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

692 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 highdose
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.
Therapeutic Uses. 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).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
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 β 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 β or γ 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