A Textbook of Clinical Pharmacology and Therapeutics

withdrawal), small doses of benzodiazepines that are

metabolized to inactive glucuronide conjugates, e.g.

oxazepamare preferred to those with longer-lived

metabolites. The hazards of narcotic analgesics to the

patient with acute or chronic liver disease cannot be over-

emphasized;

• prophylactic broad-spectrum intravenous antibiotics,
  especially if there is evidence of infection (e.g.
  spontaneous peritonitis);


• intravenousacetylcysteine(the precise value of this has
  not yet been fully confirmed).

a significant reduction in variceal pressure without effects on the

systemic vasculature. To date, a clear-cut response in variceal

bleeding has not been demonstrated. Side effects include vomit-

ing, anorexia, abdominal pain, diarrhoea, headache and dizzi-

ness. Newer vasoactive drugs, such as terlipressin, appear to

have a better therapeutic index and fewer side effects, although

terlipressinhas a short half-life and needs to be administered

frequently or as an infusion.

A number of trials have demonstrated efficacy of non-

cardioselective beta-adrenergic antagonists (propranolol,

nadolol) in reducing the incidence of gastro-intestinal bleeding

in patients with portal hypertension, especially in combination

with endoscopic sclerotherapy.

MANAGEMENT OF CHRONIC VIRAL HEPATITIS

Chronic viral hepatitis is associated with chronic liver disease,

cirrhosis and hepatocellular carcinoma. The carrier rate for

hepatitis B in the UK is 0.1–1% (it is particularly prevalent in

socially deprived areas of inner cities) and the seroprevalence

for hepatitis C is 0.1–0.7%. Chronic viral hepatitis is diagnosed

when there is evidence of continuing hepatic damage and

infection for at least six months after initial viral infection. In

hepatitis C, the liver function may remain normal for months

to years, while the patient’s blood remains infectious (con-

firmed by hepatitis C virus RNA detection). The course of the

liver damage often fluctuates. While up to 90% of patients

with acute hepatitis B clear the virus spontaneously, up to 60%

of those with hepatitis C virus do not do so. About 20% of

those with chronic active hepatitis progress insidiously to cir-

rhosis, and about 2–3% go on to develop hepatocellular carci-

noma.

Hepatitis B virus is a DNA virus that is not directly cyto-

pathic and hepatic damage occurs as a result of the host

immune response. Hepatocytes infected with hepatitis B virus

produce a variety of viral proteins, of which the ‘e’ antigen

(HBeAg) is clinically the most important. HBeAg is a marker for

continued viral replication and therefore for infectivity.

Hepatitis C virus is a single-stranded RNA virus. Controlled

trials have shown that interferon-alfa,lamivudine(a nucleo-

side analogue inhibitor of viral DNA polymerase) and adefovir

dipivoxil(a phosphorylated nucleotide analogue inhibitor of

viral DNA polymerases) are beneficial in reducing the viral

load in patients with chronic hepatitis B virus infection.

Pegylated interferon alfa-2a (peginterferon alfa-2a) may be

preferred to interferon alfa. Pegylation (polyethylene glycol-

conjugation) prolongs the interferon half-life in the blood,

allowing subcutaneous once weekly dosing. The National

Institute of Health and Clinical Excellence (NICE) has recom-

mendedadefoviras an option in chronic hepatitis B if interferon

is unsuccessful, if relapse occurs following successful initial

interferon treatment, or if interferon is poorly tolerated or con-

traindicated (see Chapters 45 and 46).

In chronic hepatitis C, the combination of peginterferon

alfaandribavarin(see Chapter 45) is recommended. Details

on the regimens can be found at http://www.nice.org.uk/TA075.

LIVERDISEASE 261

Key points

Treatment of hepatic encephalopathy

• Supportive.


• Measures to reduce absorption of ammonia from the
  gut (e.g. low-protein diet, lactuloseneomycin).


• Prophylactic broad spectrum antibiotics, prompt
  treatment of infection.


• Prophylactic vitamin K.


• Fresh frozen plasma/platelets as indicated.


• H 2 antagonist (e.g. ranitidine) or proton-pump inhibitor
  (e.g. omeprazole) to prevent gastric erosions and
  bleeding.


• i.v. acetylcysteine (unproven).


• Avoidance of sedatives, potassium-losing diuretics,
  opioids, drugs that cause constipation and hepatotoxic
  drugs whenever possible.

DRUG THERAPY OF PORTAL HYPERTENSION AND

OESOPHAGEAL VARICES

Oesophageal varices form a collateral circulation in response to
raised blood pressure in the portal system and are of clinical
importance because of their tendency to bleed. Two-thirds of
patients with varices die as a result and of these, one-third die
of the first bleed, one-third rebleed within six weeks and only
one-third survive for one year. Sclerotherapy and surgical shunt
procedures are the mainstay of treatment, and drug therapy
must be judged against these gloomy survival figures. In add-
ition to resuscitation, volume replacement and, when necessary,
balloon tamponade using a Sengstaken–Blakemore tube, the
emergency treatment of bleeding varices may include vasocon-
strictor drugs, e.g vasopressinanalogues. These reduce portal
blood flow through splanchnic arterial constriction.
Drugs currently used for the management of acute variceal
haemorrhage include octreotide(the long-acting analogue of
somatostatin),vasopressinandterlipressin(a derivative of
vasopressin).Terlipressinandoctreotideare used to reduce
portal pressure urgently, to control bleeding before more defini-
tive treatment, such as sclerotherapy or variceal banding. Beta-
blockers and vasodilators, such as nitrates, are used for
long-term therapy to reduce portal pressure. Somatostatinand
its long-acting analogue octreotidereduce blood flow and cause