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Antiplatelet drugs are used to inhibit the growth of cyclooxygenase in platelets.Antiplatelet drugs mainly include aspirin, a thromboxane A2 (TXA2) inhibitor, and P2Y12 receptor antagonists, including thiophene pyridine (clopidogrel, prasugrel) and non thiophene pyridine (tigrinol), as well as glycoprotein (GP) lIb/IIIa receptor inhibitors (acizumab and tirofiban).And phosphodiesterase inhibitors (such as dipyridamole and cilostazol).
Platelets are produced by megakaryocytes and play an important role in 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 thrombosis. Antiplatelet therapy is carried out for different segments in the process of platelet activation. With the in-depth understanding of the mechanism of platelet activation,The understanding of more signal transduction pathways provides new ideas for antiplatelet therapy.
Antiplatelet drugs mainly include aspirin, a thromboxane A2 (TXA2) inhibitor, and P2Y12 receptor antagonists, including thiophene pyridine (clopidogrel, prasugrel) and non thiophene pyridine (tigrinol), as well as glycoprotein (GP) lIb/IIIa receptor inhibitors (acizumab and tirofiban).And phosphodiesterase inhibitors (such as dipyridamole and cilostazol).
1. Drugs affecting platelet activation and expansion
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1.1. Thromboxane A2 (TXA2) inhibitor
TXA2 is a powerful agonist for platelet activation and vasoconstriction. By binding to G-protein-coupled receptors, TXA2 causes phospholipase C (PLC) β activation, intracellular calcium ions increase, and then platelets are activated.Aspirin is the most widely studied and applied antiplatelet drug in antiplatelet therapy at present. It mainly inhibits arachidonic acid cyclooxygenase (COX) to make Ser-529 and Ser-516 irreversibly acetylated, thereby blocking the synthesis of TXA2 and playing an antiplatelet role.Although the resistance of aspirin and the side effects of bleeding cannot be ignored, because of its exact protective effect, aspirin is still the gold standard for the prevention of cardiovascular diseases.A large number of experimental studies have shown that active substances extracted from various plants can inhibit platelet aggregation by inhibiting TXA2 synthesis.However, aspirin has no effect on platelet aggregation induced by other agonists, such as collagen and adenosine diphosphate.Aspirin is absorbed rapidly and completely after oral administration, and reaches the peak plasma concentration one hour after taking it. It starts to be absorbed in the stomach, most of it is absorbed in the upper part of the small intestine, and excreted from the kidney as a combined metabolite and free salicylic acid.Chewing aspirin takes effect quickly.3. Adverse reactions: The common adverse reactions of aspirin are gastrointestinal discomfort and gastrointestinal bleeding, and the risk of bleeding is related to the dose.A few may also have allergic reactions, mainly manifested as asthma and urticaria.Try to avoid using non steroidal anti-inflammatory drugs at the same time, especially ibuprofen can affect the antiplatelet effect of aspirin.When combined with other antiplatelet and anticoagulant drugs, the risk of bleeding increases.Contraindications: hemorrhagic disease;Active bleeding, such as bleeding from important organs (intracranial bleeding, gastrointestinal bleeding, urogenital bleeding, etc.);Active peptic ulcer;Hypertension with serious poor control;Severe allergic reaction or intolerance (manifested as asthma and nasal polyps), etc.
After the ADP receptor antagonist binds to the ADP receptor on the surface of platelet membrane, it prevents the exposure of the binding site of GP Ⅱ b/Ⅲ a receptor coupled to the ADP receptor, making the ligand unable to bind, and inhibiting platelet aggregation.There are mainly two subtypes of ADP receptors: P2Y1 and P2Y12;Compared with P2Y1, ADP combined with P2Y12 can trigger the formation of stable and lasting platelet aggregation effect.
1.2.1 Thiophenylpyridines
At present, there are three thiophene pyridine derivatives blocking P2Y12 for clinical use: ticlopidine, clopidogrel and prasugrel. Large scale randomized clinical trials have provided clear evidence for its antithrombotic effect.These three compounds are prodrugs, which need to be metabolized into active metabolites through the hepatocyte cytochrome P450 system in vivo to play an antithrombotic role.In clinical practice, ticlopidine has been replaced by clopidogrel with higher safety and better tolerance. Clopidogrel has a fast onset, low risk of bleeding, and few side effects.However, clopidogrel is currently facing the challenge of prasugrel, which has a faster and more powerful effect.Compared with individual response or tolerance of clopidogrel, prasugrel has a more consistent effect, but the risk of bleeding also increases.
