What Is Involved in Platelet Production?

Antiplatelet drugs are drugs used to inhibit the growth of platelet cyclooxygenase. Antiplatelet drugs mainly include aspirin, a thromboxane A2 (TXA2) inhibitor, and P2Y12 receptor antagonists, including thiophenepyridine (clopidogrel, prasugrel) and non-thiophenepyridines (tegrelor), and glycoprotein (GP ) Ib / IIIa receptor inhibitors (Axiomab and tirofiban). And phosphodiesterase inhibitors (such as dipyridamole and cilostazol).

Antiplatelet drugs are drugs used to inhibit the growth of platelet cyclooxygenase. Antiplatelet drugs mainly include aspirin, a thromboxane A2 (TXA2) inhibitor, and P2Y12 receptor antagonists, including thiophenepyridine (clopidogrel, prasugrel) and non-thiophenepyridines (tegrelor), and glycoprotein (GP ) Ib / IIIa receptor inhibitors (Axiomab and tirofiban). And phosphodiesterase inhibitors (such as dipyridamole and cilostazol).

Chinese name

Antiplatelet drugs

Function

Platelet cyclooxygenase

Effect

Impedes the synthesis of prostaglandin G2 and H2

Purpose

Inhibition of platelet synthesis of thromboxane A2

Platelets are produced by megakaryocytes and play an important role in the initial hemostasis and thrombosis. Platelet activation plays an important role in the occurrence and development of atherosclerosis, arterial thrombosis, and other cardiovascular and cerebrovascular diseases. Therefore, antiplatelet therapy has become an important strategy for the prevention and treatment of arterial system thrombosis. The development of antiplatelet therapy, along with a deeper understanding of the mechanism of platelet activation, and the understanding of more signal transduction pathways provide new ideas for antiplatelet therapy.

Antiplatelet drugs mainly include aspirin, a thromboxane A2 (TXA2) inhibitor, and P2Y12 receptor antagonists, including thiophenepyridine (clopidogrel, prasugrel) and non-thiophenepyridines (tegrelor), and glycoprotein (GP ) Ib / IIIa receptor inhibitors (Axiomab and tirofiban). And phosphodiesterase inhibitors (such as dipyridamole and cilostazol).

1. Antiplatelet drugs 1. Drugs that affect platelet activation and expansion

1.1. TXA2 (TXA2) Inhibitors

TXA2 is a powerful agonist of platelet activation and vasoconstriction. By binding to G-protein coupled receptors, TXA2 causes the activation of phospholipase C (PLC) , increases intracellular calcium ions, and subsequently platelets are activated. Aspirin is currently the most widely studied and applied antiplatelet drug in antiplatelet therapy. It mainly inhibits TX-A2 by inhibiting arachidonic acid epoxidase (COX) and irreversibly acetylating Ser-529 and Ser-516. Synthesize and exert anti-platelet effect. Although resistance to aspirin and adverse reactions to bleeding cannot be ignored, due to its exact protective effect, it is still the gold standard for the prevention of cardiovascular disease. The results of a large number of experimental studies show that the active substances extracted from various plants can inhibit the synthesis of TXA2, thereby inhibiting the aggregation of platelets. However, aspirin has no effect on platelet aggregation caused by other agonists (such as collagen and adenosine diphosphate). Aspirin is absorbed quickly and completely after oral administration. Peak blood concentration is reached 1 hour after taking aspirin, and absorption begins in the stomach. Most of it is absorbed in the upper small intestine, and is excreted from the kidney by combining metabolites and free salicylic acid. Chewing aspirin works quickly. 3 Adverse reactions: Aspirin common adverse reactions are gastrointestinal upset and gastrointestinal bleeding, and the risk of bleeding is dose-related. A few can also occur allergic reactions, mainly asthma, urticaria. Try to avoid concurrent use of non-steroidal anti-inflammatory drugs, especially ibuprofen can affect the antiplatelet effect of aspirin. The risk of bleeding increases when combined with other antiplatelet and anticoagulant drugs. Contraindications: bleeding disorders; active bleeding, such as bleeding from important organs (intracranial hemorrhage, gastrointestinal bleeding, genitourinary bleeding, etc.); active peptic ulcer; severely poorly controlled hypertension; severe allergic reaction or inability Tolerance (asthma and nasal polyps).

