Natriuretic agents

Pyrazines. N-Amidino-3-amino-6-chloropyrazinecarboxamide (Xl) previously was shown to reverse the electroi e excretion effects of deoxycorticosterone acetate in the adrenalectomized rat and was shown to be a potassium-sparing natriuretic agent in the intact rat and dog. ... 

An interesting new development has been the discovery that certain pteridine compounds promote sodium excretion and, at the same time, potassium retention. Clinical studies in hypertensive patients carried out with triamterene indicated that the drug was not in itself sufficiently potent as a natriuretic agent in hypertensive patients to be clinically useful (10). When combined with half-strength doses of hydrochlorothiazide, however, its natriuretic effect was comparable to that obtained with full doses of hydrochlorothiazide but without significant urinary loss of potassium or reduction in serum potassium concentration. Thus, triamterene may represent a beginning in the development of new compounds with more specific natriuretic properties. 

Recently, pteridine derivatives have been shown to be natriuretic agents. Triamterene, developed in the Smith Kline and French Laboratories, pro-... 

The pharmacodynamic properties of the natriuretic/uricosuric agent indacrinone have been studied in subjects given varying ratios of the (-b) and (—) enantiomers [68]. With respect to stereoselectivity in pharmacodynamic properties, (—)-indacrinone is a more potent natriuretic agent than the (-b) enantiomer. On the other hand, both enantiomers are equipotent with respect to uricosuric activity. The complexities of the pharmacodynamics of indacrinone and the merits of using different ratios of the enantiomers of indacrinone (instead of 1 1 in the racemate) are discussed in Chap. 5 (Sec. 3.3). 

Amiloride a drug which inhibits the influx of Na into cells. It was discovered as a natriuretic agent which increases Na excretion but does not affect K excretion (Baer et al. J. Pharmacol. Exp. Ther. 157 (1967) 472). Animal cells have 2 systems for Na transport. The Na /K ATPase (inhibited by ouabain) exports Na and imports K, each against its concentration gradient. In addition, there is a pump which imports Na and exports H, and this is inhibited by A., hence the designation amiloride-sensitive Na pump . A. has subsequently been found to be relatively unspecific, e.g. it also inhibits protein synthesis Its derivative, dimethylamiloride, is a more spedfic... 

Because renal vasodilatation and hyperfiltration are often associated with a natriuretic response, a number of activators or inhibitors of endogenous vasoactive systems can cause increased NaCl excretion, and some of these may be developed into compounds of clinical interest in special situations. Such agents include natriuretic pqDtides most notably B-type natriuretic peptide (nesiritide), neutral endopeptidase (NEP) inhibitors (thiorphan, phosphoramidon), mixed NEP and ACE inhibitors (omapatrilat), guanylin and uroguanylin, kinins, prostaglandins of the E series, adrenomedullin, relaxin, prolactin, and others. 

Hydrochlorothiazide has its proposed site of action at the distal convoluted tubule or, more specifically, at the early portion of the distal tubule. Hydrochlorothiazide inhibits the reabsorption of Na and Cl. It also promotes the reabsorption of Ca back into the blood, but inhibits the re absorption of Mg from the renal tubular fluid. The K-sparing diuretic agents (spironolactone, triamterene, and amiloride) have their site of action in the nephron at the late distal tubule and the collecting duct. These diuretic agents only cause a mild natriuretic effect... 

Modern diuretics (natriuretics, saluretics), as used in the treatment of hypertension and heart failure, are administered with the aim to enhance the renal excretion of sodium ions and water. Older diuretics, such as the osmotic diuretic agents, are of little interest in the treatment of the aforementioned cardiovascular disorders, but may be used to lower intracranial pressure associated with brain edema. 

The endogenous hormone atrial natriuretic peptide (ANP), which acts to increase blood pressure, is, like many other effector peptides, excised from a longer native chain by an endopeptidase enzyme, that is, an agent that cleaves bonds well along the chain of amino acids. A small-molecule endopeptidase inhibitor lowers blood pressure by inhibiting the release of ANP. The inhibitor candoxatril (6-8) is now... 

Some pharmacokinetic characteristics and the initial and usual maintenance dosages of hydrochlorothiazide are listed in Table 11-2. Although thiazide diuretics are more natriuretic at higher doses (up to 100-200 mg of hydrochlorothiazide), when used as a single agent, lower doses (25-50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose. 

Technically, a "diuretic" is an agent that increases urine volume, whereas a "natriuretic" causes an increase in renal sodium excretion. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics (see under Agents That Alter Water Excretion) are diuretics that are not directly natriuretic. 

Amiloride is far more soluble than triamterene, and is the most widely-studied potassium-sparing diuretic. Its natriuretic effect is minimal because only 2 to 3% of the filtered sodium ion load reaches the collecting tubules of the nephron. Etozolm is a newer, long-lasting agent that has a gradual onset of action. 

A newer class of drugs that inhibit both ACE and neutral endopeptidase, an enzyme that inactivates bradykinin and natriuretic peptide (see below), has been introduced into clinical trials recently. Omapatrilat is the first of these agents and has been shown in early studies to increase exercise tolerance and to reduce morbidity and mortality. Unfortunately, it causes a significant incidence of angioedema. 

A variety of renal diseases may interfere with the kidney s critical role in volume homeostasis. Although renal disorders will occasionally cause salt wasting, most kidney diseases cause retention of salt and water. When loss of renal function is severe, diuretic agents are of little benefit, because there is insufficient glomerular filtration to sustain a natriuretic response. However, a large number of patients with milder degrees of renal insufficiency can be treated with diuretics when they retain sodium. 

A number of other agents have been studied but have not been found to yield significant benefit including dopamine, fenoldopam, diuretics dihydropyridine calcium channel blockers, and atrial natriuretic peptide. 

The required properties of such an agent Included (1) selectivity for peripheral vascular dopaminergic receptors versus < -and 6-adrenerglc receptors which could mediate pressor and cardiac effects, (2) absence of central dopaminergic and emetic effects, and (3) potent oral renal vasodilator effects. Dopamine has been associated with diuresis and natriuresls. Possible mechanisms include a direct tubular effect on sodium transport, indirect effects produced by changes in total or regional renal blood flow, or effects resulting from a dopamine Induced decrease in aldosterone release from the adrenal (9). Since diuretics play a key role in antihypertensive therapy, the addition of a natriuretic/diuretic component to the renal vasodilator profile would be valuable and appeared to be feasible. 

Also shown in Table I is diuretic and antihypertensive activity in a spontaneously hypertensive rat screen. Dopamine was not significantly active at 0.5 mg/kg i.p. presumably due to its short biological half-life. SK F 38393 is active both as a natriuretic and an antihypertensive agent. The diuretic activity has been characterized in other studies (26,27). It is natriuretic given i.p. or orally to saline-loaded, water-loaded, and... 

In the spontaneously hypertensive rat (SHR) SK F 82526 was inactive as a natriuretic, but was active as an antihypertensive agent. The weaker natriuretic activity of SK F 82526 compared to SK F 38393 was also seen in conscious dog renal clearance studies (27). SK F 82526 given 5 mg/kg p.o. increased renal plasma flow 81%, glomerular filtration rate 15%, but elevated sodium excretion only about half the amount observed with SK F 38393, and this in a somewhat delayed response. SK F 82526 when given in the drinking water at 200 mg/kg/day for 30 days in developing SHR blunted the onset of hypertension and also lowered blood pressure acutely in anesthetized SHR. It did not lower blood pressure in anesthetized Dahl salt sensitive hypertensive rats. 

---