Ariel J. Reyes

Cardiovascular drugs and serum uric acid.

Uric acid (UA) is the final product of purine catabolism in man, and it is excreted mainly by the kidneys when renal function is not impaired. Consequently, serum (S) UA increases as a function of purine intake, and it varies inversely to uricosuria. The latter variable diminishes in response to low-sodium intakes and vice versa. Insofar as the diet is not usually controlled in studies in which the response of SUA to drugs is evaluated, most reports are to be considered cautiously. Common diuretics elevate SUA in healthy subjects, hypertensives and patients with heart failure, apparently by elevating net UA reabsorption in the nephronal proximal tubule. This drug action, which becomes noticeable shortly after the institution of treatment and remains throughout it, starts at low doses (e.g., 12.5 mg hydrochlorothiazide or 1.25 mg bendrofluazide once daily in subjects with uncomplicated hypertension) and increases in dose-dependent fashion. Beta-blockers tend to elevate SUA. The angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril and ramipril have been found to increase uricosuria mildly, likely by lowering the net reabsorption of UA in the proximal tubule. These three drugs and lisinopril can blunt the rise in SUA provoked by diuretics in hypertensives if used at sufficiently high doses relative to the dose of the diuretic. The angiotensin II antagonist losartan augments uricosuria mildly and thereby decreases SUA. The cardiovascular implications of the response of SUA to drugs remain speculative. Uric acid can scavenge various reactive oxygen species and thus reduce oxidative stress, which seems to contribute to the development and/or progress of various cardiovascular conditions, including hypertension, atherosclerosis and heart failure. Consequently, it may be theorised that the elevations in SUA induced by diuretics might contribute to the established favourable action of these agents on cardiovascular prognosis. Conversely, diuretic-induced increases in SUA are to be considered detrimental according to an old hypothesis that maintains that SUA is a cardiovascular risk factor; this construct is largely based upon the results of selected epidemiological undertakings. The cardiovascular implications of the effects of drugs on SUA, if any, should be elucidated through purposive research.

Diuretics in cardiovascular therapy: the new clinicopharmacological bases that matter.

Diuretics in current use include early distal tubular (i.e., thiazide-type), loop (i.e., furosemide-type), and potassium-and-hydrogen-retaining substances.Available oral formulations of diuretics differ in terms of their renal excretory potency in man, as formally assessed through the effect of a single dose on 24-hour natriuresis in healthy subjects. The 2.5 mg formulation of the loop diuretic torasemide does not increase mean 24-hour natriuresis, and it is therefore considered a very-low-dose formulation. Amiloride 5 mg and torasemide 5 mg and 10 mg, which increase mean 24-hour natriuresis by less than 40%, are considered low-dose or low-potency diuretic formulations of diuretic substances. Hydrochlorothiazide 25 and 50 mg, furosemide 40 and 80 mg, and torasemide 20 mg, which increase mean 24-hour natriuresis by more than 40%, are considered high-dose or high-potency formulations. A rebound in natriuresis follows the early-after-dosing increase in this variables caused by loop diuretics; hence many oral formulations of loop substances are less potent natriuretics than most oral formulations of thiazide-type diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar natriuretic potencies.During once-daily administration of diuretic formulations of diuretics to subjects without edema and normal renal function, the increases in 24-hour natriuresis and diuresis that follow the first dose disappear or attenuate markedly. This is due to neuroendocrine reactions to diuretic-induced sodium loss and its attendant hemodynamic shifts. Some of these reactions, e.g. the increase in plasma aldosterone that takes place, account for an elevation in kaliuresis that occurs during once-daily treatment with a high-dose formulation of a thiazide-type diuretic. Common fixed-dose combinations of a thiazide-type or a loop diuretic and a potassium-and-hydrogen-retaining subtance generally do not change kaliuresis, but they increase natriuresis strikingly.Thiazide-type and loop diuretics decrease and increase calciuresis respectively; none of these actions wanes during prolonged administration.Plasma renin activity and aldosterone do not rise in response to very-low-dose formulations of loop diuretics taken once daily.Glomerular filtration rate tends to fall in the course of once-daily administration of high-dose formulations of diuretics, but not during prolonged once-daily treatment with very-low-dose formulations of loop diuretics.