1. 2. Adenosine diphosphate (ADP) P2Y12 receptor antagonist

The binding of the ADP receptor antagonist to the ADP receptor on the surface of the platelet membrane prevents the exposure of the binding site of the GPIIb / IIIa receptor coupled to the ADP receptor, making it impossible for the ligand to bind, and the platelet aggregation is inhibited. There are two main types of ADP receptors: P2Y1 and P2Y12; compared with P2Y1, ADP and P2Y12 can trigger the formation of stable and long-lasting platelet aggregation effect.

1.2.1 Thiophyridines

There are currently three thiophenepyridine derivatives that block P2Y12 for clinical use: ticlopidine, clopidogrel, and prasugrel. Large-scale randomized clinical trials provide clear evidence for its antithrombotic effect. These three compounds are prodrugs, and they need to be metabolized into active metabolites by the liver cytochrome P450 system in order to exert antithrombotic effects. In clinical practice, ticlopidine has been replaced by clopidogrel, which is safer and better tolerated. Clopidogrel has a fast onset of action, has a low risk of causing bleeding, and has few toxic and side effects. However, clopidogrel is currently facing the challenge of faster and more potent prasugrel. Prasugrel is more consistent in effect or tolerated than clopidogrel in individuals, but at the same time the risk of bleeding increases.

(1) Ticlopidine

Ticlopidine is a thiazolidine compound that blocks the ADP receptor coupled to the Gi protein. Pharmacokinetics: Clopidine is rapidly absorbed after oral administration. The blood peak was reached 1-3 h after oral administration. When the healthy subjects took 50 or 1000 mg orally at one time, the peak plasma concentrations were 0.61 and 2.13 mg / L, respectively, and they could be distributed throughout the body tissues, with higher concentrations in urine and fecal blood and sleep fluid. 59% were excreted via urine, 25% were excreted via stool, and T1 / 2 was 14 h (8-25 h). This product is a prodrug, which needs to be converted into active metabolites by liver cytochrome P450. It is mainly metabolized by N-demensing and oxidation to open the thiophene ring. Ticlopidine can inhibit platelet aggregation response caused by thrombin, collagen, epinephrine, arachidonic acid, ristocin, and platelet activating factor. A large number of clinical applications of ticlopidine have proved that various adverse reactions caused by ticlopidine include agranulocytosis, aplastic anemia, liver toxicity, etc. The symptoms disappear after stopping the drug, but its severe bone marrow suppression constitutes a patient's life Threat.

(2) Clopidogrel

As a second-generation P2Y12 receptor antagonist, clopidogrel is a derivative of ticlopidine. Clopidogrel can selectively and irreversibly block the binding of ADP and platelet P2Y12 receptors, thereby inhibiting platelet aggregation. Mechanism of action: Clopidogrel is a thiophene pyridine, which irreversibly inhibits platelet adenosine diphosphate (ADP) receptors, thereby inhibiting

Platelet release ADP-induced platelet aggregation. Clopidogrel is a prodrug that requires the liver cytochrome P450 enzyme to metabolize to form an active metabolite, and irreversibly binds to the P2Y12 receptor. After oral absorption through the gastrointestinal tract, it is rapidly metabolized in the liver. The concentration of the protodrug in the plasma is extremely low. The peak time of the plasma concentration is about 1 hour, and the plasma is cleared in half. Adverse reactions: The main adverse reactions are bleeding (the incidence of severe bleeding events is 1.4%), gastrointestinal upset, rash, headache,

Dizziness, dizziness, and paresthesia. A few patients have allergic reactions, manifested as urticaria and pruritus. Clopidogrel results in a significantly lower incidence of neutropenia and thrombocytopenic purpura than ticlopidine, and routine monitoring of platelet counts is not required. Contraindications: bleeding disorders; active bleeding, such as bleeding from vital organs (intracranial hemorrhage, gastrointestinal bleeding, urogenital bleeding, etc.); severe liver damage, etc.

(3) Prasugrel

It is a third-generation P2Y12 receptor antagonist. It is a prodrug that needs to be metabolized into active metabolites in the liver before it can play an irreversible blockade of ADP. Compared with clopidogrel, prasugrel produces more metabolites

Faster and more active. Ma Xiaobing randomly divided 160 patients with coronary heart disease into two groups and gave prasugrel and clopidogrel respectively. The results showed that the platelet aggregation rate (MPA) and average platelet response index (PRI) of the two groups were significantly better than before and after treatment. The control group (P <0.05), which shows that prasugrel is better than clopidogrel in the treatment of coronary heart disease. Ruff et al. Grouped a total of 13,608 patients with acute coronary syndrome in different regions and gave them

Lagrele and clopidogrel found that prasugrel is superior to clopidogrel in terms of safety and clinical efficacy.

1.2.2 Non-thiophene pyridines

(1) Ticagrelor

Ticarelor works similarly to cangrelor, and does not require conversion into active metabolites in the liver, but competes directly and reversibly to inhibit the P2Y12 receptor. Wallentin et al. Compared randomized double-blind trials of 18 624 hospitalized patients with acute coronary syndrome (with or without ST-segment elevation) in the prevention of cardiovascular disease. Effect. The results showed that ticarrelol significantly reduced the incidence of cardiovascular death, myocardial infarction or stroke in patients compared with clopidogrel. Large-scale clinical studies such as Lindholm have also demonstrated that ticarrel is superior to clopidogrel in reducing the incidence of ischemic disease and overall mortality in patients.

(2) Cangrelor

It is a reversible P2Y12 receptor antagonist. Unlike clopidogrel and prasugrel, which are thiophenes, cangrelor does not need to be converted into active metabolites in the liver, and can directly block the effect of ADP. Storey observed the clinical effects of using clopidogrel and cangrelor before and after percutaneous coronary intervention (PCI), and found that the cangrelor group, which directly blocks the receptor, has a mortality rate within 48 hours. Lower than the clopidogrel group, confirming the safety of cangrelor clinical treatment.

(3) Ticagrelor

Tigrelor is a novel P2Y12 receptor antagonist that directly and reversibly inhibits platelet P2Y12 receptors without the need for metabolic activation. The plasma half-life of ticagrelor is 8-12 hours, and it needs to be administered twice daily. Within 30 minutes after taking the loading dose of ticagrelor, platelet activity can be significantly inhibited, and it takes 2 h to reach the maximum efficacy. After discontinuation, platelet function recovered quickly. In addition to acting on the P2Y12 receptor, ticagrelor can also inhibit the reuptake of adenosine by red blood cells. Serum adenosine has antiplatelet and vasodilator effects, but at the same time, adverse reactions such as difficulty breathing and bradycardia increase. Tigrelor adverse reactions: Bleeding can manifest as minor or severe bleeding. In addition, there are dyspnea and gastrointestinal symptoms such as vomiting, diarrhea, abdominal pain, nausea and so on. Dyspnea is usually mild to moderate and dose-related. Some patients can be relieved without stopping the drug. Patients with asthma / chronic obstructive pulmonary disease may have an increased absolute risk of dyspnea during treatment with ticagrelor and should be used with caution. Clinical studies have shown that ticagrelor can cause bradyarrhythmias, which should be used with caution in patients with bradycardia. In addition, caution should be exercised when ticagrelor is combined with drugs known to cause bradycardia. Combination use with CYP3A4 potent inhibitors should be avoided; simvastatin and lovastatin doses should not be greater than 40 mg when combined with ticagrelor. Ticagrelor contraindications: bleeding disorders; active bleeding, such as bleeding from important organs (intracranial hemorrhage, gastrointestinal bleeding, urogenital bleeding, etc.); patients with a history of intracranial hemorrhage; patients with moderate to severe liver damage; Taking strong CYP3A4 antagonists (such as ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir, etc.).

1.3. Thrombin receptor antagonists

The protease-activated receptor (PAR) of the thrombin receptor belongs to the G protein coupled receptor family. It has 4 subtypes, of which PAR-1 and PAR-4 are expressed in human platelets. Since PAR-4 induces platelet aggregation only under conditions of high concentration of thrombin, and PAR-4 is not expressed when PAR-1 function is fully expressed, PAR-1 is the most important thrombin receptor. Thrombin receptor antagonists are currently the most concerned and promising antiplatelet drugs.

1.3.1 Vorapaxar (SCH-530348) is a potent, selective, high affinity and orally active PAR-1 antagonist. Although multiple phase II clinical trials have confirmed its safety and tolerability. However, large-scale clinical studies such as Morrow have shown that although Vorapaxar can reduce the risk of cardiovascular death or ischemia in atherosclerosis patients receiving standard treatment, it increases the risk of moderate or severe bleeding, including intracranial bleeding, causing Concerned researchers. Merck has identified some potential bleeding issues in Vorapaxar clinical trials, delaying the launch of Vorapaxar. In July 2013, the FDA accepted Mercap's Vorapaxar marketing application. Recent reports indicate that the FDA's Cardiovascular and Renal Drug Advisory Committee (CRDAC) has recommended approval of the company's antiplatelet drug Vorapaxar.

