Pharmacological treatment of upper gastrointestinal bleeding in portal hypertension began in 1980 with the use of ponerol, and over the past 20 years, the number of related studies has reached thousands of cases, and the studies have included a variety of methods and drugs for the prevention and treatment of upper gastrointestinal bleeding in portal hypertension, with remarkable results establishing the place of drugs in the prevention and treatment of upper gastrointestinal bleeding in portal hypertension. This article discusses the pharmacological treatment of ruptured esophageal variceal bleeding in portal hypertension. Pharmacological treatment of upper gastrointestinal bleeding in portal hypertension consists of three main aspects: prevention of first bleeding, treatment of acute bleeding and prevention of rebleeding. I. Prevention of first bleeding According to statistics, the new incidence of esophageal varices in cirrhosis is about 8% each year, and ruptured esophageal vein bleeding occurs in about 1/3 of patients with cirrhosis, and rebleeding can occur in 70% of patients. Risk factors associated with variceal bleeding include the degree of impaired liver function, the size of the varices, and characteristic endoscopic findings such as the red sign. The mortality rate for variceal hemorrhage in cirrhosis can be as high as 50% 1 month after bleeding, although with the development of endoscopic treatment techniques and pharmacologic therapy and improved intensive care conditions, the current mortality rate is still 20%. Prophylaxis includes surgical, pharmacological and endoscopic treatments, of which surgical prevention of bleeding has been rarely used. Non-selective β-blockers are the most widely used in pharmacological prevention. Non-selective β-blockers (ponerol, nadolol) are the first choice for prophylactic pharmacotherapy, which works by blocking β-receptors. Nadolol has a longer half-life than pranolol, is more convenient to use, and has the advantage of not crossing the blood-brain barrier. The role of nonselective β-blockers in the prevention of variceal bleeding has been compared in at least 9 randomized controlled trials to date. Among them, a 2-year follow-up study showed a 45% reduction in the relative risk of bleeding and a 20% reduction in morbidity and mortality in the non-selective beta-blocker group compared to the placebo group. The drug dose should be determined based on changes in blood pressure and heart rate after the patient takes the drug. The heart rate is usually maintained at no less than 55 beats/min and the arterial pressure at no less than 90 mmHg, ideally resulting in a 25% decrease in the patient’s heart rate. However, some studies have pointed out that the change in heart rate is not a criterion for the effectiveness of the drug because at least 30% of patients who meet the criteria for heart rate reduction after taking the drug do not have a reduction in portal venous pressure sufficient to prevent venous bleeding. Increasing the dose to the maximum tolerable dose in this group of patients would increase the therapeutic effectiveness. In approximately 30% of patients, hepatic venous wedge pressure (HVPG) does not decrease significantly with the use of ponerol. Since heart rate does not accurately reflect changes in HVPG, it has been suggested that changes in HVPG should be monitored during the first bleeding prophylaxis with the drug to see if treatment is effective. Contraindications to the use of non-selective β-blockers include moderate to severe congestive heart failure, severe chronic obstructive pulmonary disease, and peripheral vascular disease, with a relative contraindication for insulin-dependent diabetes mellitus. The incidence of adverse reactions ranges from 3% to 27%, with about half of the patients requiring discontinuation of the drug. Common adverse reactions include malaise, shortness of breath (usually associated with slow heart rate), sleep disturbance, etc. They are usually mild and can be improved by stopping the drug. The protective effect of non-selective beta-blockers disappears upon discontinuation, and the risk of venous bleeding increases, thus requiring lifelong use. Studies in animal models of portal hypertension have confirmed that early use of ponerol improves the formation of collateral circulation, suggesting that the use of nonselective beta-blockers may help prevent the appearance of esophageal varices. cales et al. observed the effect of ponerol in preventing the formation of esophageal varices and did not find that nonselective beta-blockers prevented the formation of esophageal varices at 2 years of follow-up. To date there is no evidence that drugs can prevent the development and progression of esophageal varices. In addition to nonselective β-blockers, a variety of vasodilators have been used in studies to prevent first bleeding. Nitrates reduce portal vein pressure through nitric oxide-mediated venodilation and decreased hepatic sinusoidal resistance. One of the most studied is isosorbide 5-mononitrate, which is a long-acting vasodilator capable of reducing HVPG and esophageal variceal