Page 283 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 269

If lithium is being used for a psychiatric disorder, nephrogenic therefore produce more than an additive diuretic response. Second,
diabetes insipidus can be treated with a thiazide diuretic or thiazide diuretics often produce a mild natriuresis in the proximal
amiloride (see Diabetes Insipidus, below). tubule that is usually masked by increased reabsorption in the TAL.
The combination of loop diuretics and thiazides can therefore
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B. Renal Failure reduce Na reabsorption, to some extent, from all three segments.
Both lithium and demeclocycline have been reported to cause Metolazone is the thiazide-like drug usually used in patients
acute renal failure. Long-term lithium therapy may also cause refractory to loop agents alone, but it is likely that other thiazides
chronic interstitial nephritis. at equipotent doses would be just as effective. Moreover, metola-
zone is available only in an oral preparation, whereas chlorothia-
C. Other zide can be given parenterally.
Dry mouth and thirst are common with many of these drugs. The combination of loop diuretics and thiazides can mobilize
Tolvaptan may cause hypotension. Multiple adverse effects asso- large amounts of fluid, even in patients who have not responded
ciated with lithium therapy have been found and are discussed to single agents. Therefore, close hemodynamic monitoring is
in Chapter 29. Demeclocycline should be avoided in patients essential. Routine outpatient use is not recommended but may be
with liver disease (see Chapter 44) and in children younger than possible with extreme caution and close follow-up. Furthermore,
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12 years. Tolvaptan may also cause an elevation in liver function K wasting is extremely common and may require parenteral K
tests and is relatively contraindicated in patients with liver disease. administration with careful monitoring of fluid and electrolyte
status. The first large-scale randomized controlled trial of combi-
nation loop and thiazide diuretic therapy in patients with heart
UREARETICS failure is currently under way in the CLOROTIC (Combination
of Loop with Thiazide-type Diuretics in Patients with Decom-
Medullary urine concentration depends in large part on urea pensated Heart Failure) trial. Clinical experience suggests that in
movement in the kidney. Two families of urea transporters have outpatients, adverse effects of thiazides as add-on therapy to loop
been described. UT-A is present in inner medullary collecting duct diuretics can be mitigated by infrequent low-dose therapy. Add-on
cells and the thin descending limb of Henle. UT-B is present in diuretic therapy with metolazone is started at 2.5 mg weekly and
the descending vasa recta and several extrarenal tissues. Inhibitors titrated up slowly as needed, with close monitoring of the patient’s
of both UT-A and UT-B (eg, PU-14) have been developed and blood pressure and serum potassium concentration.
are currently in preclinical studies. These agents are aquaretics
that increase urea and water excretion but not sodium excretion.
Urea transport inhibitors have been shown to blunt the increase POTASSIUM-SPARING DIURETICS &
in urine osmolality seen after desmopressin administration. These PROXIMAL TUBULE DIURETICS, LOOP
agents may prove to be useful in edematous states and even in AGENTS, OR THIAZIDES
SIADH; however, their potential clinical role as compared to that
of vaptans remains to be established. Hypokalemia often develops in patients taking carbonic anhydrase
inhibitors, loop diuretics, or thiazides. This can usually be man-
DIURETIC COMBINATIONS aged by dietary NaCl restriction or by taking dietary KCl supple-
ments. When hypokalemia cannot be managed in this way, the
LOOP AGENTS & THIAZIDES addition of a K -sparing diuretic can significantly lower K excre-
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tion. Although this approach is generally safe, it should be avoided
Some patients are refractory to the usual dose of loop diuretics in patients with renal insufficiency and in those receiving angioten-
or become refractory after an initial response. Since these agents sin antagonists such as ACE inhibitors, in whom life-threatening
have a short half-life (2–6 hours), refractoriness may be due to hyperkalemia can develop in response to K -sparing diuretics.
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an excessive interval between doses. Renal Na retention may
be greatly increased during the time period when the drug is no
longer active. It was hoped that continuous loop diuretic infusions ■ CLINICAL PHARMACOLOGY OF
would be useful in treating patients with heart failure and diuretic
resistance, but one high-quality study did not show a benefit for DIURETIC AGENTS
continuous loop diuretic infusion as opposed to bolus doses.
However, after the dosing interval for loop agents is minimized A summary of the effects of diuretics on urinary electrolyte
or the dose is maximized, the use of two drugs acting at different excretion is shown in Table 15–2.
nephron sites may exhibit dramatic synergy. Loop agents and thia-
zides in combination often produce diuresis when neither agent EDEMATOUS STATES
acting alone is even minimally effective. There are several reasons
for this phenomenon. A common reason for diuretic use is for reduction of peripheral
First, salt reabsorption in either the TAL or the DCT can or pulmonary edema that has accumulated as a result of cardiac,
increase when the other is blocked. Inhibition of both can renal, or vascular diseases that reduce blood flow to the kidney.