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New approaches in the pharmacologic treatment of portal hypertension
Journal of Hepatology, 1993; 17(Suppl. 2): $41-$45
$41
@ 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00 HEPAT 01428
New approaches in the pharmacologic treatment of portal hypertension
Jaime Bosch, Juan C. Garcia-Pag~n, Faust Feu, Angelo Luca, Mercedes Fern~indez, Pilar Pizcueta and Juan Rod6s Hepatic Haemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, University of Barcelona, Spain
To alleviate the risk of variceal bleeding, the portal pressure gradient - - usually evaluated as the hepatic venous pressure gradient (HVPG) - - must be reduced to _< 12 mmHg. Although B-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to _< 12 mmHg in only 12% of patients, while only 24% of patients have a >_20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorblde-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolact6ne, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a B-blocker, a nitrate and spironolactone may be feasible. Serotonin constricts rnesenteric veins in experimental models of portal hypertension and may also play a role in portal hypertension secondary to cirrhosis. Serotonin S2-receptor blockers, such as ritanserin and ketanserin, have been shown to lower portalcollateral resistance in animal models and patients with cirrhosis. These serotonin antagonists should be assessed for their potential in coadministration with non-selective B-blockers, perhaps with the addition of spironolactone.
Key words: Isosorbide-5-mononitrate; Oesophagogastric varices; Propranolol; Serotonin S2-receptor blockers; Spironolactone
The pharmacologic treatment of portal hypertension is based on the assumption that a sustained reduction in portal pressure reduces the incidence of hypertensive complications. For varices to develop and rupture, the portal pressure gradient (usually evaluated as the hepatic venous pressure gradient (HVPG)) must increase above 12 mmHg (1,2). Recent studies have confirmed that when HVPG is reduced below this threshold gradient, the patient is no longer at risk for variceal
haemorrhage, the varices progressively decrease in size and survival is significantly increased (3). In addition, it is likely that when HVPG is very high, a substantial reduction (i.e. >20% of baseline value) may also translate into a significant decrease in risk of variceal bleeding, even if the final value is above the 12 mmHg threshold gradient. This potential exists because variceal rupture apparently occurs when variceal wall tension, which is directly related to variceal pressure, exceeds a
Correspondence to: Jaime Bosch, M.D., Hepatic Haemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, Villarroel 170, 08036 Barcelona, Spain.
$42 critical value (4,5). Therefore, a m a r k e d decrease in portal pressure (which leads to at least a similar fall in variceal pressure) (6,7) will m a r k e d l y decrease variceal tension and the likelihood o f variceal h a e m o r r h a g e (7).
Limitations of 3-blocker therapy Propranolol and nadolol are now well accepted as therapeutic agents for the prevention of variceal bleeding or rebleeding (8-10). However, in only 24% of patients does H V P G decrease by more than 20% after propranolol administration and in only 12% is the final H V P G _< 12 m m H g (11). On the other hand, nearly 40% of patients fail to exhibit a reduction in H V P G following propranolol use (12,13). It appears, therefore, that to improve the results of pharmacologic therapy with propranolol, we must either select patients who exhibit a better h a e m o d y n a m i c response (which would limit the applicability of the therapy) (11) or develop combination therapies that can offer effective reductions in H V P G in a greater p r o p o r t i o n of patients. Other limitations of therapy with non-selective 3blockers are related to contraindications and side effects. A m o n g the former, the more frequently encountered are chronic obstructive lung disease, atrioventricular heart block, arrhythmias, psychosis and insulin-dependent diabetes if the patient has a history o f hypoglycaemia (10). Side effects are relatively c o m m o n ( - 1 5 % of patients), but severe events (e.g. bronchospasm) are rare (10). The more frequent complaints are fatigue, which is often associated with marked bradycardia (heart rate < 5 0 beats/min) and sleep disorders. Although complications resulting from propranolol therapy for cirrhosis have never been lethal (8,9), side effects are important inasmuch as they detract from compliance. Nadolol is more convenient to use because its prolonged half-life allows once-a-day administration (14,15) and its primarily renal elimination makes accurate dosing easier to ascertain than with propranolol. Also, since nadolol does not cross the bloodbrain barrier, it m a y be less likely to cause central nervous system effects (14,15). However, this has not been adequately investigated in cirrhosis.
j. BOSCH et al. (Table 1). Vasodilators m a y reduce portal pressure by decreasing the vascular resistance to portal and collateral blood flow and by p r o m o t i n g reflex splanchnic vasoconstriction as a response to reduced mean arterial and cardiac filling pressures (16). A theoretical advantage of vasodilators over 3-blockers is that the former m a y allow reduction of portal pressure without impairing liver perfusion (16). An important limitation is that all vasodilators lower arterial blood pressure; this may
TABLE I Alternatives to E-blocker use in long-term treatment of portal hypertension Drug
The possible use of vasodilators and other agents in this setting has attracted a lot of attention in recent years
Mean reduction in HVPG (%)
10 mg (1 20 mg (I 5 mg (1 5 mg (I
Nitrovasodilators
lsosorbide dinitrate Blei (17) Merkel (18) Mols (19) lsosorbide-5-mononitrate Hayes (20) Navasa (16) Garcia-Pag~in (21) Molsidomine Vinel (22) Ruiz del Arbol(23)
dose dose dose dose
p.o.) p.o.) p.o.) s.I.)
