Potassium conservation with amiloride/hydrochlorothiazide (‘Moduret’) in thiazide-induced hypokalaemia in hypertension

Summary

A double-blind study was carried out in 24 hypertensive patients with thiazide-induced hypokalaemia (serum potassium <3.2 mmol/l) to compare the effects of treatment with an amiloride/hydrochlorothiazide combination or hydrochlorothiazide alone. The study was divided into three phases: (i) potassium repletion (Weeks 0 to 4) with oral potassium chloride (40 mmol/day), (ii) stabilization (Weeks 4 to 6) of normokalaemia, and (Hi) active drug treatment (Weeks 6 to 14), patients being allocated at random to receive one or other of the two treatments. Dosage was 2 tablets per day of the 5?mg amiloride plus 50?mg hydrochlorothiazide combination or of 50?mg hydrochlorothiazide alone. The results showed that blood pressure control was comparable in both treatment groups but hydrochlorothiazide alone caused a statistically significant reduction in serum potassium levels compared to the drug combination. Apart from 1 patient who developed hypokalaemia on hydrochlorothiazide alone, no other side-effects of treatment were reported.     

Do all diuretics have equal hypotensive efficacy?

Summary

An open parallel study was carried out in general practice on 70 patients with uncomplicated mild to moderate hypertension to compare the hypotensive efficacy of hydrochlorothiazide/amiloride with that of cyclopenthiazide/potassium. After a 2-week baseline period on placebo, patients were allocated at random to receive treatment with one or other of the diuretics starting with 1 tablet per day and increasing up to a maximum of 4 tablets per day or until their supine diastolic blood pressure was 90 mmHg or less. They were then continued at their optimum dose for a further 4 weeks. Analysis of the results from 62 patients showed that the hydrochlorothiazide/amiloride preparation produced both a greater decrease and better control of blood pressure in a greater percentage of patients than did the comparison diuretic. In addition, the beneficial effects were attained with fewer tablets, of importance for patient compliance.     

A single-blind, comparative study of hydrochlorothiazide/amiloride ('Moduret' 25) and hydrochlorothiazide/triamterene ('dyazide') in elderly patients with congestive heart failure

The efficacy and biochemical effects of two low-dose thiazide plus potassium-sparing diuretic preparations were compared in the treatment of elderly patients with stable, mild to moderate congestive heart failure. Sixty patients (mean age 80 years) were randomly allocated to treatment with 1 tablet daily of either 25 mg hydrochlorothiazide/2.5 mg amiloride or 25 mg hydrochlorothiazide/50 mg triamterene. The dose was increased to 2 tablets daily if necessary, after 2 weeks, for a further 6 weeks. Patients' response to treatment was assessed at 2, 4 and 8 weeks using a simple clinical scoring system for signs and symptoms of their condition, and routine biochemical analysis was carried out at baseline and the end of treatment. One patient was withdrawn from the study due to a rash which was probably related to hydrochlorothiazide/amiloride treatment. A further 11 patients were excluded from the analysis because of intercurrent illness or inadequate records. Analysis of the results from 48 patients showed that both treatments resulted in an improvement in clinical score and weight reduction, with more than three-quarters of the patients responding to treatment. No serious biochemical disturbances occurred; in particular, no new cases of hyponatraemia (serum sodium less than 130 mmol/l) developed. Both preparations, therefore, were effective and tolerated forms of treatment for mild to moderate congestive heart failure in the elderly and there were no significant differences between them.     

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics.The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min^–1, amiloride; and from 418 to 157 ml·min^–1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml^–1, C_ss,max; from 2 to 8 ng·ml^–1, C_ss,min; and from 4 to 14 ng·ml^–1, C_av; Hydrochlorothiazide: from 184 to 651 ng·ml^–1, C_ss,max; from 31 to 121 ng·ml^–1, C_ss,min; and from 89 to 273 ng·ml^–1, C_av).The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly).As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.     

