Abnormal increase in portal vein pressure is a key pathological feature in the progression of chronic liver diseases such as cirrhosis. Its essence is the hemodynamic disorder caused by abnormal reduction of visceral vascular resistance and excessive vascular flow stagnation. If not effectively regulated for a long time, it can induce a series of serious complications and seriously threaten the prognosis of patients. Terlipressin Tablet, as an artificially synthesized long-acting vasopressin analog, focuses on selectively regulating visceral vascular tension through precise activation of vascular smooth muscle V1 receptors. It effectively contracts visceral arterioles, reduces portal vein and splenic vascular flow perfusion, and achieves rapid downregulation of portal vein pressure, providing a key targeted pathway for patient-based intervention of portal hypertension. The specificity of its functional pathway of action and the stability of its efficacy make it one of the key drugs for regulating portal vein pressure.
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Key pharmacological properties of Terlipressin selective activation of V1 receptor
The selective excitatory effect of Terlipressin Tablet on vascular smooth muscle V1 receptors is the basis for achieving visceral vascular constriction and reducing portal vein pressure. Its specificity and advantages can be analyzed from two dimensions:
01.High specificity and targeting of receptor binding
After this drug enters the body, it slowly releases active metabolites through endogenous enzymolysis. This product can specifically recognize and bind V1 receptor on vascular smooth muscle cell membrane. Its binding affinity with V2 receptor and V3 receptor is extremely low, which can effectively avoid peripheral vascular over contraction, water and sodium retention and other unrelated effects caused by non-specific receptor binding. Compared with endogenous vasopressin, its binding efficiency to V1 receptors is increased by 3-5 times, and its action site is highly concentrated in the visceral vascular area, especially for vascular smooth muscle V1 receptors in the gastrointestinal tract, spleen and other parts, with stronger targeted binding ability, providing a molecular basis for precise contraction of visceral vascular structures.
02.Signal transduction functional pathway after receptor activation
When the V1 receptor is activated by this, it can activate the intracellular calcium ion signaling pathway, promote the release of stored calcium in vascular smooth muscle cells and the influx of extracellular calcium, increase intracellular calcium ion concentration, and mediate smooth muscle cell contraction, achieving vascular lumen stenosis and increased vascular resistance. The signal transduction process is efficient and stable, without relying on other auxiliary factors, and has a long duration of action, which can avoid fluctuations in vascular constriction caused by signal transduction disorders, ensuring the continuity and controllability of visceral vascular constriction.
Information source:
Angeli P, Gines P, Gerbes A, et al. EASL patient-based Practice Guidelines: management of cirrhosis and its complications[J]. Journal of Hepatology, 2022, 77(3): 687-716.
Bosch J, Garcia-Tsao G. Portal hypertension: a multifaceted syndrome[J]. Gastroenterology, 2017, 153(1): 30-44.
The potent contractile effect and targeting characteristics of Terlipressin on visceral arterioles
Terlipressin Tablet has strong, targeted, and mild effects on the contraction of visceral arterioles, which can accurately target the affected area and avoid significant interference with the systemic vascular system. The specific manifestations are as follows:
The potency and controllability of the contractile effect
This drug can effectively mediate the smooth muscle contraction of visceral arterioles, especially the contraction of portal vein branches, gastrointestinal arterioles, and splenic arterioles, which can reduce the diameter of visceral arterioles by 30% -50% and significantly increase internal vascular resistance. The strength of its contraction can be precisely controlled by the dosage of the drug administered. The loading dose can quickly achieve strong vascular contraction, while the maintenance dose can maintain moderate vascular contraction, avoiding insufficient tissue perfusion caused by excessive vascular contraction and achieving a balance between contraction effect and safety.
Targeted selectivity of contraction site
It's contraction effect is mainly concentrated on small arteries in the visceral region, and its contraction effect on non visceral vascular structures such as peripheral arteries and coronary arteries is extremely weak. It can effectively avoid adverse reactions such as sudden blood pressure rise and myocardial ischemia caused by systemic vascular contraction. Patient-basedstudies have confirmed that after administration of this, visceral vascular resistance significantly increases, while peripheral vascular resistance remains unchanged, fully demonstrating its targeted constriction advantage on visceral arterioles and providing a guarantee for precise regulation of portal vein pressure.
Information source:
Tripathi D, Stanley AJ, Hayes PC, et al. UK guidelines on the management of variceal haemorrhage in cirrhotic patients (2015 update)[J]. Gut, 2015, 64(11): 1680-1704.
