P h a r m a c o l o g i c Ma n a g e m e n t o f Portal Hypertension Annalisa Berzigotti,
MD, PhD,
Jaime Bosch,
MD, PhD, FRCP*
KEYWORDS Chronic liver disease Portal pressure Hepatic resistance Splanchnic blood flow Drug therapy KEY POINTS Drugs for portal hypertension should decrease portal pressure without adverse effects on the systemic circulation and liver function. Targets of pharmacologic treatment of portal hypertension include increased hepatic resistance, increased splanchnic blood flow, and hyperdynamic circulation. Nonselective b-blockers (NSBBs) are the mainstay of chronic oral treatment of portal hypertension, whereas terlipressin and somatostatin/somatostatin analogues are used parenterally in acute variceal bleeding and hepatorenal syndrome. Carvedilol is a new and increasingly used NSBB with anti-a-1 adrenergic activity that has greater portal pressure decreasing effect than standard NSBBs. Most drugs currently under investigation are aimed at reducing hepatic resistance (hepatic vascular tone) and include statins, antioxidants, RAAS inhibitors, as well as antifibrotic stategies (structural changes).
INTRODUCTION
Portal hypertension (PH) is a frequent and severe clinical syndrome, which almost invariably complicates liver cirrhosis and is responsible for most of its clinical consequences, such as gastroesophageal varices, ascites, hepatorenal syndrome, hepatic encephalopathy, bacteremia, and hypersplenism.1 Longitudinal studies assessing clinical-hemodynamic correlations have demonstrated that, in patients with cirrhosis, all the complications of PH do not appear until portal pressure, estimated by its clinical equivalent the hepatic venous pressure gradient (HVPG), increases to greater than 10 mm Hg.2 This threshold value therefore defines clinically significant portal hypertension (CSPH), whereas subclinical PH is defined by HVPG between 6 and 9 mm Hg.2
Disclosure: The authors declare that they have no conflict of interest to disclose in relation with the contents discussed in this publication. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-IDIBAPS, Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), University of Barcelona, c/Villarroel 170, Barcelona 08036, Spain * Corresponding author. E-mail address: [email protected] Clin Liver Dis 18 (2014) 303–317 http://dx.doi.org/10.1016/j.cld.2013.12.003 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
304
Berzigotti & Bosch
The aim of therapy in patients with PH is to decrease portal pressure, because elevated portal pressure is the driving force of all the clinical consequences of the syndrome. In pragmatic terms the goal of therapy in subclinical PH should be to avoid CSPH, whereas asymptomatic patients with CSPH should be treated to decrease portal pressure below the threshold of 10 mm Hg, as CSPH markedly increases the risk of clinical complications (“decompensation”). In compensated patients without varices, there is evidence that even a small reduction in HVPG (10% of baseline value) is beneficial, decreasing the rate of varices formation.3 In patients with symptomatic PH, therapy should be more aggressive, aimed at decreasing portal pressure ideally to less than 12 mm Hg or, in patients not achieving this goal, a 20% decrease in HVPG versus pretreatment value, as this decreases the risk of both bleeding/rebleeding from varices, developing clinical decompensation, and reduces mortality.4 Drugs for PH should be able to decrease portal pressure without decreasing mean arterial pressure, which could worsen hyperdynamic circulation and increase the risk of renal failure. In addition, pharmacologic treatments should be ideally able to maintain or even improve effective liver perfusion, because this may improve liver function. DRUGS USED IN CLINICAL PRACTICE
Most drugs used in clinical practice are splanchnic vasoconstrictors, acting by reducing splanchnic blood flow and hyperkinetic circulation (Fig. 1). Box 1 summarizes the most commonly used drugs, further described herein. Vasopressin Derivatives
Terlipressin (triglycyl lysine vasopressin) is a synthetic analogue of vasopressin with longer biologic activity and better safety profile5–8 that is indicated for the treatment of acute variceal bleeding (AVB) and of type 1 hepatorenal syndrome (HRS). Its effects encompass a marked vasoconstriction of the splanchnic circulation, an increase in arterial blood pressure and systemic vascular resistance, and a decrease in cardiac output. Altogether these induce a rapid and prolonged decrease in portal pressure of about 20% after a single injection.7 The effects are maintained up to 4 hours, allowing its administration as intermittent intravenous injections, although continuous intravenous infusion is also possible.8–10 In adults (>40 kg of body weight) the recommended dose for variceal bleeding is 2 mg every 4 hours for the first 24 to 48 hours, followed by 1 mg every 4 hours for 2 to 5 days.11–13 In patients with HRS terlipressin is used in combination with albumin infusion at an initial dose of 0.5 to 1 mg intravenously every 4 hours, which is increased up to 3 mg every 4 hours if there is no