Angiotensin I converting enzyme inhibitors and the renal excretion of urate

SummaryHyperuricaemia carries with it a high risk of tophi development affecting connective tissue in kidney, skin and joints, its overt clinical expression being gout. Diuretics, which are invariably prescribed in congestive heart failure and widely used for the treatment of essential hypertension, may cause hyperuricaemia and predispose to gout by inducing renal retention of urate.The angiotensin I converting enzyme inhibitors captopril and enalapril have been found to augment renal urate excretion both in normal volunteers and in hypertensive patients. Current evidence appears to indicate that the uricosuric effect of captopril and enalapril could be due to the rises in renin and angiotensin I these drugs elicit by angiotensin I converting enzyme inhibition, and/or to pharmacological actions not related, at least directly, to the renin-angiotensin-aldosterone system. Serum urate levels have been significantly reduced by monotherapy with captopril in hypertensive patients suffering from hyperuricaemia. Diuretic-induced hyperuricaemia in hypertensive patients can be prevented or counteracted by the administration of captopril and enalapril.Available clinical data support the argument that captopril and enalapril should be used as first choice drugs for the treatment of hyperuricaemic hypertensive patients. When diuretic-induced hyperuricaemia develops in patients suffering from congestive heart failure, captopril or enalapril should be added to the therapeutic regime in doses capable of countering the shift in plasma urate concentration, provided the clinical condition of the patients permits such additional pharmacological treatment.Therapy with captopril and enalapril should preferably be instituted in a gradual manner, especially in patients with hyperuricaemia, in order to prevent the precipitation of urate in the kidney and in the urinary tract.

Renal excretory responses to single and repeated administration of diuretics in healthy subjects: Clinical connotations

SummaryAdministration of an initial oral dose of hydrochlorothiazide 25 mg to healthy subjects is followed by increased 24-hour urinary outputs of sodium, chloride, and potassium. On the fourth day of once-daily dosing with hydrochlorothiazide 25 mg, 24-hour natriuresis and chloriuresis are no longer augmented, but the elevation in 24-hour kaliuresis that follows the first dose remains unchanged. Twenty-four-hour urinary calcium output is consistently reduced during repeated once-daily administration of hydrochlorothiazide 25 mg.The first oral dose of the loop diuretic torasemide augments the average natriuresis and kaliuresis in the 6 hours immediately after dosing in healthy subjects, in a dose-dependent fashion, within the 2.5 to 10-mg range. These increased urinary outputs are followed by rebounds below postplacebo values between 6 and 24 hours after dosing. As a result of this biphasic response, torasemide 2.5 mg qualifies as a nondiuretic formulation (it does not elevate 24-hour natriuresis), whereas torasemide 5 and 10 mg qualify as diuretic formulations. After the seventh dose of torasemide 5 or 10 mg during a regimen of once-daily therapy, 24-hour urinary sodium and chloride outputs no longer differ from their postplacebo counterparts. Twenty-four-hour kaliuresis tends to increase in a dose-dependent fashion after the first dose of torasemide (torasemide 2.5 and 5 mg do not augment it significantly), but this tendency is no longer present after the seventh once-daily dose, when torasemide (2.5, 5, or 10 mg) does not elevate the mean 24-hour kaliuresis. Twenty-four-hour calciuresis tends to increase in a dose-dependent manner (torasemide 2.5 mg does not elevate it significantly) after the first dose of torasemide; this calciuretic effect does not change in intensity after 7 days of once-daily treatment.The time course of natriuresis over the 24 hours following the administration of any given formulation of a loop or of an early distal tubular diuretic to healthy subjects is alike after the first and after thenth once-daily dose; therefore, it constitutes a definite characteristic of any given oral formulation. In the case of torasemide, lower doses have more protracted effects on natriuresis, to the extent that the time course of natriuresis over the 24 hours after administration of torasemide 2.5 mg to healthy subjects resembles the time course after administration of hydrochlorothiazide 25 mg, rather than the time course after administration of the overtly diuretic formulation torasemide 10 mg.

Effects of captopril, hydrochlorothiazide, and their combination on timed urinary excretions of water and solutes.

The effects of single doses of captopril 100 mg, hydrochlorothiazide 25 mg, and a combination of both on 24-h outputs of fluid and several solutes were compared in healthy volunteers. Thirteen subjects were studied in a metabolic ward under strictly controlled conditions. Single doses of placebo, captopril, hydrochlorothiazide, and a combination of captopril and hydrochlorothiazide were given double-blind in random order on 4 separate days. Urine was collected at regular intervals for 24 h after medication. The combination of captopril and hydrochlorothiazide and hydrochlorothiazide alone significantly increased the 24-h urinary outputs of Cl-, Na+, fluid, and K+ compared with placebo and also accelerated the corresponding urinary flows. Captopril did not change the 24-h urinary excretions of Cl-, Na+, fluid, and K+ significantly, though it advanced the time courses of their urinary flows. All medications significantly increased the 24-h renal outputs of Mg2+ and creatinine. Captopril significantly increased the 24-h urinary output of urate and advanced its urinary flow. Hydrochlorothiazide significantly decreased the output and retarded the flow. The combination of captopril and hydrochlorothiazide did not change the 24-h urinary output and retarded its flow. It is concluded that the renal excretory actions of captopril are more prolonged than the plasma levels of the drug would indicate. Captopril has diuretic effects which may vary in potency with aldosterone concentrations and uricosuric properties unrelated to aldosterone status.

Allopurinol or oxypurinol in heart failure therapy - a promising new development or end of story?

SummaryThe plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD+ as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.

The ALLHAT and the Cardioprotection Conferred by Diuretics in Hypertensive Patients: A Connection with Uric Acid?

T he results of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) show that cardiovascular prognosis in patients suffering from hypertension is improved more effectively by antihypertensive treatment with a diuretic (chlorthalidone at 12.5–25 mg once daily) than by therapy with a calcium antagonist or an angiotensinconverting enzyme inhibitor [1]. Even though these results could have been determined by several factors, including various differential properties of the drug classes that were compared, it can be hypothesized that the added cardiovascular benefit conveyed by antihypertensive therapy with diuretics could be mediated, at least in part, by the elevation in serum uric acid that these agents provoke [2]. The view that increased serum uric acid is an independent cardiovascular risk factor, which stemmed from the early Framingham Study results and changed later when the authors realized that serum uric acid concentration is a correlate of blood pressure [3], has recently been revived amidst inconsistent findings and controversy [4,5]. At variance with the case of established cardiovascular risk factors, no mechanism whereby elevated serum uric acid might impair cardiovascular prognosis in man is readily apparent or has been substantiated by research. Serum uric acid concentration is positively associated not only with blood pressure [3] but also with various conditions that have been confirmed as cardiovascular risk factors and that form part of the so-called metabolic syndrome, including increased reabsorption of filtered sodium in the proximal tubule of the nephron [6], glucose intolerance [7], obesity, and certain derangements in the plasma lipid profile [8]. These associations have lead some to regard hyperuricemia as one of the components of the metabolic syndrome detrimental to cardiovascular health. In fact, the increased fractional reabsorption of sodium in the proximal tubule that is also associated with hypertension [9,10] is accompanied by retention of uric acid at the same nephronal level and therefore by a rise in serum uric acid concentration [6]. This explanation for the link between hypertension and the level at which sodium and, epiphenomenologically, uric acid are handled by the proximal tubule of the nephron is sustained by the fact that hypertension-associated high serum uric acid concentration is due to a lower than usual renal excretion of this metabolite [11]. However, neither the associations described above nor any other statistically defined associations necessarily connote causality. Moreover, elevated uric acid could well be the associated factor at odds with the other components of the metabolic syndrome in terms of cardiovascular consequences. The lack of any causal explanation for the contention that serum uric acid is an independent cardiovascular risk factor is expressly acknowledged by some of those supporters of this view who approach this question through rigorous scientific criteria [4]. The generation of uric acid from xanthine results in the production of hydrogen peroxide and of the superoxide radical, which interact and yield oxygen, the hydroxyl anion and the hydroxyl radical [12]. Nonetheless, uric acid is endowed with powerful oxidant scavenging capacity [13,14], and consequently the balance between the pro-oxidant reactive oxygen species and their antioxidant counterpart that result from the formation of uric acid must be weighed within the context of the total balance between oxidative burden and antioxidant capacity that affects cardiovascular tissues during certain acute pathophysiological circumstances, such as myocardial reperfusion, or in the course of some prolonged situations such as the impairment in the capacity for vasodilatation of the resistance vessels that occurs in heart failure. Avoiding uric acid generation by treatment with allopurinol has beneficial effects in both circumstances [15,16], i.e. it appears that the benefit conveyed by the antioxidant action of newly generated uric acid is surpassed by the damage caused by the co-generation of reactive oxygen species. These findings notwithstanding, it may safely be presumed

Renal excretory profiles of loop diuretics: consequences for therapeutic application.

