Aliment. Pkarmacol. Tker. (1992) 6, 521-540.

Review article ; the pathophysiology and pharmacological treatmenf of portal hypertension

R. D. GROSE & P. C. HAYES

Departmenf of Medicine, Royal Infirmary, Edinburgh, UK Accepted for publication 5 May 1992

SUMMARY

The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.

INTRODUCTION Cirrhosis and portal hypertension are among the worlds commonest disease entities. The two most important causative agents underlying the problem are excessive alcohol ingestion, principally a Western society problem, and the very high worldwide prevalence of hepatitis B, particularly in Africa and the Far East. In the Middle East, the development of hepatic fibrosis due to schistosomiasis accounts for a high percentage of portal hypertensive patients. The most important complications of cirrhosis are hepatocellular carcinoma and portal hypertension. The latter results in the development of ascites, portal-systemic encephalopathy and oesophageal varices. Correspondence to: Dr R. D. Grose, Falkirk & District Royal Infirmary, Major’s Loan, Falkirk FKI 5QE, UK. 521 30-2

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Many studies have addressed the prognosis of the patient with oesophageal varices. Overall approximately 30% of patients with varices will bleed at some time’ and the mortality rate from this initial bleed is around 50%.’,’ After this initial haemorrhage 70% of these patients will rebleed within one year, 30% doing so within the first six weeks.3 The mortality rates depend largely upon the Child’s class, being as high as 90% within 12 months for those in Child’s grades C.4 However, the corollary is that approximately 60% of patients will not bleed from their varices. Hence the task facing investigators has been the identification of those at risk to allow treatment to be targeted appropriately. Various parameters usedclinical, laboratory, endoscopic and haemodynamic-have to date found few consistently reliable variables to identify the ’at risk’ patients.’ The treatment of oesophageal varices can be subdivided into those techniques used to arrest active variceal haemorrhage, those to reduce the frequency of rebleeding and those to prevent the first bleed. This article reviews the pathophysiology of portal hypertension with the concomitant development of oesophageal varices, explores the mechanisms of pharmacological manipulation of portal haemodynamics and considers the various treatments which have been shown to be effective.

Oesophageal varices Traditional opinion sees oesophageal varices as ’varicose veins ’ of the oesophagus and some anatomical studies do confirm this.6 More complex post-mortem and angiographic methods would, however, suggest that varices are normal oesophageal mucosal folds, distended by a tortuous dilated intertwining capillary network, produced by dilatation of the normal superficial venous network of the o e s ~ p h a g u sThe . ~ truth probably lies somewhere between, and a combined view of the previous two theories has been proposed by Hashizume’ whose studies found ’varices upon varices’, namely the aforementioned latter type upon the former. Pathogenesis of portal hypertension The classical concept of the pathogenesis of portal hypertension is the so-called ‘backwards ’/resistance theory. Here the fibrosis and distorted architecture of the cirrhotic liver crush the intrahepatic vascular network principally at sinusoidal level, cause resistance to flow and elevate portal pressure. At a histological level the portal pressure in liver disease has been shown to correlate with increased hepatocyte size’ whilst the importance of Disse space fibrosis remains controversial.lor Further studies suggest that the extent of hepatocyte necrosis and architectural disruption are perhaps the best correlates with portal hypertension.” This theory alone would predict that such resistance is fixed. However, studies examining the response of the isolated perfused cirrhotic rat liver to various vasoactive substances have shown that resistance to flow across such a liver can be altered.I3 Hence a dynamic component to hepatic resistance exists in tandem with the fixed component and histological studies reveal perivenular and perisinusoidal myo-

