Page 280 - Basic _ Clinical Pharmacology ( PDFDrive )

266 SECTION III Cardiovascular-Renal Drugs

long half-lives (12–20 and approximately 14 hours, respectively). TABLE 15–7 Potassium-sparing diuretics and
Spironolactone binds with high affinity and potently inhibits the combination preparations.
androgen receptor, which is an important source of side effects in
males (notably, gynecomastia and decreased libido). Eplerenone Potassium-Sparing
is a spironolactone analog with much greater selectivity for the Trade Name Agent Hydrochlorothiazide
mineralocorticoid receptor. It is several hundredfold less active Aldactazide Spironolactone 25 mg 50 mg
on androgen and progesterone receptors than spironolactone, and Aldactone Spironolactone 25, 50, —
therefore, eplerenone has considerably fewer adverse effects (eg, or 100 mg
gynecomastia). Finerenone is a new investigational agent in this Dyazide Triamterene 37.5 mg 25 mg
class. It is a nonsteroidal mineralocorticoid antagonist that reduces Dyrenium Triamterene 50 or —
nuclear accumulation of mineralocorticoid receptors more effi- 100 mg
ciently than spironolactone. Like eplerenone, it binds less avidly to Inspra 1 Eplerenone 25, 50, —
the androgen and progesterone receptors. Finerenone accumulates or 100 mg
similarly in the heart and the kidneys, whereas eplerenone has Maxzide Triamterene 75 mg 50 mg
three times higher drug concentration in the kidney than the heart Maxzide-25 mg Triamterene 37.5 mg 25 mg
and spironolactone is even more preferentially concentrated in the
kidneys. Because of this effect, finerenone may prove to be useful Midamor Amiloride 5 mg —
for cardioprotection. Finerenone results in less hyperkalemia than Moduretic Amiloride 5 mg 50 mg
spironolactone or eplerenone for poorly understood reasons but 1 Eplerenone is currently approved for use only in hypertension.
possibly from its decreased tendency to accumulate in the kidneys.
It also does not have as great a blood pressure-lowering effect as adrenocorticotropic hormone production) or secondary hyperal-
spironolactone or eplerenone. DSR-71167 is an investigational dosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic
agent in this class that is believed to have carbonic anhydrase syndrome, or other conditions associated with diminished effective
inhibitory activity in addition to antimineralocorticoid activity intravascular volume). Use of diuretics such as thiazides or loop
and is thus less likely to cause hyperkalemia. agents can cause or exacerbate volume contraction and may cause
+
Amiloride and triamterene are direct inhibitors of Na influx secondary hyperaldosteronism. In the setting of enhanced mineralo-
in the CCT. Triamterene is metabolized in the liver, but renal corticoid secretion and excessive delivery of Na to distal nephron
+
excretion is a major route of elimination for the active form and sites, renal K wasting occurs. Potassium-sparing diuretics of either
+
the metabolites. Because triamterene is extensively metabolized, type may be used in this setting to blunt the K secretory response.
+
it has a shorter half-life and must be given more frequently than It has also been found that low doses of eplerenone (25–50 mg/d)
amiloride (which is not metabolized).
may interfere with some of the fibrotic and inflammatory effects of
aldosterone. By doing so, it can slow the progression of albuminuria
Pharmacodynamics in diabetic patients. It is notable that eplerenone has been found
+
Potassium-sparing diuretics reduce Na absorption in the collect- to reduce myocardial perfusion defects after myocardial infarction.
ing tubules and ducts (Figure 15-5). Potassium absorption (and In one clinical study, eplerenone reduced mortality rate by 15%
+
K secretion) at this site is regulated by aldosterone, as described (compared with placebo) in patients with mild to moderate heart
above. Aldosterone antagonists interfere with this process. Similar failure after myocardial infarction.
+
effects are observed with respect to H handling by the interca- Liddle’s syndrome is a rare autosomal dominant disorder that
lated cells of the collecting tubule, in part explaining the meta- results in activation of sodium channels in the cortical collecting
bolic acidosis seen with aldosterone antagonists (Table 15–2). ducts, causing increased sodium reabsorption and potassium secre-
Spironolactone and eplerenone bind to mineralocorticoid tion by the kidneys. Amiloride has been shown to be of benefit in
receptors and blunt aldosterone activity. Amiloride and triamterene this condition, while spironolactone lacks efficacy. Amiloride is also
+
do not block aldosterone but instead directly interfere with Na useful for treatment of nephrogenic diabetes insipidus although
+
entry through the epithelial Na channels (ENaC; Figure 15–5) in only studied in patients with lithium-induced diabetes insipidus.
+
the apical membrane of the collecting tubule. Since K secretion
+
is coupled with Na entry in this segment, these agents are also Toxicity
+
effective K -sparing diuretics. A. Hyperkalemia
The actions of the aldosterone antagonists depend on renal +
+
prostaglandin production. The actions of K -sparing diuretics can Unlike most other diuretics, K -sparing diuretics reduce urinary
+
excretion of K (Table 15–2) and can cause mild, moderate, or
be inhibited by NSAIDs under certain conditions.
even life-threatening hyperkalemia. The risk of this complication
+
Clinical Indications & Dosage (Table 15–7) is greatly increased by renal disease (in which maximal K excre-
tion may be reduced) or by the use of other drugs that reduce
Potassium-sparing diuretics are most useful in states of mineralo- or inhibit renin (β blockers, NSAIDs, aliskiren) or angiotensin II
corticoid excess or hyperaldosteronism (also called aldosteronism), activity (angiotensin-converting enzyme [ACE] inhibitors, angio-
due either to primary hypersecretion (Conn’s syndrome, ectopic tensin receptor inhibitors). Since most other diuretic agents lead to