Acute ischemic stroke, also known as acute cerebral infarction, has the characteristics of high incidence, high disability rate and high fatality rate, which seriously threatens human health.
In mainland China, acute ischemic stroke generally refers to mild stroke within 2 weeks after the onset of the disease, including mild stroke within 1 week and severe stroke within 1 month, acute ischemic stroke is the most common type of stroke, accounting for 69.6% of the population with stroke in mainland China. There are about 11 million stroke patients in mainland China, with an increase of 2.4 million per year, and 1.1 million people die of stroke every year, of which the one-year disability rate of acute ischemic stroke patients who are hospitalized is 33.4%.
Acute ischemic stroke occurs due to cerebral tissue ischemia, infarction, and post-activation damage to neurons, astrocytes, and oligodendrocytes due to occlusion of cerebral arteries. Its drug treatment mainly includes improving cerebral blood circulation, statins and neuroprotective drugs.
Improves cerebral blood circulation
1
Intravenous thrombolytic
Intravenous thrombolysis is currently the most important medical treatment to restore blood flow. Cerebral artery thrombosis is mainly composed of platelets, a small number of red blood cells and fibrin crosslinking, thrombolytic drugs by activating plasminogen to form plasmin, destroy the crosslinking between fibrin molecules, to achieve the effect of dissolving blood clots.
Thrombolytic agents include recombinant tissue plasminogen activators (rt-PA), urokinase, and tenectaplase. The main thrombolytic drugs currently used in mainland China are rt-PA and urokinase, and the effective thrombolytic time window is limited, that is, the effective rescue of semi-dark belt tissue time window is within 4.5 hours or 6 hours.
▎ Recombinant tissue type plasminogen activator
Also known as alteplase, t-PA can be produced by the body's normal cell culture method and rt-PA can be synthesized using recombinant DNA technology. RT-PA is a glycoprotein containing 526 amino acids that binds to fibrin through its lysine residue and activates fibrinolysin-bound plasminogen to plasmin.
Because rt-PA selectively activates fibrin-bound plasminogen, it does not produce the bleeding complications common with streptokinase application. In vitro studies have shown that rt-PA can still inhibit platelet activity.
The same principle as intravascular intervention is that thrombolytic therapy must be done as early as possible. Patients within 3 hours and 3-4.5 hours of onset of ischemic stroke should be strictly screened according to indications, contraindications, and relative contraindications (see Tables 1 and 2), and rt-PA thrombolysis should be given intravenously as soon as possible.
The standard dose of rt-PA is 0.9 mg/kg, and the risk of bleeding in small doses of 0.6 mg/kg intravenous thrombolysis is lower than the standard dose, which can reduce the mortality rate but does not reduce the disability rate. RT-PA is administered intravenously, 10% of which is infused intravenously within the initial 1min, the rest are continuously infused for 1h, and the patient should be closely monitored during the administration period and within 24 hours of medication.
▎ Urokinase
Urokinase is a proteolytic enzyme extracted from healthy human urine, which can also be prepared by human kidney cell culture, no antigenicity, composed of low molecular weight and high molecular weight, and the high molecular weight is faster and stronger than the low molecular weight thrombolytic ability. Urokinase can directly convert plasminogen into plasmin, which in turn dissolves blood clots, especially for neotherms.
Within 6 hours of onset, patients can be strictly selected to administer urokinase intravenous thrombolysis according to the indications and contraindication criteria (see Table 3).
The recommended dose of urokinase is 1 million to 1.5 million IU dissolved in 100-200 ml of normal saline for 30 minutes, and the patient should be closely monitored during the medication.
2
Antiplatelet drugs
▎ Aspirin
Aspirin inhibits the release and aggregation of platelets, prolongs bleeding time in the body, and reduces the formation of blood clots. Its antiplatelet mechanism of action lies in the acetylation of platelet epoxygenase, thereby inhibiting the formation of intracyclic peroxides, reducing the production of thromboxane A2 (TXA2), in addition, it can also acetylate platelet membrane proteins and inhibit platelet membrane enzymes, which helps inhibit platelet function.
