and other plasma proteins. This alters the pharmacokinetics of
many drugs, but is seldom clinically important. Phenytoin
is an exception, because therapy is guided by plasma concen-
tration and routine analytical methods detect total (bound
and free) drug. In renal impairment, phenytoinprotein bind-
ing is reduced by competition with accumulated molecules
normally cleared by the kidney and which bind to the same
albumin drug-binding site as phenytoin. Thus, for any meas-
ured phenytoinconcentration, free (active) drug is increased
compared to a subject with normal renal function and the
same measured total concentration. The therapeutic range
therefore has to be adjusted to lower values in patients with
renal impairment, as otherwise doses will be selected that
cause toxicity.
Tissue binding of digoxinis reduced in patients with
impaired renal function, resulting in a lower volume of distri-
bution than in healthy subjects. A reduced loading dose of
digoxinis therefore appropriate in such patients, although the
effect of reduced glomerular filtration on digoxinclearance is
even more important, necessitating a reduced maintenance
dose, as described below.
The blood–brain barrier is more permeable to drugs in
uraemia. This can result in increased access of drugs to the
central nervous system, an effect that is believed to contribute
to the increased incidence of confusion caused by cimetidine,
ranitidineandfamotidinein patients with renal failure.
METABOLISM
Metabolism of several drugs is reduced in renal failure. These
include drugs that undergo phase I metabolism by CYP3A4.
Drugs that are mainly metabolized by phase II drug metabol-
ism are less affected, although conversion of sulindacto its
active sulphide metabolite is impaired in renal failure, as is the
hepatic conjugation of metoclopramidewith glucuronide and
sulphate.
RENAL EXCRETION
Glomerular filtration and tubular secretion of drugs usually
fall in step with one another in patients with renal impair-
ment. Drug excretion is directly related to glomerular filtra-
tion rate (GFR). Some estimate of GFR (eGFR) is therefore
essential when deciding on an appropriate dose regimen.
Serum creatinine concentration adjusted for age permits cal-
culation of an estimate of GFR per 1.73 m^2 body surface area.
This is now provided by most chemical pathology labora-
tories, and is useful in many situations. Alternatively, Figure 7.2
shows a nomogram given plasma creatinine, age, sex and
body weight and is useful when a patient is markedly over- or
underweight. The main limitation of such estimates is that
they are misleading if GFR is changing rapidly as in acute
renal failure. (Imagine that a patient with normal serum creati-
nine undergoes bilateral nephrectomy: an hour later, his serum
creatinine would still be normal, but his GFR would be zero.
Creatinine would rise gradually over the next few days as it con-
tinued to be produced in his body but was not cleared.) A nor-
mal creatinine level therefore does not mean that usual doses
can be assumed to be safe in a patient who is acutely unwell.
36 EFFECTS OF DISEASE ON DRUG DISPOSITION
eGFR is used to adjust the dose regimen in patients with
some degree of chronic renal impairment for drugs with a low
therapeutic index that are eliminated mainly by renal excre-
tion. Dose adjustment must be considered for drugs for which
there is 50% elimination by renal excretion. The British
National Formulary tabulates drugs to be avoided or used
with caution in patients with renal failure. Common examples
are shown in Table 7.2.Clearance
(ml/min) Weight
(kg)Serum
creatinine
R (mg/100 ml)Age
(years)5.0
4.0
3.0
2.0
1.7
1.3
1.00.9
0.80.7
0.6
0.5
0.41.5
1.2959530405060708090100110120150
130
110
100
90
80
70
60
50403020108585 75(^7565)
(^55654555)
(^35452535)
25
Figure 7.2:Nomogram for rapid evaluation of endogenous
creatinine clearance – with a ruler joining weight to age. Keep
ruler at crossing point on R, then move the right-hand side of the
ruler to the appropriate serum creatinine value and read off
clearance from the left-hand scale. To convert serum creatinine in
mol/L to mg/100 mL, as is used on this scale, simply divide by
88.4. (Reproduced with permission from Siersbaek-Nielson K
et al. Lancet1971; 1 : 1133. © The Lancet Ltd.)
Table 7.2:Examples of drugs to be used with particular caution or avoided
in renal failure
Angiotensin-converting enzyme Angiotensin receptor
inhibitorsa blockersa
Aldosterone antagonists Aminoglycosides
Amphotericin Atenolol
Ciprofloxacin Cytotoxics
Digoxin Lithium
Low molecular weight heparin Metformin
NSAIDs Methotrexate
aACEI and ARB must be used with caution, but can slow progressive renal
impairment (see Chapter 28).