Session 7: Antiplatelet and Fibrinolytic Drugs Flashcards
Appearane of venous thrombi.
High red blood cell and fibrin content.
Low platelet content.
Apperance of arterial thrombi.
Lower fibrin content and much higher platelet content.
Will also have lines of Zahn
Explain the functions of the healthy endothelium in regards to platelets.
Prostacyclin is produced and released by endothelial cells in order to inhibit platelet aggregation.
PGI2 binds to platelet receptors leading to an increase in cAMP in platelets.
This leads to a decrease in calcium. This prevents platelet aggregation.
This stabilises and inactivates GP IIb/IIIa receptors.
Briefly explain platelet activation and aggregation.
Damaged endothelium leads to some activation of the resting platelets that can be found on endothelium.
The activated platelets cover and adhere to exposed subendothelial surface of damaged endothelium and will start to release chemical mediators such as thromboxane A2, ADP, serotonin and PAF.
This attracts and activates more platelets leading to a plug formation.
Why is it important to give anti-platelet drugs if there is a presence of an atheroma?
Because the platelet activation and aggregation can be found in the latter process in the atherogenic pathway (fibrous cap, plaque rupture and thrombus formation)
In a bit more detail explain the activation and aggregation of platelets.
There is a release of thromboxane A2, ADP, serotonin, PAF, thrombin.
This causes activation and aggregation ultimately through GPIIb/IIIa where they are no longer inactive and bind to eachother via fibrinogen.
Calcium increases and cAMP decreases in platelets.
There is a cascade and amplification from platelet to platelet.
What drugs target platelet rich white arterial thrombi?
Antiplatelet and fibrinolytic drugs.
What drugs target lower platelet content red venous thrombi?
Anticoagulants such as heparin and warfarin.
Give an example of a cyclo-oxygenase inhibitor.
Aspirin
Explain the mechanism of aspirin.
Arachidonic acid is converted in prostaglandin H2 which is then converted into thromboxane A2.
The conversion of arachidonic acid to prostaglandin H2 is via cyclo-oxygenase 1 (COX-1).
Aspirin inhibits COX-1 by binding to it irreversibly.
Why does aspirin not completely inhibit platelet aggregation?
Because there are other aggregators independent of thromboxane A2.
How does the dose of aspirin depend on its effect?
Low doses of aspirin have non-analgesic effects where as higher doses also have analgesic effects.
Explain the action of higher doses of aspirin.
Inhibit endothelial prostacyclin (PGI2)
Explain the pharmacokinetics of aspirin.
Absorbed by passive diffusion and then hydrolysed by the liver to form its active component salicylic acid.
ADRs of aspirin.
Prolonged bleeding time
Haemorrhagic stroke
GI bleed
Reye’s syndrome
Hypersensitivity
Premature closure of ductus arteriosus due to the inhibition of prostaglandin production.
Contraindications of aspirin.
Other antiplatelets and anticoagulants due to additive or synergistic action.
Why does inhibition caused by aspirin last the lifespan of platelets (7-10 days)?
Because it binds irreversibly and platelets don’t have a nucleus so won’t produce new COX-1.
Why might there be a lack of efficacy of aspirin in some individuals?
Due to COX-1 polymorphism.
Uses of aspirin.
Secondary prevention of stroke and TIA
Secondary prevention of ACS
Post primary percutaneous coronary intervention and stent to reduced ischaemic complications
Secondary prevention of MI in stable angina or peripheral vascular disease
Often co-prescribed with other anti-platelet drugs.
How is aspirin used in ACS e.g. a STEMI.
Initial 300mg loading dose (usually chewable)
Then 300 mg daily for 2 weeks and then lower the dose.
What other drug is usually taken in the case of given aspirin for a long period of time?
PPis due to gastric protection as it can affect the prostaglandin in the stomach as well.
Give examples of ADP receptor antagonists
Clopidogrel
Prasugrel
Ticagrelor
Explain the mechanism of ADP receptor antagonists.
Inhibits binding of ADP to P2Y12 receptor leading to inhibition of activation of GPIIb/IIIa receptors.
Clopidogrel and prasugrel are irreversible inhibitors of P2Y12.
Pharmacokinetics of clopidogrel and prasugrel.
Prodrugs which are activated by the liver.
Clopidogrel has a slow onset of action without loading dose.
State the difference in speed of onset of clopidogrel, ticagrelor and prasugrel.
Clopidogrel has a slow onset of action.
Ticagrelor and prasugrel have more rapid onset.
How does ticagrelor differ in PD/PK compared to clopidogrel.
Acts reversibly at different site to clopidogrel.
ADRs of ADP receptor antagonists.