25 25 34 22
20 mg (1 dose 20 mg (I dose 40 mg (1 dose 40 mg (b.i.d. x 3 months
p.o.) p.o.) p.o.)
9 10 18
p.o.)
8
4 mg (I dose p.o.) 2 mg (1 dose p.o.) 4 mg (I dose p.o.)
15 I1 19
Serotonin S2-receptor blockers
Ritanserin Mastai (25)a
Nevens (26)b Ketanserin Hadengue (28) Vorobioff (29)
0.63 mg/kg (I dose i.v.) 0.7 mg/kg (I dose i.v.) 10 mg (1 dose i.v.) 40-80 mg/day ix I month p.o.)
17c 20c 23 15
Clonidine
Willet (30) Moreau (31) Albillos (33)
2.5 ~g/kg (I dose i.v.) 150 #g/kg (1 dose i.v.) 0.30-0.45 mg/day (x 2 months p.o.)
20
100 mg/day (x 4 weeks p.o.) 100 mg/day (x 2 months p.o.)
22
27 d
15
Spironolactone
Okumura (34) Garcia-Pag~in (35)
Alternative pharmacologic treatment for portal hypertension
Dose (regimen)
13
b.i.d., twice daily; HVPG, hepatic venous pressure gradient; i.v., intravenously; p.o., orally; s.l., sublingually. aCCl4-cirrhotic rats. bpartial portal vein-ligated rats. CPortal pressure. dWedged hepatic venous pressure.
PHARMACOTHERAPY FOR PORTAL HYPERTENSION
$43 Liver injury
be poorly tolerated in patients with advanced cirrhosis (especially when ascites and oedema exist), who are frequently hypotensive.
Nodular regeneration Fibrosm
Nitrovasodilators With acute administration, nitrovasodilators such as isosorbide dinitrate (17-19) and isosorbide-5-mononitrate (16,20) cause marked reductions in HVPG, but this effect is much smaller during long-term therapy (21). Tolerance to nitrovasodilators may be due to true pharmacologic tolerance, to the activation of endogenous neurohumoral vasoactive systems and to plasma volume expansion (21). The latter suggests the possibility that combination with a diuretic may enhance the effects of these compounds on HVPG (analogous with findings in the treatment of arterial hypertension). Otherwise, it is unlikely that nitrovasodilators can become useful agents as monotherapy for portal hypertension because of their minimal effect on portal pressure. Molsidomine (22,23), which has effects similar to those of isosorbide dinitrate, is thought not to cause tolerance; however, this has not been assessed by longterm comparative studies in patients with portal hypertension.
t Sinusotdal pressure Sp~ronolactone intervention I Portalhypertenslon I Splanchntc vasodJlat~on
'1'Gastroesophageal collaterals
,1.Effective blood volume
t Vanx formatlon/stze
t' Aldosterone
t, Vanx wall tension
t Na+ retenlion
Vanx rupture
I
Fig. 1.
I
Portal hypertensive syndrome with spironolactone intervention (Lauler, 1992).
TABLE 2
Serotonin S:-receptor blockers Following the observation that mesenteric veins from portal hypertensive animals are hypersensitive to the venoconstrictor effects of serotonin (24) came the introduction of serotonin S2-receptor blockers. Ritanserin and other serotonin S2-receptor blockers (such as ketanserin) have been shown to reduce portal pressure in models of portal hypertension and/or in patients with cirrhosis (25-29). This lowering of portal pressure is in part due to a lowering of portal-collateral resistance. It is notable that selective S2-receptor antagonists do not cause a decrease in arterial pressure (25-27). The potential for the use of these drugs, either alone or in combination with other agents, requires further investigation. Clonidine A centrally acting a2-adrenergic agonist, clonidine causes a reduction in adrenergic output. Clonidine reduces portal pressure by decreasing portal resistance and splanchnic inflow (30-33). Arterial pressure is also markedly reduced by this agent, but it does not appear to be associated with adverse effects on renal function or sodium handling (32). The magnitude of the fall in portal pressure with clonidine use is slightly greater than that achieved with propranolol (33). Spironolactone The aldosterone antagonist spironolactone has been shown to lower HVPG in patients with cirrhosis (34,35).
Drug combinations with proven or probable synergistic effects in reducing portal pressure Combination
Mean reduction in HVPG
(%) Propranolol + isosorbide-5-mononitrate ( ls-5-Mn )
Garcia-Pag~in (37) Propranolol: 0.1 mg/kg, then 2 mg/h (i.v.) Is-5-Mn: 20 or 40 mg (1 dose p.o.) Garcia-Pag~in (38) Propranolol: dose increased until heart rate reduced 25% (x 3 months p.o.) ls-5-Mn: 40 mg b.i.d. (x 3 months p.o.)
