Principles of
Diuretic Action
By definition, diuretics are drugs that increase the rate
of urine flow; however, clinically useful diuretics also increase the rate of
Na+ excretion (natriuresis) and of an accompanying anion, usually Cl–.
NaCl in the body is the major determinant of extracellular fluid volume, and
most clinical applications of diuretics are directed toward reducing
extracellular fluid volume by decreasing total-body NaCl content. A sustained
imbalance between dietary Na+ intake and Na+ loss is
incompatible with life. A net positive Na+ balance would result in
volume overload with pulmonary edema, and a net negative Na+ balance
would result in volume depletion and cardiovascular collapse. Although
continued diuretic administration causes a sustained net deficit in total-body
Na+, the time course of natriuresis is finite because renal
compensatory mechanisms bring Na+ excretion in line with Na+
intake, a phenomenon known as diuretic braking. These compensatory, or
braking, mechanisms include activation of the sympathetic nervous system,
activation of the rennin–angiotensin–aldosterone axis, decreased arterial blood
pressure (which reduces pressure natriuresis), renal epithelial cell
hypertrophy, increased renal epithelial transporter expression, and perhaps
alterations in natriuretic hormones such as atrial natriuretic peptide
(Ellison, 1999). This is shown in Figure 25–5.
Historically, the classification of diuretics was based
on a mosaic of ideas such as site of action (loop diuretics), efficacy
(high-ceiling diuretics), chemical structure (thiazide diuretics), similarity
of action with other diuretics (thiazide-like diuretics), and effects on K+
excretion (K+-sparing diuretics). However, since the mechanism of
action of each of the major classes of diuretics is now well understood, a
classification scheme based on mechanism of action is used in this chapter.
Diuretics not only alter the excretion of Na+
but also may modify renal handling of other cations (e.g., K+, H+,
Ca2+, and Mg2+), anions (e.g., Cl–, HCO3–,
and H2PO4–), and uric acid. In addition,
diuretics may alter renal hemodynamics indirectly. Table 25–1 gives a
comparison of the general effects of the major diuretic classes.
|
|
|
Diuretic
Mechanism
|
CATIONS
|
ANIONS
|
URIC ACID
|
RENAL HEMODYNAMICS
|
|
(Primary
site of action)
|
Na+
|
K+
|
H+b
|
Ca2+
|
Mg2+
|
Cl–
|
HCO3–
|
H2PO4–
|
Acute
|
Chronic
|
RBF
|
GFR
|
FF
|
TGF
|
|
Inhibitors
of CA (proximal tubule)
|
+
|
++
|
–
|
NC
|
V
|
(+)
|
++
|
++
|
I
|
–
|
–
|
–
|
NC
|
+
|
|
Osmotic
diuretics (loop of Henle)
|
++
|
+
|
I
|
+
|
++
|
+
|
+
|
+
|
+
|
I
|
+
|
NC
|
–
|
I
|
|
Inhibitors
of Na+-K+-2Cl– symport (thick ascending
limb)
|
++
|
++
|
+
|
++
|
++
|
++
|
+c
|
+c
|
+
|
–
|
V(+)
|
NC
|
V(–)
|
–
|
|
Inhibitors
of Na+-Cl– symport (distal convoluted tubule)
|
+
|
++
|
+
|
V(–)
|
V(+)
|
+
|
+c
|
+c
|
+
|
–
|
NC
|
V(–)
|
V(–)
|
NC
|
|
Inhibitors
of renal epithelial Na+ channels (late distal tubule, collecting
duct)
|
+
|
–
|
–
|
–
|
–
|
+
|
(+)
|
NC
|
I
|
–
|
NC
|
NC
|
NC
|
NC
|
|
Antagonists
of mineralocorticoid receptors (late distal tubule, collecting duct)
|
+
|
–
|
–
|
I
|
–
|
+
|
(+)
|
I
|
I
|
–
|
NC
|
NC
|
NC
|
NC
|
|
|
aExcept for uric acid, changes are for
acute effects of diuretics in the absence of significant volume depletion,
which would trigger complex physiological adjustments. bH+,
titratable acid and NH4+. cIn
general, these effects are restricted to those individual agents that inhibit
carbonic anhydrase. However, there are notable exceptions in which symport
inhibitors increase bicarbonate and phosphate (e.g., metolazone, bumetanide).
++, +, (+),–,
NC, V, V(+), V(–) and I indicate marked increase, mild to moderate increase,
slight increase, decrease, no change, variable effect, variable increase,
variable decrease, and insufficient data, respectively. For cations and
anions, the indicated effects refer to absolute changes in fractional
excretion.
RBF, renal blood
flow; GFR, glomerular filtration rate; FF, filtration fraction; TGF,
tubuloglomerular feedback; CA, carbonic anhydrase.
|
Inhibitors of Carbonic Anhydrase
Acetazolamide (
DIAMOX, others) is the prototype of a class of
agents that have limited usefulness as diuretics but have played a major role
in the development of fundamental concepts of renal physiology and
pharmacology.
Mechanism and Site of Action
Proximal tubular epithelial cells are
richly endowed with the zinc metalloenzyme carbonic anhydrase, which is found
in the luminal and basolateral membranes (type IV carbonic anhydrase, an enzyme
tethered to the membrane by a glycosylphosphatidylinositol linkage), as well as
in the cytoplasm (type II carbonic anhydrase). Carbonic anhydrase plays a key
role in NaHCO3 reabsorption and acid secretion.
