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

Thiazide diuretics decrease blood pressure in hypertensive
patients by increasing the slope of the renal pressure-natriuresis
relationship (Figure 26–7), and thiazide diuretics are used widely
for the treatment of hypertension either alone or in combination
with other antihypertensive drugs (Chapter 28). In this regard, thiazide
diuretics are inexpensive, as efficacious as other classes of
antihypertensive agents, and well tolerated. Thiazides can be
administered once daily, do not require dose titration, and have
few contraindications. Moreover, thiazides have additive or synergistic
effects when combined with other classes of antihypertensive
agents. A common dose for hypertension is 25 mg/day of
hydrochlorothiazide or the dose equivalent of another thiazide.
The ALLHAT study (ALLHAT Officers and Coordinators for the
ALLHAT Collaborative Research Group, 2002) provides strong
evidence that thiazide diuretics are the best initial therapy for
uncomplicated hypertension, a conclusion endorsed by the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (Chobanian et al., 2003)
(Chapter 27). Studies also suggest that the antihypertensive
response to thiazides is influenced by polymorphisms in the
angiotensin-converting enzyme and α-adducin genes (Sciarrone
et al., 2003).
Thiazide diuretics, which reduce urinary Ca 2+ excretion,
sometimes are employed to treat Ca 2+ nephrolithiasis and may be
useful for treatment of osteoporosis (Chapter 44). Thiazide diuretics
also are the mainstay for treatment of nephrogenic diabetes
insipidus, reducing urine volume by up to 50%. Although it may
seem counterintuitive to treat a disorder of increased urine volume
with a diuretic, thiazides reduce the kidney’s ability to
excrete free water. They do so by increasing proximal tubular
water reabsorption (secondary to volume contraction) and by
blocking the ability of the distal convoluted tubule to form dilute
urine. This latter effect results in an increase in urine osmolality.
Since other halides are excreted by renal processes similar to those
for Cl – , thiazide diuretics may be useful for the management of
Br – intoxication.
INHIBITORS OF RENAL EPITHELIAL Na +
CHANNELS (K + -SPARING DIURETICS)
Triamterene (DYRENIUM) and amiloride (MIDAMOR, others)
are the only two drugs of this class in clinical use.
Both drugs cause small increases in NaCl excretion and
usually are employed for their antikaliuretic actions to
offset the effects of other diuretics that increase K + excretion.
Consequently, triamterene and amiloride, along
with spironolactone (described in the next section), often
are classified as potassium (K + )-sparing diuretics.
Chemistry. Amiloride is a pyrazinoylguanidine derivative, and triamterene
is a pteridine (Table 25–6). Both drugs are organic bases
and are transported by the organic base secretory mechanism in
proximal tubule.
Mechanism and Site of Action. Available data suggest
that triamterene and amiloride have similar mechanisms
of action, which is illustrated in Figure 25–10.
Principal cells in the late distal tubule and collecting duct
have, in their luminal membranes, epithelial Na + channels that provide
a conductive pathway for Na + entry into the cell down the electrochemical
gradient created by the basolateral Na + pump. The
higher permeability of the luminal membrane for Na + depolarizes
the luminal membrane but not the basolateral membrane, creating a
lumen-negative transepithelial potential difference. This transepithelial
voltage provides an important driving force for the secretion of
K + into the lumen by K + channels (ROMK) in the luminal membrane.
Carbonic anhydrase inhibitors, loop diuretics, and thiazide
diuretics increase Na + delivery to the late distal tubule and collecting
duct, a situation that often is associated with increased K + and H +
excretion. It is likely that the elevation in luminal Na + concentration
in distal nephron induced by such diuretics augments depolarization
Table 25–6
Inhibitors of Renal Epithelial Na + Channels (K + -Sparing Diuretics)
RELATIVE ORAL t 1/2
ROUTE OF
DRUG STRUCTURE POTENCY AVAILABILITY (HOURS) ELIMINATION
Amiloride O NH
1 15–25% ~21 R
(DYRENIUM)
CI
N C N C NH 2
H
H 2 N N NH 2
Triamterene H 2 N N N NH 2 0.1 ~50% ~4 M
(MIDAMOR)
N
N
NH 2
Abbreviations: R, renal excretion of intact drug; M, metabolism; however, triamterene is transformed into an active metabolite that is excreted
in the urine.