(1) Ticlopidine
Ticlopidine is a thiazole pyridine compound, which can block the ADP receptor coupled with Gi protein.Pharmacokinetics Longclopidine can be rapidly absorbed after oral administration.The blood drug peak value was reached 1-3 hours after oral administration.When the healthy subjects took 501000mg orally once, the peak plasma concentrations were 0.61 and 2.13 mg/L respectively, which could be distributed in the whole body tissues, and the concentrations in urine, feces, blood and sleeping liquid were higher.59% can be excreted by urine, 25% by stool, and T1/2 is 14 h (8-25 h).This product is a prodrug, which needs to be transformed into an active metabolite through hepatocyte cytochrome P450.It is mainly metabolized by opening the thiophene ring through N-demethylation and oxidation.Ticlopidine can inhibit platelet aggregation induced by thrombin, collagen, adrenaline, arachidonic acid, ristocetin 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, hepatotoxicity, etc. The symptoms disappear after drug withdrawal, but its severe bone marrow suppression poses a threat to patients' lives.
(2) Clopidogrel
As the second generation P2Y12 receptor antagonist, clopidogrel is a derivative of ticlopidine.Clopidogrel can selectively and irreversibly block the binding of ADP and platelet P2Y12 receptor to inhibit platelet aggregation.Mechanism of action: clopidogrel belongs to thiophene pyridines, which irreversibly inhibits the platelet adenosine diphosphate (ADP) receptor, thereby inhibiting the viability
Platelet aggregation induced by the release of ADP.Clopidogrel is a precursor drug, which requires the metabolism of liver cytochrome P450 enzyme to form an active metabolite and irreversibly binds to P2Y12 receptor.After oral administration, it is rapidly metabolized in the liver after absorption through the gastrointestinal tract. The concentration of prototype drug in the plasma is extremely low. The peak time of the plasma concentration is about 1 hour, and the plasma clearance is half. 3. Adverse reactions: the main adverse reactions are bleeding (the incidence of serious bleeding events is 1.4%), gastrointestinal discomfort, rash, headache
Vertigo, dizziness and abnormal sensation. A few patients have allergic reactions, which are manifested as urticaria and itching.The incidence of neutropenia and thrombotic thrombocytopenic purpura caused by clopidogrel was significantly lower than that of ticlopidine, and there was no need to routinely monitor the platelet count.Contraindications: hemorrhagic disease;Active bleeding, such as bleeding of important organs (intracranial bleeding, gastrointestinal bleeding, urogenital bleeding, etc.);Severe liver damage, etc.
(3) Prasugrel
It is the third-generation P2Y12 receptor antagonist. It is a precursor drug, which can play an irreversible role in blocking ADP only after being metabolized into active metabolites in the liver.Compared with clopidogrel, prasugrel produces more metabolites
Fast, more active.Ma Xiaobing randomly divided 160 patients with coronary heart disease into two groups, who were given prasugrel and clopidogrel respectively. The results showed that the platelet aggregation rate (MPA) and mean platelet reaction index (PRI) of the two groups before and after treatment were significantly better than those of the control group (P<0.05), which showed that prasugrel was superior to clopidogrel in the treatment of coronary heart disease.Ruff et al. grouped 13608 patients with acute coronary syndrome in different regions and gave them
Lagrel and clopidogrel found that prasugrel was superior to clopidogrel in terms of safety and clinical efficacy.
1.2.2 Non thiophene pyridines
(1) Ticagelor
The effect of ticarenol is similar to that of cangrello. It does not need to be converted into active metabolites in the liver, but directly and reversibly competes to inhibit P2Y12 receptor.Wallentin et al. compared the effect of ticarenol and clopidogrel on the use of load dose in a randomized double-blind trial of 18624 inpatients with acute coronary syndrome (with or without ST segment elevation) to prevent cardiovascular disease.The results showed that compared with clopidogrel, ticarenol could significantly reduce the incidence of cardiovascular death, myocardial infarction or stroke.Lindholm and other large-scale clinical studies have also confirmed that ticarenol is superior to clopidogrel in reducing the incidence of ischemic diseases and overall mortality.