Moreau R, Jalan R, Gines P. Vasoactive drugs in portal hypertension: functional pathway of action and patient-based applications[J]. Journal of Hepatology, 2019, 70(2): 362-375.
The regulatory functional pathway of Terlipressin on portal vein and splenic vascular flow
The direct effect of the contraction of visceral arterioles is the reduction of portal vein and splenic vascular flow. Terlipressin regulates vascular flow perfusion through multiple pathways, achieving a fundamental reduction in portal vein pressure. The specific functional pathway can be divided into two key aspects:
Precise reduction of portal vein vascular flow:
The vascular flow of the portal vein mainly comes from the venous return of internal organs such as the gastrointestinal tract and spleen. This contracts small arteries in the gastrointestinal tract, mesentery, and other parts to reduce the arterial blood supply to these organs, thereby reducing the venous return flow and achieving a significant reduction in portal vein vascular flow. Research has shown that after treatment with Terlipressin Tablet, portal vein vascular flow can be reduced by 25% -40%, effectively alleviating venous stasis in the portal vein, reducing portal vein pressure from the root, and breaking the pathological cycle of "visceral vascular dilation venous stasis pressure increase".
Collaborative regulation of splenic vascular flow:
As an important component of the portal vein system, an abnormal increase in splenic vascular flow will further exacerbate portal vein pressure load. Terlipressin can reduce arterial blood supply to the spleen, decrease blood storage and reflux, and synergistically reduce portal vein vascular flow by constricting splenic arterioles. At the same time, the contraction of splenic arterioles can alleviate the state of splenic congestion and enlargement, further reduce the pressure burden on the portal vein, form a synergistic effect on the regulation of portal vein vascular flow, and enhance the downregulation effect of portal vein pressure.
Information source:
Ginè s P, Schrier RW, Arroyo V, et al. Diagnosis and treatment of portal hypertension: an update[J]. Hepatology, 2018, 67(6): 2380-2393.
Lui HF, Chan AC. Drug in the management of portal hypertension: A comprehensive review[J]. World J Gastroenterol, 2020, 26(38): 5892-5905.
The efficacy and patient-based significance of Terlipressin in rapidly reducing portal vein pressure
Terlipressin can achieve rapid and stable downregulation of portal vein pressure through the above-mentioned series of effects. Its efficacy characteristics and patient-based significance are mainly reflected in the following two points:
(I)Rapid and stable pressure reduction
It's active metabolite has a long half-life, with a duration of action of up to 4-6 hours. After a single loading dose administration, portal vein pressure reduction can be initiated within 1-2 hours, and the best antihypertensive effect can be achieved within 4-8 hours, rapidly reducing portal vein pressure from the pathological state to a safe threshold below 12mmHg. Compared with traditional vasoactive drugs, its antihypertensive effect is faster and smoother, which can avoid vascular damage caused by pressure fluctuations and provide an efficient solution for acute intervention of portal hypertension.
(II)The key value of patient-based application
Rapid and effective regulation of portal vein pressure is the key to preventing complications related to portal hypertension. It can effectively alleviate venous stasis in the portal vein system and delay further dilation of visceral vascular structures by precisely reducing portal vein pressure, providing support for disease control in patients with chronic liver disease. The specificity and safety of its action make it suitable for long-term or short-term intervention in patients with different degrees of portal hypertension, especially for patients with acute exacerbation of portal vein pressure. It creates a stable pathological environment for subsequent etiological treatment and is of great significance for improving the long-term prognosis of patients.
Information source:
Hepatology Branch of the Chinese Medical Association Guidelines for Diagnosis and Treatment of Cirrhotic Ascites and Complications (2022 Edition) [J]. Chinese Journal of Hepatology, 2022, 30 (12): 1361-1382
References
Selvaggi P, Angeli P, Kravet S, et al. Terlipressin for the treatment of portal hypertension: a systematic review and meta-analysis[J]. Alimentary Pharmacology & Therapeutics, 2021, 53(6): 789-801.
Gines J, Rimola J, Navasa M, et al. Efficacy of it in reducing portal pressure in patients with cirrhosis[J]. Journal of Hepatology, 2019, 70(4): 688-695.
European Association for the Study of the Liver. EASL patient-based Practice Guidelines on the management of ascites in cirrhosis[J]. Journal of Hepatology, 2021, 74(3): 622-647.
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