response14; therapy is maintained up to 14 days. In HRS continuous intravenous infusion (beginning from 3 mg/d) might be beneficial, reducing daily dose and severity of adverse events.15 The most common side effects associated with the use of terlipressin are abdominal pain and increased blood pressure that reverse after drug withdrawal. In the setting of AVB, serious side effects such as peripheral, intestinal, or myocardial ischemia occur in less than 3% of the patients.12 In patients with HRS included in 2 recent randomized controlled trials (RCT), treatment-related serious adverse events, mostly cardiovascular and leading to treatment discontinuation, were observed in 9% to 22% of patients.16,17 Given the risk of ischemic and arrhythmic complications, terlipressin should not be used in patients with a history of ischemic heart or cerebral disease limb or gut vascular disease,18 and caution should be used in elderly and/or hypertensive subjects. Hyponatremia, in some cases symptomatic, can arise during treatment19 and reverses after drug discontinuation. Interestingly, terlipressin-associated
Pharmacologic Management of Portal Hypertension
Fig. 1. Pathophysiological basis for pharmacologic therapy. PH is due to both increased hepatic resistance to portal blood flow and increased portal-collateral blood flow.57 Hepatic resistance increases primarily by the structural changes caused by cirrhosis (fibrosis, regenerative nodules formation, vascular occlusion, and remodeling). Increased hepatic vascular tone due to sinusoidal endothelial dysfunction further increases by w30% the hepatic resistance. As portal-systemic collaterals develop, splanchnic vasodilatation and hyperkinetic circulation contribute to maintain and worsen PH. The lower panel illustrates the multiple rational targets for the therapy for PH. These therapies include (1) increased structural resistance through the cirrhotic liver (1a in the figure); (2) increased hepatic vascular tone (1b in the figure), mainly mediated by an insufficient availability of NO due to hepatic endothelial dysfunction; (3) increased splanchnic blood flow (2 in the figure) and hyperkinetic circulation (3 in the figure). The figure further summarizes specific drugs acting on these targets. P-S, portosystemic; SMT, somatostatin; SNS, sympathetic nervous system.
hyponatremia is more commonly observed in patients with preserved liver function and is associated with better response to treatment.18 Somatostatin and Long-Acting Somatostatin Analogues
Somatostatin is a 14-amino-acid peptide secreted by neural, endocrine, and enteroendocrine cells in the hypothalamus and in the digestive system (in the stomach,
305
306
Box 1 Available drugs for PH Injection drugs used in the acute setting Terlipressin Long-acting vasopressin analogue with affinity for vascular receptors higher than that of vasopressin Induces marked splanchnic vasoconstriction and arterial pressure increase Given intravenously as injections of 2 mg/4 hours for 24–48 hours, then 1 mg/4 hours for 2–5 days Well validated in placebo controlled RCTs and meta-analysis Somatostatin Very short biologic half-life Induces moderate vasoconstriction due to glucagon inhibition and facilitation of adrenergic vasoconstriction Given as intravenous infusion of 250–500 mg/hour, after a bolus of 250 mg, for up to 5 days Analogues of somatostatin (Octreotide, Vapreotide) Longer half life than somatostatin Short effects on portal pressure due to rapid desensitization Given as intravenous infusion of 50 mg/hour, after an optional bolus of 50 mg for up to 5 days Effective in RCTs when evaluated in addition to endoscopic sclerotherapy Oral drugs used for chronic therapy Propranolol b-1 and b-2 adrenergic receptor antagonist (NSBB) Induces decrease in cardiac output and splanchnic vasoconstriction Given orally beginning with 10–20 mg twice a day, increasing the dose every 2–3 days up to the maximum tolerated dose (provided systolic arterial pressure is >100 mm Hg and heart rate not less than 50 bpm). Dose should not exceed 320 mg/d. Should be maintained lifelong. Well validated in several studies Maximal efficacy in cirrhosis is obtained when HVPG is reduced 100 mm Hg and heart rate not less than 50 bpm). Dose should not exceed 160 mg/d. Should be maintained lifelong. Well validated in several studies Maximal efficacy in cirrhosis is obtained when HVPG is reduced 100 mm Hg). Not fully validated yet
Pharmacologic Management of Portal Hypertension