Defect of the potassium transport process in the kidney of spontaneously hypertensive rats.

We investigated the natriuretic and kaliuretic effect of distal tubular diuretics in saline-loaded spontaneously hypertensive Wistar rats (SHR) from three different sources and normotensive Wistar rats (NWR). Orally administered early distal tubular diuretics (hydrochlorothiazide, chlorthalidone, metolazone, indapamide and cicletanine) caused much less potassium excretion in SHR than in NWR, whereas the magnitude of concurrent natriuresis was similar in both NWR and SHR. The intriguing renal handling of potassium excretion was exemplified by hydrochlorothiazide, for which enhanced kaliuresis was dose dependent in NWR but not in SHR. The doses tested ranged from 1 to 100 mg/kg, p.o. Amiloride, a late distal tubular diuretic, was also evaluated for its effect on sodium and potassium excretion in NWR and SHR. Amiloride produced potassium retention more effectively in NWR than in SHR, although the magnitude of natriuresis was similar. The difference between SHR and NWR with regard to potassium-retaining activity of amiloride was consistent at all doses tested (1-30 mg/kg, p.o.). In conclusion, it was suggested that SHR appear to have a genetic defect in potassium transport in the distal nephron.     

Effect of tienilic acid and amiloride in healthy volunteers and in hypertensives with normal renal function

1 A double-blind comparison of the effect of tienilic acid (250 mg) and amiloride (5 mg) on renal function in healthy volunteers and of tienilic acid plus amiloride compared to hydrochlorothiazide (50 mg) plus amiloride in patients with mild to moderate essential hypertension for safety and hypotensive efficacy was made.

2 Renal plasma flow ([I¹²⁵] iodohippurate clearance) and glomerular filtration rate ([I¹³¹] iothalamate clearance and 24 h creatinine clearance) were not affected by tienilic acid or amiloride alone or in combination despite a rise in plasma urea and plasma creatinine (within the normal range) in healthy volunteers.

3 In hypertensive patients tienilic acid and tienilic acid plus amiloride treatments caused a rise in plasma urea and plasma creatinine similar to hydrochlorothiazide and hydrochlorothiazide plus amiloride but no significant change in creatinine clearance occurred with any of the treatments.

4 Tienilic acid and hydrochlorothiazide caused hypokalaemia in the patients which was normalized by addition of amiloride. Fewer subjects became hypokalaemic when amiloride was added to tienilic acid than when tienilic acid was given alone.

5 The antihypertensive effect of tienilic acid and tienilic acid plus amiloride was similar to hydrochlorothiazide and hydrochlorothiazide plus amiloride in patients with hypertension. No effect on blood pressure was observed in the healthy volunteers.

6 Plasma uric acid was significantly reduced by tienilic acid alone and in combination in patients and subjects whereas a significant elevation occurred with hydrochlorothiazide.

7 Side effects were increased when amiloride was added to either tienilic acid or hydrochlorothiazide, but side effects were less common after treatment with tienilic acid than following hydrochlorothiazide.

8 The combination of tienilic acid plus amiloride significantly reduces blood pressure and appears to be well tolerated with no adverse effects on renal function or plasma potassium in patients with mild to moderate hypertension and normal renal function. Addition of amiloride may be useful if hypokalaemia occurs following tienilic acid therapy in such patients.

     

Effects of short-term addition of NSAID to diuretics and/or RAAS-inhibitors on blood pressure and renal function