Antiplatelet therapy has long been the cornerstone of treatment for non-cardiogenic ischemic stroke. Patients with ischemic stroke who do not meet the indications for intravenous thrombolysis or endovascular embolization and do not have contraindications should be given oral aspirin 150 to 300 mg/day as soon as possible after onset, and can be changed to a prophylactic dose of 50 to 300 mg/day after the acute phase. In thrombolytic therapy, antiplatelet drugs such as aspirin should be started after 24 hours of thrombolysis.
In the 2018 American Stroke Association/American Heart Association Guidelines for the Early Management of Patients with Acute Ischemic Stroke, antithrombotic therapy strategies clearly state that aspirin therapy is initiated 24-48 hours after the onset of acute ischemic stroke and the initial dose is removed; for the first time, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for light stroke patients within 24 hours of onset, which helps reduce the recurrence rate of stroke within 90 days.
▎ Clopidogrel
The inhibition mechanism of platelet aggregation in clopidogrel is mainly to selectively inhibit the binding of adenosine diphosphate (ADP) to platelet receptors and inhibit the activation of ADP-mediated glycoprotein GP complexes, thereby inhibiting platelet aggregation. It can also inhibit platelet aggregation caused by non-ADP, and the effect on platelet ADP receptors is irreversible.
For those who cannot tolerate aspirin, antiplatelet therapy such as clopidogrel may be considered. If the patient is resistant to aspirin, clopidogrel does not improve resistance to the drug, because aspirin resistance patients are mostly resistant to clopidogrel.
3
Anticoagulant drugs
For most patients with acute ischemic stroke, indiscriminate early anticoagulation is not recommended. For a small number of patients with special acute ischemic stroke such as the placement of heart mechanical valves, it is necessary to comprehensively evaluate the lesion, individual function, physiological state, etc., such as the risk of bleeding is small, the risk of cerebral embolism disability is high, and it can be carefully selected after full communication.
Statin drugs
Observational studies have shown statins to improve prognosis in patients with acute ischemic stroke, but have yet to be further confirmed by high-quality randomized controlled studies. Patients taking statins prior to the onset of acute ischemic stroke can continue statin therapy to improve prognosis. Secondary prophylaxis with statins should be carried out as early as possible after the onset of the disease in patients with atherosclerotic cerebral infarction.
Neuroprotective
In theory, neuroprotective drugs can improve the prognosis of patients with ischemic stroke, and animal studies have also shown that neuroprotective drugs can improve the degree of neurological deficits. However, the conclusions of the clinical research are not consistent, and the translation results in clinical trials are not good.
Edaravone is an antioxidant and free radical scavenger that inhibits the activity of xanthine oxidase and hypoxanthine oxidase, stimulates the production of prostacyclin, reduces the production of leukotriene, and reduces the concentration of cerebral artery embolism and hydroxyl radicals.
Clinical studies have suggested that N-acetylspartic acid is a marker of specific surviving nerve cells, and the content of cerebral infarction is sharply reduced at the beginning of the onset of cerebral infarction, and the administration of edaravon in patients with acute stage of cerebral infarction can inhibit the reduction of local cerebral blood flow around the infarction, so that the content of N-acetylsasampine in the brain on the 28th day after the onset of the disease is significantly higher than that of the control group.
A number of randomized, double-blind, placebo-controlled trials at home and abroad suggest that edalafen can improve the functional outcomes and safety of acute cerebral infarction, and can also improve early neurological function in patients receiving alteplase intravenous thrombolysis.
Citicoline, also known as citicoline, as a normal component of the human body, has the effect of improving brain tissue metabolism and promoting the recovery of brain function, by changing cerebrovascular resistance, increasing cerebral blood flow, and improving cerebral circulation. The efficacy of citicoline in the acute phase of stroke has been evaluated in a number of randomized, double-blind, placebo-controlled trials, and no single trial has shown a statistically significant difference, and its efficacy has yet to be further confirmed.
In addition, drugs such as fiber reduction and improved microcirculation also play a pharmacological role in the treatment of acute ischemic stroke and improve prognosis.