intestine, and pancreatic delta cells). It regulates the release of numerous secondary peptides, such as growth hormone, glucagon, insulin, gastrin, and secretin, and also plays a role in neural transmission. Once released, somatostatin binds to G-proteincoupled receptors (somatostatin receptor subtypes 1–5) that activate ion channels and enzymes mediating the synthesis/degradation of intracellular second messengers, including cyclic AMP, cyclic GMP, inositol trisphosphate, and diacylglycerol.20 The administration of somatostatin in portal hypertensive patients induces splanchnic vasoconstriction and consequently reduces portal pressure.21 Somatostatin also blocks the brisk increase in HVPG induced by meals and blood transfusion,22 which is considered a risk factor for rebleeding from portal hypertensive sources. The mechanisms leading to these effects are not fully known but include the inhibition of glucagon and other vasodilatory peptides, and the facilitation of adrenergic vasoconstriction.23 Given that somatostatin has a short half-life, ranging from 1.2 to 4.8 minutes in patients with chronic liver disease,20 it should be administered by continuous intravenous infusion to maintain an adequate plasma concentration. In AVB a dose of 250 mg/h intravenously preceded by a 250 mg intravenous bolus is empirically recommended because it slightly lowers the HVPG in stable conditions24; bolus injections can be repeated up to 3 times during the first hour if required. However, the use of a double infusion dose (500 mg/h) causes a greater reduction in HVPG25 and a marked and sustained decrease in azygos blood flow. In the setting of AVB the 500 mg/h dose is required to significantly reduce the HVPG.10 The greater hemodynamic effects of high doses translate into higher effectiveness in high-risk patients.26 Severe side effects are rare. Usual side effects include vomiting and hyperglycemia that are usually easy to manage20,26 and occur in about 21% of patients. To overcome a main limitation of somatostatin, namely its short half-life, long-acting analogues have been developed.20 Octreotide, Vapreotide, Lanreotide, and Seglitide (the latter has not been tested for PH) belong to this drug class. Their mechanism of action is probably similar to that of somatostatin, although their affinity for SMT receptors is different from that of the natural hormone. Octreotide is effective in preventing the postprandial splanchnic hyperemia in portal hypertensive patients27,28 and this effect is long-lasting.28,29 A single injection of octreotide and vapreotide is able to decrease portal pressure.20 Empiric doses of octreotide and vapreotide in portal hypertensive patients are 50 mg/h as a continuous intravenous infusion with an optional initial intravenous or subcutaneous bolus of 50 mg. Unfortunately, even though the half-life of these compounds is much longer than that of somatostatin, the duration of their hemodynamic effects on portal pressure is short. In particular, the effects on portal pressure of continuous infusion and repeated injections progressively decrease,30 probably because of the rapid development of desensitization or tachyphylaxis. Nonselective b-Blockers Alone and Combined with Vasodilators
Lebrec and colleagues31 in 1980 first demonstrated that oral administration of propranolol, a nonselective b-blocker (NSBB) at doses that reduced the heart rate by w25%, causing a sustained decrease in portal venous pressure in cirrhotic patients with PH. The same group showed that continued propranolol prevented variceal rebleeding.32,33 Since then, NSBBs are the mainstay of chronic therapy for PH.34 Available NSBBs include propranolol, nadolol, and timolol, the latter the less commonly used. NSBBs decrease portal pressure by decreasing portal-collateral blood flow. They act by blocking both b-1 cardiac receptors leading to decreased cardiac output, and b-2 vascular receptors, allowing unopposed a-1 adrenergic activity that results
307
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in splanchnic vasoconstriction; this latter effect explains why selective (b-1) b-blockers are not as effective in reducing portal pressure. Other beneficial effects of NSBBs include the reduction of azygos blood flow and variceal pressure, as well as shortening the intestinal transit time which has been related to decreased bacterial overgrowth and thereby reduced risk of bacterial translocation.34 NSBBs are cheap, safe, and easy to use, decrease the risk of all main complications related to PH, and improve survival.4 The recommended doses of propranolol and nadolol are listed in Box 1. However, it has been shown that only 30% to 40% of the patients under long-term therapy with NSBB show a good hemodynamic response (reduction of HVPG
MD, PhD,
Jaime Bosch,
MD, PhD, FRCP*
KEYWORDS Chronic liver disease Portal pressure Hepatic resistance Splanchnic blood flow Drug therapy KEY POINTS Drugs for portal hypertension should decrease portal pressure without adverse effects on the systemic circulation and liver function. Targets of pharmacologic treatment of portal hypertension include increased hepatic resistance, increased splanchnic blood flow, and hyperdynamic circulation. Nonselective b-blockers (NSBBs) are the mainstay of chronic oral treatment of portal hypertension, whereas terlipressin and somatostatin/somatostatin analogues are used parenterally in acute variceal bleeding and hepatorenal syndrome. Carvedilol is a new and increasingly used NSBB with anti-a-1 adrenergic activity that has greater portal pressure decreasing effect than standard NSBBs. Most drugs currently under investigation are aimed at reducing hepatic resistance (hepatic vascular tone) and include statins, antioxidants, RAAS inhibitors, as well as antifibrotic stategies (structural changes).