Background The combined post-operative use of diuretics and/or renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of nonsteroidal anti-inflammatory drug (NSAID) associated renal failure because of a drug?Cdrug interaction. Objective The aim of this study was to investigate the effect of the short-term (<4 days) post-operative combined use of NSAIDs with diuretics and/or RAAS inhibitors on renal function and blood pressure. Setting One teaching hospital in the Netherlands. Method The study-design was a prospective, observational cohort-study. Based on postoperative treatment with NSAIDs, the intervention-group was compared to a control-group (no NSAIDs treatment). Main outcome measure Systolic blood pressure and renal function expressed by the estimated glomular filtration rate (eGFR) calculated with the modification of renal desease formula. Results 97 patients were included in the intervention-group, 53 patients in the control-group. Patient characteristics were comparable except for one variable: ??combined use of a diuretic with a RAAS inhibitor?? which was higher in the control-group (62 vs. 43?%, p?=?0.046). Odds ratio for clinically relevant increase in systolic blood pressure was 0.66 (CI95?% 0.3?C1.5). Odds ratio for clinical relevant decrease in renal function was 2.44 (CI95?% 1.1?C5.2). On day 4 eGFR of 3 patients in the intervention- and 1 in the control-group was <50?ml/min/1.73?m². Conclusion Odds ratios showed no significant difference of a clinically relevant increase in systolic blood pressure but showed a higher risk for a clinically relevant decrease in renal function in the intervention group. However this decrease resulted in a relevant impaired renal function (<50?ml/min/1.73?m²) in only 3 patients in the interventiongroup and 1 patient in the control-group. In the post-operative patient, without preexisting impaired renal function, concurrent diuretics and/or renin-angiotensinaldosterone system inhibitor therapy can be combined with short-term NSAID treatment.     

The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man.

We have studied the effect of a single dose challenge of naproxen (500 mg) and sulindac (200 mg) on renal function in five volunteers, and the effect of a single dose challenge of the thiazide, hydrochlorothiazide (100 mg), and loop diuretic, piretanide (6 mg) on renal function when the diuretics were given alone or when superimposed on chronic therapy of either naproxen or sulindac. None of the nonsteroidal anti-inflammatory drug (NSAID) or diuretic exposures significantly influenced glomerular filtration rate, as measured by creatinine clearance. Over the first 4 h of the study, both naproxen and sulindac reduced fractional excretion of sodium by approximately 50%. Sulindac also caused a significant uricosuria whilst naproxen promoted urate retention. Similar changes were observed over 8 h. Superimposition of either hydrochlorothiazide or piretanide on top of chronic sulindac therapy resulted in a blunting of the natriuresis by approximately 30% compared to when these diuretics were given alone: the action of the diuretics was unchanged by naproxen. Sulindac pretreatment did not alter the urinary excretion of either hydrochlorothiazide or piretanide; naproxen did not alter hydrochlorothiazide excretion. On the basis of these findings, it is concluded that NSAIDs exert direct tubular effects that do not necessarily interfere with the delivery of diuretics to their sites of action within the nephron.     

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects.

1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double-blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l-1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide-induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3-16.2:1). Amiloride but not spironolactone was associated with a dose-related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium-sparing agent in diuretic-treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.     

Intraerythrocyte sodium content and transmembrane sodium flux in hypertensive patients treated with diuretics or β-adrenoceptorblockers

Abstract: Forty-seven male patients with essential hypertension were randomized to treatment with either a ß-adrenoceptorblocker (metoprolol), (n = 24), or a diuretic (hydrochlorothiazide), (n = 23). If their diastolic blood pressure was not lowered below 95 mm Hg by the maximum dose of either drug, hydralazine (15 patients) and in a few cases (6 patients) spironolactone was given. After five years of treatment all the patients were examined with respect to intraerythrocyte sodium (IeNa) and potassium (leK). sodium influx and sodium efflux. Patients treated with the diuretic (D) tended to have a higher leNa (9.8±0.4 mmol/l red cells) and sodium influx (0.044±0.002 mmol Na/1 X min) compared with those taking the ß-adrenoceptoblocker (B) (8.9±0.3 mmol/l and 0.041±0.002 mmol Na/l X min). but neither of these differences was statistically significant. Sodium efflux, however, was significantly increased in D (0.073+0.003 mmol Na/l X min vs 0.061 ± 0.003 mmol/l X min). No difference in leK was noted between the two groups. Six patients taking spironolactone had a low leNa (7.3±0.4 mmol/l), sodium influx (0.039±0.001 mmol Na/l X min) and sodium efflux (0.050±0.006 mmol Na/l X min).     

