Thiazide Diuretics Chemische Eigenschaften,Einsatz,Produktion Methoden
Biologische Funktion
Thiazide diuretics consist of two distinct groups: those
containing a benzothiadiazine ring, such as hydrochlorothiazide
and chlorothiazide, referred to as thiazide
diuretics, and those that lack this heterocyclic structure
but contain an unsubstituted sulfonamide group.The latter
are called thiazidelike diuretics; they include metolazone,
xipamide, and indapamide. The major thiazide and
thiazidelike drugs available in the United States are
bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide,
hydroflumethiazide, methyclothiazide,
polythiazide, and trichlormethiazide; and chlorthalidone,
indapamide, metolazone, and quinethazone, respectively.
Despite the structural distinctions, the drugs share
the functional attribute of increasing sodium and chloride
excretion by inhibiting Na
+–Cl
- cotransport in distal
convoluted tubules.
Although chlorothiazide and its subsequently developed
congeners retain the sulfamyl group
SO
2NH
2, which is necessary for carbonic anhydrase inhibition,
their primary effect does not rely on carbonic
anhydrase inhibition.
The thiazidelike compounds, including chlorthalidone
(Hygroton), quinethazone (Hydromox), and
metolazone (Zaroxolyn) have similar mechanisms of
action, but they differ substantially from one another in
their duration of action, the degree of carbonic anhydrase
inhibition, and the dose required for maximum
natriuretic activity.
Mechanism of action
Thiazide diuretics act in the distal convoluted tubule,
where they block Na
+–Cl
- cotransport. The
Na
+–Cl
- cotransport takes place on the luminal surface
of distal convoluted tubules.Thus, to exert their diuretic
action, the thiazides must reach the luminal fluid. Since
the thiazide diuretics are largely bound to plasma proteins
and therefore are not readily filtered across the
glomeruli, access to the luminal fluid is accomplished by
the proximal tubule organic acid secretory system. The
drugs then travel along the nephron, presumably being
concentrated as fluid is abstracted, until they reach their
site of inhibitory action in the distal convoluted tubule.
Especially at higher doses, administration of some of
the thiazides results in some degree of carbonic anhydrase
inhibition. However, at usual doses, only chlorothiazide
shows any appreciable carbonic anhydrase inhibitory
activity.
Clinical Use
Thiazides, especially hydrochlorothiazide (Dyazide,
Esidrix, HydroDIURIL, Oretic), are useful adjunctive therapy in controlling the edema associated with congestive
heart failure, cirrhosis, premenstrual tension,
and hormone therapy.They are widely used in the treatment
of hypertension whether or not it is accompanied
by edema.They can be used in patients
with renal disease; however, their diuretic activity is
proportional to the residual tubular functional capacity
of the kidney. The thiazides do not prevent toxemia in
pregnancy, nor are they useful in the treatment of it.
Nebenwirkungen
Thiazides should be used cautiously in the presence of
severe renal and hepatic disease, since azotemia and
coma may result. The most important toxic effect associated
with this class of diuretics is hypokalemia, which
may result in muscular and central nervous system
symptoms, as well as cardiac sensitization. Periodic examination of serum electrolytes
for possible imbalances is strongly recommended.
Appropriate dietary and therapeutic measures
for controlling hypokalemia are described later in this
chapter. The thiazides also possess some diabetogenic
potential, and although pancreatitis during thiazide
therapy has been reported in a few cases, the major
mechanism contributing to the potential for glucose intolerance
is not known.
Stoffwechsel
Orally administered thiazides are rapidly absorbed from
the gastrointestinal tract and begin to produce diuresis
in about 1 hour. Approximately 50% of an oral dose is
excreted in the urine within 6 hours. These compounds
are organic acids and are actively secreted into the proximal
tubular fluid by the organic acid secretory mechanism.
There also appears to be an extrarenal pathway for
their elimination involving the hepatic–biliary acid secretory
system that is particularly important for thiazide
elimination when renal function is impaired.
The thiazides have a variable effect on elimination
of uric acid, which also is secreted by the renal acid secretory
mechanism. Administration of thiazide diuretics,
especially at low doses, may elevate serum uric acid
levels and cause goutlike symptoms. Following large
doses, thiazides may compete with uric acid for active
reabsorption and thereby may promote uric acid elimination
rather than impair it.
Thiazide Diuretics Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