In healthy subjects, 24-h natriuresis, kaliuresis, calciuresis, and magnesiuresis increase in response to the first oral dose of a standard (diuretic) formulation of a loop diuretic, such as furosemide 40 mg. However, low-dose formulations of loop diuretics, such as torasemide 2.5 mg, do not elevate 24-h natriuresis after the first dose is administered to normal individuals who are in steady-state habitual sodium balance; these formulations of loop diuretics are consequently labeled as nondiuretic formulations (of diuretic substances). Nondiuretic formulations of loop diuretics do not increase the 24-h urinary outputs of sodium, potassium, calcium, or magnesium after the first dose or in the course of repeated once-daily administration to healthy subjects. The 24-h natriuretic response to the first dose of standard (diuretic) formulations of loop diuretics wanes during repeated once-daily administration to healthy individuals, whereas the kaliuretic response becomes slightly attenuated, and calciuresis and magnesiuresis bear little change. Once-daily treatment with any formulation of a loop diuretic may result in an increase in plasma urate concentration. Nondiuretic formulations of loop diuretics, which are efficacious as once-daily monopharmacotherapy for high blood pressure, should be tried before standard (diuretic) formulations of diuretics are used in the treatment of uncomplicated essential hypertension. When loop diuretics are employed in the treatment of congestive heart failure, the minimal dose compatible with the attainment of clinical objectives should be used.

Clinicopharmacological reappraisal of the potency of diuretics

SummaryFrom a clinicopharmacological standpoint, the urinary excretory potency of diuretics should be assessed comparatively on the basis of the changes in 24-hour natriuresis, with respect to 24-hour natriuresis after placebo, caused by single oral doses administered to healthy adult subjects who are in habitual and steady-state external sodium balance. The potency of various formulations of loop (e.g., furosemide), of early distal tubular (e.g., the thiazides), and of potassium-retaining diuretics, as well as of several combinations of diuretics, has been evaluated in a series of studies. Two formulations of loop diuretics (muzolimine 20 mg and torasemide 2.5 mg) are definitely nondiuretic. The majority of the other formulations of loop diuretics studied are, in general, comparatively less potent than most of the common formulations of early distal tubular diuretics studied. As a general rule, most common formulations of early distal tubular diuretics are at least not less potent than the majority of common formulations of loop diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar potencies. Loop diuretics increase mean renal sodium output strikingly within the first few (0–6) hours after dosing, but this forced excretion is followed by a rebound with respect to postplacebo mean urinary sodium flow; the rebound usually takes place between 6 and 24 hours after dosing. However, no rebound in mean urinary sodium flow occurs during the 24 hours following a single dose of a distal tubular diuretic; these substances increase urinary sodium excretion with lower maximal intensity but more protractedly than loop diuretics. The presence of the rebound after the administration of loop diuretics and the absence of rebound after the first or a single dose of a thiazide-type diuretic make most common formulations of the latter more potent than most common formulations of the former.

Loop diuretics versus others in the treatment of congestive heart failure after myocardial infarction

SummaryMost frequently, diuretic therapy in congestive heart failure has as its main objective ridding the lungs of water. The work of the muscles of external respiration is thus decreased, the fraction of cardiac output that is distributed to vascular beds other than that of the respiratory muscles is consequently increased, and the functional and clinical condition of the patient improves. Diuretic therapy does not change cardiac output significantly in most cases; in some circumstances diuretic therapy may increase cardiac output in a clinically relevant fashion, and in some other cases diuretic therapy may lower cardiac output to the extent of impairing the overall functional situation. The dose of diuretics should be the minimal compatible with the prosecution of the main clinical objective (class betterment), to minimize possible increases in the afterload to the left ventricle (intravenous administration), to minimize hemodynamically detrimental decreases in the preload, and to minimize the likelihood of development or the severity of undesired changes in plasma biochemistry (hyponatremia, hypokalemia, hypomagnesemia, hyperuricemia, etc.). Loop diuretics are preferred shortly after myocardial infarction, given the ample dose-effect range of these substances and their relatively benign effect on renal blood flow. During chronic therapy, loop diuretics at low doses may be tried first, and the dose may be increased if necessary, provided higher doses do not cause symptomatic falls in cardiac output through the striking renal excretory response that these drugs elicit shortly after dosing. Thiazide-type drugs should be used if the brisk diuresis induced by loop diuretics causes a symptomatic fall in cardiac output and/or when it is necessary that once-daily (oral) diuretic therapy exert a highly potent 24-hour natriuretic action.