Effect of Penicillin on the clinical course of streptococcal pharyngitis in general practice

Summary The diuretic and natriuretic response to an intravenous dose of frusemide 40 mg was assessed in the erect and supine positions in 10 patients with cardiac failure who were being treated with enalapril 10 mg twice daily in addition to diuretics (Enalapril group) and in 10 patients with cardiac failure taking diuretics alone (Control group).Total 4 h diuresis in the erect position was 728 ml and in the supine position was 824 ml in the patients taking enalapril compared to 655 ml in the erect position and 1166 ml in the supine position in those patients taking diuretics alone. Total 4 h natriuresis in the erect positions was 78 mmol and in the supine position was 85 mmol in patients taking enalapril 10 mg twice daily but in those patients taking diuretics alone total 4 h natriuresis in the erect position was 67 mmol increasing to 120 mmol in the supine position.Measurements of plasma renin activity and plasma angiotensin II concentration confirmed effective converting enzyme inhibition, in the group of patients taking enalapril, but in those patients taking diuretics alone the erect position was associated with an increase in plasma renin activity, and plasma concentrations of angiotensin II and aldsterone.We conclude that the renin angiotensin system is a major factor in mediating the effect of posture on loop diuretic drugs.     

Effect of chronic diuretics on epinephrine-induced ventricular arrhythmias: a comparison of hydrochlorothiazide and amiloride in the rat

The purpose of this study was to determine if chronic administration of the diuretics hydrochlorothiazide and amiloride alters the response to catecholamine-induced ventricular arrhythmias. The protocol consisted of four groups of Wistar rats. Group I, or control group, received daily subcutaneous injections of saline; group II received hydrochlorothiazide, 100 mg/kg/day s.c.; group III received amiloride, 0.5 or 1.0 mg/kg/day s.c.; and group IV received amiloride, 0.5 mg/kg/day, plus hydrochlorothiazide, 100 mg/kg/day. The treatment period lasted 18 days. After completion of the treatment period, under pentobarbital anesthesia, epinephrine was infused and the electrocardiogram and blood pressure recorded. Hydrochlorothiazide produced a significant (p less than 0.05) leftward shift in the dose-response relationship, that is, a smaller epinephrine concentration produced earlier onset of ventricular arrhythmias and mortality from fatal ventricular arrhythmias. Amiloride, at the higher dose, significantly (p less than 0.05) shifted to the right the dose-response relationship between epinephrine and occurrence of arrhythmias--i.e., a larger epinephrine dose was necessary to produce the same amount of arrhythmias. There were no significant differences in heart rate or blood pressure responses to epinephrine among the four groups. Serum and myocardial electrolytes were measured in a separate group of rats that did not receive epinephrine. There were no significant differences among groups for myocardial electrolytes. After hydrochlorothiazide administration, serum calcium and magnesium were decreased and bicarbonate was increased compared with the control group. In the amiloride group, only serum sodium was significantly changed, being slightly increased. This suggests that serum electrolyte levels may account for the effects of hydrochlorothiazide but do not account for the effect of amiloride.     

Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle carbonic anhydrase by a direct mechanism of action

