DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

792
Normal
Congestive
symptoms
ototoxicity is reduced by continuous infusion when
compared to repetitive, intermittent intravenous dosing
(Lahav et al., 1992).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Stroke volume
Low
output
symptoms
I+V+D
D
I+V
Ventricular filling pressure
Figure 28–2. Hemodynamic responses to pharmacologic interventions
in heart failure. The relationships between diastolic filling
pressure (preload) and stroke volume (ventricular
performance) are illustrated for a normal heart (green line; the
Frank- Starling relationship) and for a patient with heart failure
due to predominant systolic dysfunction (red line). Note that positive
inotropic agents (I), such as cardiac glycosides or dobutamine,
move patients to a higher ventricular function curve (lower
dashed line), resulting in greater cardiac work for a given level
of ventricular filling pressure. Vasodilators (V), such as
angiotensin- converting enzyme (ACE) inhibitors or nitroprusside,
also move patients to improved ventricular function curves
while reducing cardiac filling pressures. Diuretics (D) improve
symptoms of congestive heart failure by moving patients to lower
cardiac filling pressures along the same ventricular function
curve.
evident fluid retention, furosemide typically is started at
a dose of 40 mg once or twice daily, and the dosage is
increased until an adequate diuresis is achieved. A
larger initial dose may be necessary in patients with
advanced CHF and azotemia. Serum electrolytes and
renal function are monitored frequently in these patients
or in those for whom a rapid diuresis is necessary. If
present, hypokalemia from therapy may be corrected
by oral or intravenous K + supplementation or by the
addition of a K + -sparing diuretic. When appropriate,
diuretics are decreased to the minimum effective concentration
for maintaining euvolemia.
Diuretics in the Decompensated Patient. In patients with
decompensated CHF warranting hospital admission,
repetitive intravenously administered boluses or a constant
infusion titrated to achieve a desired response may
be needed to provide expeditious (and reliable) diuresis
(Dormans et al., 1996). One advantage to intravenous
infusion is that sustained natriuresis is achieved as a
consequence of consistently elevated drug levels within
the lumen of the renal tubules. In addition, the risk of
V
I
A typical continuous furosemide infusion is initiated with a
40-mg bolus injection followed by a constant rate of 10 mg/h, with
uptitration as necessary. If renal perfusion is reduced, drug efficacy
may be enhanced by co- administration of drugs that increase cardiac
output (e.g., dobutamine).
Diuretic Resistance. As mentioned earlier, a compensatory
increase in renal tubular Na + reabsorption may prevent
effective diuresis when dosed daily; as a result,
reduction of diuretic dosing intervals may be warranted.
In advanced CHF, invasive assessment of intracardiac
filling pressures and cardiac output may be required to
distinguish between low intravascular volume from
aggressive diuresis versus low cardiac output states,
although both states are aligned with lower diuretic
delivery and drug efficacy. Furthermore, edema,
decreased bowel- wall motility, and reduced splanchnic
blood flow impair absorption and may delay or attenuate
peak diuretic effect.
Atherosclerotic renal artery disease is associated
with reduced renal perfusion pressures to levels below
that necessary for adequate drug delivery. In patients
with reduced renal arterial perfusion pressure (e.g.,
renal artery stenosis or low cardiac output), AngIImediated
efferent glomerular arteriole tone is important
for preservation of normal glomerular filtration
pressure. Angiotensin- converting enzyme (ACE)
inhibitors or AT 1
receptor antagonists in combination
with loop diuretics may, therefore, be met with a
decline in creatinine clearance that is associated with
low diuretic delivery and decreased drug efficacy
(Ellison, 1999). Other common causes of diuretic
resistance are listed in Table 28–1.
Metabolic Consequences of Diuretic Therapy. The side effects
of diuretics are discussed in Chapter 25. With regard to diuretic use
in CHF, the most important adverse sequelae of diuretics are electrolyte
abnormalities, including hyponatremia, hypokalemia, and
hypochloremic metabolic alkalosis. The clinical importance (or even
existence) of significant Mg 2+ deficiency with chronic diuretic use is
controversial (Bigger, 1994).
Adenosine A 1
Receptor Antagonists. Adenosine A 1
receptor
antagonists may provide a renal protective therapeutic
strategy for enhanced volume loss in decompensated
CHF. Adenosine is secreted from the macula densa in
the renal arteriole in response to diuretic- induced
increases in Na + and Cl − tubular flow concentrations.
This results in increased Na + resorption, a volume- loss
counterregulatory mechanism (see Chapter 26). Na +
reabsorption, in addition to adenosine- induced renal