27 19
Propranolol + ketanserin
Hadengue (39) Propranolol: 15 mg (1 dose i.v.) Ketanserin: 5 mg (I dose i.v.)
19
Spironolactone + propranolol
Garcia-Pag~n (35) Spironolactone: 100 mg/day (x 2 months p.o.) Propranolol: 0.15 mg/kg (1 dose i.v.)
25
Nitrovasodilator + diuretic
Not evaluated
B-blocker + nitrovasodilator + diuretic
Not evaluated
f3-blocker + S2-receptor blocker + diuretic
Not evaluated HVPG, hepatic venous pressure gradient; i.v., intravenously; p.o., orally.
$44
J. BOSCH
WHVP
mmHg
30-
15-
24-
25-
10-
19-
20
i B
I P
i P+ls
5
al.
HVPG
FHVP mmHg
mmHg
et
1
i B
~ P
I P+ls
14
I
I
I
B
P
P+ls
* p < 0.001 vs baseline Fig. 2. Effects of administering propranolol (P), and propranolol plus isosorbide-5-mononitrate (P + Is) on wedged hepatic venous pressure (WHVP), free hepatic venous pressure (FHVP) and hepatic venous pressure gradient (HVPG). Values are expressed as mean ± standard error; B, baseline values. (Garcia-Pagfin et al., 1990).
This beneficial effect of the drug is based on the known relationship between plasma volume and portal pressure (Fig. 1) (36). In addition, the reduction in plasma volume caused by spironolactone attenuates the increase in cardiac output observed in cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow (35). Spironolactone thus has the potential to maintain and enhance the decrease in portal pressure caused by nitrovasodilators or propranolol. Clearly, the degree of plasma volume expansion is an important variable influencing portal pressure that has not been taken into account in the past. Concomitant use of diuretics may be responsible in part for the conflicting results observed in previous studies and clinical trials.
Combination therapy It is unlikely that any single agent can lower portal pressure enough to eliminate the risk of variceal bleeding or rebleeding in most patients with cirrhosis. A risk-reducing drop in portal pressure is probably easier to achieve by using combinations of drugs that act through different mechanisms (Table 2) (35,37-39). Again, the strategy for managing portal hypertension may profit from experience gained in the treatment of systemic hypertension. Concomitant use of propranolol and isosorbide-5mononitrate (37,38) causes a significantly greater reduction in HVPG than is possible with either drug alone (Fig. 2). Acute and long-term haemodynamic studies have shown that this drug combination decreases the
number of patients whose portal pressure remains elevated, while it increases the proportion of patients in whom HVPG markedly drops (37,38). This may result from isosorbide-5-mononitrate preventing the increase in portal resistance that is caused by propranolol (37). This drug combination is also superior to propranolol alone in maintaining liver perfusion and hepatic function, while the beneficial effect of reducing azygos blood flow is unchanged (38). Whether the enhanced haemodynamic effects of this combination therapy translate into better clinical results must be verified by randomised, controlled studies. As already mentioned, other drug combinations also have potential for synergistic effects in reducing portal pressure. Possible combinations for double-drug therapy include propranolol or nadolol with an S2receptor blocker, propranolol or nadolol with spironolactone and a nitrovasodilator or molsidomine with a diuretic. Triple-drug therapy might include a/3blocker with a nitrovasodilator and spironolactone or a B-blocker with an S2-antagonist and spironolactone. Further research is needed to clarify the clinical value of each of these options.
Acknowledgements Supported in part by grants from Fondo de Investigaci6n Sanitaria (91/0374) and Fundaci6 Catalana per a l'Estudi de les Malalties del Fetge i Gastroenterologiques.
PHARMACOTHERAPY FOR PORTAL HYPERTENSION
References 1 Viallet A, Marleau D, Huet M, et al. Hemodynamic evaluation of patients with intrahepatic portal hypertension: relationship between bleeding varices and the portohepatic gradient. Gastroenterology 1975; 69: 1297-1300. 2 Garcia-Tsao G, Groszmann R J, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5: 419-24. 3 Groszmann R J, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99: 1401-7. 4 Polio J, Groszmann RJ. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 1986; 6: 318-31. 5 Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology 1989; 96: 873-80. 6 Bosch J, Bordas JM, Mastai R, et al. Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: comparison with the effects on portal pressure. Hepatology 1988; 8: 861-5. 7 Feu F, Bordas JM, Garcia-Pag;in JC, Bosch J, Rodds J. Doubleblind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension. Hepatology 1991; 13: 917-22. 8 Pagliaro L, Burroughs AK, Sorensen TIA, et al. Therapeutic controversies and randomised controlled trials (RCTs): prevention of bleeding and rebleeding in cirrhosis. Gastroenterol Int 1989; 2: 71-84. 9 Poynard T, Calks P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 1991; 324: 1532-8. 10 Conn HO, Grace ND, Bosch J, et al. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: a multicenter, randomized clinical trial. Hepatology 1991; 13: 902-12. 11 Pereira O, Garcia-Pag~in JC, Feu F, et al. Factors influencing the portal pressure response to propranolol administration in patients with cirrhosis. Hepatology 1991; 14: 133A. 12 Bosch J, Mastai R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology 1984; 4: 1200-5. 13 Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology 1986; 6: 101-6. 14 ld6o G, Bellati G, Fesce E, Grimoldi D. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomized study. Hepatology 1988; 8: 6-9. 15 Lebrec D, Poynard T, Capron J-P, et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis: a randomized trial. J Hepatol 1988; 7: 118-25. 16 Navasa M, Chesta J, Bosch J, Rod6s J. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function. Gastroenterology 1989; 96: I 110-18. 17 Blei AT, Garcia-Tsao G, Groszmann RJ, et al. Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions. Gastroenterology 1987; 93: 576-83. 18 Merkel C, Finucci G, Zuin R, et al. Effects of isosorbide dinitrate 'on portal hypertension in alcoholic cirrhosis. J Hepatol 1987; 4: 174-80.
