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

Summary Most 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.     

Effects of thiazide- and loop-diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: a randomized controlled study

OBJECTIVE: Diuretics are commonly used drugs that in addition to their effect on the cardiovascular system also affect calcium homeostasis and bone metabolism. We evaluated the effects of loop diuretics (LD) and thiazide diuretics (TD) on calcitropic hormones and biochemical bone markers. DESIGN: A total of 50 postmenopausal women were randomized to 7 days of treatment with either the TD bendroflumethiazide, the LD bumetanide, bendroflumethiazide plus bumetanide, or placebo. Blood and urine (24 h) were sampled on each day. Statistical inferences were made versus the concomitant changes in the placebo group. RESULTS: Bendroflumethiazide increased the tubular reabsorption of calcium (TRCa) (+0.46 +/- 0.11%, P=0.009), plasma levels of parathyroid hormones (PTH) (+24 +/- 10%, P=0.06), and 1,25(OH)2D (+12 +/- 6%, P=0.03). Bumetanide decreased the TRCa (-0.5 +/- 0.1%, P=0.01) and increased plasma PTH and 1,25(OH)2D levels (+27 +/- 9%, P=0.02 and +36 +/- 12%, P=0.006, respectively). Treatment with either of the drugs did not alter plasma calcium, osteocalcin, bone alkaline phosphatase (bone-ALP) or urinary NTx/creatinine ratio. However, treatment with both drugs caused an increased plasma calcium level (+2.7 +/- 1.0%, P=0.007) and decreased plasma levels of bone-ALP (-21 +/- 3%, P=0.001), osteocalcin (-6 +/- 3%, P=0.03), and urinary NTx/creatinine ratio (-39 +/- 6%, P=0.001). CONCLUSION: Calcium homeostasis and bone metabolism are to a major degree influenced by diuretic treatment. Surprisingly, LD and TD exerted a similar effect on calcitropic hormones despite their opposite effects on the renal calcium excretion. In clinical practice, treatment with diuretics has to be considered as a cause of parathyroid stimulation.     

The Use of Diuretics in Varying Degrees of Renal Impairment: An Overview

Administration of diuretics during acute renal failure in animals has been demonstrated to be of value with mannitol and/or loop-blocking diuretics, furosemide or ethacrynic acid. There is evidence that if these drugs are given very early in the controlled experimental environment that there will be some beneficial effect in maintaining renal function. However, in man the temporal relationship between the acute onset and the successful response to the administration of the drugs is, at best, coincidental and the use of diuretics in acute renal failure may not produce the same results as seen in the laboratory. One of the best guides to the underlying disease when there is acute decompensation in renal function is the utility of the renal failure index which utilizes urine and plasma sodium and urine and plasma creatinine ratios.

Large doses of loop-blocking diuretics can be of benefit in patients with mild to moderate chronic renal insufficiency and fluid retention and/or hypertension. When renal insufficiency is severe in the pre-dialysis setting, furosemide, bumetanide or muzolimine may be of some benefit; however, as renal failure worsens the response of the kidney is sluggish and it is wise to begin to dialyze when glomerular filtration deteriorates below 5 ml per minute.     

