A Textbook of Clinical Pharmacology and Therapeutics

RENALDISEASE 35

DISTRIBUTION

Drug distribution is altered by cardiac failure. The apparent
volume of distribution (Vd) of, for example, quinidineand
lidocainein patients with congestive cardiac failure is markedly
reduced because of decreased tissue perfusion and altered
partition between blood and tissue components. Usual doses
can therefore result in elevated plasma concentrations, pro-
ducing toxicity.

ELIMINATION

Elimination of several drugs is diminished in heart failure.
Decreased hepatic perfusion accompanies reduced cardiac
output. Drugs such as lidocainewith a high hepatic extraction
ratio of 70% show perfusion-limited clearance, and steady-
state levels are inversely related to cardiac output (Figure 7.1).
Duringlidocaineinfusion, the steady-state concentrations are
almost 50% higher in patients with cardiac failure than in healthy
volunteers. The potential for lidocainetoxicity in heart failure
is further increased by the accumulation of its polar metab-
olites, which have cardiodepressant and pro-convulsant prop-
erties. This occurs because renal blood flow and glomerular
filtration rate are reduced in heart failure.
Theophyllineclearance is decreased and its half-life is
doubled in patients with cardiac failure and pulmonary oedema,
increasing the potential for accumulation and toxicity. The
metabolic capacity of the liver is reduced in heart failure both
by tissue hypoxia and by hepatocellular damage from hepatic
congestion. Liver biopsy samples from patients with heart
failure have reduced drug-metabolizing enzyme activity.
Heart failure reduces renal elimination of drugs because of
reduced glomerular filtration, predisposing to toxicity from
drugs that are primarily cleared by the kidneys, e.g. amino-
glycosides and digoxin.

RENAL DISEASE

RENAL IMPAIRMENT

Renal excretion is a major route of elimination for many drugs
(Chapter 6), and drugs and their metabolites that are excreted
predominantly by the kidneys accumulate in renal failure.
Renal disease also affects other pharmacokinetic processes
(i.e. drug absorption, distribution and metabolism) in more
subtle ways.

ABSORPTION

Gastric pH increases in chronic renal failure because urea is
cleaved, yielding ammonia which buffers acid in the stomach.
This reduces the absorption of ferrous iron and possibly also of
other drugs. Nephrotic syndrome is associated with resistance

to oral diuretics, and malabsorption of loop diuretics through

the oedematous intestine may contribute to this.

DISTRIBUTION

Renal impairment causes accumulation of several acidic sub-

stances that compete with drugs for binding sites on albumin

0

0.1

1

10

60 120 180 240

Heart

failure

Control

Lidocaine concentration (

g/ml)

Time after injection (min)

0 250 500 750 1000125015001750

Estimated hepatic blood

flow (ml/min/m^2 )

1.0

1.4

1.8

2.2

2.6

3.0

3.4

Steady-state arterial

concentration of lidocaine (

g/ml)

3.2

3.0

2.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.51.0 2.0 2.5 3.0 3.5 4.0 4.5

Cardiac index (I/min/m^2 )

Arterial lidocaine (

g/ml)

(c)

(b)

(a)

Figure 7.1:(a) Mean values (and standard deviations) of plasma

lidocaine concentrations in seven heart failure patients and

controls following a 50-mg intravenous bolus. (b) Relationship

between arterial lidocaine level and cardiac index (dotted

vertical line is lower limit of normal cardiac index, square is mean

for low cardiac index patients, triangle is mean for patients with

normal cardiac index). (c) Relationship of steady-state arterial

lidocaine level following 50-mg bolus and infusion of

40 mg/kg/min (vertical line is lower limit of normal hepatic blood

flow, square is mean for patients with low hepatic blood flow,

triangle is mean for patients with normal flow). (Reproduced

from: (a) Thompson PD et al. American Heart Journal1971; 82 ,

417; (b,c) Stenson RE et al. Circulation1971; 43 : 205. With

permission of the American Heart Association Inc.)