INTRODUCTION
Portal hypertension (PH) is a frequent and severe clinical syndrome, which almost invariably complicates liver cirrhosis and is responsible for most of its clinical consequences, such as gastroesophageal varices, ascites, hepatorenal syndrome, hepatic encephalopathy, bacteremia, and hypersplenism.1 Longitudinal studies assessing clinical-hemodynamic correlations have demonstrated that, in patients with cirrhosis, all the complications of PH do not appear until portal pressure, estimated by its clinical equivalent the hepatic venous pressure gradient (HVPG), increases to greater than 10 mm Hg.2 This threshold value therefore defines clinically significant portal hypertension (CSPH), whereas subclinical PH is defined by HVPG between 6 and 9 mm Hg.2
Disclosure: The authors declare that they have no conflict of interest to disclose in relation with the contents discussed in this publication. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-IDIBAPS, Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), University of Barcelona, c/Villarroel 170, Barcelona 08036, Spain * Corresponding author. E-mail address: [email protected] Clin Liver Dis 18 (2014) 303–317 http://dx.doi.org/10.1016/j.cld.2013.12.003 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
304
Berzigotti & Bosch
The aim of therapy in patients with PH is to decrease portal pressure, because elevated portal pressure is the driving force of all the clinical consequences of the syndrome. In pragmatic terms the goal of therapy in subclinical PH should be to avoid CSPH, whereas asymptomatic patients with CSPH should be treated to decrease portal pressure below the threshold of 10 mm Hg, as CSPH markedly increases the risk of clinical complications (“decompensation”). In compensated patients without varices, there is evidence that even a small reduction in HVPG (10% of baseline value) is beneficial, decreasing the rate of varices formation.3 In patients with symptomatic PH, therapy should be more aggressive, aimed at decreasing portal pressure ideally to less than 12 mm Hg or, in patients not achieving this goal, a 20% decrease in HVPG versus pretreatment value, as this decreases the risk of both bleeding/rebleeding from varices, developing clinical decompensation, and reduces mortality.4 Drugs for PH should be able to decrease portal pressure without decreasing mean arterial pressure, which could worsen hyperdynamic circulation and increase the risk of renal failure. In addition, pharmacologic treatments should be ideally able to maintain or even improve effective liver perfusion, because this may improve liver function. DRUGS USED IN CLINICAL PRACTICE
Most drugs used in clinical practice are splanchnic vasoconstrictors, acting by reducing splanchnic blood flow and hyperkinetic circulation (Fig. 1). Box 1 summarizes the most commonly used drugs, further described herein. Vasopressin Derivatives
Terlipressin (triglycyl lysine vasopressin) is a synthetic analogue of vasopressin with longer biologic activity and better safety profile5–8 that is indicated for the treatment of acute variceal bleeding (AVB) and of type 1 hepatorenal syndrome (HRS). Its effects encompass a marked vasoconstriction of the splanchnic circulation, an increase in arterial blood pressure and systemic vascular resistance, and a decrease in cardiac output. Altogether these induce a rapid and prolonged decrease in portal pressure of about 20% after a single injection.7 The effects are maintained up to 4 hours, allowing its administration as intermittent intravenous injections, although continuous intravenous infusion is also possible.8–10 In adults (>40 kg of body weight) the recommended dose for variceal bleeding is 2 mg every 4 hours for the first 24 to 48 hours, followed by 1 mg every 4 hours for 2 to 5 days.11–13 In patients with HRS terlipressin is used in combination with albumin infusion at an initial dose of 0.5 to 1 mg intravenously every 4 hours, which is increased up to 3 mg every 4 hours if there is no response14; therapy is maintained up to 14 days. In HRS continuous intravenous infusion (beginning from 3 mg/d) might be beneficial, reducing daily dose and severity of adverse events.15 The most common side effects associated with the use of terlipressin are abdominal pain and increased blood pressure that reverse after drug withdrawal. In the setting of AVB, serious side effects such as peripheral, intestinal, or myocardial ischemia occur in less than 3% of the patients.12 In patients with HRS included in 2 recent randomized controlled trials (RCT), treatment-related serious adverse events, mostly cardiovascular and leading to treatment discontinuation, were observed in 9% to 22% of patients.16,17 Given the risk of ischemic and arrhythmic complications, terlipressin should not be used in patients with a history of ischemic heart or cerebral disease limb or gut vascular disease,18 and caution should be used in elderly and/or hypertensive subjects. Hyponatremia, in some cases symptomatic, can arise during treatment19 and reverses after drug discontinuation. Interestingly, terlipressin-associated
Pharmacologic Management of Portal Hypertension
Fig. 1. Pathophysiological basis for pharmacologic therapy. PH is due to both increased hepatic resistance to portal blood flow and increased portal-collateral blood flow.57 Hepatic resistance increases primarily by the structural changes caused by cirrhosis (fibrosis, regenerative nodules formation, vascular occlusion, and remodeling). Increased hepatic vascular tone due to sinusoidal endothelial dysfunction further increases by w30% the hepatic resistance. As portal-systemic collaterals develop, splanchnic vasodilatation and hyperkinetic circulation contribute to maintain and worsen PH. The lower panel illustrates the multiple rational targets for the therapy for PH. These therapies include (1) increased structural resistance through the cirrhotic liver (1a in the figure); (2) increased hepatic vascular tone (1b in the figure), mainly mediated by an insufficient availability of NO due to hepatic endothelial dysfunction; (3) increased splanchnic blood flow (2 in the figure) and hyperkinetic circulation (3 in the figure). The figure further summarizes specific drugs acting on these targets. P-S, portosystemic; SMT, somatostatin; SNS, sympathetic nervous system.
hyponatremia is more commonly observed in patients with preserved liver function and is associated with better response to treatment.18 Somatostatin and Long-Acting Somatostatin Analogues
Somatostatin is a 14-amino-acid peptide secreted by neural, endocrine, and enteroendocrine cells in the hypothalamus and in the digestive system (in the stomach,
305
306
Box 1 Available drugs for PH Injection drugs used in the acute setting Terlipressin Long-acting vasopressin analogue with affinity for vascular receptors higher than that of vasopressin Induces marked splanchnic vasoconstriction and arterial pressure increase Given intravenously as injections of 2 mg/4 hours for 24–48 hours, then 1 mg/4 hours for 2–5 days Well validated in placebo controlled RCTs and meta-analysis Somatostatin Very short biologic half-life Induces moderate vasoconstriction due to glucagon inhibition and facilitation of adrenergic vasoconstriction Given as intravenous infusion of 250–500 mg/hour, after a bolus of 250 mg, for up to 5 days Analogues of somatostatin (Octreotide, Vapreotide) Longer half life than somatostatin Short effects on portal pressure due to rapid desensitization Given as intravenous infusion of 50 mg/hour, after an optional bolus of 50 mg for up to 5 days Effective in RCTs when evaluated in addition to endoscopic sclerotherapy Oral drugs used for chronic therapy Propranolol b-1 and b-2 adrenergic receptor antagonist (NSBB) Induces decrease in cardiac output and splanchnic vasoconstriction Given orally beginning with 10–20 mg twice a day, increasing the dose every 2–3 days up to the maximum tolerated dose (provided systolic arterial pressure is >100 mm Hg and heart rate not less than 50 bpm). Dose should not exceed 320 mg/d. Should be maintained lifelong. Well validated in several studies Maximal efficacy in cirrhosis is obtained when HVPG is reduced 100 mm Hg and heart rate not less than 50 bpm). Dose should not exceed 160 mg/d. Should be maintained lifelong. Well validated in several studies Maximal efficacy in cirrhosis is obtained when HVPG is reduced 100 mm Hg). Not fully validated yet
Pharmacologic Management of Portal Hypertension