In the proximal tubule, the
free energy in the Na
+ gradient established by the basolateral Na
+
pump is used by an Na
+-H
+ antiporter (also referred to as
an Na
+-H
+ exchanger [NHE]) in the luminal membrane to
transport H
+ into the tubular lumen in exchange for Na
+
(Figure 25–6). In the lumen, H
+ reacts with filtered HCO
3–
to form H
2CO
3, which decomposes rapidly to CO
2
and water in the presence of carbonic anhydrase in the brush border. Normally,
the reaction occurs slowly, but carbonic anhydrase reversibly accelerates this
reaction several thousand times. CO
2 is lipophilic and rapidly
diffuses across the luminal membrane into the epithelial cell, where it reacts
with water to form H
2CO
3, a reaction catalyzed by
cytoplasmic carbonic anhydrase (Figure 25–6). Continued operation of the Na
+-H
+
antiporter maintains a low proton concentration in the cell, so H
2CO
3
ionizes spontaneously to form H
+ and HCO
3–,
creating an electrochemical gradient for HCO
3– across the
basolateral membrane. The electrochemical gradient for HCO
3–
is used by an Na
+-HCO
3– symporter (also
referred to as the Na
+-HCO
3– co-transporter
[NBC]) in the basolateral membrane to transport NaHCO3 into the interstitial
space. The net effect of this process is transport of NaHCO
3 from
the tubular lumen to the interstitial space, followed by movement of water
(isotonic reabsorption). Removal of water concentrates Cl
– in the
tubular lumen, and consequently, Cl
– diffuses down its concentration
gradient into the interstitium by the paracellular pathway
Other Actions
Carbonic anhydrase is
present in a number of extrarenal tissues, including the eye, gastric mucosa,
pancreas, central nervous system (CNS), and erythrocytes. Carbonic anhydrase in
the ciliary processes of the eye mediates formation of large amounts of HCO
3–
in aqueous humor. Inhibition of carbonic anhydrase decreases the rate of
formation of aqueous humor and consequently reduces intraocular pressure.
Acetazolamide frequently causes paresthesias and somnolence, suggesting an
action of carbonic anhydrase inhibitors in the CNS. The efficacy of
acetazolamide in epilepsy is due in part to the production of metabolic
acidosis; however, direct actions of acetazolamide in the CNS also contribute
to its anticonvulsant action. Owing to interference with carbonic anhydrase
activity in erythrocytes, carbonic anhydrase inhibitors increase CO
2
levels in peripheral tissues and decrease CO
2 levels in expired gas.
Large doses of carbonic anhydrase inhibitors reduce gastric acid secretion, but
this has no therapeutic application. Acetazolamide causes vasodilation by
opening vascular Ca
2+-activated K
+ channels; however, the
clinical significance of this effect is unclear.
Absorption and Elimination
Carbonic anhydrase inhibitors are
avidly bound by carbonic anhydrase, and accordingly, tissues rich in this
enzyme will have higher concentrations of carbonic anhydrase inhibitors
following systemic administration. See Table 25–2 for structures and
pharmacokinetic data.
Therapeutic Uses
Although acetazolamide is used for
treatment of edema, the efficacy of carbonic anhydrase inhibitors as single
agents is low, and carbonic anhydrase inhibitors are not employed widely in
this regard. The combination of acetazolamide with diuretics that block Na
+
reabsorption at more distal sites in the nephron causes a marked natriuretic
response in patients with low basal fractional excretion of Na
+
(<0.2%) who are resistant to diuretic monotherapy (Knauf and Mutschler,
1997). Even so, the long-term usefulness of carbonic anhydrase inhibitors often
is compromised by the development of metabolic acidosis.
The major indication for
carbonic anhydrase inhibitors is open-angle glaucoma. Two products developed
specifically for this use are dorzolamide (
TRUSOPT,
others) and brinzolamide (
AZOPT), which
are available only as ophthalmic drops. Carbonic anhydrase inhibitors also may
be employed for secondary glaucoma and preoperatively in acute angle-closure
glaucoma to lower intraocular pressure before surgery (Chapter 64).
Acetazolamide also is used for the treatment of epilepsy (Chapter 21). The
rapid development of tolerance, however, may limit the usefulness of carbonic
anhydrase inhibitors for epilepsy.
Acetazolamide can provide
symptomatic relief in patients with
high-altitude illness or
mountain
sickness; however, it is more appropriate to give acetazolamide as a
prophylactic measure. Acetazolamide also is useful in patients with familial
periodic paralysis. The mechanism for the beneficial effects of acetazolamide
in altitude sickness and familial periodic paralysis is not clear, but it may
be related to the induction of a metabolic acidosis. Other off-label clinical
uses include the treatment of dural ectasia in individuals with Marfan
syndrome, of sleep apnea, and of idiopathic intracranial hypertension. Finally,
carbonic anhydrase inhibitors can be useful for correcting a metabolic
alkalosis, especially one caused by diuretic-induced increases in H
+
excretion.
Osmotic Diuretics
Osmotic diuretics are agents that are
freely filtered at the glomerulus, undergo limited reabsorption by the renal
tubule, and are relatively inert pharmacologically. Osmotic diuretics are
administered in doses large enough to increase significantly the osmolality of
plasma and tubular fluid. Table 25–3 lists four osmotic diuretics—glycerin (
OSMOGLYN), isosorbide, mannitol (
OSMITROL, others), and urea (currently not
available in the U.S.).
Mechanism and Site of Action
For many years it was thought that
osmotic diuretics act primarily in the proximal tubule as nonreabsorbable
solutes that limit the osmosis of water into the interstitial space and thereby
reduce luminal Na
+ concentration to the point that net Na
+
reabsorption ceases. Although early micropuncture studies supported this
concept, subsequent studies suggested that this mechanism, while operative, may
be of only secondary importance and that the major site of action of osmotic
diuretics is the loop of Henle.
By extracting water from
intracellular compartments, osmotic diuretics expand extracellular fluid
volume, decrease blood viscosity, and inhibit renin release. These effects
increase RBF, and the increase in renal medullary blood flow removes NaCl and
urea from the renal medulla, thus reducing medullary tonicity. Under some
circumstances, prostaglandins may contribute to the renal vasodilation and
medullary washout induced by osmotic diuretics. A reduction in medullary
tonicity causes a decrease in the extraction of water from the DTL, which in
turn limits the concentration of NaCl in the tubular fluid entering the ATL.
