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Prescribing in hepatic impairment
Liver disease may alter the response to drugs in several
ways as indicated below, and drug prescribing should be
kept
to a minimum in all
patients with severe liver
disease.
The main problems
occur
in patients
with
jaundice,
ascites,
or evidence of encephalopathy.
Impaired drug metabolism
Metabolism by the liver
is the main route of
elimination for
many drugs,
but
hepatic reserve is large and liver
disease has to be
severe before important
changes in drug metabolism
occur.
Routine liver-function tests are a poor guide to
the capacity of the liver to metabolise drugs, and in the
individual patient it is not possible to predict the extent
to which the metabolism of
a particular drug may be
impaired.
A few drugs,
e.g.
rifampicin and fusidic
acid,
are
excreted in the bile unchanged and can accumulate in
patients with intrahepatic or
extrahepatic obstructive
jaundice.
Hypoproteinaemia
The hypoalbuminaemia in severe
liver disease is associated with reduced protein binding
and increased toxicity of
some highly protein-bound
drugs such as phenytoin and prednisolone.
Reduced clotting
Reduced hepatic
synthesis
of
blood-clotting
factors,
indicated
by
a
prolonged
prothrombin time,
increases the sensitivity to oral anti-
coagulants such as warfarin and phenindione.
Hepatic encephalopathy
In severe liver
disease
many drugs can further
impair cerebral
function and
may precipitate hepatic encephalopathy.
These include
all sedative drugs, opioid analgesics, those diuretics that
produce hypokalaemia,
and drugs that cause constipa-
tion.
Fluid overload
Oedema and ascites in chronic liver
disease can be exacerbated by drugs that give rise to
fluid retention,
e.g.
NSAIDs and corticosteroids.
Hepatotoxic drugs
Hepatotoxicity is either
dose-
related or
unpredictable
(idiosyncratic).
Drugs
that
cause dose-related toxicity may do so at
lower doses
in the presence of
hepatic impairment
than in indivi-
duals with normal
liver function,
and some drugs that
produce reactions of the idiosyncratic kind do so more
frequently in patients with liver disease.
These drugs
should be avoided or used very carefully in patients with
liver disease.
Where care is
needed when prescribing in hepatic
impairment,
this is indicated under the relevant
drug
in the BNF.
Prescribing in renal impairment
The use of drugs in patients with reduced renal function
can give rise to problems for several reasons:
.
reduced renal excretion of a drug or its metabolites
may cause toxicity;
.
sensitivity to some drugs is increased even if elim-
ination is unimpaired;
.
many side-effects are tolerated poorly by patients
with renal impairment;
.
some drugs are not effective when renal function is
reduced.
Many of these problems can be avoided by reducing the
dose or by using alternative drugs.
Principles of dose adjustment in renal
impairment
The level
of
renal
function below which the dose of
a
drug must be reduced depends on the proportion of the
drug eliminated by renal excretion and its toxicity.
For many drugs with only minor or no dose-related side-
effects very precise modification of the dose regimen is
unnecessary and a simple scheme for dose reduction is
sufficient.
For
more toxic drugs with a small
safety margin or
patients at
extremes of
weight,
dose regimens based
on creatinine clearance (see below for details) should be
used. When both efficacy and toxicity are closely related
to plasma-drug concentration, recommended regimens
should be regarded only as a guide to initial treatment;
subsequent doses must be adjusted according to clinical
response and plasma-drug concentration.
Renal function declines with age; many elderly patients
have renal impairment but,
because of reduced muscle
mass,
this may not
be indicated by a raised serum
creatinine. It is wise to assume at least mild impairment
of renal function when prescribing for the elderly.
The total
daily maintenance dose of
a drug can be
reduced either
by reducing the size of
the individual
doses or by increasing the interval between doses.
For
some drugs, although the size of the maintenance dose
is reduced it is important to give a loading dose if
an
immediate effect
is required.
This is because it
takes
about
five times the half-life of
the drug to achieve
steady-state
plasma
concentrations.
Because
the
plasma half-life of
drugs
excreted by the kidney is
prolonged in renal
impairment it can take many doses
for the reduced dosage to achieve a therapeutic plasma
concentration.
The loading dose should usually be the
same size as the initial
dose for a patient with normal
renal function.
Nephrotoxic drugs should,
if
possible,
be avoided in
patients with renal disease because the consequences of
nephrotoxicity are likely to be more serious when renal
reserve is already reduced.
Dose recommendations are based on the severity of
renal impairment.
BNF 61
Prescribing in hepatic impairment
17
Prescribing in renal impairment