Lecture 12- Anti-platelet and fibrinolytic drugs Flashcards
Thrombus
- a clot adhered to vessel wall
Embolus
- intravascular clot distal to site of origin
Thromboembolic diseases are common
· deep vein thrombosis (DVT) and pulmonary embolism (PE)
· consequence of atrial fibrillation (AF)
· transient ischaemic attacks (TIA)
· ischaemic stroke
· myocardial infarction (MI
arterial thrombosis
- Usually forms at site of atherosclerosis following plaque rupture
- Lower fibrin content and much higher platelet content than venous thrombosis
Venous thrombosis
- Associated with stasis of blood and or damage to the veins – less likely to see endothelial damage
- High red blood cell and fibrin content, low platelet content evenly distributed
healthy endothelium
‘resting platelets’
- Prostacyclin (PGI2) produced and released by endothelial cells- inhibits platelet aggregation
- PGL2 binds to platelet receptors increase [cAMP] in platelets
- Increased cAMP decreases calcium- preventing aggregation
- Decrease in platelet aggregatory agents
- Stabilises inactive GPIIb/IIIa receptors
what inhibits platelt aggregation
prostacylin (PGI2) produced by healthy endothelium
Platelet lifespan
8-10 days
- 10% replaced each day turnover
Platelet activation and aggregation
1) Platelet adhesion
- Damage to vessel wall (endothelium)
- Exposure of underlying tissues
- Resting platelets adhere to collagen via vWF/receptors
2) Platelet activation
- platelets secrete granules (ADP, thromboxane A2, serotonin, platelet activation factor (PAF) and thrombin) to become activated and activate other platelets
3) Platelet aggregation
- Cross linking of platelets to form platelet plug
- activation and aggregation ultimately through GPIIb/IIIa receptors and fibrinoge
- increase calcium and decrease cAMP in platelets
- increase platelet aggregation
- cascade and amplification from platelet to platelet
-
Mediating factors
- Thromboxane A2
- Von Willebrand’s factors
- Fibrinogen
- Collagen
- ADP
Reduction of pathological platelet aggregation essential in
reducing cardiovascular events and reducing mortality
Therapeutic agents available disrupt various stages of signalling cascade
- Platelet rich “white” arterial thrombi – antiplatelet and fibrinolytic drugs used
- Lower platelet content, “red” venous thrombi – parenteral anticoagulants heparins etc. and oral anticoagulants warfarin etc. (session 11)
- A combination of both may be used in some patients often
in secondary prevention – targeting multiple sites and mechanisms of thromboembolic cascades
name the antiplatelet classes
- Cyclo-oxygenase inhibitors
- ADP receptor antagonists
- Phosphodiesterase inhibitors
- glycoprotein IIb/IIIa inhibitors
clot busters
fibrinolytic agents - mediate thrombolysis
name a drug under the class cyclo-oxygenase inhibitor
aspirin
uses of aspirin (cyclo-oxygenase inhibitor)
- Antiplatelet
- Atrial fibrillation
- Secondary prevention pf stroke and TI
- Secondary prevention for acute coronary syndrome
- Post primary percutaneous coronary intervention and stent to reduce ischaemic complications
- NSTEMI/STEMI (initial once only 300 mg loading dose- chewable is best)
- Acute ischaemic stroke- 300mg daily for 2 weeks
Pharmacokinetics Aspirin (Cyclo-oxygenase inhibitor)
- Absorbed by passive diffusion
- Hepatic hydrolysis to salicylic acid (active form)
- COX-1 polymorphism results in lack of efficacy in some
mode of action of aspirin
- aspirin inhibits COX-1
- COX-1 mediates arachidonic acid convertion to Prostaglandin H2 (PGH2) which then becomes–> thromboxane A2 (TXA2)
- thromboxane A2 (TXA2) potent platelet aggregating agent
- therefore reduction in platelet aggregation
- irreversible
low dose aspirin
Daily low-dose aspirin is a blood thinning medicine- 75mg
Adverse drug response: aspirin
- GI irritation (gastric protection required for long term use in at risk pts (PPIs needed)
- GI bleeding (peptic ulcer)
- Haemorrhage (stroke)
- Hypersensitivity to aspirin
Contraindications: aspirin
- Reyes syndrome – avoid <16 years
- Causes liver disease and brain damage
- Hypersensitivity to aspirin
- 3rd trimester- premature closure of ductus arteriosus
Drug-drug interaction: aspirin
Caution- other antiplatelets and anticoagulants (additive/ synergistic action)
