Shirley Anderson

Response to furosemide in chronic renal insufficiency: rationale for limited doses.

Patients with renal insufficiency often undergo therapy with large doses of loop diuretics. We tested the hypotheses that remaining nephrons respond normally to amounts of diuretic reaching them, and that more limited doses than are commonly used are sufficient to reach effective portions of the dose‐response curve. In eight patients with creatinine clearance <20 ml/min/1.73 m2, the amount of diuretic causing half‐maximal response was identical to that in normal subjects, but the maximal response expressed as fractional excretion of sodium was increased approximately 60%. The upper plateau of the dose‐response curve was attained with single intravenous doses of furosemide, 120 to 160 mg. In conclusion, remnant nephrons appear to demonstrate an exaggerated response to furosemide. Because maximal response was attained with single intravenous doses of furosemide of 120 to 160 mg, there appears to be no need to administer larger single doses in such patients.

Bumetanide and furosemide

We assessed the response to and handling of furosemide and bumetanide in 30 experiments with the former and 46 with the latter in normal subjects. Oral doses of furosemide (20, 40, and 80 mg) were used, and subjects received oral doses of 0.5, 1, and 2 mg bumetanide and intravenous doses of 0.5 and 1 mg bumetanide. Both drugs were quickly absorbed and peak urinary amounts were reached at 75 min (median). Approximately 30% of an oral dose of each drug was excreted unchanged in the urine with no evidence of dose‐dependent elimination. After intravenous injection, 36% of the bumetanide was excreted unchanged. Consequently, bumetanide has an estimated bioavilability of 80% (approximately 40% for furosemide). The relationship between the logarithm of the urinary bumetanide excretion rate and the logarithm of the sodium excretion rate was described by a sigmoid‐shaped dose‐response curve, with a dose inducing half‐maximal response of 1 ± 0.04 μg/min; it was 69.8 μg/min for furosemide. Overall, the distinguishing features between the two drugs are the 200% greater bioavailability and the much greater potency of bumetanide.

Azosemide, a "loop" diuretic, and furosemide.

Azosemide is a new monosulfamyl diuretic which inhibits solute transport throughout the thick ascending limb of the loop of Henle. This study compared equal amounts of azosemide and furosemide (20, 40, and 80 mg) in normal subjects. No differences occurred at any dose in volume, sodium, or chloride excretion when analyzed as cumulative excretion at 4, 8, or 12 hr. Azosemide 40 mg caused less potassium excretion than 40 mg of furosemide but there was no significant difference in the sodium/potassium excretion ratio. Analysis of the time course of effect showed that compared to furosemide azosemide tended to have a slower onset of effect. Differences in site of action studies between azosemide and furosemide did not manifest as differences in urinary or electrolyte excretion in our normal subjects.

Effects of Nonsteroidal Antiinflammatory Drugs on Renal Function in Patients With Renal Insufficiency and in Cirrhotics

We have assessed the effects of acute and chronic administration of etodolac, ketoprofen, and indomethacin on renal function in patients with mild to moderate chronic renal insufficiency (CRI). We studied 18 normal volunteers and 24 patients with CRI due to hypertension and/or diabetes mellitus with creatinine clearances between 19 and 83 mL/min/1.73 m2. Clearance studies were performed with the first dose of nonsteroidal antiinflammatory drug (NSAID) to compare acute effects of the agent with a no-drug control. Subjects then received the NSAID for three to five days and, on the last day of study, underwent another clearance study to assess the effects of a single dose of NSAID superimposed on chronic dosing. With each dose of each NSAID, inulin and paraaminohippurate (PAH) clearances and fractional excretion of NA+ decreased. However, the baseline control collections after chronic dosing did not differ from the no-drug control periods. Hence, the decline in renal function with each dose is transient, and no overall adverse effect on renal function occurred with chronic dosing. In five patients with cirrhosis, we assessed the renal sparing effects of sulindac. After equilibration on a fixed sodium intake, they received a 200-mg dose of sulindac. In one patient, no adverse effect occurred; the remaining patients suffered declines in creatinine clearance of 29%, 87%, 37%, and 37%, respectively. This effect was transient and returned to control values six to eight hours after sulindac administration. At the time of maximal depression of renal function, serum concentrations of sulindac sulfide were comparable to those in subjects with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of piretanide in normal subjects

Piretanide is a new loop diuretic similar to furosemide in pharmacologic properties and approximately six times as potent. We gave 3‐, 6‐, and 12‐mg oral doses to 21 normal subjects and collected serial blood and urine samples for assessment of the drugs kinetics and dynamics. There was no evidence for dose‐dependent elimination with the doses we used. Peak serum concentrations and urinary excretion rates appeared between 30 and 60 min. Elimination t½s were 60 to 90 min. Approximately 45% of a dose was recovered unchanged in the urine. Renal clearance rate was 90 to 100 ml/min and oral clearance was 200 ml/min. Examination of the relationship between urinary excretion rate of piretanide and sodium excretion allowed determination of potency at the tubular level. The piretanide dose that induced half‐maximal response was 12.1 ± 2.6 μg/min; it is 69.8 μg/min for furosemide and 1 μg/min for bumetanide. Piretanide kinetics, therefore, resemble those of furosemide and bumetanide, but piretanide is five or six times as potent as furosemide and one tenth as potent as bumetanide.