(2) Cangrelor
It is a reversible P2Y12 receptor antagonist. Unlike clopidogrel and prasugrel of thiophene, it does not need to be converted into active metabolites in the liver, and can directly block the action of ADP.Storey observed the clinical effects of clopidogrel and cantalore before and after percutaneous coronary intervention (PCI) in patients. It was found that the mortality rate within 48 hours of patients in the cantalore group, as a direct receptor blocker, was lower than that in the clopidogrel group, which confirmed the safety of clinical treatment of cantalore.
(3) Ticagelor
Tigrilol, a new P2Y12 receptor antagonist, directly and reversibly inhibits P2Y12 receptor in platelets without metabolic activation.The plasma half-life of tegrenol is 8-12 h, and it needs to be administered twice a day.The platelet activity can be significantly inhibited within 30 minutes after taking the load dose of tegrilol, and it takes 2 hours to reach the maximum efficacy.The platelet function recovered quickly after drug withdrawal.In addition to acting on P2Y12 receptor in vitro, tegrenol can also inhibit the red blood cell's re uptake of adenosine. Serum adenosine has antiplatelet and vasodilator effects, but at the same time, adverse reactions such as dyspnea and bradycardia increase.Adverse reaction of tegrenol: bleeding may be mild or severe.In addition, there are dyspnea, gastrointestinal symptoms such as vomiting, diarrhea, abdominal pain, nausea, etc.Dyspnea is usually mild to moderate and dose related.Some patients can be relieved without stopping the drug, and the absolute risk of dyspnea in patients with asthma/chronic obstructive pulmonary disease may be increased during the treatment of Tigrilol, which should be used with caution.Clinical studies have shown that tegrenol can cause bradyarrhythmia, and patients with bradycardia should use it with caution.In addition, Tigrenol should be cautious when combined with drugs known to cause bradycardia.The combination with CYP3A4 potent inhibitor should be avoided;The dosage of simvastatin and lovastatin shall not be more than 40 mg when used in combination with tegrilol.Contraindications of tegrenol: hemorrhagic disease;Active bleeding, such as bleeding of important organs (intracranial bleeding, gastrointestinal bleeding, urogenital bleeding, etc.);Have a history of intracranial hemorrhage;Patients with moderate to severe liver damage;He is taking powerful CYP3A4 antagonists (such as ketoconazole, clarithromycin, nefazodone, ritonavir and azanavir).
1.3. Thrombin receptor antagonist
The protease activated receptor (PAR) of thrombin receptor belongs to the G protein coupled receptor family.It has four subtypes, of which PAR-1 and PAR-4 are expressed in human platelets.PAR-4 can only induce platelet aggregation under the condition of high concentration of thrombin, and PAR-4 is not expressed when PAR-1 function is fully expressed, so PAR-1 is the most important thrombin receptor.Thrombin receptor antagonists are also the most concerned and promising antiplatelet drugs.
1.3.1 Vorapaxar (SCH-530348) is a potent, selective, high affinity and oral PAR-1 antagonist.Although many phase II clinical trials have confirmed its safety and tolerance.However, Morrow and other large-scale clinical studies 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 hemorrhage, which has caused concern of researchers.Merck found some potential bleeding problems in the clinical trial of Vorapaxar, which delayed the launch of Vorapaxar.In July 2013, FDA accepted Merck's Vorapaxar listing application.According to the latest report, the FDA Cardiovascular and Renal Drug Advisory Committee (CRDAC) recommended approval for the listing of the company's antiplatelet drug Vorapaxar.