1.3.2 Atopaxar (E5555) is a new type of reversible PAR-1 antagonist, which is rapidly absorbed and highly bioavailable after oral administration. Serebruany and other studies have confirmed that Atopaxar can also antagonize PAR-1 receptors in vitro and can cooperate with aspirin to exert antiplatelet effects. Goto et al. In a phase II clinical double-blind trial of Japanese patients with acute coronary syndrome or high-risk coronary artery disease found that 50, 100, and 200 mg of Atopaxar did not increase clinically significant bleeding (ACS: 6.6% placebo vs 5.0% E5555, P> 0.73; CAD: 4.5% placebo vs 1.0% E5555, P> 0.066), and platelet inhibitory levels were significantly achieved at all test doses (100 mg and 200 mg E5555, inhibition rate> 90 %, 50 mg E5555, inhibition rate> 20% to 60%), confirming the safety and effectiveness of Atopaxar.

1.4 Serotonin (5-HT) receptor antagonist

As a neurotransmitter and vasoactive substance, more than 90% of 5-HT in the human body is stored in platelets. There are two types of 5-HT receptors on platelets: 5-HT1 receptor and 5-HT2 receptor. Blood 5-HT2 can activate platelet and 5-HT2 receptors of vascular smooth muscle and promote the formation of thrombus [25]. Therefore, the study of vascular 5-HT2 receptors to develop antiplatelet drugs is of great significance for the treatment of cardiovascular diseases.

1.4.1 Sarpogrelate

Sarpogrelate (SARP) is a 5-HT2 receptor blocker produced by Japan's Mitsubishi Pharmaceutical Corporation and can specifically bind to 5-HT2 receptors. SARP is clinically applied to peripheral vascular diseases, such as chronic ischemic vaso-occlusive disease, coronary heart disease, neurological diseases, and thrombotic diseases. The pharmacological effects of SARP include the following aspects: inhibition of platelet aggregation; inhibition of vascular contraction caused by 5-HT and platelet aggregation; antithrombotic formation; improvement of collateral circulation, etc. It can specifically bind to 5-HT2 receptors to inhibit platelet aggregation, and can be clinically used in various thrombotic diseases such as chronic ischemic vascular occlusion. Kajiwara and other studies have shown that administration of sagrelide on the basis of aspirin can reduce platelet aggregation in patients with stable angina pectoris, indicating that sagrelide has an adjuvant treatment effect on patients with stable angina pectoris.

1.4.2 Citalopram

Citalopram is widely used as a selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, and is being used to study its role in antiplatelet aggregation. Tseng et al. Used normal human blood to prepare PRP, and tested the inhibitory effect of citalopram on bovine Achilles tendon collagen-induced platelet aggregation under specific conditions. Effects of citalopram on integrin IIB3 platelet activation results indicate that citalopram

Puland failed to inhibit collagen-induced integrin IIB3 antibody binding site expression; in the verification and speculation that citalopram may affect the secretion of granules to stimulate collagen, it was confirmed that citalopram directly inhibited collagen-induced platelet release and caused platelet aggregation, but only Partial inhibition of collagen-induced aggregation.

2 Antiplatelet drugs 2 Drugs that inhibit platelet aggregation

2.1. Platelet glycoprotein (GP) II b / IIIa receptor inhibitors are the last key step in platelet aggregation due to the interaction of fibrin with GPb / a, and GPb / a is expressed only on platelets. Obviously, the development of GPb / IIIa receptor antagonists are one of the most powerful means of antiplatelet therapy, which can exert a strong inhibitory effect on platelet aggregation.

2.1.1 Azizumab

Abciximab is a chimeric antigen-binding fragment (Fab) mouse monoclonal antibody against the human GPIIb / IIIa receptor, which blocks the binding of the ligand to GPIIb / IIIa through steric hindrance. Clinically, abciximab is used as adjuvant therapy in percutaneous transluminal coronary intervention (PCI), including balloon angioplasty, atherectomy, and major stent implantation. However, abciximab is potentially immunogenic and prone to allergic reactions; irreversibly antagonizing the GPIIb / a receptors, bleeding reactions are more common and the cost is higher. The subsequent development of tirofiban and etibeptide has a relatively low molecular weight and reversibly binds to the GPIIb / a receptor, reducing the occurrence of allergic reactions and bleeding.

