A Textbook of Clinical Pharmacology and Therapeutics

260 ALIMENTARY SYSTEM AND LIVER
LIVER DISEASE
PRINCIPLES UNDERLYING DRUG TREATMENT OF
HEPATIC ENCEPHALOPATHY AND LIVER FAILURE
In severe liver dysfunction, neuropsychiatric changes occur
and can progress to coma. The mechanism which produces
these changes is not established, but it is known that in hepatic
coma and pre-coma, the blood ammonia concentration
increases. In many patients, the time-course of encephalopathy
parallels the rise in blood ammonia concentrations. Orally
administered nitrogenous compounds (e.g. protein, amino
acids, ammonium chloride) yield ammonia in the gut, raise
blood ammonia concentrations and provoke encephalopathy.
The liver is the only organ that extracts ammonia from the
blood and converts it to urea. Bacterial degradation products
of nitrogenous material within the gut enter the systemic circulation
because of a failure of first-pass hepatic extraction
(due to hepatocellular damage), or due to bypass of the hepatocytes
by collateral circulation or intrahepatic shunting.
Another source is urea, which undergoes enterohepatic
circulation and yields approximately 3.5 g/day of ammonia
(see Figure 34.3).
Ammonia diffuses into the blood across the large intestine
epithelium, where it is trapped by becoming ionized due to
the lower pH of blood compared to colonic contents.
Ammonia is not the only toxin involved, as perhaps 20% of
patients with encephalopathy have normal blood ammonia
concentrations, and methionine can provoke encephalopathy
without causing a significant rise in blood ammonia concentration.
Furthermore, ammonia toxicity affects the cortex but
not the brainstem, which is also involved in encephalopathy.
Other toxins of potential relevance include the following:
• Intestinal bacterial decarboxylation produces
hydroxyphenyl amines, such as octopamine (from
tyramine), which could replace normal transmitters at
nerve endings in the central and peripheral nervous
systems, thus acting as ‘false transmitters’ and changing
the balance of inhibition and excitation at central
synapses.
Other
nitrogenous
substrates
LIVER
Systemic
circulation
Hepatic
portal vein
Urea
Urine
Protein
Ammonia
• Changes in fatty acid metabolism increase plasma free
fatty acids, some of which have anaesthetic properties.
In addition, these determine the availability of
tryptophan to the brain and hence have an effect on
5-hydroxytryptamine synthesis.
Glutathione synthesis is impaired in severe liver disease.
Cellular damage due to free radical excess can produce multiorgan
dysfunction. Intravenous administration of acetylcysteine
is used prophylactically in some centres to enhance
glutathione synthesis and thereby reduce oxidant (free radical)
stresses by scavenging these reactive entities.
Treatment of hepatic encephalopathy includes the following
measures:
• dietary protein restriction to as little as 20 g/day, while
ensuring an adequate intake of essential amino acids;
• emptying the lower bowel by means of enemas and
purgatives to reduce the bacterial production of ammonia;
• oral or rectal administration of non-absorbable antibiotics,
such as neomycin, to reduce the bacterial population of
the large bowel. Neomycin, 1–2 g four times daily, is often
used. It should be remembered, if the patient also has
renal impairment, that neomycin may accumulate and
produce toxicity;
• oral lactulose improves encephalopathy. This disaccharide
is not a normal dietary constituent and humans do not
possess a lactulase enzyme, so lactulose is neither
digested nor absorbed but reaches the colon unchanged,
where the bacterial flora breaks it down to form lactate,
acetate and other acid products. These trap ammonia and
other toxins within the intestinal lumen by reducing its
pH, and in addition they act as a cathartic and reduce
ammonia absorption by reducing the colonic transit time;
• bleeding may occur due to interference with clotting
factor synthesis or thrombocytopenia. Vitamin K is given
and fresh frozen plasma or platelets are used as required.
H 2 antagonists (e.g. ranitidine) or proton-pump inhibitors
(e.g. omeprazole) are often used to prevent gastric
erosions and bleeding;
• sedatives should be avoided as patients with liver disease
are extremely sensitive to such drugs. If sedation is
essential (e.g. because of agitation due to alcohol
Gut
bacteria
Bacterial
urease
Urea
GUT
Figure 34.3: Enterohepatic circulation of urea and
ammonia.