1.3.2 Atopaxar (E5555) is a new reversible PAR-1 antagonist, which is rapidly absorbed after oral administration and has high bioavailability.Serebruany and other researchers confirmed that Atopaxar can also antagonize PAR-1 receptor in vitro, and can cooperate with aspirin to play an antiplatelet role.Goto et al. found in the Phase II double-blind clinical trial of Japanese patients with acute coronary syndrome or high-risk coronary artery disease that atopaxar of 50, 100 and 200 mg would not increase clinical major bleeding (ACS: 6.6% placebo vs 5.0% E5555, P>0.73; CAD: 4.5% placebo vs 10% E5555, P>0.066), and the platelet inhibition level significantly reached by all test doses (100 mg and 200 mg E5555, inhibition rate>90%, 50 mg E5555, inhibition rate>20%~60%), which confirmed the safety and effectiveness of Atopaxar.
As a neurotransmitter and vasoactive substance, more than 90% of 5-HT in human body is stored in platelets.There are two types of 5-HT receptors in platelets: 5-HT1 receptor and 5-HT2 receptor.Blood 5-HT2 can activate the 5-HT2 receptor of platelets and vascular smooth muscle, and promote the formation of thrombus [25].Therefore, it is of great significance to study the vascular 5-HT2 receptor to develop antiplatelet drugs for the treatment of cardiovascular diseases.
1.4.1 Sarpogrelate
Sarpogrelate (SARP) is a 5-HT2 receptor blocker produced by Mitsubishi Pharmaceutical Company of Japan, which can specifically bind to the 5-HT2 receptor.SARP is clinically applied to peripheral vascular diseases, such as chronic ischemic vascular occlusion, coronary heart disease, nervous system diseases, thrombotic diseases, etc.The pharmacological effects of SARP mainly include the following aspects: inhibiting platelet aggregation;Inhibiting the vasoconstriction caused by 5-HT and platelet agglutination;Antithrombotic;Improve collateral circulation.It can specifically bind to 5-HT2 receptor to inhibit platelet aggregation. It can be used in many thrombotic diseases such as chronic ischemic vascular occlusion.Kajiwara and other studies have shown that, on the basis of taking aspirin, the administration of zagrate can reduce the level of platelet aggregation in patients with stable angina pectoris, indicating that zagrate has an auxiliary therapeutic effect on patients with stable angina pectoris.
1.4.2 Citalopram
Citalopram is widely used as selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, and is being used to study its role in anti platelet aggregation.Tseng et al. took the blood of normal people to prepare PRP, and tested the inhibitory effect of citalopram on bovine Achilles tendon collagen induced platelet aggregation under specific conditions.In the effect of citalopram on integrin α IIB β 3, the results of platelet activation showed that
Pullan failed to inhibit the expression of collagen induced integrin α IIB β 3 antibody binding site;In the verification of collagen stimulating proteins that may affect the secretion of granules, citalopram directly inhibits collagen induced platelet release and causes platelet aggregation, but can only partially inhibit collagen induced aggregation.
2 Drugs that inhibit platelet aggregation
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2.1. Because the interaction between fibrin and GP Ⅱ b/Ⅲ a is the last key step of platelet aggregation, and GP Ⅱ b/Ⅲ a is only expressed in platelets, obviously, the development of GP Ⅱ b/Ⅲ a receptor antagonists is the most powerful means of anti platelet therapy, which can play a powerful role in inhibiting platelet aggregation.
2.1.1 Acezumab
Aciximab is a mouse monoclonal antibody against human GP Ⅱ b/Ⅲ a receptor that chimes with an antigen binding fragment (Fab). It blocks the binding of ligand to GP Ⅱ b/Ⅲ a through steric hindrance.In clinical practice, abciximab is used as an auxiliary treatment in percutaneous coronary intervention (PCI), including balloon angioplasty, atherosclerotic plaque resection and major stent implantation.However, abciximab has potential immunogenicity and is prone to allergic reaction;Irreversibly antagonizing GP Ⅱ b/Ⅲ a receptor, bleeding reaction is common, and the cost is high.The later developed tirofiban and etibacide have low relative molecular weight and can reversibly bind to GP Ⅱ b/Ⅲ a receptor, reducing the occurrence of allergic reaction and bleeding.