This latter effect diminishes the passive reabsorption of NaCl in the ATL. In
addition, the marked ability of osmotic diuretics to inhibit Mg
2+
reabsorption, a cation that is reabsorbed mainly in the thick ascending limb,
suggests that osmotic diuretics also interfere with transport processes in the
thick ascending limb. The mechanism of this effect is unknown.
In summary, osmotic diuretics act
both in proximal tubule and loop of Henle, with the latter being the primary
site of action. Also, osmotic diuretics probably act by an osmotic effect in
the tubules and by reducing medullary tonicity.
Effects on Urinary Excretion
Osmotic diuretics increase urinary
excretion of nearly all electrolytes, including Na
+, K
+,
Ca
2+, Mg
2+, Cl
–, HCO
3–,
and phosphate
Therapeutic Uses
One use for mannitol is in the
treatment of dialysis disequilibrium syndrome. Too rapid a removal of solutes
from the extracellular fluid by hemodialysis results in a reduction in the
osmolality of extracellular fluid. Consequently, water moves from the
extracellular compartment into the intracellular compartment, causing
hypotension and CNS symptoms (headache, nausea, muscle cramps, restlessness,
CNS depression, and convulsions). Osmotic diuretics increase the osmolality of
the extracellular fluid compartment and thereby shift water back into the
extracellular compartment.
By increasing the osmotic
pressure of plasma, osmotic diuretics extract water from the eye and brain. All
osmotic diuretics are used to control intraocular pressure during acute attacks
of glaucoma and for short-term reductions in intraocular pressure both
preoperatively and postoperatively in patients who require ocular surgery.
Also, mannitol and urea are used to reduce cerebral edema and brain mass before
and after neurosurgery.
Inhibitors of Na+-K+-2Cl–
Symport (Loop Diuretics, High-Ceiling Diuretics)
Drugs in this group of diuretics
inhibit activity of the Na
+-K
+-2Cl
– symporter
in the thick ascending limb of the loop of Henle; hence these diuretics also
are referred to as
loop diuretics. Although the proximal tubule
reabsorbs ~65% of filtered Na
+, diuretics acting only in the
proximal tubule have limited efficacy because the thick ascending limb has a
great reabsorptive capacity and reabsorbs most of the rejectate from the
proximal tubule. Diuretics acting predominantly at sites past the thick ascending
limb also have limited efficacy because only a small percentage of the filtered
Na
+ load reaches these more distal sites. In contrast, inhibitors of
Na
+-K
+-2Cl
– symport in thick ascending limb
are highly efficacious, and for this reason, they sometimes are called
high-ceiling
diuretics. The efficacy of inhibitors of Na
+-K
+-2Cl
–
symport in the thick ascending limb of the loop of Henle is due to a
combination of two factors: (1) approximately 25% of the filtered Na
+
load normally is reabsorbed by the thick ascending limb, and (2) nephron
segments past the thick ascending limb do not possess the reabsorptive capacity
to rescue the flood of rejectate exiting the thick ascending limb.
Mechanism and
Site of Action
Inhibitors of Na+-K+-2Cl–
symport act primarily in the thick ascending limb. Micropuncture of the DCT
demonstrates that loop diuretics increase delivery of solutes out of the loop
of Henle. Also, in situ microperfusion of the loop of Henle and in
vitro microperfusion of CTAL indicate inhibition of transport by low
concentrations of furosemide in the perfusate. Some inhibitors of Na+-K+-2Cl–
symport may have additional effects in the proximal tubule; however, the
significance of these effects is unclear.
It was thought initially that Cl– was
transported by a primary active electrogenic transporter in the luminal
membrane independent of Na+. Discovery of furosemide-sensitive Na+-K+-2Cl–
symport in other tissues prompted a more careful investigation of the Na+
dependence of Cl– transport in isolated perfused rabbit CTAL.
Scrupulous removal of Na+ from the luminal perfusate demonstrated
the dependence of Cl– transport on Na+.
It is now well accepted that flux of Na+, K+,
and Cl– from the lumen into epithelial cells in thick ascending limb
is mediated by an Na+-K+-2Cl– symporter
(Figure 25–7). This symporter captures free energy in the Na+
electrochemical gradient established by the basolateral Na+ pump and
provides for "uphill" transport of K+ and Cl–
into the cell. K+ channels in the luminal membrane (called ROMK)
provide a conductive pathway for the apical recycling of this cation, and
basolateral Cl– channels (called CLC-Kb) provide a basolateral exit
mechanism for Cl–. Luminal membranes of epithelial cells in thick
ascending limb have a large conductive pathway (channels) for K+;
therefore, apical membrane voltage is determined by the equilibrium potential
for K+ (EK) and is hyperpolarized. In contrast,
the basolateral membrane has a large conductive pathway (channels) for Cl–,
so the basolateral membrane voltage is less negative than EK;
that is, conductance for Cl– depolarizes the basolateral membrane.
Hyperpolarization of the luminal membrane and depolarization of the basolateral
membrane result in a transepithelial potential difference of ~10 mV, with the
lumen positive with respect to the interstitial space. This lumen-positive
potential difference repels cations (Na+, Ca2+, and Mg2+)
and thereby provides an important driving force for the paracellular flux of
these cations into the interstitial space.
Figure 25–7. 
|
|
|
|
NaCl reabsorption in thick ascending limb and mechanism
of diuretic action of Na+-K+-2Cl symport inhibitors.
Numbers in parentheses indicate stoichiometry. Designated voltages are the
potential differences across the indicated membrane or cell. The mechanisms
illustrated here apply to the medullary, cortical, and postmacular segments
of the thick ascending limb. S, symporter; CH, ion channel; BL, basolateral
membrane; LM, luminal membrane.
|
|
Inhibitors of Na+-K+-2Cl–
symport bind to the Na+-K+-2Cl– symporter in
the thick ascending limb and block its function, bringing salt transport in
this segment of the nephron to a virtual standstill. The molecular mechanism by
which this class of drugs blocks the Na+-K+-2Cl–
symporter is unknown, but evidence suggests that these drugs attach to the Cl–
binding site located in the symporter's transmembrane domain (Isenring and
Forbush, 1997). Inhibitors of Na+-K+-2Cl–
symport also inhibit Ca2+ and Mg2+ reabsorption in the
thick ascending limb by abolishing the transepithelial potential difference
that is the dominant driving force for reabsorption of these cations.