How to use diuretics in heart failure

Systemic and pulmonary congestion is a central aspect of both acute and chronic heart failure and directly leads to many of the clinical manifestations of these syndromes. Therefore, diuretic therapy to treat congestion plays a fundamental role in heart failure management. However, although diuretics are the most common drugs prescribed for heart failure, there is limited quality evidence to guide their use. Unlike other components of the heart failure armamentarium, such as β-blockers and angiotensin-converting enzyme inhibitors, diuretics (with the exception of aldosterone antagonists) have not been shown to decrease heart failure progression or improve mortality. Additionally, some observational data suggest that diuretics may actually be harmful in heart failure, contributing to neurohormonal activation, renal dysfunction, and potentially mortality. Despite these concerns, diuretics remain ubiquitous in heart failure management because of the need to address symptoms of congestion and the lack of alternative strategies. Recently, the development of a variety of potential adjuncts or alternatives to diuretic therapy has suggested the need for an active reappraisal of diuretic therapy for heart failure. The main classes of diuretics are the loop diuretics, potassium-sparing diuretics, and thiazides. Loop diuretics, the mainstay of acute and chronic therapy for heart failure, are “threshold drugs”; therefore, an adequate dose to achieve a pharmacodynamic effect (ie, to increase urine output) must be prescribed for effective therapy. The minimum dose to achieve diuresis and manage congestion should be used to minimize adverse effects. For patients refractory to initial dosing of intravenous diuretics, options include dose escalation, use of continuous infusion rather than intermittent boluses, or combination therapy with the addition of a thiazide or thiazide-like diuretic (eg, metolazone). Management of chronic heart failure often includes patient-directed titration of diuretics based on changes in symptoms or body weight in an attempt to decrease hospitalizations, although the efficacy of this strategy has not been tested in well-designed trials. Aldosterone antagonists, which are used primarily as neurohormonal agents rather than for their diuretic effects, are indicated for patients with systolic failure and moderate to severe symptoms, as long as renal function and serum potassium are stable and monitored closely. All diuretic therapy requires careful monitoring of electrolytes and renal function. Whether newer modalities for managing congestion (vasopressin antagonists, adenosine A1 antagonists, and ultrafiltration therapy) will be an improvement over diuretic therapy will be determined by the results of multiple ongoing clinical trials.     

Atrial natriuretic factor in cirrhotic patients with tense ascites. Effect of large-volume paracentesis

The plasma levels of atrial natriuretic factor in liver cirrhosis can be affected by various factors, such as ascites, renal function, use of diuretics drugs and dietary sodium intake. Moreover, the influence of high intra-abdominal pressure on cardiac atrial natriuretic factor release in patients with tense ascites has not been investigated. The aim of the present study was to evaluate the circulating levels of atrial natriuretic factor and their relationships to plasma renin activity, aldosterone concentration, and urinary sodium excretion in 45 cirrhotic patients divided into 4 groups: (a) cirrhotics without ascites; (b) nonazotemic cirrhotics with ascites; (c) cirrhotics with ascites and functional renal failure; and (d) cirrhotics with ascites taking diuretics. In some patients with tense ascites, atrial natriuretic factor was also measured after rapid abdominal relaxation by large volume paracentesis. Plasma levels of atrial natriuretic factor obtained in 13 healthy control subjects after 5 days on a 40-50 mEq sodium daily intake were 22.8 +/- 3.3 pg/ml. Mean plasma atrial natriuretic factor levels were normal in patients without ascites (35.1 +/- 11.4 pg/ml) and in those with ascites taking diuretics (27 +/- 9.2 pg/ml), but elevated in patients with ascites not taking diuretics (59.6 +/- 12 pg/ml) and in those with ascites and functional renal failure (58.5 +/- 16.6 pg/ml). These data show that plasma atrial natriuretic factor levels are elevated only in cirrhotic patients who are ascitic and not taking diuretics. In these patients atrial natriuretic factor levels were directly correlated with urinary sodium excretion, even though sodium balance was positive. This could be the consequence of the contrasting effects of antinatriuretic factors, as suggested by the inverse relationships between atrial natriuretic factor and urinary sodium on the one hand and plasma renin activity and plasma aldosterone concentration on the other. Twenty-six patients with tense ascites (12 taking diuretics and 14 not) were treated with rapid large-volume paracentesis (6500 +/- 330 ml of ascitic fluid removed in 168 +/- 16 min). At the end of the procedure, plasma atrial natriuretic factor levels had increased in all patients (from 45.5 +/- 10.1 to 100 +/- 17 pg/ml), whereas plasma renin activity and plasma aldosterone concentration had decreased (from 10.3 +/- 1.6 to 7 +/- 1.3 ng/ml/h, and 1160 +/- 197 to 781 +/- 155 pg/ml, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)     

