A Textbook of Clinical Pharmacology and Therapeutics

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 encephalo-
pathy 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 cir-
culation because of a failure of first-pass hepatic extraction
(due to hepatocellular damage), or due to bypass of the hepa-
tocytes 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 concen-
tration. 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.
  
  
  • 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 multi-
    organ dysfunction. Intravenous administration of acetyl-
    cysteineis used prophylactically in some centres to enhance
    glutathione synthesis and thereby reduce oxidant (free rad-
    ical) stresses by scavenging these reactive entities.
    Treatment of hepatic encephalopathy includes the follow-
    ing 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 neomycinmay 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
  
  
  
  

260 ALIMENTARY SYSTEM ANDLIVER

Other
nitrogenous
substrates

Systemic

circulation

Hepatic

portal vein

LIVER

Urine

Protein

Ammonia

Urea

GUT

Bacterial

urease

Gut

bacteria

Urea

Figure 34.3:Enterohepatic circulation of urea and

ammonia.