Five years ago, our in vitro and in vivo studies demonstrated for the first time that diuretic agents such as furosemide, hydrochlorothiazide, amiloride, triamterene and spironolactone inhibit carbonic anhydrase (CA) I, II and renal CA IV by a direct mechanism of action. In this paper we investigate the relationship between diuretics and CA I in the vasodilatory mechanism. Both in vitro (on purified CA I, erythrocyte CA I and smooth muscle CA I) and in vivo (in human and rabbits) we studied the effect of acetazolamide, hydrochlorothiazide, indapamide, furosemide, amiloride and triamterene on purified CA I, on human erythrocyte CA I, as well as on CA I isolated from vascular smooth muscle. Our results demonstrate that in vitro all diuretics inhibit CA I by a direct mechanism of action. Inhibition reached 100% with acetazolamide, 45% with hydrochlorothiazide, 82% with indapamide, 85% with furosemide, 68% with amiloride and 58% with triamterene. In vivo, similar inhibition of erythrocyte and smooth muscle CA I was obtained, being parallel with a reduction in arterial blood pressure values. Our data show that in addition to their already known mechanisms, diuretics also inhibit CA in vascular smooth muscle. Our results suggest that this mechanism is achieved by means of pH changes induced by CA I inhibition.     

Lisinopril: a new angiotensin-converting enzyme inhibitor

Lisinopril is a synthetic, nonsulfhydryl, angiotensin-converting enzyme inhibitor. Its bioavailability is approximately 25% and is not affected by food. Hepatic metabolism is not required for pharmacologic effect, which occurs 1 hour after administration. Peak serum concentration and effect are delayed, occurring 6-8 hours after a single dose and lasting for at least 24 hours. The drug is eliminated primarily by the kidneys. The elimination half-life is 12.6 hours and is prolonged in renal impairment. Lisinopril 10-80 mg once a day is effective in lowering blood pressure in all grades of essential and renovascular hypertension. It is as effective as hydrochlorothiazide, atenolol, metoprolol, and nifedipine. Combining lisinopril with hydrochlorothiazide produces a greater degree of blood pressure reduction. Patients with congestive heart failure have demonstrated immediate and prolonged beneficial hemodynamic effects and increased exercise tolerance. Lisinopril is well tolerated. Clinically significant drug interactions have not been reported, but caution should be used when lisinopril is administered with diuretics, nifedipine, or agents that may increase concentrations of potassium. The usual initial oral dosage of lisinopril is 10 mg once a day (range 20-40 mg/day). Lower dosages may be necessary in patients with renal impairment or congestive heart failure, elderly persons, and those receiving diuretics.     

Hydrochlorothiazide increases plasma or tissue angiotensin-converting enzyme-inhibitor drug levels in rats with myocardial infarction: differential effects on lisinopril and zofenopril

Sodium depletion with diuretics augments the efficacy of angiotensin-converting enzyme-inhibitor therapy for hypertension and renal dysfunction, and possibly for left ventricular dysfunction after myocardial infarction. Underlying mechanisms may involve altered angiotensin-converting enzyme-inhibitor pharmacokinetics. We hypothesized that the diuretic hydrochlorothiazide causes increased steady-state levels of the angiotensin-converting enzyme-inhibitors lisinopril and zofenopril in rats with myocardial infarction. Rats were subjected to coronary ligation to induce myocardial infarction. After 1 week, rats were randomized to 50 mg/kg/day hydrochlorothiazide or control treatment for 3 weeks. The last week, rats received lisinopril or zofenopril in equipotentent dosages (3.3 and 10 mg/kg/day, respectively). Rats were sacrificed at Tmax after the last dose of angiotensin-converting enzyme-inhibitor, and tissues were collected for analysis of drug concentrations. Lisinopril concentrations in plasma were significantly increased by hydrochlorothiazide, at unchanged tissue concentrations. This increase could be fully explained by decreased renal function, as evidenced by increased plasma creatinine levels (lisinopril + hydrochlorothiazide 82+/-5 microM versus lisinopril 61+/-5 microM, P < 0.001). In contrast, zofenoprilat levels in kidney and non-infarcted left ventricle were markedly increased by hydrochlorothiazide, whereas plasma concentrations were unchanged. Although hydrochlorothiazide tended to increase plasma creatinine in zofenopril-treated rats as well, this increase was less pronounced (zofenopril + hydrochlorothiazide 61+/-3 microM versus zofenopril 54+/-2 microM, P = 0.15). Hydrochlorothiazide increases steady-state angiotensin-converting enzyme-inhibitor drug levels, most likely by affecting their renal clearance. Notably, the lipophilic angiotensin-converting enzyme-inhibitor zofenopril accumulated in tissue, whereas the hydrophilic lisinopril increased in plasma. Whether combining different angiotensin-converting enzyme-inhibitors with hydrochlorothiazide translates into distinct clinical profiles requires further study.     