Is the Development of Diabetes With Antihypertensive Therapy a Problem?—Pro

Some questions about new-onset diabetes (NOD) must still be completely addressed: 1) its incidence; 2) the possible association between NOD and some classes of antihypertensive drugs; and 3) its prognostic impact. It is well known that diuretics and beta blockers can increase plasma glucose and, in available hypertension trials, diuretics and beta blockers caused a higher incidence of NOD than new antihypertensive drugs. NOD heralds a high risk of major cardiovascular events, but the absolute difference between old and new drugs was too small to significantly drive the differences in cardiovascular event rates between the two groups of treatment. This evidence suggests a judicious use of drugs more frequently associated with NOD in subjects at high risk of diabetes (impaired fasting glucose, overweight, family history of diabetes, low high-density lipoprotein cholesterol levels). The lowest effective dose of these drugs should be used, plasma glucose should be checked periodically, and concomitant lifestyle measures to prevent diabetes should be implemented with resolution.     

Drug therapy in the elderly

Drug dosage in the elderly requires an understanding of the age-dependent changes in drug disposition and sensitivity. The most important pharmacokinetic alteration is a decline in renal function, the elderly should therefore be treated as renally insufficient patients. Metabolic clearance is primarily reduced with drugs that display high hepatic extraction, whereas the metabolism of drugs with low hepatic extraction usually is not diminished. The reduction of metabolic clearance is especially pronounced in malnourished or frail patients. The water content of the aging body decreases, the fat content rises. Hence the distribution volume of hydrophilic drugs may be reduced in the elderly, resulting in increased plasma concentrations. In contrast, the distribution volume of liphophilic drugs is increased, their plasma concentrations may decrease. Intestinal absorption of most drugs is not altered in the elderly. Aside of these pharmacokinetic changes, one of the characteristics of old age is a progressive decline in counterregulatory (homeostatic) mechanisms. Therefore, drug effects are attenuated less, the responses are usually stronger than in younger subjects, the rate and intensity of adverse effects are higher. Examples of drug actions augmented is this manner are postural hypotension with agents that lower blood pressure, dehydration and electrolyte disturbances in response to diuretics, bleeding complications with oral anticoagulants, hypoglycemia with antidiabetics, and gastrointestinal irritation with non-steroidal anti-inflammatory drugs. The brain is an especially sensitive drug target in old age. Psychotropic drugs, anticonvulsants, and centrally acting antihypertensives may impede intellectual function and motor coordination. Hence drugs should be used restrictively in geriatric patients.     

The effect of nonsteroidal anti-inflammatory drugs on blood pressure in patients treated with different antihypertensive drugs

Hypertension and arthritis are both common diseases in the older age group and require pharmacologic treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) alter renal function if given in high enough doses, reducing renal blood flow and the glomerular filtration rate and causing sodium retention. In salt sensitive subjects, this retention of sodium will cause blood pressure to rise. Salt sensitivity is more common in elderly patients, in diabetics, and in people with renal failure. When most antihypertensive drugs are used, people become salt sensitive, as shown by the additive effect of salt restriction or diuretics on blood pressure response. The responses to dihydropyridine and possibly other calcium channel blocking drugs are not affected to any major extent by sodium intake or by diuretics. Studies are described which indicate that indomethacin elevates blood pressure in elderly people treated with enalapril, but not in people whose blood pressure is controlled with amlodipine or felodipine. It is unclear whether the various NSAIDs have different effects on blood pressure. It is proposed that if the same analgesic effect is achieved with the same amount of cyclooxygenase inhibition, the response will be similar. Aspirin, used in a prophylactic dose, does not inhibit to this extent and does not elevate blood pressure. If elderly people require NSAIDs, it would appear that dihydropyridine calcium channel blocking drugs are more effective at lowering and maintaining blood pressure control and should be one of the drugs used. If patients are on other antihypertensive agents, it is important to monitor blood pressure when a NSAID is added to therapy.     

