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

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.
Table 25–3
Osmotic Diuretics
ROUTE OF
DRUG STRUCTURE ORAL AVAILABILITY t 1/2
(HOURS) ELIMINATION
Glycerin (OSMOGLYN) Orally active 0.5-0.75 ~80% M
~20% U
Isosorbide (ISMOTIC) Orally active 5-9.5 R
Mannitol (OSMITROL) Negligible 0.25-1.7 a ~80% R
~20% M + B
Urea (UREAPHIL) Negligible ID R
a
In renal failure, 6–36. Abbreviations: R, renal excretion of intact drug; M, metabolism; B, excretion of intact drug into bile; U, unknown pathway of
elimination; ID, insufficient data.