name 3 drugs under the class ADP receptor antagonist
-
Clopidogrel
- monotherapy when aspirin is contraindicated
- NSTEMI- pts -3 months
- STEMI pts- up to 4 weeks
- Prasugrel- with aspirin in ACS patients (undergoing PCI) for up to 12 months)
- Ticagrelor - with aspirin in ACS patients (undergoing PCI) for up to 12 months)
when are ADP receptor antagonists used e.g. clopidogrel
- MI
- ischaemic stroke
Mode of action
- ADP receptor antagonist- inhibits binding of ADP to P2Y12 receptor
- Inhibiting activation of GPIIb/IIIa receptors (independent of COX pathway)
clopidogrel pharmacokinetics
- Irreversible inhibitor of P2Y12
- Prodrugs- need hepatic metabolism to produce active metabolites
- Slow onset of action without loading dose
- Inter-individual variability in antiplatelet action
prasugrel pharmacokinetics
- Irreversible inhibitors of P2Y12
- Prodrugs- need hepatic metabolism to produce active metabolites
- rapid onset
Ticagrelor pharmacokinetics
Acts reversibly at different sites to clopidogrel and has active metabolites
Adverse drug response: ADP receptro antagonists e.g. clopidogrel
- Bleeding
- GI upset- dyspepsia and diarrhoea
- thrombocytopenia
Contraindications ADP receptor antagonists e.g. clopidogrel
- caution in high bleed risk pts with renal and hepatic impairment
- clopidogrel needs stopping 7 days prior to surgery
Drug-drug interaction: ADP receptor antagonist e.g. clopidogrel
- clopidogrel requires CYPs for activation
- CYP inhibitors: omeprazole, ciprofloxacin, erythromycin, some SSRIs
- PPIs
- Ticagrelor can interact with CYP inhibitors and inducers
- Caution when prescribed with other antiplatelet and anticoagulant agents or NSAIDS- increased bleeding risk
name a drug under the class phosphodietserase inhibitors
dipyridamole
dipyridamole (Phosphodiesterase inhibitor) uses
- Secondary prevention of ischaemic stroke and TIAs
- Adjunct for prophylaxis of thromboembolism following valve replacement
- Stroke- modified release
Mode of action: Dipyridamole
- Inhibits cellular reuptake of adenosine–> increased plasma [adenosine] –> inhibits platelet aggregation via adenosine (A2) receptors
- Also acts as a phosphodiesterase inhibitor which prevents cAMP degradation –> inhibits expression of GP IIb/IIIa
- inhibits activation of platelets
Adverse drug response: Phosphodiesterase inhibitors (dipyridamole)
- Vomiting and diarrhoea
- Dizziness
Drug-drug interaction: Phosphodiesterase inhibitors (dipyridamole)
- Antiplatelets
- Anticoagulants
- Adenosine
name a drug under the class glycoprotein IIb/IIIa inhibitors
abciximab
abciximab mode of action
- Blocks binding of fibrinogen and von Willebrand factor (vWF)
- Abciximab= antibody- blocks GPIIb/IIIa receptors >80% reduction in aggregation – bleeding risk
- IV admin
- Abciximab= antibody- blocks GPIIb/IIIa receptors >80% reduction in aggregation – bleeding risk
- Target final common pathway- more complete platelet aggregation
Adverse drug response: abciximab
Bleeding (dose adjustment for body weight)
DDI abciximab
name 2 drugs under the class Fibrinolytic agents (thrombolysis) “clot busters”
Alteplase and streptokinase
uses of Alteplase and streptokinase
- Acute ischaemic stroke <4.5 hours from symptoms
- Following STEMI diagnosis acutely
- Vs Primary PCL
Mode of action of fibrinolytic agens alteplase and streptokinase
activates plasminogen (tissue plasminogen activator) to plasmin which causes fibrinolysis of fibrin clot
Adverse drug response: Fibrinolytic agents (thrombolysis)
- Bleeding –> tranexamic acids can be used to stop bleeding
Drug-drug interaction: Fibrinolytic agents (thrombolysis)
Other antiplatelet and anticoagulant agents
Thrombolysis vs primary PCI following MI
- Offer primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI if
- Presentation within 12hours of onset of symptoms and primary PCI can be delivered within 120 mins
- Time critical- ‘time is muscle’
- Presentation within 12hours of onset of symptoms and primary PCI can be delivered within 120 mins
- Insertion of catheter up femoral artery to reach coronary vessel
- Stent and balloon mechanism
If PCI can not be given within 120 mins i.e. in the cath lab… then give fibrinolysis (alteplase/streptokinase)
what shoudl be offered to all patients post MI once haemodynamically stable
ACEi