Comparative cardiovascular effects of loop-acting, thiazide-type and potassium-sparing diuretics in spontaneously hypertensive rats

Studies were carried out in conscious, chronically-cannulated, spontaneously hypertensive (SH) rats to determine the comparative cardiovascular actions of a series of diuretic compounds. The effects of three oral doses of hydrochlorothiazide, trichlormethiazide, chlorthalidone, metolazone, spironolactone, triamterene, amiloride, furosemide, ethacrynic acid, MK-447, hydrochlorothiazide + amiloride, and MK-447 + amiloride on blood pressure and heart rate were monitored continuously for four hr and again 24 hr post-dose. Thiazides, thiazide derivatives and antikaliuretic diuretics exerted little or no antihypertensive effects, while the loop-acting diuretics (except ethacrynic acid) and combinations markedly reduced blood pressure. Antihypertensive responses to furosemide, MK-447 and the diuretic combinations were associated with either stable heart rate or paradoxical bradycardia, but not compensatory tachycardia. Heart rate remained relatively unaltered by individual doses of the remaining compounds.     

Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme

Hyponatraemia (HN) can be a life-threatening medical condition which may lead to severe neurological and psychiatric symptoms. The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicentre drug surveillance programme that assesses severe or new adverse drug reactions during psychopharmacological treatment in psychiatric inpatients. We report on a total of 263 864 psychiatric inpatients monitored from 1993 to 2007 in 80 psychiatric hospitals in Germany, Switzerland and Austria. During this period plasma sodium levels below 130 mmol/l (severe HN according to AMSP) were reported in 93 patients (relative frequency 0.04%). On average, the plasma sodium levels of all cases were 119.7 mmol/l (±5.8 s.d.); median 121 mmol/l (range 104-129 mmol/l). Patients who showed no clinical signs (n=65, 70%) had a mean sodium level of 121.3 mmol/l (±5.0 s.d.); median 122 mmol/l (range 114-129 mmol/l). By contrast, patients with clinical symptoms (n=28, 30%) had a mean sodium level of 116.0 mmol/l (±6.0 s.d.); median 117 mmol/l (range 104-125 mmol/l). HN was mainly observed during treatment with selective serotonin reuptake inhibitors (SSRIs) (0.06%), Serotonin noradrenaline reuptake inhibitors (SNRIs) (0.08%), carbamazepine (0.10%) and oxcarbazepine (1.29%); the highest rate was found for oxcarbazepine. Antipsychotics, mirtazapine and tricyclic antidepressants were only rarely involved in HN (0.003-0.005%). Combinations of several drugs known to induce HN significantly increased the risk of HN, e.g. more than 10-fold for SSRI+diuretics+ACE inhibitors (0.37%) vs. SSRI given alone (0.02%). This is clinically relevant because such combinations, e.g. SSRI+diuretics may occur especially in elderly patients, who are in general at higher risk of developing HN.     