Pharmacokinetics in renal disease

The physiologic perturbations associated with renal disease can have a pronounced effect on the kinetics of elimination of drugs and their metabolites from the body. Drugs are ordinarily cleared from the body by a number of routes, each of which can be characterized by a clearance value. The sum of these clearances (renal, hepatic, etc.) is the total or body clearance which is inversely proportional to the steady-state plasma concentration produced by a given drug dosage regimen. The quantitative contribution of each route of elimination to the metabolic fate of a drug is proportional to the clearance value of that route relative to the body clearance. As a first approximation, the reduction in the renal clearance of a drug caused by renal disease is proportional to the reduction in the renal clearance of creatinine. The metabolic (biotransformation) clearance of many extensively plasma protein bound drugs is proportional to their free fraction (ratio of concentrations of free to total drug) in plasma. Since severe renal disease causes a reduction in the plasma protein binding of many drugs, the metabolic clearance of such drugs will be increased. The contribution of hemodialysis to the total clearance of a drug depends on the magnitude of the clearance obtained by hemodialysis relative to the magnitude of the body clearance of the drug on a day between dialyses. To compensate for the increased elimination of a drug during hemodialysis, the dosing rate (i.e., the dose per unit of time) must be increased by the factor (hemodialysis clearance and body clearance): body clearance, where body clearance is that during a day between dialyses. Further dosage compensation may be needed if body clearance is increased during hemodialysis due to decreased plasma protein binding of the drug. Under certain conditions, an increased accumulation of pharmacologically active drug metabolites during renal failure becomes a matter of serious concern.     

Diuretic use in renal disease

Diuretics are agents commonly used in diseases characterized by excess extracellular fluid, including chronic kidney disease, the nephrotic syndrome, cirrhosis and heart failure. Multiple diuretic classes, including thiazide-type diuretics, loop diuretics and K(+)-sparing diuretics, are used to treat patients with these diseases, either individually or as combination therapies. An understanding of what determines a patient's response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodium-retaining states that are directly or indirectly associated with renal disease. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fluid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diuretic-related adverse events that involve the uric acid, Na(+) and K(+) axes are not uncommon; therefore the clinician must be vigilant in looking for biochemical disturbances. As a result of diuretic-related adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.     

Effect of ACE inhibitors and beta-blockers on homocysteine levels in essential hypertension

Recent studies have shown that antihypertensive drugs like diuretics increase plasma homocysteine (Hcy) levels. However, the effect of other antihypertensive drugs on plasma Hcy levels has not been tested extensively. The aim of present study was to investigate the effect of antihypertensive therapy (AHT) on Hcy levels in essential hypertensive subjects. A case-control study of 273 patients with essential hypertension (EH) and 103 normotensive controls was undertaken. Plasma Hcy levels were measured before and after 6 weeks of AHT. The genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers significantly decreased and hydrochlorothiazides significantly increased the plasma Hcy levels in hypertensive patients (P<0.05). No significant association between MTHFR C677T genotypes and changes in Hcy levels in response to antihypertensive was observed in EH patients. The decrease in Hcy induced by beta-blockers and ACE inhibitors observed in our study may be due to the improvement of endothelial function along with improved renal function. Thus, our results suggest that ACE inhibitors and beta-blockers may provide additional beneficial therapeutic effects to the EH patients by decreasing Hcy levels.     

Excretion of Trimethoprim and Suiphamethoxazole in Patients with Renal Failure

Summary: The excretion and plasma level of trimethoprim and sulphamethoxazole has been studied in normal subjects and in patients with renal failure. Trimethoprim was assayed by measuring the fall in pH in a liquid culture medium and the technique was found to be simple, rapid and reproducible.
Patients with renal failure showed de-creased renal clearance and urine concentration of both drugs but even in severe renal failure urinary levels of the combination usually greatly exceeded that required for eradication of most of the common urinary pathogens. Al-though the drugs are handled differently by the kidney, variations due to changes in urine flow rate and pH are not likely to be readily achieved by patients in renal failure. Under the conditions studied the ratio of trimethoprim to free sulphamethoxazole in urine and plasma was relatively constant and independent adjustment of the dose of each drug to achieve an optimum ratio seems unlikely to be of any practical importance.     