2.1.2 Tirofiban

Tirofiban is a specific non-peptide GPIIb / a receptor antagonist, which mimics the GPb / a receptor to recognize arginine-glycine-aspartate (RGD) peptides, and it is acute for ST segment elevation. Treatment of patients with myocardial infarction is effective. Etibabatide is a cyclic heptapeptide that mimics the KGD sequence in snake venom barbourin. It safely and effectively reduces the acute adverse consequences of patients undergoing PCI, and is also effective in the treatment of unstable angina pectoris. Lamfiban is a synthetic, non-cyclic, non-peptide small molecule GPb / a receptor antagonist. Compared with abciximab, antiplatelet effect is enhanced, and adverse reactions to bleeding are more common. limit. Evaluations in many clinical trials and meta-analyses have shown that treatment with GPIIb / IIIa receptor antagonists can reduce patient mortality during long-term follow-up, but the adverse effects of bleeding and thrombocytopenia need to be noted, albeit with a lower incidence.

2.2. Phosphodiesterase inhibitors

Cyclic adenosine monophosphate (cAMP), as an important second messenger for intracellular signaling, plays an important role in platelet aggregation. cAMP rises and inhibits platelet aggregation. Phosphodiesterase (PDE) hydrolyzes cAMP, reduces intracellular cAMP levels, and promotes platelet aggregation. Therefore, inhibition of phosphodiesterase can effectively inhibit platelet aggregation. Cilostazol is a PDE inhibitor that relaxes blood vessels and inhibits platelet aggregation caused by various agonists.

2.2.1 Dipyridamole

Also known as pansentin, it was used in the clinic as a vasodilator in 1960. Later in vitro experiments found that dipyridamole has the effect of inhibiting platelet aggregation, so it has gradually been used as an antiplatelet drug. Its main mechanism of action is to inhibit platelet phosphodiesterase, and then activate platelet adenosyl cyclase, increase the cAMP concentration in platelets, and play an anti-platelet aggregation effect. However, with the emergence of new antiplatelet drugs, the use of pansentin in coronary heart disease has become less common.

2.2.2 Cilostazol

Cilostazol is a quinoline derivative, and itself and its metabolites inhibit platelet phosphodiesterase activity (especially phosphodiesterase III), thereby inhibiting the degradation and transformation of cAMP, leading to intravascular and platelet cAMP concentrations Elevated, eventually play a role in dilating blood vessels and inhibiting platelet aggregation. We recently performed a meta-analysis of 19 randomized controlled studies and included a total of 7464 patients.The results found that: for patients after coronary stent implantation, cilostazol-based triple antiplatelets (aspirin, clopidogrel, and Cilostazol) treatment compared with conventional dual antiplatelet (aspirin, clopidogrel) treatment significantly reduced the late loss of the smallest diameter and the occurrence of in-stent restenosis, and reduced the revascularization of target vessels or target lesions. rate. However, compared with dual antiplatelet therapy, triple antiplatelet therapy did not significantly reduce the main endpoints of death, non-fatal myocardial infarction, ischemic stroke, and stent thrombosis. Therefore, cilostazol should be suitable for patients with coronary heart disease who are at high risk of restenosis after stent implantation, such as combined diabetes, small blood vessels, long lesions, and bifurcation lesions after PCI.

Summary of antiplatelet drugs

In summary, the activation processes such as platelet activation, aggregation, and release are closely related to the pathophysiology of ischemic cerebrovascular disease. Antiplatelet drugs prevent and treat ischemic stroke and acute coronary syndrome (ACS). The value of a variety of mechanisms acting on different targets has been confirmed by a large number of clinical trials. It is believed that with the in-depth study of platelet activation mechanism and in-depth understanding of anti-platelet drug activity, more and more new anti-platelet drugs with small toxic and side effects, strong efficacy and good selectivity will be developed and used.

Antiplatelet References:

[1] Chen Hang. New advances in antiplatelet drugs [J]. Advances in Cardiology, 2009, 30 (1): 105-109.

[2] Yang Hongyan, Wang Xiaoliang. Research progress of antiplatelet drugs [J]. Chinese Pharmaceutical Journal. 2012, 47 (4): 250-255 ..

[3] Qiao Wenhao et al. Research progress on pharmacological effects and clinical application of antiplatelet drugs [J]. Anhui Medical Journal. 2014, 18 (9): 1621-1625.