TREATMENT OF PORTAL HYPERTENSION 523

fibroblasts which are the likely mediators of the dynamic ~ o m p o n e n t .Additionally '~ it is likely that the porto-collateral smooth muscle vasculature itself can be directly influenced and also plays a dynamic role within the resistance theory.'' One problem with the concept of increased resistance causing portal hypertension which has long been realized is that as collateral channels open up, portal pressure would be expected to fall. Systemic haemodynamics are profoundly altered in portal hypertension and liver disease. Early work by Kowalski & Abelman" first clearly demonstrated an increased cardiac output and lowered systemic vascular resistance in cirrhosis. This has been shown to occur not only in cirrhosis but in the non-cirrhotic portal hypertensive rat model,17 in humans with prehepatic portal hypertension due to portal vein thrombosis'' and also in acute liver disease." Subsequently CohnZoelucidated that accompanying the systemic changes described above there was also a notable increase in portal venous inflow, and this has been confirmed by others." This increased inflow into the portal circulation resulted in the 'forward flow' hypothesis of portal hypertension. Recently it has been estimated that 40% of the rise in portal pressure in portal hypertension is contributed by this increase in portal venous inflow and 60 % by the resistance to flow." The possible evolution of such relative contributions from resistance and in-flow was demonstrated by Sikuler.'' In rats with portal vein ligation portal pressure initially rose due to increased resistance to flow and portal venous in-flow fell. Subsequently, the portal venous resistance fell to what was a relatively normal figure and this fall was accomplished by the means of extensive collateral vessel formation. After 8 days portal venous inflow had risen markedly and the portal pressure remained high. Evidence for a humoral mechanism underlying these haemodynamic changes is strong. An early study by KorthiusZ3illustrated that blood from a portal hypertensive rat would reduce systemic vascular resistance in normal rats. Because these haemodynamic changes occurred in both acute and chronic liver disease and in isolated prehepatic portal hypertension, the possible mechanisms behind these changes include portosystemic shunting of vasoactive agents, reduced metabolism of such vasoactive agents by a functionally impaired liver and direct release of vasoactive substances from a damaged liver. In all probability a combination of these is involved. The nature of the putative substance(s) and mechanism(s) involved in producing the vasodilated hyperdynamic systemic and splanchnic circulations are discussed below.

Glucagon Glucagon is a potent v a ~ o d i l a t o r BenoitZ5 .~~ showed that glucagon could cause a reduction in splanchnic vascular resistance of a similar magnitude in normal and portal vein ligated rats and later demonstrated that glucagon anti-sera could reduce portal venous in-flow by up to 30 %." Increased glucagon levels have been shown to correlate with raised cardiac output and portal venous inflow in the portcaval shunted rat.27Other studies have, however, suggested a more restricted role in the

524

R. D. G R O S E & P. C. HAYES

splanchnic bed.'" 29 These contradictory observations are perhaps reconciled by the theory that chronically elevated glucagon levels cause down-regulation of the vasculature in response to glucagon. The precise mechanism of action of glucagon may be at the post-receptor level where it modulates the effects of pressor substances including n~radrenaline.~"'~' Whether reductions in the level of glucagon effected by somatostatin are responsible for its portal hypotensive effect of whether this is due to direct vasoconstriction32will be considered later.

Adrenergic system Serum noradrenaline levels are increased in patients with This is prob35 but considerable evidence ably due to enhanced sympathetic nervous exists to suggest that its effects are attenuated. The intestinal hyperaemia of rats with portal hypertension shows diminished reactivity to n ~ r a d r e n a l i n eand ~ ~ in cirrhotic rats aortic muscle strip also appears hyposensitive to its effect.37 A diminished number of /3-2 receptors on human mononuclear cells from patients with cirrhosis38and desensitisation of /3-1 receptors on the cirrhotic rat myocard i ~ have m ~ both ~ been shown. A recent study, however, suggests that the diminished pressor effects of noradrenaline are perhaps more centrally based and due to the withdrawal of sympathetic tone from vascular resistance beds.4"It is certainly true the autonomic nervous system is frequently abnormal in cirrhosis regardless of aeti~logy.~' There is therefore much evidence for adrenergic dysfunction in cirrhosis and portal hypertension and whilst this may be due to a post-receptor modulating effect of glucagon3' (or perhaps other substances) aberrant central autonomic control may also contribute. Endothelium-derived relaxing factor In 1980 the role of the vascular endothelium in the modulation of vascular smooth muscle tone was first recognized and the existence of an endothelium-derived relaxing factor (EDRF) proposed.42 Initially EDRF was thought to be the free nitric oxide (NO) radical,43but subsequent work has shown that a bound form of NO such as nitrosothiol is more likely.44EDRF promotes vasodilatation, arterial hypotension and t a ~ h y c a r d i a . ~ ~ Such a hyperdynamic circulation accompanied by neurohumoral activation is seen in cirrhosis and portal hypertension in man.i6 Recent work by Claria et al.46 has demonstrated that specific competitive inhibition of NO synthesis by N-nitro-Larginine produces a significantly greater rise in arterial pressure and fall in heart rate in cirrhotic rats with ascites than in normal rats, supporting the hypothesis that increased systemic NO activation may be of importance in the pathogenesis of the circulatory disturbances seen in cirrhosis with ascites. Vallance & M ~ n c a n d ahave ~ ~ proposed that endotoxaemia frequently seen in cirrhosis4' due to portal-systemic shunting of gut-derived bacterial e n d ~ t o x i n , ~ ~