Diuretika bei kardiorenalen Syndromen

Cardiorenal syndromes are well-defined diseases of the heart and kidneys and five forms can be distinguished which are divided into acute and chronic, as well as primary cardiac and primary renal forms. Triggering and predisposing factors contribute to the development of acute renal failure. Diuretics are necessary and indispensible drugs in cases of fluid overload in acute cardiorenal syndromes. In acute decompensated heart failure diuretics are recommended for the symptomatic treatment of hyperhydration. A benefit of diuretics with respect to hard endpoints (e.g. cardiovascular events and mortality) has not been demonstrated in chronic heart failure and chronic cardiorenal syndromes. Loop diuretics, thiazide diuretics, potassium-sparing diuretics and vasopressin V2 antagonist are available with varying mechanisms and sites of action. The maximum recommended dose of diuretics depends on renal function. Major side effects include electrolyte disturbances (e.g. hypokalemia, hyponatremia and hypomagnesemia), disorders of acid-base balance, increased insulin resistance and ototoxicity. The use of diuretics in cases of renal failure reduces the chance of recovery of renal function. A sequential nephron blockade and/or transient ultrafiltration or renal replacement therapy (e.g. hemodialysis and peritoneal dialysis) might be of benefit in cardiorenal syndromes and resistance to conventional treatment but evidence from controlled studies is still lacking.     

Diuretics in the therapy of hypertension

Antihypertensive monopharmacotherapy with diuretics renders blood pressure (BP) values under control in a large percentage of patients suffering from essential hypertension, and it reduces cardiovascular morbidity and mortality. Diuretics are effective in adult and elderly hypertensive subjects, independently of their race. Treatments with classic (high) doses of antihypertensive diuretics, such as 25 mg hydrochlorothiazide once daily, raise the activity of the RAA system, decrease plasma potassium and magnesium concentrations, and cause untoward changes in carbohydrate metabolism and in the plasma lipid profile. These changes appear to limit the positive response of cardiovascular prognosis to antihypertensive therapy with classic doses of diuretics. Lower doses of diuretics reduce high BP to the sought extent in many patients, and they do not elicit or cause only mild unfavourable neuroendocrine and metabolic changes. When a low dose of an antihypertensive diuretic substance is used as monopharmacotherapy, it may take 12-14 weeks after the initiation of treatment for BP to attain final stable values. The following low-dose oral formulations of diuretics constitute effective once-daily monopharmacotherapies for mild-to-moderate uncomplicated essential hypertension: bendrofluazide 1.25 mg, chlorthalidone 12.5 and 15 mg, cicletanine 50 mg, cyclopenthiazide 0.125 mg, HCTZ 12.5 mg, and torasemide 2.5 and 5 mg. These formulations are safer than classically used high-dose formulations such as hydrochlorothiazide 25 and 50 mg.     

Diuretic use in the elderly: potential for diuretic-induced hypokalemia

The more potent "loop" diuretics are being used with increasing frequency. The elderly constitute a growing portion of the population undergoing treatment with diuretics. The alterations in renal function and pharmacokinetics in the elderly (over 60 years of age) may result in the development of certain adverse effects. In patients over 70 years old, there is a progressive decline in overall renal function, resulting in a more than 50% decrease in glomerular filtration rate. Most of the pharmacokinetic changes in the elderly consist of alterations resulting in enhanced plasma levels of any given drug; diminished hepatic drug extraction, detoxification/metabolism or prodrug conversion; decreased renal excretion of drug; and diminished volume of distribution of drug. Adverse reactions to diuretics may be grouped into metabolic changes (e.g., hypokalemia), physiologic alteration (e.g., volume contraction), toxic manifestation (e.g., interstitial nephritis) and allergic or idiosyncratic phenomena (e.g., rash or thrombocytopenia). There is general agreement that significant hypokalemia, particularly among elderly patients receiving digitalis glycosides, is significant and requires therapy. Diuretic-associated hypokalemia reflects the potency and duration of action of a diuretic, factors modulating potassium balance including dietary intake and concurrent medical processes. The short duration of action and greater natriuresis relative to kaliuresis characteristic of loop diuretics may result in a lesser degree of hypokalemia than that seen with traditional thiazide diuretics.     