19
20
Mols P, Hallemans R, Melot C, Lejeune P, Naeije R. Systemic and regional hemodynamic effects of isosorbide dinitrate in patients with liver cirrhosis and portal hypertension. J Hepatol 1989; 8: 316-24. Hayes PC, Westaby D, Williams R. Effect and mechanism of action of isosorbide-5-mononitrate. Gut 1988; 29: 752-5.
$45 21
Garcia-Pagfin JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990; I1: 189-95.
22
Vinel JP, Monnin J-L, Combis J-M, Cal6s P, Desmorat H, Pascal J-P. Hemodynamic evaluation of molsidomine: a vasodilator with antianginal properties in patients with alcoholic cirrhosis. Hepatology 1990; I1: 239-42. 23 Ruiz del Arbol L, Garcia-Pag~in JC, Feu F, Pizcueta MP, Bosch J, Rod6s J. Effects of molsidomine, a long acting venous dilator, on portal hypertension. A hemodynamic study in patients with cirrhosis. J Hepatol 1991; 13: 179-86. 24 Cummings SA, Groszmann R J, Kaumann AJ. Hypersensitivity of mesenteric veins to 5-hydroxytryptamine- and ketanserininduced reduction of portal pressure in portal hypertensive rats. Br J Pharmacol 1986; 89: 501-13. 25 Mastai R, Giroux L, Semret M, Huet P-M. Ritanserin decreases portal pressure in conscious and unrestrained cirrhotic rats. Gastroenterology 1990; 98: 141-5. 26 Nevens F, Pizcueta MP, Fernfindez M, Bosch J, Rod6s J. Effects of ritanserin, a selective and specific S2-serotonergic antagonist, on portal pressure and splanchnic hemodynamics in portal hypertensive rats. Hepatology 1991; 14: 1174-8. 27 Kaumann A J, Morgan JS, Groszmann RJ. ICI 169,369 selectively blocks 5-hydroxytryptamin2 receptors and lowers portal pressure in portal hypertensive rats. Gastroenterology 1988; 95: 1601-6. 28 Hadengue A, Lee SS, Moreau R, Braillon A, Lebrec D. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: possible role of serotonergic mechanisms in portal hypertension. Hepatology 1987; 7: 644-7. 29 Vorobioff J, Garcia-Tsao G, Groszmann R J, et al. Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology 1989; 9: 88-91. 30 Willett IR, Jennings G, Esler M, Dudley FJ. Sympathetic tone modulates portal venous pressure in alcoholic cirrhosis. Lancet 1986; 2: 939-42. 31 Moreau R, Lee SS, Hadengue A, Braiilon A, Lebrec D. Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis. Hepatology 1987; 7: 149-54. 32 Debinski H, Colman J, Wood M, et al. The acute effects of inhibition of SNS activity on renal function in cirrhosis. Hepatology 1989; 10: 588A. 33 AlbiNos A, Banares R, Barrios C, et al. Oral administration of clonidine in patients with alcoholic cirrhosis: hemodynamic and liver function effects. Gastroenterology 1992; 102: 248-54. 34 Okumura H, Aramaki T, Katsuta Y, et al. Reduction in hepatic venous pressure gradient as a consequence of volume contraction due to chronic administration of spironolactone in patients with cirrhosis and no ascites. Am J Gastroenterol 1991; 86: 46-52. 35 Garcia-Pag:in JC, Salmeron JM, Feu F, et al. Spironolactone (Sp) decreases portal pressure in patients with compensated cirrhosis. J Hepatol 1991; 13 (Suppl. 2): $30 (Abstr). 36 Lauler DP. Overview. The pathology and management of portal hypertension and ascites. In: The Pathophysiology and Management of Portal Hypertension and Ascites. Abstracts from an International Symposium, Palma de Mallorca, Spain, September 1991. Wilton, Connecticut, Medical Education Programs, Ltd., 1992. 37 Garcia-Pagfin JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rod,s J. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 1990; 11: 230-8. 38 Garcia-Pag:in JC, Feu F, Bosch J, Rod6s J. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study. Ann Intern Med 1991; 114: 869-73. 39 Hadengue A, Moreau R, Cerini R, Koshy A, Lee SS, Lebrec D. Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: search for an additive effect. Hepatology 1989; 9: 83-7.