TREATMENT OF PORTAL HYPERTENSION 525

induces NO synthase (and hence EDRF production) and is a possible trigger of the hyperdynamic circulation of cirrhosis. However, many substances have been shown to stimulate the production of EDRF including ATP, ADP, 5HT, thrombin, substance P and shear stress on the e n d ~ t h e l i u m ~and ~ ~ the ' precise nature of the substance(s) which may be responsible for increased EDRF production in cirrhosis and portal hypertension has yet to be elucidated.

Bile acids Early studies discounted the role of bile acids as being involved in the development 54 However, the elevation of of the systemic and splanchnic hyperdynamic serum bile acids has been shown to correlate with the degree of portosystemic and bile salt depletion in rats with portal hypertension can diminish portal venous in-flow, though not to control levels.56Ursodeoxycholic acid has recently been shown to prevent the biliary cirrhosis and the hyperkinetic circulation induced by bile duct ligation in the rat.57However, the case implicating bile acids as having a major role in the haemodynamics of cirrhosis remains unproven. Adenosine Adenosine is a potent systemic va~odilator.~' It is produced during ethanol metabolism and the effect of ethanol on portal blood flow can be ameliorated by specific adenosine-receptor blockade.59Whilst adenosine may have a wider role to play in cirrhosis in general, evidence at present is limited to ethanol-related liver damage. Angiotensin Angiotensin I1 levels are elevated in patients with cirrhosis. However, its pressor effects, like noradrenaline, are attenuated.60It does seem important in maintaining the mean arterial pressure in patients with cirrhosis and ascites and may directly raise the resistance of hepato-portal vasculature.61The mechanism for its reduced activity appears to be at post-receptor Prosfaglandins Prostacyclin levels are increased in cirrhosis and splanchnic hyperaemia has been reduced by indomethacin which blocks its ~ y n t h e s i sThe . ~ ~ elevated cardiac output and reduced peripheral vascular resistance in patients with cirrhosis has been shown to be favourably altered by i n d ~ m e t h a c i nFurther, .~~ the diminished pressor response to angiotensin I1 has been shown to be improved by i n d ~ m e t h a c i n . ~ ~ Serofonin Many exciting discoveries relating to the role of serotonin in health and disease have been made over the last decade. A great diversity of receptors in vascular beds, non-vascular smooth muscle and in the central nervous system have now been shown to exisP and pathological roles in m i g ~ a i n e , ~ chemotherapy~,~' induced emesis,69aberrant gut motility7' and coronary artery disease7' have all

526

R. D. GROSE & P. C. HAYES

prompted attempts, some successful, in pharmacological manipulation. The discovery that 5-HT2-receptorsmediate intense vasoconstriction in the portacollateral bed7z has led to the use of HT,-receptor antagonists as a way to reduce portal pressure and preliminary studies have been encouraging (see later).

Others Gamma aminobutyric acid (GABA)73and the endogenous peptides leucine enbeen proposed as vasodilators in cephalin and methionine e n ~ e p h a l i n75~ ~have ! cirrhosis. Roles have also been suggested for platelet activating factor,76vasoactive intestinal polypeptide (VIP)77and histamine78but convincing evidence is lacking. In summary much progress has been made in our understanding of the pathogenesis of portal hypertension and its concomitant systemic abnormalities. Portal hypertension develops due to a mixture of increased resistance and increased portal inflow. The mechanism underlying the hyperdynamic splanchnic and systemic circulation is incompletely understood. The strongest evidence to date suggests that glucagon at a post-receptor level causes vasodilatation by modulating the effect of endogenous pressor agents. The abnormality seen in the adrenergic system may be secondary to this although may have a more central cause.

