Clinical Pharmacology and Therapeutics

LIVER DISEASE 261
withdrawal), small doses of benzodiazepines that are
metabolized to inactive glucuronide conjugates, e.g.
oxazepam are preferred to those with longer-lived
metabolites. The hazards of narcotic analgesics to the
patient with acute or chronic liver disease cannot be overemphasized;
• prophylactic broad-spectrum intravenous antibiotics,
especially if there is evidence of infection (e.g.
spontaneous peritonitis);
• intravenous acetylcysteine (the precise value of this has
not yet been fully confirmed).
Key points
Treatment of hepatic encephalopathy
• Supportive.
• Measures to reduce absorption of ammonia from the
gut (e.g. low-protein diet, lactulose neomycin).
• 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 addition
to resuscitation, volume replacement and, when necessary,
balloon tamponade using a Sengstaken–Blakemore tube, the
emergency treatment of bleeding varices may include vasoconstrictor
drugs, e.g vasopressin analogues. 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), vasopressin and terlipressin (a derivative of
vasopressin). Terlipressin and octreotide are used to reduce
portal pressure urgently, to control bleeding before more definitive
treatment, such as sclerotherapy or variceal banding. Betablockers
and vasodilators, such as nitrates, are used for
long-term therapy to reduce portal pressure. Somatostatin and
its long-acting analogue octreotide reduce blood flow and cause
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 vomiting,
anorexia, abdominal pain, diarrhoea, headache and dizziness.
Newer vasoactive drugs, such as terlipressin, appear to
have a better therapeutic index and fewer side effects, although
terlipressin has a short half-life and needs to be administered
frequently or as an infusion.
A number of trials have demonstrated efficacy of noncardioselective
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 (confirmed
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 cirrhosis,
and about 2–3% go on to develop hepatocellular carcinoma.
Hepatitis B virus is a DNA virus that is not directly cytopathic
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 nucleoside
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 glycolconjugation)
prolongs the interferon half-life in the blood,
allowing subcutaneous once weekly dosing. The National
Institute of Health and Clinical Excellence (NICE) has recommended
adefovir as 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 contraindicated
(see Chapters 45 and 46).
In chronic hepatitis C, the combination of peginterferon
alfa and ribavarin (see Chapter 45) is recommended. Details
on the regimens can be found at www.nice.org.uk/TA075.