$41
@ 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00 HEPAT 01428
New approaches in the pharmacologic treatment of portal hypertension
Jaime Bosch, Juan C. Garcia-Pag~n, Faust Feu, Angelo Luca, Mercedes Fern~indez, Pilar Pizcueta and Juan Rod6s Hepatic Haemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, University of Barcelona, Spain
To alleviate the risk of variceal bleeding, the portal pressure gradient - - usually evaluated as the hepatic venous pressure gradient (HVPG) - - must be reduced to _< 12 mmHg. Although B-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to _< 12 mmHg in only 12% of patients, while only 24% of patients have a >_20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorblde-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolact6ne, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a B-blocker, a nitrate and spironolactone may be feasible. Serotonin constricts rnesenteric veins in experimental models of portal hypertension and may also play a role in portal hypertension secondary to cirrhosis. Serotonin S2-receptor blockers, such as ritanserin and ketanserin, have been shown to lower portalcollateral resistance in animal models and patients with cirrhosis. These serotonin antagonists should be assessed for their potential in coadministration with non-selective B-blockers, perhaps with the addition of spironolactone.
Key words: Isosorbide-5-mononitrate; Oesophagogastric varices; Propranolol; Serotonin S2-receptor blockers; Spironolactone
The pharmacologic treatment of portal hypertension is based on the assumption that a sustained reduction in portal pressure reduces the incidence of hypertensive complications. For varices to develop and rupture, the portal pressure gradient (usually evaluated as the hepatic venous pressure gradient (HVPG)) must increase above 12 mmHg (1,2). Recent studies have confirmed that when HVPG is reduced below this threshold gradient, the patient is no longer at risk for variceal
haemorrhage, the varices progressively decrease in size and survival is significantly increased (3). In addition, it is likely that when HVPG is very high, a substantial reduction (i.e. >20% of baseline value) may also translate into a significant decrease in risk of variceal bleeding, even if the final value is above the 12 mmHg threshold gradient. This potential exists because variceal rupture apparently occurs when variceal wall tension, which is directly related to variceal pressure, exceeds a
Correspondence to: Jaime Bosch, M.D., Hepatic Haemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, Villarroel 170, 08036 Barcelona, Spain.
$42 critical value (4,5). Therefore, a m a r k e d decrease in portal pressure (which leads to at least a similar fall in variceal pressure) (6,7) will m a r k e d l y decrease variceal tension and the likelihood o f variceal h a e m o r r h a g e (7).
Limitations of 3-blocker therapy Propranolol and nadolol are now well accepted as therapeutic agents for the prevention of variceal bleeding or rebleeding (8-10). However, in only 24% of patients does H V P G decrease by more than 20% after propranolol administration and in only 12% is the final H V P G _< 12 m m H g (11). On the other hand, nearly 40% of patients fail to exhibit a reduction in H V P G following propranolol use (12,13). It appears, therefore, that to improve the results of pharmacologic therapy with propranolol, we must either select patients who exhibit a better h a e m o d y n a m i c response (which would limit the applicability of the therapy) (11) or develop combination therapies that can offer effective reductions in H V P G in a greater p r o p o r t i o n of patients. Other limitations of therapy with non-selective 3blockers are related to contraindications and side effects. A m o n g the former, the more frequently encountered are chronic obstructive lung disease, atrioventricular heart block, arrhythmias, psychosis and insulin-dependent diabetes if the patient has a history o f hypoglycaemia (10). Side effects are relatively c o m m o n ( - 1 5 % of patients), but severe events (e.g. bronchospasm) are rare (10). The more frequent complaints are fatigue, which is often associated with marked bradycardia (heart rate < 5 0 beats/min) and sleep disorders. Although complications resulting from propranolol therapy for cirrhosis have never been lethal (8,9), side effects are important inasmuch as they detract from compliance. Nadolol is more convenient to use because its prolonged half-life allows once-a-day administration (14,15) and its primarily renal elimination makes accurate dosing easier to ascertain than with propranolol. Also, since nadolol does not cross the bloodbrain barrier, it m a y be less likely to cause central nervous system effects (14,15). However, this has not been adequately investigated in cirrhosis.
j. BOSCH et al. (Table 1). Vasodilators m a y reduce portal pressure by decreasing the vascular resistance to portal and collateral blood flow and by p r o m o t i n g reflex splanchnic vasoconstriction as a response to reduced mean arterial and cardiac filling pressures (16). A theoretical advantage of vasodilators over 3-blockers is that the former m a y allow reduction of portal pressure without impairing liver perfusion (16). An important limitation is that all vasodilators lower arterial blood pressure; this may
TABLE I Alternatives to E-blocker use in long-term treatment of portal hypertension Drug
The possible use of vasodilators and other agents in this setting has attracted a lot of attention in recent years
Mean reduction in HVPG (%)
10 mg (1 20 mg (I 5 mg (1 5 mg (I
Nitrovasodilators
lsosorbide dinitrate Blei (17) Merkel (18) Mols (19) lsosorbide-5-mononitrate Hayes (20) Navasa (16) Garcia-Pag~in (21) Molsidomine Vinel (22) Ruiz del Arbol(23)
dose dose dose dose
p.o.) p.o.) p.o.) s.I.)