Age-dependent changes of the kidneys: pharmacological implications.

About 40% of the intoxications after drug administration occur in the elderly. A significant proportion of the disease states in elderly patients is related to adverse reactions to prescribed drugs. Declining renal function, a reduction in both renal blood flow and glomerular filtration rate, is a major contributor to drug toxicity in the elderly. Therefore, a review (based on newer papers from Medline) of age-dependent changes of the kidneys and their consequences for drug therapy in geriatric patients is presented. Renal changes that occur with aging are: a decrease of renal weight, a thickening of the intrarenal vascular intima, sclerogenous changes of the glomeruli, and infiltration of chronic inflammatory cells and fibrosis in the stroma. Altered renal tubular function, including impaired handling of water, sodium, acid, and glucose, is also frequently present in old age. Impaired 'endocrinologic' functioning manifested by changes of the renin-angiotensin system, vitamin D metabolism, and antidiuretic hormone responsiveness has been reported. The aging kidney is constantly exposed to the effects of a variety of potential toxic processes, i.e., drugs and chronic illnesses including hypertension, diabetes, and atherosclerotic disease. Renal changes that occur with aging also consist of impairment in the ability to concentrate urine and to conserve sodium and water. These physiological changes increase the risks of volume depletion and prerenal type of acute renal failure. A frequent cause of acute renal failure in the elderly is drug-induced nephropathy. Nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics are most often involved. Due to the age-dependent decline of renal function, the pharmacokinetics of many drugs are altered in elderly patients. Therefore, the most important renal function to monitor with aging is the creatinine clearance. Changes in pharmacokinetics of many drugs and most decisions on drug dosage can be based on this information alone, as tubular functions of the kidney decrease at rates paralleling the age-dependent decrease in glomerular filtration rate (which is approximately measured by the creatinine clearance). As a conclusion, age-dependent changes of renal function are not only responsible for changes in pharmacokinetics and pharmacodynamics. In many cases, the kidneys are the target organ of adverse drug reactions too.     

Diuretics and transmembrane ionic exchanges: structure-activity relations and clinical applications.

The study of membrane ion transport has facilitated the discovery of potent and quite specific inhibitory drugs. Some of these compounds are therapeutic agents acting on basic transport mechanisms as in the case of the cardiac glycosides on the myocardial sodium ion (Na+), potassium ion (K+) pump, and the loop diuretics on the renal Na+, K+, chloride (Cl-) co-transport system. The development of inhibitors for other transport systems such as Na+/hydrogen ion (H+), Na+/calcium ion (Ca2+) and bicarbonate (HCO3-)/Cl- exchangers requires the screening of a large number of molecules. For several reasons, the human red blood cell is one of the best models for screening the effect of drugs on ion transport mechanisms. The use of human red cells for pharmacologic studies of ion transport has increased the understanding of the structure-activity relations of diuretics. For instance, loop diuretics that are chemically neutral were considered for many years as drugs that act similarly to classic acid loop diuretics. They are now considered as potent inhibitors of HCO3-/Cl- anion exchange. A brief summary of the more recent results is given together with the perspectives of new fundamental and therapeutic applications of these compounds.     

The rational use of diuretics in the treatment of arterial hypertension.