Na
+-K
+-2Cl
–
symporters are an important family of transport molecules found in many
secretory and absorbing epithelia. The rectal gland of the dogfish shark is a
particularly rich source of the protein, and a cDNA encoding an Na
+-K
+-2Cl
–
symporter was isolated from a cDNA library obtained from the dogfish shark
rectal gland by screening with antibodies to the shark symporter (Xu et al.,
1994). Molecular cloning revealed a deduced amino acid sequence of 1191
residues containing 12 putative membrane-spanning domains flanked by long N and
C termini in the cytoplasm. Expression of this protein resulted in Na
+-K
+-2Cl
–
symport that was sensitive to bumetanide. The shark rectal gland Na
+-K
+-2Cl
–
symporter cDNA was used subsequently to screen a human colonic cDNA library,
and this provided Na
+-K
+-2Cl
– symporter cDNA
probes from this tissue. These latter probes were used to screen rabbit renal
cortical and renal medullary libraries, which allowed cloning of the rabbit
renal Na
+-K
+-2Cl
– symporter (Payne and
Forbush, 1994). This symporter is 1099 amino acids in length, is 61% identical
to the dogfish shark secretory Na
+-K
+-2Cl
–
symporter, has 12 predicted transmembrane helices, and contains large N- and
C-terminal cytoplasmic regions. Subsequent studies demonstrated that Na
+-K
+-2Cl
–
symporters are of two varieties (Kaplan et al., 1996). The
"absorptive" symporter (called
ENCC2, NKCC2, or
BSCl)
is expressed only in the kidney, is localized to the apical membrane and subapical
intracellular vesicles of the thick ascending limb, and is regulated by cyclic
AMP/PKA (Obermüller et al., 1996; Plata et al., 1999). At least six different
isoforms of the absorptive symporter are generated by alternative mRNA splicing
(Mount et al., 1999), and alternative splicing of the absorptive symporter
determines the dependency of transport on K
+ (Plata et al., 2001).
The "secretory" symporter (called
ENCC3, NKCCl, or
BSC2)
is a "housekeeping" protein that is expressed widely and, in epithelial
cells, is localized to the basolateral membrane. The affinity of loop diuretics
for the secretory symporter is somewhat less than for the absorptive symporter
(e.g., 4-fold difference for bumetanide). A model of Na
+-K
+-2Cl
–
symport has been proposed based on ordered binding of ions to the symporter
(Lytle et al., 1998). Mutations in genes coding for the absorptive Na
+-K
+-2Cl
–
symporter, the apical K
+ channel, the basolateral Cl
–
channel, or the chloride channel subunit Barttin are causes of Bartter syndrome
(inherited hypokalemic alkalosis with salt wasting and hypotension) (Simon and
Lifton, 1998).
Other Actions
Loop diuretics may cause
direct vascular effects. Loop diuretics, particularly furosemide, acutely
increase systemic venous capacitance and thereby decrease left ventricular
filling pressure. This effect, which may be mediated by prostaglandins and
requires intact kidneys, benefits patients with pulmonary edema even before
diuresis ensues. Furosemide and ethacrynic acid can inhibit Na
+,K
+-ATPase,
glycolysis, mitochondrial respiration, the microsomal Ca
2+ pump,
adenylyl cyclase, phosphodiesterase, and prostaglandin dehydrogenase; however,
these effects do not have therapeutic implications.
In vitro, high doses
of inhibitors of Na
+-K
+-2Cl
– symport can
inhibit electrolyte transport in many tissues. Only in the inner ear, where
alterations in the electrolyte composition of endolymph may contribute to
drug-induced ototoxicity, is this effect important clinically. Irreversible
ototoxicity is more common at high doses, with rapid IV administration, and
during concommitant therapy with other drugs known to be ototoxic (e.g.,
aminoglycoside antibiotics, cisplatin, vancomycin).
Therapeutic Uses
All loop diuretics except torsemide
are available as oral and injectable formulations. Bumetanide is labeled for
once daily administration and may be used in patients allergic to furosemide
(the bumetamide:furosemide conversion ratio is approximatly 1:40). A major use
of loop diuretics is in the treatment of acute pulmonary edema. A rapid
increase in venous capacitance in conjunction with a brisk natriuresis reduces
left ventricular filling pressures and thereby rapidly relieves pulmonary
edema. Loop diuretics also are used widely for treatment of chronic congestive
heart failure when diminution of extracellular fluid volume is desirable to
minimize venous and pulmonary congestion (Chapter 28). In this regard, a
meta-analysis of randomized clinical trials demonstrates that diuretics cause a
significant reduction in mortality and the risk of worsening heart failure, as
well as an improvement in exercise capacity (Faris et al., 2002).
Diuretics are used widely for
treatment of hypertension (Chapter 28), and controlled clinical trials
demonstrating reduced morbidity and mortality have been conducted with Na
+-Cl
–
symport (thiazides and thiazide-like diuretics) but not Na
+-K
+-2Cl
–
symport inhibitors. Nonetheless, Na
+-K
+-2Cl
–
symport inhibitors appear to lower blood pressure as effectively as Na
+-Cl
–
symport inhibitors while causing smaller perturbations in the lipid profile.
However, the relative potency and short elimination half-lives of loop
diuretics render them less useful for hypertension than thiazide-type diuretics.