25 25 34 22
20 mg (1 dose 20 mg (I dose 40 mg (1 dose 40 mg (b.i.d. x 3 months
p.o.) p.o.) p.o.)
9 10 18
p.o.)
8
4 mg (I dose p.o.) 2 mg (1 dose p.o.) 4 mg (I dose p.o.)
15 I1 19
Serotonin S2-receptor blockers
Ritanserin Mastai (25)a
Nevens (26)b Ketanserin Hadengue (28) Vorobioff (29)
0.63 mg/kg (I dose i.v.) 0.7 mg/kg (I dose i.v.) 10 mg (1 dose i.v.) 40-80 mg/day ix I month p.o.)
17c 20c 23 15
Clonidine
Willet (30) Moreau (31) Albillos (33)
2.5 ~g/kg (I dose i.v.) 150 #g/kg (1 dose i.v.) 0.30-0.45 mg/day (x 2 months p.o.)
20
100 mg/day (x 4 weeks p.o.) 100 mg/day (x 2 months p.o.)
22
27 d
15
Spironolactone
Okumura (34) Garcia-Pag~in (35)
Alternative pharmacologic treatment for portal hypertension
Dose (regimen)
13
b.i.d., twice daily; HVPG, hepatic venous pressure gradient; i.v., intravenously; p.o., orally; s.l., sublingually. aCCl4-cirrhotic rats. bpartial portal vein-ligated rats. CPortal pressure. dWedged hepatic venous pressure.
PHARMACOTHERAPY FOR PORTAL HYPERTENSION
$43 Liver injury
be poorly tolerated in patients with advanced cirrhosis (especially when ascites and oedema exist), who are frequently hypotensive.
Nodular regeneration Fibrosm
Nitrovasodilators With acute administration, nitrovasodilators such as isosorbide dinitrate (17-19) and isosorbide-5-mononitrate (16,20) cause marked reductions in HVPG, but this effect is much smaller during long-term therapy (21). Tolerance to nitrovasodilators may be due to true pharmacologic tolerance, to the activation of endogenous neurohumoral vasoactive systems and to plasma volume expansion (21). The latter suggests the possibility that combination with a diuretic may enhance the effects of these compounds on HVPG (analogous with findings in the treatment of arterial hypertension). Otherwise, it is unlikely that nitrovasodilators can become useful agents as monotherapy for portal hypertension because of their minimal effect on portal pressure. Molsidomine (22,23), which has effects similar to those of isosorbide dinitrate, is thought not to cause tolerance; however, this has not been assessed by longterm comparative studies in patients with portal hypertension.
t Sinusotdal pressure Sp~ronolactone intervention I Portalhypertenslon I Splanchntc vasodJlat~on
'1'Gastroesophageal collaterals
,1.Effective blood volume
t Vanx formatlon/stze
t' Aldosterone
t, Vanx wall tension
t Na+ retenlion
Vanx rupture
I
Fig. 1.
I
Portal hypertensive syndrome with spironolactone intervention (Lauler, 1992).
TABLE 2
Serotonin S:-receptor blockers Following the observation that mesenteric veins from portal hypertensive animals are hypersensitive to the venoconstrictor effects of serotonin (24) came the introduction of serotonin S2-receptor blockers. Ritanserin and other serotonin S2-receptor blockers (such as ketanserin) have been shown to reduce portal pressure in models of portal hypertension and/or in patients with cirrhosis (25-29). This lowering of portal pressure is in part due to a lowering of portal-collateral resistance. It is notable that selective S2-receptor antagonists do not cause a decrease in arterial pressure (25-27). The potential for the use of these drugs, either alone or in combination with other agents, requires further investigation. Clonidine A centrally acting a2-adrenergic agonist, clonidine causes a reduction in adrenergic output. Clonidine reduces portal pressure by decreasing portal resistance and splanchnic inflow (30-33). Arterial pressure is also markedly reduced by this agent, but it does not appear to be associated with adverse effects on renal function or sodium handling (32). The magnitude of the fall in portal pressure with clonidine use is slightly greater than that achieved with propranolol (33). Spironolactone The aldosterone antagonist spironolactone has been shown to lower HVPG in patients with cirrhosis (34,35).
Drug combinations with proven or probable synergistic effects in reducing portal pressure Combination
Mean reduction in HVPG
(%) Propranolol + isosorbide-5-mononitrate ( ls-5-Mn )
Garcia-Pag~in (37) Propranolol: 0.1 mg/kg, then 2 mg/h (i.v.) Is-5-Mn: 20 or 40 mg (1 dose p.o.) Garcia-Pag~in (38) Propranolol: dose increased until heart rate reduced 25% (x 3 months p.o.) ls-5-Mn: 40 mg b.i.d. (x 3 months p.o.)
27 19
Propranolol + ketanserin
Hadengue (39) Propranolol: 15 mg (1 dose i.v.) Ketanserin: 5 mg (I dose i.v.)
19
Spironolactone + propranolol
Garcia-Pag~n (35) Spironolactone: 100 mg/day (x 2 months p.o.) Propranolol: 0.15 mg/kg (1 dose i.v.)
25
Nitrovasodilator + diuretic
Not evaluated
B-blocker + nitrovasodilator + diuretic
Not evaluated
f3-blocker + S2-receptor blocker + diuretic
Not evaluated HVPG, hepatic venous pressure gradient; i.v., intravenously; p.o., orally.
$44
J. BOSCH
WHVP
mmHg
30-
15-
24-
25-
10-
19-
20
i B
I P
i P+ls
5
al.
HVPG
FHVP mmHg
mmHg
et
1
i B
~ P
I P+ls
14
I
I
I
B
P
P+ls
* p < 0.001 vs baseline Fig. 2. Effects of administering propranolol (P), and propranolol plus isosorbide-5-mononitrate (P + Is) on wedged hepatic venous pressure (WHVP), free hepatic venous pressure (FHVP) and hepatic venous pressure gradient (HVPG). Values are expressed as mean ± standard error; B, baseline values. (Garcia-Pagfin et al., 1990).
This beneficial effect of the drug is based on the known relationship between plasma volume and portal pressure (Fig. 1) (36). In addition, the reduction in plasma volume caused by spironolactone attenuates the increase in cardiac output observed in cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow (35). Spironolactone thus has the potential to maintain and enhance the decrease in portal pressure caused by nitrovasodilators or propranolol. Clearly, the degree of plasma volume expansion is an important variable influencing portal pressure that has not been taken into account in the past. Concomitant use of diuretics may be responsible in part for the conflicting results observed in previous studies and clinical trials.
Combination therapy It is unlikely that any single agent can lower portal pressure enough to eliminate the risk of variceal bleeding or rebleeding in most patients with cirrhosis. A risk-reducing drop in portal pressure is probably easier to achieve by using combinations of drugs that act through different mechanisms (Table 2) (35,37-39). Again, the strategy for managing portal hypertension may profit from experience gained in the treatment of systemic hypertension. Concomitant use of propranolol and isosorbide-5mononitrate (37,38) causes a significantly greater reduction in HVPG than is possible with either drug alone (Fig. 2). Acute and long-term haemodynamic studies have shown that this drug combination decreases the
number of patients whose portal pressure remains elevated, while it increases the proportion of patients in whom HVPG markedly drops (37,38). This may result from isosorbide-5-mononitrate preventing the increase in portal resistance that is caused by propranolol (37). This drug combination is also superior to propranolol alone in maintaining liver perfusion and hepatic function, while the beneficial effect of reducing azygos blood flow is unchanged (38). Whether the enhanced haemodynamic effects of this combination therapy translate into better clinical results must be verified by randomised, controlled studies. As already mentioned, other drug combinations also have potential for synergistic effects in reducing portal pressure. Possible combinations for double-drug therapy include propranolol or nadolol with an S2receptor blocker, propranolol or nadolol with spironolactone and a nitrovasodilator or molsidomine with a diuretic. Triple-drug therapy might include a/3blocker with a nitrovasodilator and spironolactone or a B-blocker with an S2-antagonist and spironolactone. Further research is needed to clarify the clinical value of each of these options.
Acknowledgements Supported in part by grants from Fondo de Investigaci6n Sanitaria (91/0374) and Fundaci6 Catalana per a l'Estudi de les Malalties del Fetge i Gastroenterologiques.
PHARMACOTHERAPY FOR PORTAL HYPERTENSION
References 1 Viallet A, Marleau D, Huet M, et al. Hemodynamic evaluation of patients with intrahepatic portal hypertension: relationship between bleeding varices and the portohepatic gradient. Gastroenterology 1975; 69: 1297-1300. 2 Garcia-Tsao G, Groszmann R J, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5: 419-24. 3 Groszmann R J, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99: 1401-7. 4 Polio J, Groszmann RJ. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 1986; 6: 318-31. 5 Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology 1989; 96: 873-80. 6 Bosch J, Bordas JM, Mastai R, et al. Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: comparison with the effects on portal pressure. Hepatology 1988; 8: 861-5. 7 Feu F, Bordas JM, Garcia-Pag;in JC, Bosch J, Rodds J. Doubleblind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension. Hepatology 1991; 13: 917-22. 8 Pagliaro L, Burroughs AK, Sorensen TIA, et al. Therapeutic controversies and randomised controlled trials (RCTs): prevention of bleeding and rebleeding in cirrhosis. Gastroenterol Int 1989; 2: 71-84. 9 Poynard T, Calks P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 1991; 324: 1532-8. 10 Conn HO, Grace ND, Bosch J, et al. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: a multicenter, randomized clinical trial. Hepatology 1991; 13: 902-12. 11 Pereira O, Garcia-Pag~in JC, Feu F, et al. Factors influencing the portal pressure response to propranolol administration in patients with cirrhosis. Hepatology 1991; 14: 133A. 12 Bosch J, Mastai R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology 1984; 4: 1200-5. 13 Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology 1986; 6: 101-6. 14 ld6o G, Bellati G, Fesce E, Grimoldi D. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomized study. Hepatology 1988; 8: 6-9. 15 Lebrec D, Poynard T, Capron J-P, et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis: a randomized trial. J Hepatol 1988; 7: 118-25. 16 Navasa M, Chesta J, Bosch J, Rod6s J. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function. Gastroenterology 1989; 96: I 110-18. 17 Blei AT, Garcia-Tsao G, Groszmann RJ, et al. Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions. Gastroenterology 1987; 93: 576-83. 18 Merkel C, Finucci G, Zuin R, et al. Effects of isosorbide dinitrate 'on portal hypertension in alcoholic cirrhosis. J Hepatol 1987; 4: 174-80.
19
20
Mols P, Hallemans R, Melot C, Lejeune P, Naeije R. Systemic and regional hemodynamic effects of isosorbide dinitrate in patients with liver cirrhosis and portal hypertension. J Hepatol 1989; 8: 316-24. Hayes PC, Westaby D, Williams R. Effect and mechanism of action of isosorbide-5-mononitrate. Gut 1988; 29: 752-5.
$45 21
Garcia-Pagfin JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990; I1: 189-95.
22
Vinel JP, Monnin J-L, Combis J-M, Cal6s P, Desmorat H, Pascal J-P. Hemodynamic evaluation of molsidomine: a vasodilator with antianginal properties in patients with alcoholic cirrhosis. Hepatology 1990; I1: 239-42. 23 Ruiz del Arbol L, Garcia-Pag~in JC, Feu F, Pizcueta MP, Bosch J, Rod6s J. Effects of molsidomine, a long acting venous dilator, on portal hypertension. A hemodynamic study in patients with cirrhosis. J Hepatol 1991; 13: 179-86. 24 Cummings SA, Groszmann R J, Kaumann AJ. Hypersensitivity of mesenteric veins to 5-hydroxytryptamine- and ketanserininduced reduction of portal pressure in portal hypertensive rats. Br J Pharmacol 1986; 89: 501-13. 25 Mastai R, Giroux L, Semret M, Huet P-M. Ritanserin decreases portal pressure in conscious and unrestrained cirrhotic rats. Gastroenterology 1990; 98: 141-5. 26 Nevens F, Pizcueta MP, Fernfindez M, Bosch J, Rod6s J. Effects of ritanserin, a selective and specific S2-serotonergic antagonist, on portal pressure and splanchnic hemodynamics in portal hypertensive rats. Hepatology 1991; 14: 1174-8. 27 Kaumann A J, Morgan JS, Groszmann RJ. ICI 169,369 selectively blocks 5-hydroxytryptamin2 receptors and lowers portal pressure in portal hypertensive rats. Gastroenterology 1988; 95: 1601-6. 28 Hadengue A, Lee SS, Moreau R, Braillon A, Lebrec D. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: possible role of serotonergic mechanisms in portal hypertension. Hepatology 1987; 7: 644-7. 29 Vorobioff J, Garcia-Tsao G, Groszmann R J, et al. Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology 1989; 9: 88-91. 30 Willett IR, Jennings G, Esler M, Dudley FJ. Sympathetic tone modulates portal venous pressure in alcoholic cirrhosis. Lancet 1986; 2: 939-42. 31 Moreau R, Lee SS, Hadengue A, Braiilon A, Lebrec D. Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis. Hepatology 1987; 7: 149-54. 32 Debinski H, Colman J, Wood M, et al. The acute effects of inhibition of SNS activity on renal function in cirrhosis. Hepatology 1989; 10: 588A. 33 AlbiNos A, Banares R, Barrios C, et al. Oral administration of clonidine in patients with alcoholic cirrhosis: hemodynamic and liver function effects. Gastroenterology 1992; 102: 248-54. 34 Okumura H, Aramaki T, Katsuta Y, et al. Reduction in hepatic venous pressure gradient as a consequence of volume contraction due to chronic administration of spironolactone in patients with cirrhosis and no ascites. Am J Gastroenterol 1991; 86: 46-52. 35 Garcia-Pag:in JC, Salmeron JM, Feu F, et al. Spironolactone (Sp) decreases portal pressure in patients with compensated cirrhosis. J Hepatol 1991; 13 (Suppl. 2): $30 (Abstr). 36 Lauler DP. Overview. The pathology and management of portal hypertension and ascites. In: The Pathophysiology and Management of Portal Hypertension and Ascites. Abstracts from an International Symposium, Palma de Mallorca, Spain, September 1991. Wilton, Connecticut, Medical Education Programs, Ltd., 1992. 37 Garcia-Pagfin JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rod,s J. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 1990; 11: 230-8. 38 Garcia-Pag:in JC, Feu F, Bosch J, Rod6s J. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study. Ann Intern Med 1991; 114: 869-73. 39 Hadengue A, Moreau R, Cerini R, Koshy A, Lee SS, Lebrec D. Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: search for an additive effect. Hepatology 1989; 9: 83-7.