TREATMENT

Acute variceal haernorrhage The most effective treatment for an acute variceal bleed is injection ~clerotherapy.~~ In experienced hands, it is a prompt and effective treatment of this life-threatening event. However, while such experience is readily available at larger teaching hospitals this is not the case in many other hospitals. Balloon tamponade has been shown in some studies to be as effective as sclerotherapy," but it would be an over-simplification to suggest that this can easily and proficiently be carried out by staff untrained in the procedure. Balloon tamponade is poorly tolerated by many patients and rebleeding within hours of balloon removal is common.81It would obviously be desirable therefore, particularly for centres with limited experience in treating patients with variceal bleeding, if pharmacotherapy was readily available, easy to use and efficacious in controlling bleeding from varices. Currently, two principal drug regimens are advocated for this medical emergency. Vasopressin Pitressin was first shown 25 years ago to reduce wedged hepatic venous pressure and more recently azygos blood flow." Since then, as vasopressin, it has become a standard method of arresting acute variceal bleeding. As a generalized vasoconstrictor it causes not only splanchnic but widespread systemic and coronary vasoconstriction causing significant side-effects including 84 Many patients

TREATMENT OF PORTAL HYPERTENSION 527

are unable to receive vasopressin because of co-existent coronary artery disease, limiting its value. Despite its longstanding use in acute variceal bleeding a recent meta-analysis assessing only properly con trolled clinical trials, has seriously questioned its efficacy.” The poor side effect profile has prompted pharmacological. manipulations to maintain efficacy but reduce complications. The first of these utilizes an analogue of vasopressin-triglycyl-lysine vasopressin (terlipressin/ glypressin), which requires cleavage of terminal amino acid residues to form the vasoactive substance” and is given by repeat bolus injection, as opposed to vasopressin which is now generally administered by constant i.v. infusion. Early work suggested that it was better than vasopressin with respect to h a e m o ~ t a s i s ~ ~ and a recent study by Soderlund showed better survival rates and haemostasis than placebo.” In addition it may have a better side-effect profile compared with va~opressin.‘~ An alternative method to overcome side-effects has been the combination of vasopressin with nitrovasodilatators. This appears to eliminate the unwanted systemic side effects of vasopressin regardless of the route of administration of the nitrate preparation.”! 91 Some, although not all studies have also shown additional benefits in further reducing portal pressure9’ and in the setting of acute variceal haemorrhage evidence would suggest that combination therapy is 94 Transdermal nitrate superior in arresting bleeding than vasopressin patches have been advocated but more reliable plasma levels will be obtained using either the intravenous or sublingual routes95especially in the shocked patient with compromised skin-blood flow. However, the sublingual route of administration also has limitations particularly in patients who may be vomiting. In the acute setting it would seem reasonable to recommend vasopressin at a dose of 0.4-0.8 U/min over around 12 hours combined with intravenous nitroglycerin 0.2 mg/min for the duration of the vasopressin infusion.

Somatostatin Somatostatin, by virtue of its relatively specific vasoconstrictory action on the In splanchnic arterial bed3’ avoids the unwanted side effect profile of va~opressin.’~ addition, a direct venospastic action has been noted which may also play a role in reducing portocollateral blood Although it effects a reduction in the circulatory levels of g l ~ c a g o n a, ~purported ~ mediator of the portal and systemic hyperdynamic state, the rapid onset of action when administered by bolus suggests ’ reductions of other this is not an important mechanism of a ~ t i o n . ~Likewise vasoactive peptides do not appear important for its effects on the splanchnic va~culature.~~ In most studies somatostatin has been shown to reduce portal p r e ~ s u r e , ~ ~ ~ ~ ~ although not in all.loo~’or Given that not all studies have shown a portal hypertensive effect, it is perhaps understandable that evidence supporting its efficacy in stopping acute variceal haemorrhage is also conflicting. Thulin et aI.Io2 first reported the beneficial effects of somatostatin in curtailing variceal bleeding in 1979. However, another study the same year did not support thisTo3although both of these studies

