertensives (higher adenosine plasma conc)
- antiplatelets
- anticoagulants
Uses of dipyridamole
Secondary prevention of ischaemic stroke and TIAs
Adjunct for prophylaxis of thromboembolism following valve replacement
Fibrinolytic agents
Streptokinase - promotes plasminogen expression
Alteplase - plasminogen activator
Plasmin causes fibrinolysis of a fibrin clot into fibrin degradation products
Fibrinolysis inhibitor
Tranexamic acid
When is Alteplase used
In acute ischaemic stroke - less that 4.5 hours
Side effects of fibrinolytics
Bleeding
Why can streptokinase only be used once?
Developed from streptococci therefore body will produce antibodies