The edema of nephrotic
syndrome often is refractory to less potent diuretics, and loop diuretics often
are the only drugs capable of reducing the massive edema associated with this
renal disease. Loop diuretics also are employed in the treatment of edema and
ascites of liver cirrhosis; however, care must be taken not to induce volume
contraction. In patients with a drug overdose, loop diuretics can be used to
induce a forced diuresis to facilitate more rapid renal elimination of the
offending drug. Loop diuretics, combined with isotonic saline administration to
prevent volume depletion, are used to treat hypercalcemia. Loop diuretics
interfere with the kidney's capacity to produce a concentrated urine.
Consequently, loop diuretics combined with hypertonic saline are useful for the
treatment of life-threatening hyponatremia.
Loop diuretics also are
used to treat edema associated with chronic kidney disease. Higher doses of
loop diuretics are often required in patients with chronic kidney disease. The dose-response
curve is shifted to the right (Figure 25–8). Animal studies have demonstrated
that loop diuretics increase
PGC by activating the
renin-angiotensin system, an effect that could accelerate renal injury (Lane et
al., 1998). Most patients with ARF receive a trial dose of a loop diuretic in
an attempt to convert oliguric ARF to nonoliguric ARF. However, there is no
evidence that loop diuretics prevent ATN or improve outcome in patients with
ARF, and as mentioned earlier, the appearance of undesired effects increases
with dose.
Inhibitors of Na+-Cl–
Symport (Thiazide and Thiazide-Like Diuretics)
Benzothiadiazides were synthesized in
an effort to enhance the potency of inhibitors of carbonic anhydrase. However,
unlike carbonic anhydrase inhibitors (that primarily increase NaHCO3
excretion), benzothia diazides predominantly increase NaCl excretion, an effect
shown to be independent of carbonic anhydrase inhibition.
Mechanism and
Site of Action
Some studies using split-droplet and
stationary-microperfusion techniques described reductions in proximal tubule reabsorption
by thiazide diuretics; however, free-flow micropuncture studies have not
consistently demonstrated increased solute delivery out of the proximal tubule
following administration of thiazides. In contrast, micropuncture and in
situ microperfusion studies clearly indicate that thiazide diuretics
inhibit NaCl transport in DCT. The DCT expresses thiazide binding sites and is
accepted as the primary site of action of thiazide diuretics; the proximal
tubule may represent a secondary site of action.
Figure 25–9 illustrates the current model of electrolyte
transport in DCT. As with other nephron segments, transport is powered by a Na+
pump in the basolateral membrane. Free energy in the electrochemical gradient
for Na+ is harnessed by an Na+-Cl– symporter
in the luminal membrane that moves Cl– into the epithelial cell
against its electrochemical gradient. Cl– then exits the basolateral
membrane passively by a Cl– channel. Thiazide diuretics inhibit the
Na+-Cl– symporter. In this regard, Na+ or Cl–
binding to the Na+-Cl– symporter modifies
thiazide-induced inhibition of the symporter, suggesting that the
thiazide-binding site is shared or altered by both Na+ and Cl–.
Figure 25–9. 
|
|
|
|
NaCl reabsorption in distal convoluted tubule and
mechanism of diuretic action of Na+-Cl– symport
inhibitors. Numbers
in parentheses indicate stoichiometry. S, symporter; CH, ion channel; BL,
basolateral membrane; LM, luminal membrane.
|
|
Using a functional expression strategy (Cl–-dependent
Na+ uptake in Xenopus oocytes), Gamba and colleagues (1993)
isolated a cDNA clone from the urinary bladder of the winter flounder that
codes for an Na+-Cl– symporter. This Na+-Cl–
symporter is inhibited by a number of thiazide diuretics (but not by
furosemide, acetazolamide, or an amiloride derivative) and has 12 putative
membrane-spanning domains, and its sequence is 47% identical to the cloned
dogfish shark rectal gland Na+-K+-2Cl–
symporter. Subsequently, the rat and human Na+-Cl–
symporters were cloned. The human Na+-Cl– symporter has a
predicted sequence of 1021 amino acids, 12 transmembrane domains, and 2
intracellular hydrophilic amino and carboxyl termini and maps to chromosome
16q13. The Na+-Cl– symporter (called ENCCl or TSC)
is expressed predominantly in kidney and is localized to the apical membrane of
DCT epithelial cells (Bachmann et al., 1995). Expression of the Na+-Cl–
symporter is regulated by aldosterone (Velázquez et al., 1996). Mutations in
the Na+-Cl– symporter cause a form of inherited
hypokalemic alkalosis called Gitelman syndrome (Simon and Lifton, 1998).
Effects on Urinary Excretion
As would be expected from their mechanism of action,
inhibitors of Na+-Cl– symport increase Na+ and
Cl– excretion. However, thiazides are only moderately efficacious
(i.e., maximum excretion of filtered Na+ load is only 5%) because
~90% of the filtered Na+ load is reabsorbed before reaching the DCT.
Some thiazide diuretics also are weak inhibitors of carbonic anhydrase, an
effect that increases HCO3– and phosphate excretion and
probably accounts for their weak proximal tubular effects. Like inhibitors of
Na+-K+-2Cl– symport, inhibitors of Na+-Cl–
symport increase K+ and titratable acid excretion by the same
mechanisms discussed for loop diuresis. Acute thiazide administration increases
uric acid excretion. However, uric acid excretion is reduced following chronic
administration by the same mechanisms discussed for loop diuretics. The acute
effects of inhibitors of Na+-Cl– symport on Ca2+
excretion are variable; when administered chronically, thiazide diuretics
decrease Ca2+ excretion. The mechanism involves increased proximal
reabsorption owing to volume depletion, as well as direct effects of thiazides
to increase Ca2+ reabsorption in the DCT. Thiazide diuretics may
cause a mild magnesuria by a poorly understood mechanism, and there is
increasing awareness that long-term use of thiazide diuretics may cause
magnesium deficiency, particularly in the elderly. Since inhibitors of Na+-Cl–
symport inhibit transport in the cortical diluting segment, thiazide diuretics
attenuate the kidney's ability to excrete dilute urine during water diuresis.
