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

have an arylsulfonamide structure and block the NaCl
co-transporter. Some of these are not benzothiadiazines
but have structural features and molecular functions that
are similar to the original benzothiadiazine compounds;
consequently, they are designated as members of the thiazide
class of diuretics. For example, chlorthalidone,
one of the non-benzothiadiazines, is widely used in the
treatment of hypertension, as is indapamide.
Regimen for Administration of the Thiazide-Class Diuretics
in Hypertension. Because members of the thiazide class
have similar pharmacological effects, they generally
have been viewed as interchangeable with appropriate
adjustment of dosage (see Chapter 25). However, the
pharmacokinetics and pharmacodynamics of these drugs
may differ, so they may not necessarily have the same
clinical efficacy in treating hypertension (Carter et al.,
2004). Indeed, there has been renewed debate about
whether or not this group of diuretics should be considered
as a class in terms of capacity to lower blood pressure
and also decrease adverse clinical events due to
hypertension (Sicca, 2006).
A direct comparison using 24-hour ambulatory
blood pressure monitoring suggested that the antihypertensive
efficacy of chlorthalidone is more favorable than
that of hydrochlorothiazide (Ernst et al., 2006).
Interestingly, the differences were primarily due to
greater antihypertensive efficacy during the night and not
with routine daytime office measurements of blood pressure.
It is possible that the greater effect at night arises on
account of the much longer t 1/2
of chlorthalidone (>24
hours) compared to hydrochlorothiaze (several hours).
In light of the considerable clinical trial data supporting
the capacity of chlorthalidone to diminish adverse cardiovascular
events—in comparison to that available for
currently used low doses of hydrochlorothiazide—there
is a growing concern that chlorthalidone may be an
underutilized drug in hypertensives requiring a diuretic.
When a thiazide-class diuretic is utilized as the sole antihypertensive
drug (monotherapy), its dose-response curve for lowering
blood pressure in patients with hypertension should be kept in mind.
Antihypertensive effects can be achieved in many patients with as little
as 12.5 mg daily of chlorthalidone or hydrochlorothiazide.
Furthermore, when used as monotherapy, the maximal daily dose of
thiazide-class diuretics usually should not exceed 25 mg of
hydrochlorothiazide or chlorthalidone (or equivalent). Even though
more diuresis can be achieved with higher doses of these diuretics,
some evidence suggests that doses higher than this are not generally
more efficacious in lowering blood pressure in patients with normal
renal function. For example, a large study comparing 25 and 50 mg
of hydrochlorothiazide daily in an elderly population did not show a
greater decrease in blood pressure with the larger dose (Medical
Research Council Working Party, 1987). However, these conclusions
are based on conventional rather than ambulatory blood pressure
measurements. Other studies suggest that low doses of hydrochlorothiazide
have inadequate effects on blood pressure when monitored in
this more detailed manner (Lacourcière et al., 1995). In summary,
recent critical attention has been focused on whether low doses of
hydrochlorothiazide are as efficacious as low doses of chlorthalidone
and whether low doses of hydrochlorothiazide are efficacious as
monotherapy in protecting against the cardiovascular complications
of hypertension. Relatively low doses of either thiazide are not at the
top of the dose-response curve for adverse effects such as K + wasting
and inhibition of uric acid excretion, emphasizing the importance of
knowledge about the dose-response relationships for both beneficial
and adverse effects.
In the clinical trials of antihypertensive therapy in the elderly
that demonstrated the best outcomes in cardiovascular morbidity and
mortality, 25 mg of hydrochlorothiazide or chlorthalidone was the
maximum dose given; if this dose did not achieve the target blood
pressure reduction, treatment with a second drug was initiated (SHEP
Cooperative Research Group, 1991; Dahlöf et al., 1991; Medical
Research Council Working Party, 1992). With respect to safety, a
case-control study (Siscovick et al., 1994) found a dose-dependent
increase in the occurrence of sudden death at doses of hydrochlorothiazide
>25 mg daily. This finding supports the hypothesis proposed
by the Multiple Risk Factor Intervention Trial Research Group
(1982), suggesting that increased cardiovascular mortality is associated
with higher diuretic doses. Taken together, clinical studies indicate
that if adequate blood pressure reduction is not achieved with
the 25-mg daily dose of hydrochlorothiazide or chlorthalidone, a
second drug should be added rather than increasing the dose of
diuretic. There is some concern that thiazide diuretics, especially at
higher doses and in the absence of K + -sparing diuretics or K + supplements,
may increase the risk of sudden death. However, their
overall therapeutic benefits are well established.
Urinary K + loss can be a problem with thiazides.
ACE inhibitors and angiotensin receptor antagonists will
attenuate diuretic-induced loss of K + to some degree,
and this is a consideration if a second drug is required to
achieve further blood pressure reduction beyond that
attained with the diuretic alone. Because the diuretic and
hypotensive effects of these drugs are greatly enhanced
when they are given in combination, care should be
taken to initiate combination therapy with low doses of
each of these drugs. Administration of ACE inhibitors
or angiotensin receptor antagonists together with other
K + -sparing agents or with K + supplements requires great
caution; combining K + -sparing agents with each other
or with K + supplementation can cause potentially dangerous
hyperkalemia in some patients.
In contrast to the limitation on the dose of thiazideclass
diuretics used as monotherapy, the treatment of
severe hypertension that is unresponsive to three or more
drugs may require larger doses of the thiazide-class
diuretics. Indeed, hypertensive patients may become
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION