Pharmacodynamic analysis of the furosemide-probenecid interaction in man

Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Probenecid pretreatment in man increased the overall response to furosemide in contrast to animal studies in which probenecid decreased response by inhibiting proximal renal tubular secretion of furosemide to its active site. We administered i.v. 40mg of furosemide to eight normal volunteers with and without probenecid pretreatment and measured serum and urinary furosemide concentrations by high performance liquid chromatography to determine the mechanism of probenecid's effect. Probenecid pretreatment significantly increased serum furosemide concentration. Urinary furosemide excretion rate paralleled urinary sodium excretion rate; both were initially decreased but were later increased by probenecid pretreatment. Probenecid pretreatment decreased renal and nonrenal clearance of furosemide (1.04 ± 0.31 vs. 0.29 ± 0.06 ml/kg/min, P < 0.05; and 1.00 ± 0.18 vs. 0.27 ± 0.03 ml/kg/min, P < 0.004, respectively). Although probenecid inhibited renal clearance for the duration of the study, accumulation of furosemide in serum from concomitant effects on nonrenal clearance allowed more furosemide to appear in the urine at later times, increasing response. This analysis demonstrated the importance of probenecid's effects on nonrenal elimination of furosemide in determining the overall response to furosemide. The relationship between furosemide concentrations and response depicted a sigmoid dose-response curve. Probenecid shifted the serum dose-response relationship to the right but did not affect the relationship between urinary furosemide excretion rate and response, demonstrating the importance of the urinary (as opposed to serum) concentration-response relationship of furosemide in normal man. This relationship will provide a valuable tool for assessing response to diuretics in various disease states where resistance to diuretics occurs.Analyse pharmacodynamique de l'interaction furosémide-probénécide chez l'homme. Le pré-traitement par le probénécide chez l'homme augmente la réponse globale au furosémide par opposition aux études chez l'animal où le probénécide diminue cette réponse en inhibant la sécrétion tubulaire proximale de furosémide. Nous avons administré i.v. 40mg de furosémide par voie à huit volontaires normaux, avec ou sans pré-traitement par le probénécide, et mesuré les concentrations de furosémide sériques et urinaires par chromatographie liquide à haute résolution afin d'étudier le mécanisme de l'effet du probénécide. Le pré-traitement par le probénécide augmente significativement la concentration sérique de furosémide. L'excrétion urinaire de furosémide est parallèle à l'excrétion urinaire de sodium. Ces deux dernières sont initialement diminuées mais ultérieurement augmentées par le pré-traitement au moyen de probénécide. Le pré-traitement par le probénécide diminue les clearances rénale et non-rénale du furosémide (1,04 ± 0,31 vs. 0,29 ± 0,06 ml/kg/min, P < 0,05; et 1,00 ± 0,18 vs. 0,27 ± 0,03 ml/kg/min, P < 0,004, respectivement). Bien que le probénécide diminue la clearance rénale pendant la durée de l'étude, l'accumulation sérique de furosémide due aux effets sur la clearance non rénale permet l'apparition dans l'urine de quantités plus importantes à des temps ultérieurs, ce qui augmente la réponse. Cette analyse démontre l'importance des effets du probénécide sur l'élimination non rénale de furosémide dans le déterminisme de la réponse globale au furosémide. La relation entre les concentrations de furosémide et la réponse décrit une courbe dose-réponse sigmoïde. Le probénécide déplace la courbe dose-réponse sérique vers la droite mais n'affecte pas la relation entre l'excrétion urinaire de furosémide et la réponse, ce qui démontre l'importance de la relation entre la concentration urinaire (à la différence de la concentration sérique) et la réponse. Cette relaition fournit un instrument utile pour évaluer la réponse aux diurétiques dans divers états où la résistance à ces drogues est observée

Comparative Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on Blood Pressure in Patients with Hypertension

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension. Methods We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy. Results Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant. Conclusion Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible

Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142477/1/jah32580_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142477/2/jah32580.pd

Risk of hyperkalemia associated with selective COX-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors have been linked to cardiac death. The mechanism for this adverse effect appears to be by ischemic insult; however another mechanism could involve hyperkalemia. The objective of this study was to determine the effects of selective COX-2 inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) on serum potassium concentration and the electrocardiogram

Association Between Adherence Measurements of Metoprolol and Health Care Utilization in Older Patients with Heart Failure*

Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate-release metoprolol and examine their association with health care utilization of outpatients aged 50 years or older with heart failure

Financing U.S. Graduate Medical Education: A Policy Position Paper of the Alliance for Academic Internal Medicine and the American College of Physicians

In this position paper, the Alliance for Academic Internal Medicine and the American College of Physicians examine the state of graduate medical education (GME) financing in the United States and recent proposals to reform GME funding. They make a series of recommendations to reform the current funding system to better align GME with the needs of the nation's health care workforce. These recommendations include using Medicare GME funds to meet policy goals and to ensure an adequate supply of physicians, a proper specialty mix, and appropriate training sites; spreading the costs of financing GME across the health care system; evaluating the true cost of training a resident and establishing a single per-resident amount; increasing transparency and innovation; and ensuring that primary care residents receive training in well-functioning ambulatory settings that are financially supported for their training roles

Binding inhibitors restore furosemide potency in tubule fluid containing albumin

Binding inhibitors restore furosemide potency in tubule fluid containing albumin. We have previously suggested that albumin in tubule fluid at concentrations found in the nephrotic syndrome (NS) binds furosemide, thereby diminishing diuretic effect. This mechanism may contribute to diuretic resistance in NS. If this hypothesis is correct, displacement of albumin from furosemide should restore diuretic response in tubule fluid containing albumin. To test this supposition, in vivo loop microperfusion was performed in rats using perfusates containing 6 µM furosemide in the presence or absence of 3.8 µM albumin, or furosemide and albumin to which 12 µM warfarin or 5.4mM sulfisoxazole had been added. These drugs are inhibitors of albumin-furosemide binding in plasma. Albumin in the perfusate impaired furosemide effect on loop chloride reabsorption (1248 ± 59 vs. 886 ± 65 pEq/min; P < 0.05). Addition of warfarin or sulfisoxazole to perfusate containing albumin normalized furosemide's effect. Neither drug affected furosemide response in the absence of albumin. Dansylsarcosine, a probe that binds albumin at a different site than furosemide, failed to normalize furosemide response in albumin perfusates. These data suggest that albumin in tubule fluid reduces diuretic response through a diminution in the free furosemide concentration. In as much as this mechanism contributes to diuretic resistance observed clinically in NS, displacement of furosemide from albumin binding sites may be a therapeutic strategy warranting study