However, since the DCT is not involved in the mechanism that generates a
hypertonic medullary interstitium, thiazide diuretics do not alter the kidney's
ability to concentrate urine during hydropenia.
Other Actions
Thiazide diuretics may
inhibit cyclic nucleotide phosphodiesterases, mitochondrial O
2
consumption, and renal uptake of fatty acids; however, these effects are not
clinically significant.
Absorption and Elimination
Pharmacokinetic parameters of Na
+-Cl
–
symport inhibitors are listed in Table 25–5.
Note the wide range of
half-lives for this class of drugs. Sulfonamides are organic acids and
therefore are secreted into the proximal tubule by the organic acid secretory
pathway. Since thiazides must gain access to the tubular lumen to inhibit the
Na
+-Cl
– symporter, drugs such as probenecid can attenuate
the diuretic response to thiazides by competing for transport into proximal
tubule. However, plasma protein binding varies considerably among thiazide
diuretics, and this parameter determines the contribution that filtration makes
to tubular delivery of a specific thiazide.
Toxicity, Adverse Effects,
Contraindications, Drug Interactions
Thiazide diuretics rarely
cause CNS (e.g., vertigo, headache, paresthesias, xanthopsia, and weakness), GI
(e.g., anorexia, nausea, vomiting, cramping, diarrhea, constipation,
cholecystitis, and pancreatitis), hematological (e.g., blood dyscrasias), and
dermatological (e.g., photosensitivity and skin rashes) disorders. The
incidence of erectile dysfunction is greater with Na
+-Cl
–
symport inhibitors than with several other antihypertensive agents (e.g.,
adrenergic receptor antagonists,
Ca
2+-channel blockers, or angiotensin converting enzyme inhibitors)
(Grimm et al., 1997), but usually is tolerable. As with loop diuretics, most
serious adverse effects of thiazides are related to abnormalities of fluid and
electrolyte balance. These adverse effects include extracellular volume
depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic
alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia. Thiazide diuretics
have caused fatal or near-fatal hyponatremia, and some patients are at
recurrent risk of hyponatremia when rechallenged with thiazides.
Thiazide diuretics also
decrease glucose tolerance, and latent diabetes mellitus may be unmasked during
therapy. Recent concerns have also been raised in randomized prospective
blood-pressure lowering trials regarding an increased incidence of type II
diabetes mellitus compared to other antihypertensive agents such as
angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The
mechanism of impaired glucose tolerance is not completely understood but
appears to involve reduced insulin secretion and alterations in glucose
metabolism. Hyperglycemia may be related in some way to K
+
depletion, in that hyperglycemia is reduced when K
+ is given along
with the diuretic. In addition to contributing to hyperglycemia,
thiazide-induced hypokalemia impairs its antihypertensive effect and
cardiovascular protection (Franse et al., 2000) afforded by thiazides in
patients with hypertension. Thiazide diuretics also may increase plasma levels
of LDL cholesterol, total cholesterol, and total triglycerides. Thiazide
diuretics are contraindicated in individuals who are hypersensitive to
sulfonamides.
With regard to drug
interactions, thiazide diuretics may diminish the effects of anticoagulants,
uricosuric agents used to treat gout, sulfonylureas, and insulin and may
increase the effects of anesthetics, diazoxide, digitalis glycosides, lithium,
loop diuretics, and vitamin D. The effectiveness of thiazide diuretics may be
reduced by NSAIDs, nonselective or selective COX-2 inhibitors, and bile acid
sequestrants (reduced absorption of thiazides). Amphotericin B and
corticosteroids increase the risk of hypokalemia induced by thiazide diuretics.
A potentially lethal drug
interaction warranting special emphasis is that involving thiazide diuretics
and quinidine. Prolongation of the QT interval by quinidine can lead to the
development of polymorphic ventricular tachycardia (torsades de pointes) owing
to triggered activity originating from early after-depolarizations (Chapter
29). Torsades de pointes may deteriorate into fatal ventricular fibrillation.
Hypokalemia increases the risk of quinidine-induced torsades de pointes, and
thiazide diuretics cause hypokalemia. Thiazide diuretic–induced K
+
depletion may account for many cases of quinidine-induced torsades de pointes.
In addition, alkalinization of the urine by thiazides increases the systemic
exposure to quinidine by reducing its elimination.
Thiazide diuretics are used for the
treatment of edema associated with heart (congestive heart failure), liver
(hepatic cirrhosis), and renal (nephrotic syndrome, chronic renal failure, and
acute glomerulonephritis) disease. With the possible exceptions of metolazone
and indapamide, most thiazide diuretics are ineffective when the GFR is
<30-40 mL/min.
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
-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.
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 of the luminal membrane and thereby enhances the lumen-negative VT,
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-angiotensin-aldosterone
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 (
,
, and
) (Kleyman et al., 1999).
Although the
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
subunits, one
subunit, and one
subunit. Studies in
Xenopus
oocytes expressing ENaC suggest that triamterene and amiloride bind ENaC by
similar mechanisms. The
Ki 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
or
subunits, leading to increased
basal ENaC activity
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.
Pentamidine and high-dose
trimethoprim are used often to treat
Pneumocystis jirovecii pneumonia in
patients with acquired immune deficiency syndrome (AIDS). Because these
compounds are weak inhibitors of ENaC, they too may cause hyperkalemia. Risk
with trimethoprim is related to both the dosage employed and the underlying
level of renal function. It was first reported with high-dose therapy (200
mg/kg/day) in 1983. Subsequent reports of hyperkalemia occurred in HIV-infected
patients with normal renal function on high doses of the drug. In one series of
30 such patients, 50% developed a serum K
+ concentration >5.0
mEq/L and 10% >6.0 mEq/L. In a prospective study of otherwise healthy
outpatients, the frequency was lower with a serum K
+ concentration
>5.5 mEq/L in only 6%. Within 3-10 days after onset of treatment, 10-21% of
patients develop a K
+ concentration >5.5 mEq/L (Perazella, 2000).
