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

682 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.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Effects on Renal Hemodynamics. Osmotic diuretics
increase RBF by a variety of mechanisms. Osmotic
diuretics dilate the afferent arteriole, which increases
P GC
, and dilute the plasma, which decreases Π GC
. These
effects would increase GFR were it not for the fact that
osmotic diuretics also increase P T
. In general, superficial
SNGFR is increased, but total GFR is little changed.
Absorption and Elimination. Pharmacokinetic data on
the osmotic diuretics are listed in Table 25–3. Glycerin
and isosorbide can be given orally, whereas mannitol
and urea must be administered intravenously.
Toxicity, Adverse Effects, Contraindications, and Drug
Interactions. Osmotic diuretics are distributed in the extracellular
fluid and contribute to the extracellular osmolality. Thus, water
is extracted from intracellular compartments, and the extracellular
fluid volume becomes expanded. In patients with heart failure
or pulmonary congestion, this may cause frank pulmonary edema.
Extraction of water also causes hyponatremia, which may explain
the common adverse effects, including headache, nausea, and
vomiting. On the other hand, loss of water in excess of electrolytes
can cause hypernatremia and dehydration. Osmotic diuretics are
contraindicated in patients who are anuric owing to severe renal
disease. Urea may cause thrombosis or pain if extravasation
occurs, and it should not be administered to patients with impaired
liver function because of the risk of elevation of blood ammonia
levels. Both mannitol and urea are contraindicated in patients with
active cranial bleeding. Glycerin is metabolized and can cause
hyperglycemia.
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.
Chemistry. Inhibitors of Na + -K + -2Cl – symport are a chemically diverse
group (Table 25–4). Only furosemide (LASIX, others), bumetanide
(BUMEX, others), ethacrynic acid (EDECRIN, others), and torsemide
(DEMADEX, others) are available currently in the U.S. Furosemide and
bumetanide contain a sulfonamide moiety. Ethacrynic acid is a phenoxyacetic
acid derivative and torsemide is a sulfonylurea.
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