2.1.2 Tirofiban
Tirofiban is a specific non peptide GP Ⅱ b/Ⅲ a receptor antagonist. It mimics the recognition of arginine glycine aspartate (RGD) peptide by GP Ⅱ b/Ⅲ a receptor, and is effective in the treatment of patients with acute myocardial infarction with ST segment elevation.Etibatide is a cyclic heptapeptide that mimics the KGD sequence in barbourin, a snake venom.It safely and effectively reduces the acute adverse consequences of patients undergoing PCI, and is also effective for the treatment of unstable angina pectoris.Lamifeban is a synthetic, acyclic, non peptide small molecule GP Ⅱ b/Ⅲ a receptor antagonist. Compared with abciximab, Lamifeban has enhanced antiplatelet effect, more common bleeding adverse reactions, and limited clinical application.The evaluation of many clinical trials and meta-analysis shows that the use of GP Ⅱ b/Ⅲ a receptor antagonist can reduce the mortality of patients in long-term follow-up, but the adverse reactions of bleeding and thrombocytopenia still need attention, although the incidence is low.
2.2. Phosphodiesterase inhibitor
Cyclic adenosine monophosphate (cAMP), as an important second messenger of intracellular signal transduction, plays an important role in platelet aggregation.CAMP increased and inhibited platelet aggregation.Phosphodiesterase (PDE) hydrolyzes cAMP, reduces the level of cAMP in cells, and promotes platelet aggregation.Therefore, inhibition of phosphodiesterase can effectively inhibit platelet aggregation.Cilostazole is a PDE inhibitor that relaxes blood vessels and inhibits platelet aggregation caused by various agonists.
2.2.1 Dipyridamole
Also known as dipyridamole, it was used in clinic as a vasodilator in 1960. Later, in vitro experiments found that dipyridamole could inhibit platelet aggregation, so it was gradually used as an antiplatelet drug.Its main mechanism is to inhibit platelet phosphodiesterase, and then activate platelet adenosine cyclase, so as to increase the concentration of cAMP in platelets and play an anti platelet aggregation role.However, with the emergence of new antiplatelet drugs, dipyridamole is rarely used in coronary heart disease.
2.2.2 Cilostazole
Cilostazole is a quinoline derivative, which itself and its metabolites inhibit the activity of platelet phosphodiesterase (especially phosphodiesterase III), thereby inhibiting the degradation and transformation of cAMP, leading to the increase of cAMP concentration in blood vessels and platelets, and ultimately playing a role in expanding blood vessels and inhibiting platelet aggregation.We recently conducted a meta-analysis of 19 randomized controlled studies, including 7464 patients. The results showed that the triple antiplatelet therapy based on cilostazol (aspirin, clopidogrel and cilostazol) was more common than the dual antiplatelet therapy (aspirin, clopidogrel) for patients after coronary stent implantationThe treatment significantly reduced the late loss of the minimum diameter and the occurrence of in stent restenosis, and reduced the rate of revascularization of target vessels or target lesions.However, compared with dual antiplatelet therapy, triple antiplatelet therapy did not significantly reduce the main endpoint events such as death, nonfatal myocardial infarction, ischemic stroke and stent thrombosis.Therefore, cilostazol should be applied to coronary heart disease patients with high risk of restenosis after stent implantation, such as those with diabetes, small vessels, long lesions, bifurcation lesions after PCI.
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To sum up, the activation process of platelets, such as activation, aggregation and release, is closely related to the pathophysiological mechanism of ischemic cerebrovascular disease. The prevention and treatment of antiplatelet drugs on ischemic stroke and acute coronary syndrome (ACS) play a role from a variety of mechanisms, acting on different targets, and its value has been confirmed by a large number of clinical trials.It is believed that with the in-depth study of platelet activation mechanism and the in-depth understanding of antiplatelet drug activity, more and more new antiplatelet drugs with small side effects, strong efficacy and good selectivity will be developed and utilized.
reference:
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[1] Chen Hang. New Progress of Antiplatelet Drugs [J]. Advances in Cardiology, 2009,30 (1): 105-109
[2] Yang Hongyan, Wang XiaoliangResearch progress of antiplatelet drugs [J]Chinese Journal of Pharmacy2012，47(4):250-255..
[3] Qiao Wenhao et al. Research progress on pharmacological action and clinical application of antiplatelet drugs [J]Anhui Medicine2014，18(9):1621-1625.