Risk factors for severe hyperkalemia are older age, high-dose therapy, renal
impairment, hypoaldosteronism, and treatment with other drugs that impair renal
K
+ excretion (e.g., NSAIDs and ACE inhibitors). Serum K
+
concentration should be monitored after 3-4 days of trimethoprim treatment
especially in those at increased risk. Likewise, routine monitoring of the
serum K
+ level is essential in patients receiving K
+-sparing
diuretics. Cirrhotic patients are prone to megaloblastosis because of folic
acid deficiency, and triamterene, a weak folic acid antagonist, may increase
the likelihood of this adverse event. Triamterene also can reduce glucose
tolerance and induce photosensitization and has been associated with
interstitial nephritis and renal stones. Both drugs can cause CNS, GI,
musculoskeletal, dermatological, and hematological adverse effects. The most
common adverse effects of amiloride are nausea, vomiting, diarrhea, and
headache; those of triamterene are nausea, vomiting, leg cramps, and dizziness.
Because of the mild natriuresis
induced by Na
+-channel inhibitors, these drugs seldom are used as
sole agents in treatment of edema or hypertension. Rather, their major utility
is in combination with other diuretics; indeed, each is marketed in a
fixed-dose combination with a thiazide: triamterene/hydrochlorothiazide (
DYAZIDE,
MAXZIDE,
others), amiloride/hydrochlorothiazide (generic).
Co-administration of an Na
+-channel
inhibitor augments the diuretic and antihypertensive response to thiazide and
loop diuretics. More important, the ability of Na
+-channel
inhibitors to reduce K
+ excretion tends to offset the kaliuretic
effects of thiazide and loop diuretics; consequently, the combination of an Na
+-channel
inhibitor with a thiazide or loop diuretic tends to result in normal plasma K
+
values. Liddle syndrome can be treated effectively with Na
+-channel
inhibitors. Approximately 5% of people of African origin carry a
T594M polymorphism
in the
subunit of ENaC, and amiloride
is particularly effective in lowering blood pressure in patients with
hypertension who carry this polymorphism (Baker et al., 2002). Aerosolized
amiloride has been shown to improve mucociliary clearance in patients with
cystic fibrosis. By inhibiting Na
+ absorption from the surfaces of
airway epithelial cells, amiloride augments hydration of respiratory secretions
and thereby improves mucociliary clearance. Amiloride also is useful for
lithium-induced nephrogenic diabetes insipidus because it blocks Li
+
transport into collecting tubule cells.
Antagonists of
Mineralocorticoid Receptors (Aldosterone Antagonists, K+-Sparing
Diuretics)
Mineralocorticoids cause salt and
water retention and increase K
+ and H
+ excretion by
binding to specific mineralocorticoid receptors. Early studies indicated that some
spirolactones block the effects of mineralocorticoids; this finding led to the
synthesis of specific antagonists for the mineralocorticoid receptor (MR).
Currently, two MR antagonists are available in the U.S., spironolactone (a
17-spirolactone; ALDACTONE, others) and eplerenone (
INSPRA, others); two others are available elsewhere (Table
25–7).
Mechanism and
Site of Action
Epithelial cells in late distal tubule and collecting
duct contain cytosolic MRs with a high aldosterone affinity. MRs are members of
the superfamily of receptors for steroid hormones, thyroid hormones, vitamin D,
and retinoids. Aldosterone enters the epithelial cell from the basolateral
membrane and binds to MRs; the MR-aldosterone complex translocates to the
nucleus, where it binds to specific sequences of DNA (hormone-responsive
elements) and thereby regulates the expression of multiple gene products called
aldosterone-induced proteins (AIPs). Consequently, transepithelial NaCl
transport is enhanced, and the lumen-negative transepithelial voltage is
increased. The latter effect increases the driving force for K+ and
H+ secretion into the tubular lumen.
The discovery of gene mutation responsible for rare
monogenic diseases that cause hypertension such as Liddle syndrome and apparent
mineralocorticoid excess helped clarify how aldosterone regulates Na+
transport in the distal nephron (Figure 25–11). Mutations in the
carboxy-terminal PY motif of either the or subunits of ENaC are associated with
Liddle syndrome. The PY motif is an area involved in protein-protein
interaction. The PY motif of ENaC interacts with the ubiquitin ligase Nedd4-2,
a protein that ubiquitinates ENaC. This then results in internalization of ENaC
and proteasome-mediated degradation. Subsequent studies revealed that Nedd4-2
is phosphorylated and inactivated by SGK1 (serum and glucocorticoid-stimulated
kinase) and that SGK1 is up-regulated after ~30 minutes by aldosterone. By
tracing back the pathophysiologic mechanism of Liddle syndrome, one of the
mechanisms whereby aldosterone acts in the collecting duct was identified.
Aldosterone up-regulates SGK1, which phosphorylates and inactivates Nedd4-2. As
a result, ENaC is not ubiquitinated and removed from the membrane, thereby
increasing Na+ reabsorption. When the mineralocorticoid receptor was
cloned and tested in vitro it was noted to have equal affinity for
mineralocorticoid and glucocorticoids. It had been assumed that the
mineralocorticoid receptor would have specificity for mineralocorticoids, but
surprisingly this was not the case. Given that glucocorticoids circulate at
100- to 1000-fold higher concentration than mineralocorticoids, it was unclear
how mineralocorticoids would ever bind to their receptor. The mineralocorticoid
receptor would be predominantly occupied by glucocorticoids. This mystery was
solved with the cloning of the enzyme type II 11--hydroxysteroid dehydrogenase (HSD).
Mineralocorticoid target tissues expresses type II 11--HSD, which converts cortisol to the
inactive cortisone. This allows mineralocorticoids to bind to the receptor. The
type II 11--HSD enzyme is genetically absent in
the inherited disorder of apparent mineralocorticoid excess.
