John E. Baer and I were the pharmacologists principally involved in the program in those days when I was head of pharmacological research. Baer received his degree in organic chemistry after having worked in Dr. James M. Shannon's laboratory in New York. I met Baer there while visiting that laboratory to learn renal clearance techniques. My own advanced degrees were in medical physiology and medicine. The antecedents of the discovery can be found in a renal research program set up in The first renal studies were on the excretion of some of the sulfa compounds, for crystalluria was a common problem.
Soon we took up the renal clearance of penicillin-G with the intent of inhibiting its rapid elimination. This work led to the discovery of probenecid benemid , which is an interesting story and a useful drug in its own right.
Indeed, from this research came a way of thinking and working that was to be important to the thiazide discovery. That paper said, in part: It is the purpose of this communication to illustrate Project MUSE promotes the creation and dissemination of essential humanities and social science resources through collaboration with libraries, publishers, and scholars worldwide.
Forged from a partnership between a university press and a library, Project MUSE is a trusted part of the academic and scholarly community it serves. Lack of promotion of diuretics or heavy promotion of other classes of drugs may have contributed to this decline 31 ; motivation by the desire to be up-to-date through the use of the newer modalities may also contribute. Clinical trial data, however, do not reflect this, especially when lower doses of these agents are used chlorthalidone, Because the use of angiotensin II receptor blockers ARBs is associated with fewer metabolic effects while providing approximately the same BP-lowering efficacy, some physicians believe that these medications may represent better initial therapy.
It may be true that there are beneficial effects of antihypertensive medications other than their BP lowering, as in the case of ARBs or ACE inhibitors in patients with diabetic nephropathy. However, it should be remembered that in trials demonstrating benefit of the latter agents, not only in patients with nephropathy but also in patients with left ventricular hypertrophy, the use of diuretics had been necessary to lower BP in most patients.
For example, black patients do not respond to ACE inhibitor—based therapy to as great an extent when compared with diuretic-based treatment. When diuretics are administered with these agents, BP lowering is significantly greater and outcome is improved. In general, the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 21 and many other guideline committees have suggested that a diuretic should be part of any multidrug regimen.
The investigators concluded that an ACE inhibitor—CCB combination might be a better option than an ACE inhibitor—diuretic combination if the use of 2 drugs is indicated.
Heart failure events, however, were reduced more with the diuretic-based regimen than with the ACE inhibitor—CCB combination regardless of race, sex, or lack of significant differences in BP. Moreover, when BP control was not continued, the benefits of previously improved BP control were lost. Of current diuretics, the thiazide type is the one that is most frequently used in the treatment of hypertension except in the presence of renal dysfunction.
Loop diuretics are otherwise not used for initial therapy in hypertension because of their short duration of action. While there are some comparative outcome studies to support their BP-lowering efficacy, to our knowledge there are no long-term, well-controlled outcome studies.
Some adverse effects, such as hyperuricemia, hypomagnesemia, hyperlipidemia, sexual dysfunction, and rare hypersensitivity reactions owing to thiazide's sulfonamide moiety , are relatively infrequent with thiazide therapy, but hypokalemia and hyperglycemia have been of concern, particularly at higher dosages.
Hyperglycemia associated with thiazide therapy is presumed to be at least partly due to hypokalemia. It has been suggested that the negative effects on glycemia may counteract some of the beneficial effects on BP and outcomes, but none of the trials to date have demonstrated any adverse effect, to our knowledge, perhaps because the duration of the trials has been too short years. In a year follow-up of the SHEP study, however, there was no adverse effect on outcomes despite the changes in glucose levels.
If it is true that the decline in the use of available diuretics for the treatment of hypertension may in some way be related to the perception that metabolic effects may decrease their proved outcome benefits, then other metabolically neutral agents may be better choices. There may be a reason for developing other diuretics in the future. In addition to the fact that sodium-reabsorbing sites in the nephron, with potentially better patterns of electrolyte handling, may lead to better diuretic therapy, recent identification of rare mutations that affect both renal ion handling and BP provide new insights into the molecular mechanisms underlying the hypertensive trait.
The hypertension observed in Liddle syndrome, in which there is overexpression of the epithelial sodium channel ENaC, 46 as well as the converse, pseudohypoaldosteronism type 1, in which a deficit in ENaC is present, points toward possibilities for the development of selective antagonists that could be potassium sparing and more potent than the current ENaC inhibitor amiloride.
Our increased understanding of the transport mechanisms in the kidneys, identification of the genes that code for these transporters, and recognition of genetic syndromes related to these genes that alter BP regulation may result in the development of even better diuretics in the future. In conclusion, thiazide diuretics have stood the test of time for more than 50 years in the management of hypertension.
Their use as monotherapy or in combination with other antihypertensive agents has resulted in dramatic decreases not only in cerebrovascular but also in CV events. Comparative data with other antihypertensive medications with different mechanisms of action indicate that diuretics are as, and in some instances more, effective in event reduction than other antihypertensive drugs.
We hope that better understanding of the transport mechanisms in the kidneys and more recent advances in our understanding of the molecular mechanisms and genetic traits that underlie variations in BP in the population will lead to improved diuretics and, possibly, to improved treatment of hypertension. Author Contributions: Study concept and design : Moser and Feig.
Acquisition of data : Moser and Feig. Analysis and interpretation of data : Moser and Feig. Drafting of the manuscript : Moser and Feig. Critical revision of the manuscript for important intellectual content : Moser and Feig. Administrative, technical, and material support : Moser and Feig. Study supervision : Feig. Additional Contributions: Bryan Williams, MD, University of Leicester, Leicester, England, provided invaluable inspiration, critical comments, and review of this article.
Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. Download PDF Top of Article Abstract History of the discovery and development of diuretics Mechanism of action Current role of diuretics in the prevention of cv events The future of diuretics in the treatment of hypertension Article Information References.
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Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Average Mass. Monoisotopic Mass. Roles Classification. Chemical Role s :. Biological Role s :. Application s :. Manual Xrefs. Registry Numbers.
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