pressure in a transient manner. However, several studies have confirmed that non-selective beta-blockers are more effective than 5-isosorbide mononitrate in preventing esophageal variceal bleeding. Therefore, nitrates alone are not recommended for the prevention of first variceal bleeding, and their use is often combined with nonselective β-blockers. Prazosin, an α1-adrenergic receptor blocker, can significantly reduce hepatic vascular resistance and thus HVPG in patients with cirrhosis, and some studies have shown that when used in combination with non-selective β-blockers, its effect on reducing portal pressure is more pronounced than that of nitrates in combination with non-selective β-blockers, but its significant adverse effects such as reduced arterial pressure, fluid retention and increased right atrial pressure Again, its use is limited. Colistin is a central α2-adrenergic agonist that reduces portal venous pressure by decreasing portal venous blood flow and reducing portal venous resistance. Its effect on HVPG is slightly stronger than that of pranolol, and little information has been reported on its role in preventing variceal bleeding. Effective reduction of portal venous pressure reduces the occurrence of ruptured esophageal variceal bleeding, and the combination of drugs can achieve better results. The most commonly used combination is a nonselective β-blocker plus a nitrate, which is probably one of the most effective methods available for preventing esophageal variceal bleeding. The combination offers advantages in maintaining hepatic perfusion and protecting liver function without reducing blood flow in the odd vein. A study comparing nadolol and nadolol plus isosorbide 5-mononitrate showed a reduced risk of bleeding in the combination group without a difference in survival. Another study comparing ponerolol and ponerol plus isosorbide 5-mononitrate showed no difference in bleeding rates between the two groups at 2 years of follow-up. However, all of these studies confirmed the safety of the combination, and treatment did not result in decreased renal function or significant water and sodium retention after long-term use. Studies comparing the effectiveness of nonselective beta-blockers, isosorbide 5-mononitrate, and endoscopic ligation confirmed that nonselective beta-blockers and endoscopic ligation were equally effective in preventing first venous bleeding, while isosorbide 5-mononitrate was slightly less effective. In conclusion, treatment to prevent bleeding should be considered in patients with cirrhotic esophageal varices who are at high risk of bleeding. The preferred treatment is the use of nonselective β-blockers, which should be administered long-term in patients without contraindications. For those who have contraindications, cannot tolerate nonselective β-blockers, or have failed to respond to pharmacologic therapy, endoscopic treatment may be considered. Treatment of acute bleeding In the management of ruptured variceal bleeding, the first priority is to resuscitate and try to maintain hemodynamic stability. The specific treatment is not described here. At the same time as resuscitation, targeted pharmacological therapy should be initiated. The goal of pharmacologic therapy is to reduce portal venous pressure and/or induce vasoconstriction to reduce variceal bleeding. The drugs commonly used to treat acute bleeding from varicose veins include vasopressin and growth inhibitors. Vasopressin reduces portal venous blood flow and lowers portal venous pressure by constricting visceral vessels. It controls about 60% of bleeding, but does not help prevent rebleeding from occurring or improve survival. Adverse effects of vasopressin include hypertension, bradycardia, coronary vasoconstriction, and decreased cardiac output [16]. In this case, the combination of nitroglycerin counteracts the vasoconstrictive effect of vasopressin on the vascularity of the body circulation and also reduces portal venous pressure. Triglyceride lysine pressor (terlipressin) has a longer duration of action than vasopressin and a lower incidence of adverse effects. Several studies have confirmed the significant hemostatic effect of terlipressin on venous bleeding, which is the same as the effect of balloon compression. Some data confirm that the use of terlipressin reduces mortality in patients with acute variceal rupture bleeding, with a statistically significant difference compared to the use of vasopressin. Also, terlipressin has a protective effect on renal function and is indicated in patients with hepatorenal syndrome with esophageal varices. The mechanism of action of growth inhibitor and its analogue octreotide has not been fully elucidated and may be aimed at reducing portal blood flow by blocking the vasodilatory effect of glucagon. Other possible factors include reducing circulating blood volume, preventing postprandial visceral vascular congestion and increasing visceral vascular tone. Studies have shown that growth inhibitors are more effective than vasopressin in controlling bleeding, and are as effective as balloon compression therapy, endoscopic sclerotherapy