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

Lumen
DISTAL CONVOLUTED TUBULE
Interstitial
space
Na + (1)
Cl – S
Cl – K + CH
(1)
(2) K +
ATPase
(3)
Na +
Na +
Na + -Cl –
symport
inhibitors
Cl –
LM
BL
Figure 25–9. NaCl reabsorption in distal convoluted tubule and
mechanism of diuretic action of Na + -Cl – symport inhibitors.
Numbers in parentheses indicate stoichiometry. S, symporter;
CH, ion channel; BL, basolateral membrane; LM, luminal
membrane.
diuresis. However, since the DCT is not involved in the
mechanism that generates a hypertonic medullary interstitium,
thiazide diuretics do not alter the kidney’s ability
to concentrate urine during hydropenia.
Effects on Renal Hemodynamics. In general, inhibitors
of Na + -Cl – symport do not affect RBF and only variably
reduce GFR owing to increases in intratubular
pressure. Since thiazides act at a point past the macula
densa, they have little or no influence on TGF.
Other Actions. Thiazide diuretics may inhibit cyclic nucleotide phosphodiesterases,
mitochondrial O 2
consumption, and renal uptake of
fatty acids; however, these effects are not clinically significant.
Absorption and Elimination. Pharmacokinetic
parameters of Na + -Cl – symport inhibitors are listed
in Table 25–5.
Note the wide range of half-lives for this class of drugs.
Sulfonamides are organic acids and therefore are secreted into the
proximal tubule by the organic acid secretory pathway. Since thiazides
must gain access to the tubular lumen to inhibit the Na + -Cl –
symporter, drugs such as probenecid can attenuate the diuretic
response to thiazides by competing for transport into proximal
tubule. However, plasma protein binding varies considerably among
thiazide diuretics, and this parameter determines the contribution
that filtration makes to tubular delivery of a specific thiazide.
Toxicity, Adverse Effects, Contraindications, Drug Interactions.
Thiazide diuretics rarely cause CNS (e.g., vertigo, headache, paresthesias,
xanthopsia, and weakness), GI (e.g., anorexia, nausea, vomiting,
cramping, diarrhea, constipation, cholecystitis, and pancreatitis),
hematological (e.g., blood dyscrasias), and dermatological (e.g.,
photosensitivity and skin rashes) disorders. The incidence of erectile
C H
dysfunction is greater with Na + -Cl – symport inhibitors than with several
other antihypertensive agents (e.g., β adrenergic receptor antagonists,
Ca 2+ -channel blockers, or angiotensin converting enzyme
inhibitors) (Grimm et al., 1997), but usually is tolerable. As with loop
diuretics, most serious adverse effects of thiazides are related to
abnormalities of fluid and electrolyte balance. These adverse effects
include extracellular volume depletion, hypotension, hypokalemia,
hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia,
hypercalcemia, and hyperuricemia. Thiazide diuretics have
caused fatal or near-fatal hyponatremia, and some patients are at
recurrent risk of hyponatremia when rechallenged with thiazides.
Thiazide diuretics also decrease glucose tolerance, and latent
diabetes mellitus may be unmasked during therapy. Recent concerns
have also been raised in randomized prospective blood-pressure
lowering trials regarding an increased incidence of type II diabetes
mellitus compared to other antihypertensive agents such as
angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers. The mechanism of impaired glucose tolerance is not completely
understood but appears to involve reduced insulin secretion
and alterations in glucose metabolism. Hyperglycemia may be related
in some way to K + depletion, in that hyperglycemia is reduced when
K + is given along with the diuretic. In addition to contributing to
hyperglycemia, thiazide-induced hypokalemia impairs its antihypertensive
effect and cardiovascular protection (Franse et al., 2000)
afforded by thiazides in patients with hypertension. Thiazide diuretics
also may increase plasma levels of LDL cholesterol, total cholesterol,
and total triglycerides. Thiazide diuretics are contraindicated
in individuals who are hypersensitive to sulfonamides.
With regard to drug interactions, thiazide diuretics may
diminish the effects of anticoagulants, uricosuric agents used to treat
gout, sulfonylureas, and insulin and may increase the effects of anesthetics,
diazoxide, digitalis glycosides, lithium, loop diuretics, and
vitamin D. The effectiveness of thiazide diuretics may be reduced
by NSAIDs, nonselective or selective COX-2 inhibitors, and bile
acid sequestrants (reduced absorption of thiazides). Amphotericin B
and corticosteroids increase the risk of hypokalemia induced by thiazide
diuretics.
A potentially lethal drug interaction warranting special emphasis
is that involving thiazide diuretics and quinidine. Prolongation of
the QT interval by quinidine can lead to the development of polymorphic
ventricular tachycardia (torsades de pointes) owing to triggered
activity originating from early after-depolarizations (Chapter 29).
Torsades de pointes may deteriorate into fatal ventricular fibrillation.
Hypokalemia increases the risk of quinidine-induced torsades
de pointes, and thiazide diuretics cause hypokalemia. Thiazide
diuretic–induced K + depletion may account for many cases of quinidine-induced
torsades de pointes. In addition, alkalinization of the
urine by thiazides increases the systemic exposure to quinidine by
reducing its elimination.
Therapeutic Uses. Thiazide diuretics are used for the
treatment of edema associated with heart (congestive
heart failure), liver (hepatic cirrhosis), and renal
(nephrotic syndrome, chronic renal failure, and acute
glomerulonephritis) disease. With the possible exceptions
of metolazone and indapamide, most thiazide diuretics
are ineffective when the GFR is <30-40 mL/min.
689
CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME