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

60 mV
(+) (–)
(–)
15 mV
LATE DISTAL TUBULE
AND COLLECTING DUCT
Principal cell
Principal cell
75 mV
(–) (+)
K + CH
K+
ATPase
(3)
Na + Na + Na +
CH
Na + channel inhibitors
Type A intercalated cell
(1)
H + HCO 3
–
ATPase
(1) A
H 2 CO 3
Cl –
K + Cl –
Lumen
LM
H + CA
CO 2 + H 2 O
CO 2 + H 2 O
Principal cell
CH (2)
Interstitial
space
HCO 3
–
Figure 25–10. Na + reabsorption in late distal tubule and collecting
duct and mechanism of diuretic action of epithelial Na + -
channel inhibitors. Cl – reabsorption (not shown) occurs both
paracellularly and transcellularly, and the precise mechanism of
Cl – transport appears to be species-specific. Numbers in parentheses
indicate stoichiometry. Designated voltages are the potential
differences across the indicated membrane or cell. A,
antiporter; CH, ion channel; CA, carbonic anhydrase; BL, basolateral
membrane; LM, luminal membrane.
of the luminal membrane and thereby enhances the lumen-negative
V T
, which facilitates K + excretion. In addition to principal cells, the
collecting duct also contains type A intercalated cells that mediate H +
secretion into the tubular lumen. Tubular acidification is driven by a
luminal H + -ATPase (proton pump), and this pump is aided by partial
depolarization of the luminal membrane. The luminal H + -ATPase is
of the vacuolar-type and is distinct from the gastric H + -K + -ATPase
that is inhibited by drugs such as omeprazole. However, increased
distal Na + delivery is not the only mechanism by which diuretics
increase K + and H + excretion. Activation of the renin-angiotensinaldosterone
axis by diuretics also contributes to diuretic-induced K +
and H + excretion, as discussed later in the section on mineralocorticoid
antagonists.
Considerable evidence indicates that amiloride blocks epithelial
Na + channels in the luminal membrane of principal cells in late
distal tubule and collecting duct. The amiloride-sensitive Na + channel
(called ENaC) consists of three subunits (α, β, and γ ) (Kleyman
et al., 1999). Although the α subunit is sufficient for channel activity,
maximal Na + permeability is induced when all three subunits are
coexpressed in the same cell, probably forming a tetrameric structure
consisting of two α subunits, one β subunit, and one γ subunit.
CH
BL
(+)
Studies in Xenopus oocytes expressing ENaC suggest that triamterene
and amiloride bind ENaC by similar mechanisms. The K i
of amiloride for ENaC is submicromolar, and molecular studies identified
critical domains in ENaC that participate in amiloride binding
(Kleyman et al., 1999). Liddle syndrome is an autosomal dominant
form of low-renin, volume-expanded hypertension that is due to
mutations in the β or γ subunits, leading to increased basal ENaC
activity.
Effects on Urinary Excretion. Since the late distal tubule
and collecting duct have a limited capacity to reabsorb
solutes, Na + channel blockade in this part of the
nephron only mildly increases Na + and Cl – excretion
rates (~2% of filtered load). Blockade of Na + channels
hyperpolarizes the luminal membrane, reducing the
lumen-negative transepithelial voltage. Since the
lumen-negative potential difference normally opposes
cation reabsorption and facilitates cation secretion,
attenuation of the lumen-negative voltage decreases K + ,
H + , Ca 2+ , and Mg 2+ excretion rates. Volume contraction
may increase reabsorption of uric acid in the proximal
tubule; hence chronic administration of amiloride and
triamterene may decrease uric acid excretion.
Effects on Renal Hemodynamics. Amiloride and triamterene
have little or no effect on renal hemodynamics
and do not alter TGF.
Other Actions. Amiloride, at concentrations higher than needed to
elicit therapeutic effects, also blocks the Na + -H + and Na + -Ca 2+
antiporters and inhibits Na + , K + -ATPase.
Absorption and Elimination. Pharmacokinetic data for
amiloride and triamterene are listed in Table 25–6.
Amiloride is eliminated predominantly by urinary excretion
of intact drug. Triamterene is metabolized extensively to an active
metabolite, 4-hydroxytriamterene sulfate, and this metabolite is
excreted in urine. The pharmacological activity of 4-hydroxytriamterene
sulfate is comparable with that of the parent drug.
Therefore, triamterene toxicity may be enhanced in both hepatic disease
(decreased metabolism of triamterene) and renal failure
(decreased urinary excretion of active metabolite).
Toxicity, Adverse Effects, Contraindications, Drug
Interactions. The most dangerous adverse effect of
renal Na + -channel inhibitors is hyperkalemia, which
can be life-threatening. Consequently, amiloride and triamterene
are contraindicated in patients with hyperkalemia,
as well as in patients at increased risk of
developing hyperkalemia (e.g., patients with renal
failure, patients receiving other K + -sparing diuretics,
patients taking angiotensin-converting enzyme inhibitors,
or patients taking K + supplements). Even NSAIDs can
increase the likelihood of hyperkalemia in patients
receiving Na + -channel inhibitors.
691
CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME