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

770 refractory to drugs that block the sympathetic nervous
system or to vasodilator drugs, because these drugs
engender a state in which the blood pressure is very volume
dependent. Therefore, it is appropriate to consider
the use of thiazide-class diuretics in doses of 50 mg of
daily hydrochlorothiazide equivalent when treatment
with appropriate combinations and doses of three or
more drugs fails to yield adequate control of the blood
pressure. Alternatively, there may be a need to use
higher-capacity diuretics such as furosemide, especially
if renal function is not normal, in some of these patients.
Dietary Na + restriction is a valuable adjunct to the management
of such refractory patients and will minimize
the dose of diuretic that is required. This can be achieved
by a modest restriction of Na + intake to 2 g daily. More
stringent Na + restriction is not feasible for most patients.
Because the degree of K + loss relates to the amount of
Na + delivered to the distal tubule, such restriction of Na +
can minimize the development of hypokalemia and
alkalosis. The effectiveness of thiazides as diuretics or
antihypertensive agents is progressively diminished when
the glomerular filtration rate falls below 30 mL/min. One
exception is metolazone, which retains efficacy in patients
with this degree of renal insufficiency.
Most patients will respond to thiazide diuretics with
a reduction in blood pressure within about 4-6 weeks.
Therefore, doses should not be increased more often than
every 4-6 weeks. There is no way to predict the antihypertensive
response from the duration or severity of the
hypertension in a given patient, although diuretics are
unlikely to be effective as sole therapy in patients with
stage 2 hypertension (Table 27–4). Because the effect of
thiazide diuretics is additive with that of other antihypertensive
drugs, combination regimens that include these
diuretics are common and rational. A wide range of fixeddose
combination products containing a thiazide are marketed
for this purpose. Diuretics also have the advantage
of minimizing the retention of salt and water that is commonly
caused by vasodilators and some sympatholytic
drugs. Omitting or underutilizing a diuretic is a frequent
cause of “resistant hypertension.”
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Adverse Effects and Precautions. The adverse effects of
diuretics are discussed in Chapter 25. Some of these
determine whether patients can tolerate and adhere to
diuretic treatment.
Erectile dysfunction is a troublesome adverse effect of the
thiazide-class diuretics, and physicians should inquire specifically
regarding its occurrence in conjunction with treatment with these
drugs. Gout may be a consequence of the hyperuricemia induced by
these diuretics. The occurrence of either of these adverse effects is
a reason for considering alternative approaches to therapy. However,
precipitation of acute gout is relatively uncommon with low doses of
diuretics. Hydrochlorothiazide may cause rapidly developing, severe
hyponatremia in some patients. Thiazides inhibit renal Ca 2+ excretion,
occasionally leading to hypercalcemia; although generally
mild, this can be more severe in patients subject to hypercalcemia,
such as those with primary hyperparathyroidism. The thiazideinduced
decreased Ca 2+ excretion may be used therapeutically in
patients with osteoporosis or hypercalciuria.
Some other effects of thiazide diuretics are laboratory observations
that are of concern primarily because they are putative surrogate
markers for adverse drug effects on morbidity and mortality.
The effects of diuretic drugs on several surrogate markers for adverse
outcomes merit consideration. The K + depletion produced by thiazide-class
diuretics is dose dependent and is variable among individuals,
such that a subset of patients may become substantially K +
depleted on diuretic drugs. Given chronically, even small doses lead
to some K + depletion.
There are two types of ventricular arrhythmias that are thought
to be enhanced by K + depletion. One of these is polymorphic ventricular
tachycardia (torsades de pointes), which is induced by a number
of drugs, including quinidine. Drug-induced polymorphic ventricular
tachycardia is initiated by abnormal ventricular repolarization; because
K + currents normally mediate repolarization, drugs that produce K +
depletion potentiate polymorphic ventricular tachycardia. Accordingly,
thiazide diuretics should not be given together with drugs that can
cause polymorphic ventricular tachycardia (see Chapter 29).
The most important concern regarding K + depletion is its
influence on ischemic ventricular fibrillation, the leading cause of
sudden cardiac death and a major contributor to cardiovascular mortality
in treated hypertensive patients. Studies in experimental animals
have demonstrated that K + depletion lowers the threshold for
electrically induced ventricular fibrillation in the ischemic
myocardium and also increases spontaneous ischemic ventricular
fibrillation (Curtis and Hearse, 1989). There is a positive correlation
between diuretic dose and sudden cardiac death, and an inverse correlation
between the use of adjunctive K + -sparing agents and sudden
cardiac death (Siscovick et al., 1994). One controlled clinical
trial demonstrated a significantly greater occurrence of sudden cardiac
death in patients treated with 50 mg of hydrochlorothiazide
daily in comparison with the β receptor antagonist metoprolol
(Medical Research Council Working Party, 1992).
Thiazide diuretics have been associated with changes in
plasma lipids and glucose tolerance that have led to some concern.
The clinical significance of the changes has been disputed.
Nonetheless, clinical studies demonstrate the efficacy of the thiazide
diuretics in reducing cardiovascular risk (ALLHAT Officers, 2002).
All of the thiazide-like drugs cross the placenta, but they have
not been shown to have direct adverse effects on the fetus. However,
if administration of a thiazide is begun during pregnancy, there is a
risk of transient volume depletion that may result in placental hypoperfusion.
Because the thiazides appear in breast milk, they should
be avoided by nursing mothers.
Other Diuretic Antihypertensive Agents
The thiazide diuretics are more effective antihypertensive
agents than are the loop diuretics, such as