and terlipressin in controlling acute venous bleeding, and have a significantly lower incidence of adverse effects than the latter. Some studies have shown that the combination of growth inhibitors and endoscopic sclerotherapy is more effective than drug, sclerotherapy injection, or endoscopic ligation alone. Overall, the advantages of growth inhibitors are that they have few contraindications and adverse effects and are safer to use. Bacterial infection may be an important predisposing factor for acute venous bleeding. In patients with severe varicose veins and high vascular tone, the release of endotoxin during infection may induce bleeding by inducing the release of endothelial vasoconstrictor peptides and cyclooxygenase causing further elevation of portal pressure and inhibiting platelet aggregation. It has been reported that in patients with cirrhosis who developed upper gastrointestinal bleeding, infection was present before bleeding in 20% and secondary infection after bleeding in about 50% of cases. A meta-analysis of large numbers of cases showed that prophylactic use of antibiotics resulted in a reduction in mortality from bleeding. Therefore, it has been recommended that all patients with bleeding esophageal varices should be given prophylactic antibiotics. In cases where esophageal varices are at risk of bleeding, vasoactive drugs should be started as early as possible before endoscopic treatment. Drug therapy should be performed even if endoscopy does not reveal active bleeding. Since the use of growth inhibitors is as effective as sclerotherapy injections and has a lower incidence of adverse effects, endoscopic treatment can be used only in cases where pharmacologic therapy has failed and, if necessary, balloon compression can be used temporarily to stop bleeding, after which endoscopic treatment or TIPS can be considered. The treatment of patients with acute bleeding from ruptured esophageal varices has made great progress in recent years due to the development of pharmacologic and endoscopic treatment techniques. Their treatment starts with adequate resuscitation therapy and correction of coagulation dysfunction, and hemostasis with vasopressin combined with nitroglycerin or with drugs such as growth inhibitors. Endoscopic ligatures and sclerotherapy injections are mostly used as a follow-up treatment. Prophylactic antibiotics are recommended for patients with bleeding esophageal varices. III. Prevention of rebleeding Patients with portal hypertension esophagogastric varices have up to 70% chance of rebleeding after the first bleeding. More than 50% of these rebleeds occur within 10 days of the first bleed, especially within the first 72 hours. The risk of rebleeding gradually decreases to baseline levels after 6 weeks. High-risk factors for rebleeding include a high degree of varicose veins, a large first bleed, and age greater than 60 years. The mortality rate one year after the first bleed can be as high as 70%, and the main causes of death include recurrent bleeding, liver failure, and secondary infection. Therefore, the long-term goal of treatment is to prevent rebleeding and protect liver function. Non-selective β-blockers are not only effective in preventing the first bleeding in patients with varices, but also have an important role in preventing rebleeding in patients. Non-selective β-blockers can significantly reduce the risk of early rebleeding and should be started as early as possible after bleeding. The results of the meta-analysis showed that non-selective beta-blockers significantly reduce the risk of rebleeding and improve survival. The two-year follow-up study showed that the risk of rebleeding was 21%-72% and 50%-80% for non-selective beta-blockers compared with placebo, a 40% reduction, while the two-year survival rates were 64%-96% and 44%-95%, a 20% improvement. Meanwhile, non-selective beta-blockers can similarly prevent rebleeding in bleeding caused by portal hypertensive gastropathy. According to the current data, it is not certain that the combination of drug and endoscopic treatment will be more effective, and also the cost of endoscopic treatment due to recurrence is an issue that should be considered. 459 case meta-analyses showed that treatment with non-selective beta-blockers plus sclerotherapy appeared to be more effective than non-selective beta-blockers alone, but the difference did not reach statistical significance, and there was no difference in mortality. A prospective randomized controlled trial showed that the combination of endoscopic ligatures with nonselective β-blockers and thioglycollate was more effective in reducing rebleeding rates than endoscopic ligatures. In conclusion, the use of nonselective β-blockers to prevent variceal rebleeding significantly reduces the risk of rebleeding while improving survival, and should be taken long-term if patients do not have contraindications. It has been suggested that non-selective beta-blockers alone are sufficient at the beginning of treatment. As a measure to prevent rebleeding, endoscopic treatment combined with a nonselective beta-blocker may be more effective.