Potassium-sparing effect of amiloride in a diuretic factorial study in man

1. The effects of amiloride (M, 20 mg/day), chlorothiazide (C, 1000 mg/day), ethacrynic acid (E, 100 mg/day) and frusemide (F, furosemide 80 mg/day), given alone and in combination, were investigated in eight patients in a 2⁴ factorial study. Effects between blocks of four treatments in each sixteen-treatment replicate were confounded with higher interactions to allow for differences between early and late diuresis. 2. All patients exhibited marked diuresis, with significant mean increases in daily urinary sodium excretion (P < 0·05) and urinary volume (P < 0·01) induced by chlorothiazide, frusemide and ethacrynic acid (68, 69 and 38%; and 35, 40 and 34%, respectively). Amiloride appeared to be half to one-third as potent as the other diuretics. 3. Amiloride produced a significant potassium-sparing effect (P < 0·01), reducing urinary potassium excretion by 30%, compared to significant urinary potassium wasting with frusemide (increase of 33%, P < 0·01) and chlorothiazide (increase of 31%, P < 0·05). 4. No adverse reactions occurred, but serum potassium levels twice rose to 6 mmol/l and subsided without additional therapy, and on one occasion fell to 2·5 mmol/l, requiring a potassium supplement for 4 days. 5. It was concluded from these factorial studies that amiloride is a mild diuretic and potent potassium-sparing agent acting independently and additively in combination with chlorothiazide, ethacrynic acid or frusemide. For the three latter diuretics, all two-drug interactions were simply additive also, without evidence of synergism or antagonism between drugs.     

Resistance to loop diuretics. Why it happens and what to do about it

Resistance to loop diuretics is often encountered clinically. Studies in healthy subjects have shown that overall response to loop diuretics depends upon the interplay between the total amount of drug reaching the urine, the time course of its entry into urine and the pharmacodynamics of response to diuretic in the urine. The mechanism by which diuretic resistance occurs has been elucidated in several clinical conditions. Treatment with inhibitors of prostaglandin synthesis has no effect on diuretic appearance in urine but blunts response by blocking the increase in renal blood flow produced by loop diuretics. In the elderly and in patients with moderate renal insufficiency, the mechanism of resistance appears to be purely pharmacokinetic, involving altered access of diuretic into the urine. In contrast, patients with nephrotic syndrome and hepatic cirrhosis manifest a purely pharmacodynamic form of resistance: in nephrosis, diuretic may bind to protein in the urine; in cirrhosis the mechanism of resistance is unclear. Lastly, in patients with congestive heart failure, with intravenous administration, resistance represents a pharmacodynamic phenomenon. With oral administration, however, the time course but not the extent of absorption is altered; consequently, in this setting, both pharmacokinetic and pharmacodynamic changes may contribute to the subnormal response. Strategies for overcoming resistance to loop diuretics in patients receiving NSAIDs or those with renal disease, hepatic cirrhosis or congestive heart failure include one or more of: increasing the dose size; administering frequent 'small' (but effective) doses; continuous intravenous infusion of the diuretic; or concomitant administration of another diuretic such as metolazone or hydrochlorothiazide.     

Hydrochlorothiazide-induced noncardiogenic pulmonary edema: an underrecognized yet serious adverse drug reaction

Noncardiogenic pulmonary edema is a rare but potentially life-threatening complication of hydrochlorothiazide therapy. We describe three patients who developed this serious adverse reaction. A 64-year-old woman developed dypsnea and hypotension within 60 minutes of taking a single dose of hydrochlorothiazide 25 mg. She was admitted to the critical care unit with acute respiratory failure and subsequent multiple-organ dysfunction. The second patient was a 56-year-old woman who experienced sudden onset of shortness of breath that developed 10 minutes after taking a single dose of hydrochlorothiazide 25 mg. The third was a 59-year-old woman who developed sudden onset of shortness of breath, nausea, vomiting, and diarrhea after her first dose of hydrochlorothiazide-triamterene. All three women had a history of a similar, albeit minor, reaction to a thiazide diuretic. Review of the literature identified 36 additional cases of noncardiogenic pulmonary edema after thiazide use. The patients developed symptoms 10-150 minutes after ingestion of hydrochlorothiazide or another thiazide. Symptoms can occur on first exposure to the drug or in patients taking the drug intermittently. Of interest, 90% of documented cases occurred in women. With the increasing use of thiazide diuretics in the treatment of hypertension, clinicians need to be aware of the possible association of these drugs with the development of noncardiogenic pulmonary edema.