Azosemide kinetics and dynamics

Azosemide is a loop diuretic that may also affect sodium reabsorption at the proximal tubule. We gave intravenous and oral doses of the drug to normal subjects to examine its kinetic and dynamic parameters. In the fasting state a lag time of absorption of approximately 1 hr was followed by absorption t½s and elimination t½s of approximately 0.75 and 2 to 2.5 hr. Only 2% of an oral dose was excreted unchanged in the urine. After intravenous dosing the elimination t½ was approximately 2 hr; 20% of a dose was recovered unchanged. Thus azosemide has an estimated bioavailability of 10%. The relationship between urinary azosemide excretion rate (“dose”) and natriuretic response follows a sigmoid‐shaped curve with a dose inducing half‐maximal response of 9.3 ±2.6 μg/min, whereas it is 69.8, 12.1 and 1 μg/min for furosemide, piretanide, and bumetanide respectively.

Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade with prazosin and phenoxybenzamine.

We investigated the relevance of the selective a1-adrenergic receptor blockade produced by prazosin to its blood pressure-lowering efficacy in man. The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension. These responses were also evaluated during lower body negative pressure and dynamic bicycle exercise, which produce potent but diversified activation of the sympathetic nervous system. In the acute studies, arterial blood pressure decreased to similar levels with prazosin or phenoxybenzamine; however, hemodynamic and neuroendocrine responses differed both before and during sympathetic nervous system activation. Prazosin lowered arterial blood pressure by reducing total peripheral resistance (p < 0.05). In contrast, phenoxybenzamine produced a modest reduction in cardiac output (8%, p < 0.05) with little change in total peripheral resistance, forearm vascular resistance or forearm blood flow. Additionally, plasma norepinephrine concentration and heart rate rose to significantly higher levels with prazosin (p < 0.02) than with phenoxybenzamine, a difference that was most evident with lower body negative pressure or dynamic exercise. Baroreceptor control of arterial pressure homeostasis was preserved with both agents, except during marked degrees of cardiovascular stress. With chronic therapy, the circulatory responses adapted to the a-adrenergic antagonists, and both drugs produced similar hemodynamic and neuroendocrine profiles. The differences with acute administration may be the result of a more rapid onset of action and a more marked degree of a-adrenergic blockade with prazosin than with phenoxybenzamine therapy, rather than to any difference in their a1- and a2-adrenergic receptor blocking properties. Moreover, the findings of the present study suggest that the prejunctional a2-receptor, autoinhibitory to sympathetic neuronal norepinephrine release, is of no functional significance in patients with essential hypertension.

Comparative effects of prazosin and phenoxybenzamine on arterial blood pressure, heart rate, and plasma catecholamines in essential hypertension.

Summary We investigated the possibility that selective blockade of postjunctional α-adrenergic receptors results in an enhanced antihypertensive response relative to that observed with α-adrenergic antagonists, which are less selective and thus block both pre- and postjunctional α-receptors. The antihypertensive efficacy of prazosin (a selective postjunctional antagonist) was compared with that of phenoxybenzamine (a less selective postjunctional antagonist) in a double-blind, placebo-control, randomized, crossover study in 11 patients with essential hypertension. Both drugs produced similar significant reductions in standing mean arterial pressure (MAP) from 124 ± 3 to 104 ± 5 mm Hg (p < 0.001) and 122 ± 3 to 109 ± 7 mm Hg (p < 0.025), respectively, after four weeks of therapy. However, the increments in plasma norepinephrine (PNE) concentration associated with these falls in MAP from 622 ± 90 to 1,025 ± 100 pg/ml (p < 0.01) and from 554 ± 80 to 1,029 ± 168 pg/ml (p < 0.01), respectively, were not significantly different for the two drugs. Heart rate also increased significantly, although the increase after prazosin was not sustained. In contrast to the responses in the standing position, only prazosin produced a significant fall in supine MAP from 118 ± 3 to 107 ± 3 mm Hg (p < 0.001) and an increase in PNE concentration from 283 ± 39 to 415 ± 50 pg/ml (p < 0.05). Heart rate increased marginally after prazosin and remained unchanged with phenoxybenzamine therapy. Thus prazosin is a more effective antihypertensive agent than phenoxybenzamine. However, the present study suggests that the enhanced antihypertensive efficacy of prazosin is not due to its selectivity for the postjunctional α-adrenergic receptor.

Effect of etodolac in patients with moderate renal impairment compared with normal subjects

Twenty subjects (10 with normal renal function and 10 with moderate renal insufficiency) participated in an 8‐day study to assess the effects of acute and chronic etodolac dosing on renal function. Subjects and patients were hospitalized and followed a controlled diet (150 mEq sodium, 60 to 80 mEq potassium) during the study. A 3‐day drug‐free period was followed by 4 days of etodolac, 200 mg b.i.d. Sodium balance and body weight remained unchanged in both groups. Modest reductions in renal function as measured by clearances of inulin and p‐aminohippurate occurred acutely only in the patients with renal impairment. Chronic therapy resulted in no decrements in daily creatinine clearance. In an average effective anti‐inflammatory dose, etodolac did not produce a sustained effect on renal function in either normal subjects or patients with moderate renal insufficiency.

Differences in Response of Black Hypertensives to Alpha vs. Beta Adrenergic Antagonists: Preliminary Findings

We tested our clinical impression that black hypertensives in our clinic population responded better to α-adrenergic blocking agents (clonidine and prazosin) than to β-adrenergic blockers (atenolol, nadolol and propranolol). Compared to no effect from eight weeks of therapy with β-blockers, clonidine significantly decreased erect mean arterial pressure (MAP) when assessed weekly for four weeks (p = 0.027 to 0.046). However, the decrease in supine MAP was not significant. The effects of prazosin were more modest. Supine MAP was significantly less than with β-blockade (p = 0.032) at two weeks but not at four weeks and decrements in erect MAP were not significant. In this preliminary study, black hypertensives appeared to be more responsive to α-adrenergic antagonists than to β-blockers, with clonidine more effective than prazosin. Elucidation of possible mechanisms of the difference and of its clinical importance warrant further study.