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R. D. G R O S E & P. C. HAYES

were uncontrolled. Most subsequent controlled studies do favour its efficacy in showed somatostatin to be conhalting acute variceal bleeding. Jenkins et ~d.'"~ siderably more effective than vasopressin in this regard and more recently Burdemonstrated significantly greater control of bleeding with somatoroughs et statin compared to placebo. However, the multicentre randomized double-blind trial of Valenzuela et d ' 0 6 showed somatostatin to be inferior to placebo in controlling variceal haemorrhage, although the placebo success rate of 83 % in this trial was surprisingly high. More recently, octreotide, the synthetic analogue of somatostatin has been shown to be as effective as balloon tamp~nade'"~ and superior to combined glypressin/nitroglycerinlOBin arresting variceal haemorrhage and this, given the expense of naturally occurring somatostatin, probably represents the way forward in this area. At present, however, it seems premature to recommend the routine use of somatostatin or octreotide in the treatment of acute variceal bleeding until more information from controlled clinical trials become available. PRIMARY P R E V E N T I O N A N D P R E V E N T I O N OF REBLEEDING Since Lebrec's seminal paper in the early 1980s which suggested that propranolol could reduce the frequency of the variceal haemorrhage'"' many agents have been studied mainly with respect to preventing rebleeding. Ideally treatment should be effective, safe, readily available and able to reduce the risk of primary variceal haemorrhage and the risk of rebleeding. Reduced mortality would obviously be welcome, but this is dependent on much more than isolated reductions in bleeding risk.

P-blockers This group of drugs has been most extensively studied. Lebrec's early work excited great interest, although Burroughs study the following year somewhat dampened enthusiasm."" A recent meta-analysis'" of their use in prevention of primary and secondary haemorrhage seems to confirm their usefulness in diminishing bleeding risk but with less influence on mortality rates. Most experience has been gained with the non-selective P-1 and P-2 receptor antagonist propranolol. Its principal mechanism of action is a reduction in cardiac output which decreases portal venous inflow, although its P-2 receptor blocking action may be important. This allows unopposed a-receptor mediated vasoconstriction of the splanchnic arterial bed, further reducing portal venous inflow although total liver blood flow may be maintained by hepatic artery autoregulation.'" However, the evidence is controversial. Selective P-receptor antagonism, had been shown to reduce portal pressure to similar levels as propran~lol,''~ p-I receptor but the a-agonist methoxamine had little added e f f e ~ t . "Selective ~ antagonists, atenolo1115 and betaxolo1116 have been shown to diminish portal pressure and azygos blood flow to similar levels as propranolol (although it should

TREATMENT OF PORTAL HYPERTENSION 529

p-I

be noted and p-2 receptor antagonism selectivity is relative and not absolute). The potential benefit of ‘cardioselective’ ,&blockers is a better side effect profile compared to propranolol and therefore, theoretically, better compliance. Evidence from clinical trials supporting the efficacy of cardioselective P-blockers is however lacking. In summary, ,&blockers reduce portal pressure and the risk of variceal bleeding but the exact mechanism of action is unclear. Propranolol is probably the treatment of choice with the long-acting derivative, Inderal LA offering the promise of better compliance. Where unwanted side effects such as vivid dreams and nightmares preclude its use nadolol is an a1ternati~e.I’~ Further studies are needed using the ‘cardioselective ’ P-blockers before their use can be advocated.

Ofher adrenergic drugs Due largely to severe hypotension the use of a-receptor antagonists such as prazosin is of largely historical importance.“’ Interest has been shown recently in the centrally acting a-agonist clonidine. It reduces portal pressure and portosystemic shunting in portal hypertensive rats and possibly limits the development of both.”’ In humans it reduces wedged hepatic venous pressure and azygous blood flow, as well as reducing cardiac output and mean arterial pressure.llsI It also reduces elevated levels of noradrenaline seen in cirrhosis and portal hypertension’” reflecting a diminished central nervous system sympathetic outflow.”’ Studies on the isolated perfused cirrhotic liver show clonidine has no peripheral action and relies on central agonism.IZ3Whilst it may prove to be an effective portal hypotensive agent, a poor side-effect profile may limit its use.