Figure 25–11. 
|
|
|
|
Effects of aldosterone on late distal tubule and
collecting duct and diuretic mechanism of aldosterone antagonists. A. Cortisol also has affinity
for the mineralocorticoid receptor (MR), but is inactivated in the cell by
11--hydroxysteroid dehydrogenase
(HSD) type II. B. Serum and glucorticoid-regulated kinase (SGK)-1 is
upregulated after ~30 minutes by aldosterone. SGK-1 phosphorylates and
inactivates Nedd4-2 a ubiquitin-protein ligase that acts on ENaC, leading
to its degradation. Phosphorylated Nedd4-2 no longer interacts with the PY
motif of ENaC. As a result, the protein is not ubiquitinated and remains in
the membrane, the end result of which is increased Na+ entry
into the cell. 1. Activation of membrane-bound Na+ channels. 2.
Na+ channel (ENaC) removal from the membrane is inhibited. 3. De
novo synthesis of Na+ channels. 4. Activation of
membrane-bound Na+,K+- ATPase. 5. Redistribution of
Na+,K+-ATPase from cytosol to membrane. 6. De novo
synthesis of Na+,K+-ATPase. 7. Changes in
permeability of tight junctions. 8. Increased mitochondrial production of
ATP. AIP, aldosterone-induced proteins; ALDO, aldosterone; MR,
mineralocorticoid receptor; CH, ion channel; BL, basolateral membrane; LM,
luminal membrane.
|
|
Drugs such as spironolactone and eplerenone competitively
inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone
complex, the MR-spironolactone complex is not able to induce the synthesis of
AIPs. Since spironolactone and eplerenone block biological effects of
aldosterone, these agents also are referred to as aldosterone antagonists.
Spironolactone has some
affinity toward progesterone and androgen receptors and thereby induces side
effects such as gynecomastia, impotence, and menstrual irregularities. Owing to
the 9,11-epoxide group, eplerenone has very low affinity for progesterone and
androgen receptors (<1% and <0.1%, respectively) compared with
spironolactone. High spironolactone concentrations were reported to interfere
with steroid biosynthesis by inhibiting steroid hydroxylases (e.g., CYPs 11A1,
11B1, 11B2, and C21; see Chapters 40 and 41). These effects have limited
clinical relevance.
R antagonists
are the only diuretics that do not require access to the tubular lumen to
induce diuresis.
Toxicity, Adverse Effects, Contraindications, Drug
Interactions
As with other K
+-sparing
diuretics, MR antagonists may cause life-threatening hyperkalemia. Indeed,
hyperkalemia is the principal risk of MR antagonists. Therefore, these drugs
are contraindicated in patients with hyperkalemia and in those at increased
risk of developing hyperkalemia either because of disease or administration of
other medications. MR antagonists also can induce metabolic acidosis in
cirrhotic patients.
Salicylates may reduce the
tubular secretion of canrenone and decrease diuretic efficacy of
spironolactone, and spironolactone may alter the clearance of digitalis
glycosides. Owing to its affinity for other steroid receptors, spironolactone
may cause gynecomastia, impotence, decreased libido, hirsutism, deepening of
the voice, and menstrual irregularities. Spironolactone also may induce
diarrhea, gastritis, gastric bleeding, and peptic ulcers (the drug is
contraindicated in patients with peptic ulcers). CNS adverse effects include
drowsiness, lethargy, ataxia, confusion, and headache. Spironolactone may cause
skin rashes and, rarely, blood dyscrasias. Breast cancer has occurred in
patients taking spironolactone chronically (cause and effect not established),
and high doses of spironolactone are associated with malignant tumors in rats.
Whether or not therapeutic spironolactone doses can induce malignancies remains
an open question. Strong inhibitors of CYP3A4 may increase plasma levels of
eplerenone, and such drugs should not be administered to patients taking
eplerenone, and vice versa. Other than hyperkalemia and GI disorders, the rate
of adverse events for eplerenone is similar to that of placebo (Pitt et al.,
2003).
As with other K
+-sparing
diuretics, spironolactone often is coadministered with thiazide or loop
diuretics in the treatment of edema and hypertension, and spironolactone in
combination with hydrochlorothiazide (
ALDACTAZIDE,
others) is marketed. Such combinations result in increased mobilization of
edema fluid while causing lesser perturbations of K
+ homeostasis.
Spironolactone is particularly useful in the treatment of resistant
hypertension due to primary hyperaldosteronism (adrenal adenomas or bilateral
adrenal hyperplasia) and of refractory edema associated with secondary
aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and
severe ascites). Spironolactone is considered the diuretic of choice in
patients with hepatic cirrhosis. Spironolactone, added to standard therapy,
substantially reduces morbidity and mortality (Pitt et al., 1999) and
ventricular arrhythmias (Ramires et al., 2000) in patients with heart failure
(Chapter 28).
Clinical experience with
eplerenone is less than that with spironolactone. Eplerenone appears to be a
safe and effective antihypertensive drug (Ouzan et al., 2002). It is somewhat
more specific for the MR and therefore the incidience of progesterone-related
adverse effects (e.g., gynecomastia) is lower than with spironolactone. In
patients with acute myocardial infarction complicated by left ventricular
systolic dysfunction, addition of eplerenone to optimal medical therapy
significantly reduces morbidity and mortality (Pitt et al., 2003).
All
locations of a flame are not equal in temperature, and are not equal in
fuel to oxidant ratio. The three main zones of a flame include the
primary combustion zone, secondary combustion zone, and the interzonal
region. The interzonal region is prevalent in free atoms and is the
hottest area of the flame. It is therefore the region used for
spectroscopic analysis. The flame usually rises about 5 cm above the
burner tip, with 2.5cm being the max temperature point. The portion of
the flame used for AAS is specific as to what element is being analyzed.
Due to the formation of oxides, different elements achieve max
absorbance at different distances (cm) above the burner.