intestine, and pancreatic delta cells). It regulates the release of numerous secondary peptides, such as growth hormone, glucagon, insulin, gastrin, and secretin, and also plays a role in neural transmission. Once released, somatostatin binds to G-proteincoupled receptors (somatostatin receptor subtypes 1–5) that activate ion channels and enzymes mediating the synthesis/degradation of intracellular second messengers, including cyclic AMP, cyclic GMP, inositol trisphosphate, and diacylglycerol.20 The administration of somatostatin in portal hypertensive patients induces splanchnic vasoconstriction and consequently reduces portal pressure.21 Somatostatin also blocks the brisk increase in HVPG induced by meals and blood transfusion,22 which is considered a risk factor for rebleeding from portal hypertensive sources. The mechanisms leading to these effects are not fully known but include the inhibition of glucagon and other vasodilatory peptides, and the facilitation of adrenergic vasoconstriction.23 Given that somatostatin has a short half-life, ranging from 1.2 to 4.8 minutes in patients with chronic liver disease,20 it should be administered by continuous intravenous infusion to maintain an adequate plasma concentration. In AVB a dose of 250 mg/h intravenously preceded by a 250 mg intravenous bolus is empirically recommended because it slightly lowers the HVPG in stable conditions24; bolus injections can be repeated up to 3 times during the first hour if required. However, the use of a double infusion dose (500 mg/h) causes a greater reduction in HVPG25 and a marked and sustained decrease in azygos blood flow. In the setting of AVB the 500 mg/h dose is required to significantly reduce the HVPG.10 The greater hemodynamic effects of high doses translate into higher effectiveness in high-risk patients.26 Severe side effects are rare. Usual side effects include vomiting and hyperglycemia that are usually easy to manage20,26 and occur in about 21% of patients. To overcome a main limitation of somatostatin, namely its short half-life, long-acting analogues have been developed.20 Octreotide, Vapreotide, Lanreotide, and Seglitide (the latter has not been tested for PH) belong to this drug class. Their mechanism of action is probably similar to that of somatostatin, although their affinity for SMT receptors is different from that of the natural hormone. Octreotide is effective in preventing the postprandial splanchnic hyperemia in portal hypertensive patients27,28 and this effect is long-lasting.28,29 A single injection of octreotide and vapreotide is able to decrease portal pressure.20 Empiric doses of octreotide and vapreotide in portal hypertensive patients are 50 mg/h as a continuous intravenous infusion with an optional initial intravenous or subcutaneous bolus of 50 mg. Unfortunately, even though the half-life of these compounds is much longer than that of somatostatin, the duration of their hemodynamic effects on portal pressure is short. In particular, the effects on portal pressure of continuous infusion and repeated injections progressively decrease,30 probably because of the rapid development of desensitization or tachyphylaxis. Nonselective b-Blockers Alone and Combined with Vasodilators
Lebrec and colleagues31 in 1980 first demonstrated that oral administration of propranolol, a nonselective b-blocker (NSBB) at doses that reduced the heart rate by w25%, causing a sustained decrease in portal venous pressure in cirrhotic patients with PH. The same group showed that continued propranolol prevented variceal rebleeding.32,33 Since then, NSBBs are the mainstay of chronic therapy for PH.34 Available NSBBs include propranolol, nadolol, and timolol, the latter the less commonly used. NSBBs decrease portal pressure by decreasing portal-collateral blood flow. They act by blocking both b-1 cardiac receptors leading to decreased cardiac output, and b-2 vascular receptors, allowing unopposed a-1 adrenergic activity that results
307
308
Berzigotti & Bosch
in splanchnic vasoconstriction; this latter effect explains why selective (b-1) b-blockers are not as effective in reducing portal pressure. Other beneficial effects of NSBBs include the reduction of azygos blood flow and variceal pressure, as well as shortening the intestinal transit time which has been related to decreased bacterial overgrowth and thereby reduced risk of bacterial translocation.34 NSBBs are cheap, safe, and easy to use, decrease the risk of all main complications related to PH, and improve survival.4 The recommended doses of propranolol and nadolol are listed in Box 1. However, it has been shown that only 30% to 40% of the patients under long-term therapy with NSBB show a good hemodynamic response (reduction of HVPG
