Let’s now turn our attention to the pharmacology of antiplatelet drugs – medicines which are used to inhibit the formation of blood clots (thrombi) and whose function is to decrease platelet aggregation. Platelets, or thrombocytes, are derives from larger cells called megakaryocytes – with platelets themselves containing no nucleus. They are also quite small, around a fifth of the diameter of red blood cells. Platelets clot blood in the following way:
- Platelets first adhere to substances outside the damaged endothelium (adhesion).
- They then activate receptors and secrete chemical messengers (activation).
- Platelets then link up to one another to form sturdy bridges (aggregation).
- The resulting ‘platelet plug’ is then solidified further with fibrin deposits.
Though explained in simple terms the process of forming the platelet plug is quite complex, but the details needn’t burden us here. Notwithstanding that, a fundamental knowledge of the haemostatic process is necessary to understand how antiplatelet drugs work – particularly with regard their mechanisms of action. With this in mind, below you’ll find an overview to the main classes of antiplatelet drug, how they work, and why they are used.
Pharmacology of Antiplatelet Drugs
This section looks at five main groups of antiplatelet drugs:
- COX inhibitors
- Phosphodiesterase inhibitors
- ADP receptor antagonists
- Glycoprotein IIb/IIIa receptor antagonists
With each class, we will supply some examples – while explaining their mechanism of action, pharmacokinetics, and unwanted effects. There are other classes – such as thromboxane synthase inhibitors – but their clinical use is limited hence why they are excluded from this list. The drugs we’ll study have activity in the arterial circulation, a place where other drugs – such as anticoagulants – have little activity.
The purpose of antiplatelet drugs is to arrest the clotting process. As such, antiplatelet drugs are used in the prevention and treatment of arterial thrombosis – preventing heart attacks, ischaemic heart disease, and stroke. COX inhibitors are one such class of antiplatelet drugs, which work by irreversibly inhibiting COX-1; an enzyme that forms the potent platelet aggregator thromboxane A2 in platelets.
Aspirin inhibits platelet aggregation in this way, though the effect only manifests when the drug is taken at low doses – doses, incidentally, that have little analgesic and anti-inflammatory activity. Due to COX-2 inhibition, aspirin increases the risk of gastrointestinal bleeding (this risk increases further if aspirin is taken with NSAIDs). Aspirin should be kept away from children and adolescents, as it is associated with causing Reye’s syndrome.
The next in our study of the pharmacology of antiplatelet drugs is phosphodiesterase inhibitors – examples of which include dipyridamole. Dipyridamole works by inhibiting the enzyme phosphodiesterase 5, an enzyme responsible for breaking down cyclic nucleotides. This causes cAMP concentrations to increase inside cells, thereby reducing expression of glycoprotein IIb/IIIa receptors (activation of these receptors causes platelet aggregation).
Dipyridamole is poorly absorbed from the gut, and it primarily metabolised via hepatic means. It has a moderately long half-life of 10 hours. Unwanted effects with dipyridamole include gastrointestinal effects, muscle pain, dizziness, headache, flushing, and hypotension. Some patients also experience hypersensitivity symptoms such as rash and urticaria. Cilostazol is also a PDE inhibitor, though it inhibits PDE3 and is used to treat intermittent claudication.
ADP receptor antagonists
ADP receptor antagonists include members such as clopidogrel, prasugrel, ticagrelor, ticlopidine, and cangrelor. Platelet aggregation is inhibited by irreversible binding at purinergic P2 receptors for ADP on the platelet surface (in the case of clopidogrel and prasugrel). In contrast, ticagrelor acts as a reversible allosteric antagonist of P2Y12. Ticlopidine irreversibly blocks the ADP receptor on platelet surfaces, preventing fibrinogen from binding.
See the infographic below for more information on ADP receptor antagonists:
Glycoprotein IIb/IIIa Receptor Antagonists
Glycoprotein IIb/IIIa receptor antagonists include the drugs abciximab, eptifibatide, and tirofiban – drugs which are only used intravenously. They are commonly deployed during the surgical procedure, percutaneous coronary intervention (PCI) – where stents are placed into narrowed vessels. They work by antagonising these receptors on the surface of platelets, with abciximab binding irreversibly and tirofiban binding reversibly.
Abciximab has a short half-life of around 30 mins, but its effects are longer in duration due to continuous receptor blockade. Unwanted effects with abciximab include bleeding (particularly in the elderly and those with low body mass), thrombocytopenia, nausea, vomiting, hypotension, and headache. Some patients experience hypersensitivity reactions resulting in symptoms such as fever and urticaria.
Epoprostenol is also known as PGI2, a drug that increases cAMP which – at low concentrations – inhibits platelet aggregation. Higher doses of epoprostenol reduces platelet adhesion. Epoprostenol is also an effective vasodilator. It can be used in conditions such as Reynaud’s phenomenon and pulmonary hypertension. It is given by IV infusion and is rapidly metabolised, with a half-life of 3 minutes. Unwanted effects include flushing and headache.
That’s about it for the pharmacology of antiplatelet drugs. Check out this quiz if you’d like to test your knowledge of this class of cardiovascular medicines.