Nitrafes The nitrovasodilator groups of drugs are relatively new agents in the treatment of portal hypertension. Three principal mechanisms underlying their portal hypotensive action have been proposed. Firstly, nitrates may cause vasorelaxation at sinusoidal and portal-collateral level. This reduces resistance to flow through the portal-collateral bed and therefore reduces portal pressure. l4, lZ5 A1terna tivel y, by relaxing arterial smooth muscle, nitrates can reduce mean arterial blood pressure. This triggers ‘high pressure ’ arterial barorecep tors, promoting reflex splanchnic vasoconstriction which reduces portal venous inflow and hence reduces portal pressure.IZ6 Lastly, by causing systemic vanodilatation, nitrates reduce cardiac preload. This activates ’low pressure ’ cardiopulmonary baroreceptors resulting in reflex splanchnic vasoconstriction, reduced portal venous inff ow and hence reduced portal pre~sure.”~ However, the precise effect of nitrates on the portal-collateral vasculature remains disputed. The pharmacokinetic variations in studies to date (Table I)result in unpredictable plasma nitrate levels95and drug effect136making the mechanism of action difficult to interpret. Additionally, plasma thiol levels may be low in

530

R.D. G R O S E

& P. C. HAYES

Table 1. Nitrate studies in portal hypertension

Reference

Nitrate

Dose (mg)

Portal pressure reduction*

Route

Azygos flow reduction

~

132

133

127 134 135 136 127 131 72 138 15 79 124 138 139 144 73

Isosorbide Mononitrate (ISMN) Isosorbide Dinitrate (ISDN) ISMN ISMN Nitroglycerin "G) NTG ISDN ISDN ISMN NTG NTG ISDN NTG NTG ISDN ISDN ISMN NTG ISDN

HVPG

NSt

Not done (ND)

Sub lingual

HVPG

S"

ND

20 40 0.2

0

HVPG HVPG HVPG

S S S

NS S ND

0.2-2.40 10 20 20 0.07-0.15 1.2 5 0.4-0.6 0.01-0.16 10 5 40 bd 10 5

0

DPP HVPG HVPG HVPG HVPG IVOP HVPG HVPG WHVP HVPG HVPG HVPG HVPG IVOP

S S S S NS

ND ND ND ND NS ND ND NS NS ND ND NSt ND ND

20

5

Oral

(0)

(4)

0

Intravenous (i/v) 0 0 0

i/v s/l s/l s/l i/v i/v s/l 0

Transdermal 0

s

S S NS S S S S NS

" S = significant (to at least P < 0.05). t NS = not significant. Chronic study over 3 months.

*

HVPG = hepatic venous pressure gradient = (wedged -free hepatic venous pressure); WHVP = wedged hepatic venous pressure; IVOP = intravascular oesophageal pressure; DPP = direct portal pressure.

cirrhosis128~ 12' and the formation of nitrosothiol compounds is most important at a cellular level for nitrate action.130Autonomic neuropathy, a not uncommon finding in cirrhosis, may interfere with previously mentioned important reflex arcs.I3' Lastly the unpredictable extent of the portal-collateral network may also cause a variation showed that nitrates caused in apparent nitrate effect. Garcia-Tsao & Gro~zmann'~ uniform reduction in portal pressure but with either an increase or decrease in azygos blood flow implying reduced portal venous inflow in some patients and reduced portal collateral resistance in others. Overall then the action of nitrates in reducing portal pressure is both variable and unpredictable. '~~ Tachyphylaxis to nitrate preparations is well r e c ~ g n i z e d . Dose-scheduling providing nitrate free intervals may ameliorate tolerance to some extent,141but

TREATMENT OF PORTAL HYPERTENSION

531

most authors agree that it will occur to some degree.'42This would be of concern in their use in variceal bleeding prevention, although a recent study showed continuing activity 3 months into treatment.'39Reports that nitrates may reduce both renal perfusion and tissue oxygen delivery in suggest that monitoring renal and hepatic function during treatment would be prudent. We believe that nitrates have a role to play in the prophylaxis of variceal bleeding with isosorbide mononitrate as the drug of choice. Combination therapy with propranolol or another portal hypotensive agent is the likely way ahead (see below).