The development of modern pharmacologic diuretic agents has revolutionized the therapy of arterial hypertension. The diuretics currently available are easily administered orally, are effective in the presence of alkalosis or acidosis, are non-toxic and have a low incidence of side effects which are readily circumvented or treated. Loop diuretics such as furosemide have the capacity to be effective in patients with diminished renal function or clinical situations that have a powerful stimulus to sodium retention. In clinical circumstances when renal potassium loss is to be prevented such as in patients receiving digitalis, the addition of a potassium-sparing diuretic to either a thiazide or furosemide will achieve the clinical goal of providing an effective diuresis while inhibiting potassium excretion. The mechanism of antihypertensive activity of the diuretic agents appears to be the reduction of extracellular fluid volumes and plasma volumes. Hence, the clinical dictum that to be effective as an antihypertensive agent, diuretics should be administered in diuretic doses. Besides being the cornerstone of initial antihypertensive therapy, diuretics also play an important role in antihypertensive therapy of patients with moderate to severe hypertension who are receiving potent antihypertensive drugs of the vasodilator or sympatholytic class of compounds. Indeed, one of the most important steps in the successful therapy of these patients receiving multiple drugs, is the re-assessment of the diuretic agent. The sodium retention and consequent fluid volume expansion associated with the administration of these potent antihypertensive agents may often cause these patients to develop apparent drug resistance since the thiazide diuretics are not potent enough to counteract the powerful stimulus to sodium retention caused by these antihypertensive agents. The re-evaluation of the diuretic agent at this point will usually necessitate the substitution of furosemide for thiazide or the doubling of the dose of the present loop diuretic. A working knowledge of the physiology of urine formation and the sites of action of currently available diuretic agents will enable the clinician to tailor the diuretic agent to the clinical circumstances of an individual patient and allow the clinician to rationally select a diuretic for the treatment of arterial hypertension.     

Captopril in clinical hypertension. Changes in components of renin-angiotensin system and in body composition in relation to fall in blood pressure with a note on measurement of angiotensin II during converting enzyme inhibition.

The effect of the converting enzyme inhibitor captopril on arterial pressure, the components of the renin-angiotensin-aldosterone system, and body sodium and potassium content was studied in eight hypertensive patients with renal artery stenosis and, in conjunction with diuretics, in seven patients with hypertension unresponsive to previous treatment. Two hours after the first dose, captopril caused significant falls in systolic and diastolic pressures, plasma angiotensin II, and aldosterone, with converse increases in angiotensin I and both active and total renin; the initial fall in diastolic pressure was significantly related to the drop in plasma angiotensin II. The biochemical changes were sustained during prolonged treatment, even when diuretics were added. One untreated patient with renal artery occlusion had severe secondary aldosterone excess, was sodium and potassium depleted, and severely hyponatraemic and hypokalaemic; captopril restored blood pressure, plasma electrolyte concentrations, and exchangeable sodium and total body potassium to normal. In one man with renal artery stenosis and overall renal impairment captopril led to sodium retention, and blood pressure did not fall until a diuretic was added. In the remaining patients with renal artery stenosis, pretreatment renin, angio tensin II, and aldosterone concentrations were either normal or only modestly raised, and plasma electrolyte concentrations and body content of sodium and potassium were normal. Captopril alone controlled arterial pressure in all, three cases showing a gradual fall of pressure over the first six weeks of treatment; no significant changes in exchangeable sodium or total body potassium were seen. The group of patients with previously intractable hypertension were all controlled with a combination of captopril and diuretic.     

New-onset diabetes in treated hypertensive patients

Interpretation of some recent trials in hypertension opened a debate on the clinical value of new-onset diabetes in treated hypertensive patients. It is not completely clear whether certain antihypertensive drug classes are associated with a higher risk for developing type 2 diabetes when compared with other classes. Some longitudinal studies suggest that new-onset diabetes in treated hypertensive subjects carries a risk for subsequent cardiovascular disease similar to that of previously known diabetes. In a study, plasma glucose before treatment and diuretic treatment were independent predictors of newonset diabetes in hypertensive patients, independent of confounding factors. We estimated that one cardiovascular event associated with new-onset diabetes might be prevented for every 385 to 449 patients treated with "new," rather than "old," antihypertensive drugs for approximately 4 years. These observations suggest that concern about the risk for newonset diabetes should prompt a more judicious use of diuretics and β-blockers in the treatment of hypertension. These drugs should be given cautiously in subjects who are at increased risk for new-onset diabetes, owing to impaired fasting glucose or obesity. The lowest effective dose should be used, and plasma glucose should be carefully monitored.