Bleeding
GI upset like dyspepsia and diarrhoea
Thrombocytopenia
Needs to be cautious as well in renal and hepatic impairment.
Contraindications of clopidogrel
Requires CYPs for activation so should not be taken with omeprazole, ciprofloxacin, erythromycin and some SSRIs.
Other PPis will have to be used.
Contraindications of ticagrelor.
Can interact with CYP inhibitors and inducers but caution when co-prescribed with other antiplatelet and anticoagulant drugs or NSAIDs.
This goes for clopidrogrel as well.
If a patient is on clopidogrel or ticagrelor and is going in for surgery. What is the patient instructed to do?
Need to stop being on clopidogrel 7 days prior to surgery or ticagrelor 5 days prior to surgery.
Uses of ADP receptor antagonists.
Clopidogrel is used in mono therapy where aspirin is contraindicated.
NSTEMI patients for up to 12 months
In STEMI with stent
If there is a risk of CVS events
Ischaemic stroke and TIA long term secondary prevention.
What is prasugrel especially used for?
With aspirin in ACS patients undergoing PCI up to 12 months.
Give examples of glycoprotein IIb/IIIa inhibitors.
Abciximab
Explain mechanism of abciximab.
Blocks binding of fibrinogen and von willebrand factor.
This targets the final common pathway leading to a more complete inhibition of platelet aggregation.
It is an antibody that binds to block the GP IIb/IIIa receptors.
Administration of abciximab.
IV with bolus dosing
ADRs of abciximab.
Greater risk of bleeding
Thrombocytopenia
Hypotension
Bradycardia
Contraindications of abciximab.
Antiplatelets
Anticoagulants
Use of abciximab.
Specialist use in high risk percutaneous transluminal coronary angioplasty patients.
Give an example of a phosphodiesterase inhibitor.
Dipyridamole
Explain mechanism of dipyridamole.
Inhibits the cellular reuptake of adenosine.
This leads to higher levels of plasma adenosine and inhibition of platelet aggregation via A2 receptors.
It also acts as phosphodiesterase inhibitor which prevents cAMP degradation and inhibits expression of GP IIb/IIIa
ADRs of dipyridamole.
Flushing
Headache
Hypersensitivity
Contraindications of dipyridamole.
Antihypertensives
Antiplatelets
Anticoagulants
Uses of dipyridamole.
Secondary prevention of ischaemic stroke and TIAs
Adjunct for prophylaxis of thromboembolism following valve replacement
Give examples of fibrinolytic agents/thrombolytic also called clot busters.
Streptokinase
Alteplase
Explain the mechanism of fibrinolytic agents.
Dissolve the fibrin meshwork of thrombus
Explain action of streptokinase
Promotes the activation of plasminogen.
Explain action of alteplase.
Activates plasminogen into plasmin.
Explain action of tranexamic acid.
Inhibition of fibrinolysis in order to inhibit excessive bleeding.
When is alteplase used?
In acute ischaemic stroke if it has been less than 4.5 hours.
Also following acute MI diagnosis vs. primary PCI.
ADRs of fibrinolytic agents.
Bleeding
Specific ADRs of streptokinase.
Can only be used once as antibodies develop intracranial haemorrhage.
When is primary PCI given in acute STEMI?
If presentation is within 12 hours of onset of symptoms and primary PCI can be delivered within 120 minutes of time when fibrinolysis could have been given.
What else should be offered in post acute MI?
ACE inhibitors once haemodynamically stable.
Why are antiplatelets used in secondary prevention of ACS and TIA?
Reduces the risk
Why does it take 7-10 days for antiplatelets effects to cease after terminating aspirin treatment?
Aspirin binds irreversibly to COX-1.
Platelets don’t have a nucleus and won’t produce additional COX-1.
Why is clopidogrel contraindicated in hepatic failure?
An increased risk of bleeding due to TPO usually being produced by the liver. If this cannot be produced there will be less platelets in the blood (thrombocytopenia) and a risk of increased bleeding if clopidogrel is introduced.
How do clopidogrel and ticagrelor differ in their basic pharmacodynamic properties?
Clopidrogrel binds irreversible where as ticogrelor does not.
Clopidogrel has a slow onset where as ticagrelor has a more rapid one.
Why do GP IIb/IIIa inhibitors afford more complete platelet aggregation than other agents?
Because they are the end result of the other aggregators where inhibiting ADP or Thromboxane A2 inhibit the chemical mediation of ‘calling’ platelets over.
What is tranexamic acid used for?
To prevent excessive bleeding
What are the downstream consequences of dipyridamole’s phosphodiesterase inhibiting action?
Inhibits platelet aggregation
Inhibit expression of GP IIb/IIIa.
Also causes blood vessel dilation and possible hypotension.