Serotonin anfagonisfs The portocollateral effect of serotonin at the 5-HT2-receptor level has recently provoked interest. Early work with ketanserin a non-specific HT,-antagonist, effected blockade not only at the HT2-receptor6' but also systemically at the 01receptor.'"( 146 This caused problems in determining exact mechanism of action as, although direct portocollateral relaxation seemed likely, a reduction in portal venous inflow, secondary to systemic hypotension could not be discounted. A chronic oral dosing study maintained a good portal hypotensive effect using the same agent.147However, precipitation of hepatic encephalopathy in some patients means newer receptor specific agents are now being studied. One of these, ritanserin has been shown to reduce portal pressure in cirrhotic rats'48 and those with portal vein s t e n o ~ i svia ' ~ ~portocollateral vasorelaxation, but studies in patients with cirrhosis are needed. Calcium channel blockers Verapamil was the first such agent studied and early rat studies showed a useful portal hypotensive effect.15' Subsequent human work has however been disappointing.i25,151,152 Nifedipine appears ineffective153and possibly harmfulIS4and this class of drug overall does not seem to have a role to play in the treatment of portal hypertension. Ofher agents Although the abnormalities of the renin angiotensin aldosterone system and the possible role of prostaglandins in portal hypertension have excited interest, the use of angiotensin converting enzyme inhibitors155and non-steroidal anti-inflammatory drugs (NSAIDS)'~~ (as inhibitors of prostaglandin synthesis) would seem precluded as they may cause deterioration in renal function which in cirrhotic patients may be precarious. The histamine-H,-receptor blockers have little effect on the portal and work on a new platelet activating factor antagonist B51021158is at an early stage. Promotility agents which increase lower oesophageal sphincter pressure and hence constrict varices at the point where they usually bleed have shown promise in small trial^^^^,^^' but larger studies are needed.

532

R. D. GROSE & P. C. HAYES

Combination therapy The use of combined nitrate and vasopressin treatment in the setting of acute variceal bleeding has already been discussed. The unwanted systemic side effect profile of vasopressin is ameliorated efficiently by nitrates, regardless of the route of administration of the latter and there is a further haemodynamic benefit at a portal level from the nitrate itself. Two recent reports of combination oral therapy to be used in the prophylactic setting have shown promise. The first of these combines isosorbide mononitrate with propranolol and has shown a useful additive portal hypotensive effect."' The second adds ketanserin to propranolol and has also shown a benefit over monotherapy in favourably altering portal haemodynamics.'62

CONCLUSIONS In the treatment of acute variceal haemorrhage, local expertise will dictate the preferred method of management. For speedy and effective haemostasis, injection sclerotherapy or balloon tamponade are now accepted as the treatments of choice. Where such treatments are unavailable or unsuitable, a combination of intravenous vasopressin and nitrates should be given. Somatostatin is an alternative, but debate over efficacy and cost limits its value. Prophylactic therapy for variceal haemorrhage promised a lot in the early 1980s and although propranolol would seem to be of benefit in reducing the risk of both primary and secondary variceal bleeding many patients tolerate the drug poorly. Currently it is the only pharmacotherapy indicated for the prophylaxis of variceal bleeding. Whilst large-scale controlled clinical trials of monotherapy with nitrates and the newer S-HT,-blockers are required, the way forward most probably lies in the combination of one of these groups of drugs with /3-blockade. It is to be hoped that the 1990s will produce new exciting clinical discoveries for the treatment of portal hypertension to follow the slightly tarnished promise of the 1980s. ACKNOWLEDGEMENT

We would like to thank Mrs Vanessa Campbell for her secretarial skill. REFERENCES 1 Burroughs A, dHygere F, McIntyre N.

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