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

the cell. The Na + -P i
symporter is inhibited by PTH. P i
exits the basolateral
membrane down its electrochemical gradient by a poorly
understood transport system.
Only 20-25% of Mg 2+ is reabsorbed in the proximal tubule,
and only 5% is reabsorbed by the DCT and collecting-duct system.
The bulk of Mg 2+ is reabsorbed in the thick ascending limb by a
paracellular pathway driven by the lumen-positive V T
. However,
transcellular movement of Mg 2+ also may occur with basolateral exit
by Na + -Mg 2+ antiport or an Mg 2+ -ATPase.
The renal tubules play an extremely important role in the
reabsorption of HCO 3–
and secretion of protons (tubular acidification)
and thus participate critically in the maintenance of acid-base
balance. These processes are described in the section on carbonic
anhydrase inhibitors.
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 totalbody
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.
Body weight (kg)
Na + (mEq/day)
70
69
68
0
200
150
100
50
0
Excretion > Intake
Na excretion
increases
Excretion
Intake
Diuretic
Body weight
decreases
Steady state
Days
Diuretics not only alter the excretion of Na + but also
may modify renal handling of other cations (e.g., K + , H + ,
Ca 2+ , and Mg 2+ ), anions (e.g., Cl – , HCO 3–
, and H 2
PO 4–
),
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.
INHIBITORS OF CARBONIC
ANHYDRASE
Counter regulatory
mechanisms
still in place
Intake > Excretion
Figure 25–5. Changes in extracellular fluid volume and weight
with diuretic therapy. The period of diuretic administration is
shown in the shaded box along with its effects on body weight in
the upper part of the figure and Na + excretion in the lower half
of the figure. Initially, when Na + excretion exceeds intake, body
weight and extracellular fluid volume (ECFV) decrease.
Subsequently, a new steady state is achieved where Na + intake
and excretion are equal but at a lower ECFV and body weight.
This results from activation of the renin-angiotensin-aldosterone
system (RAAS) and sympathetic nervous system (SNS), “the
braking phenomenon.” When the diuretic is discontinued, body
weight and ECFV rise during a period where Na + intake exceeds
excretion. A new steady state is then reached as stimulation of the
RAAS and SNS wane.
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.
677
CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME