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Drugs

, Volume 31, Supplement 4, pp 40–55 | Cite as

Diuretic Drugs Progress in Clinical Pharmacology

  • Ariel Lant
Section 2: Diuretics: The Current Basis for Use

Summary

Oral diuretics are amongst the most widely used drugs in clinical practice today. Their discovery close on thirty years ago remains a major milestone in therapeutic progress. Though originally designed for treating heart failure, diuretics are more commonly prescribed, worldwide, in hypertension than for relief of oedema. Since the introduction of chlorothiazide, diuretic development has passed through a series of distinct stages. The thiazide era was followed by the ‘high-ceiling’ diuretics, the antikaliuretics and, more recently, polyvalent agents that cause both saluresis and uricosuria. Alongside these synthetic achievements, major advances have occurred in the knowledge of nephron function and ion transport mechanisms. These have acted as stimulus to the design of novel categories of diuretics.

The practising clinician thus has a wide range of available diuretics to choose from. The most appropriate choice of an agent aimed at the relief of symptoms with minimal adverse effects requires an understanding of where and how diuretics act within their primary target organ, the kidney. Whereas various procedures, ranging from micropuncture to the study of brush border membrane vesicles, have been utilised experimentally, investigation of the mode and sites of action of diuretics in man has largely depended on application of clearance methodology. Refinements in analytical chemistry have encouraged study of the pharmacokinetic and metabolic fate of diuretics. Taken together, available evidence shows that most diuretics exert their saluretic action from the intraluminal aspect of the renal tubules. The time-course of drug delivery, as well as total quantity of drug transported into the lumen determine the cumulative drug response. Exceptions are muzolimine and the aldosterone antagonists which act at the peritubular membrane. Distinctive stereospeciflc effects on luminal tubular ion transport occur with indacrinone and etozoline.

The clinical use of diuretics often involves concurrent administration with other drugs. The mechanisms involved in a number of the resulting pharmacodynamic and pharmacokinetic interactions have considerable relevance in patient management. Notable examples of these interactions are the blunting of diuretic action by non-steroidal anti-inflammatory agents and the diuretic-induced diminution in the renal clearance of lithium salts.

Keywords

Thiazide HCTZ Frusemide Bumetanide Triamterene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

Les diurétiques administrés per os figurent parmi les médicaments les plus largement utilisés en médecine actuellement. Leur découverte il y après de 30 ans, reste un point de repère majeur dans les progrès de la thérapeutique. Bien qu’ils aient été au départ destinés au traitement de l’insuffisance cardiaque, les diurétiques sont en fait mondialement utilisés avant tout dans l’hypertension. Depuis l’introduction du chlorothiazide, le développement des diurétiques est passé par une série d’étapes distinctes. L’époque thiazide a été suivie par les diurétiques de l’anse, les antikaliurétiques et, plus récemment, par des diurétiques polyvalents qui sont à la fois sali-et uricodiurétiques. Au cours de cette évolution, des progrès majeurs ont été faits dans la compréhension de la fonction du néphron et dans les mécanismes de transports ioniques. Ceci a joué un rôle moteur dans la conception de nouvelles classes de diurétiques.

Le practicien dispose ainsi d’un grand éventail de diurétiques parmi lesquels il peut choisir selon les besoins. Le meilleur choix vise à guérir les troubles avec le moins d’effets indésirables et requiert la connaissance du mécanisme d’action des diurétiques sur leur organe cible, le rein. Si, expérimentalement, des méthodes diverses ont été utilisées, allant de la microponction à l’étude des vésicules de la bordure en brosse de la membrane, chez l’homme l’investigation du mode et des sites d’action des diurétiques a été largement tributaire de l’application de la méthodologie de la clairance. Les raffinements de l’analyse chimique ont facilité l’étude du métabolisme et de la cinétique des diurétiques. Au bout du compte, on a la preuve que la plupart des diurétiques exercent leur effet saliurétique à partir de la partie intraluminale des tubules rénaux. Le rythme d’administration et la quantité de médicament arrivant dans la lumière du tubule déterminent l’importance de la réponse au médicament. Font exception la muzolimine et les anti-aldostérones qui agissent sur la membrane péritubulaire. Des effets stéréospécifiques distincts sur le transport ionique dans la lumière du tubule surviennent avec l’indacrinone et l’étozoline.

L’utilisation clinique des diurétiques implique souvent l’administration simultanée d’autres médicaments. Les mécanismes responsables d’interactions pharmacodynamiques et pharmacocinétiques sont alors importants à connaître pour conduire le traitement du malade. Des exemples connus de ces interactions possibles sont la baisse d’efficacité des diurétiques due aux antiinflammatoires non stéroïdiques et la diminution de la clairance rénale des sels de lithium par les diurétiques.

Zusammenfassung

Orale Diuretika gehören heute zu den am meisten verwendeten Pharmaka in der klinischen Praxis. Ihre Entdeckung vor fast 30 Jahren bleibt ein bedeutender Meilenstein im therapeutischen Fortschritt. Obwohl ursprünglich zur Behandlung des Herzversagens entwickelt, werden Diuretika weltweit häufiger bei der Hypertonie als für die Beseitigung von Oedemen verschrieben. Seit der Einführung von Chlorothiazid verlief die diuretische Entwicklung durch eine Reihe bestimmter Stufen. Der Thiazid-Ära folgten die Schleifendiuretika, die Antikaliuretika und neuerdings polyvalente Pharmaka, die sowohl eine Salurese als auch eine Uricosurie verursachen. Mit diesen synthetischen Errungenschaften traten bedeutende Fortschritte in der Kenntnis über die Funktion des Nephron und die Mechanismen des Ionen-transports auf. Sie wirkten als Stimulus für die Entwicklung von neuen Diuretikakategorien.

Der praktizierende Kliniker besitzt damit einen weiten Bereich verfügbarer Diuretika zur A uswahl. Die geeignetste Wahl eines Medikaments zur Beseitigung der Symptome bei minimalen Nebenwirkungen erfordert ein Verständnis darüber, wo und wie Diuretika in ihrem Hauptangriffsorgan, der Niere, wirken. Während verschiedene Verfahren, die von der Mikropunktur bis zum Studium der Bürstenrand-Membranvehikel reichen, experimentell eingesetzt wurden, hängen Untersuchungen über die Art und Angriffspunkte der Diuretika beim Menschen hauptsächlich von der Anwendung der Clearance-Methode ab. Verfeinerungen in der analytischen Chemie begünstigten das Studium der Pharmakokinetik und der metabolischen Veränderungen der Diuretika. Zusammengenommen zeigen die zur Verfügung stehenden Hinweise, daβ die meisten Diuretika ihre saluretische Wirkung über den intraluminaren Aspekt der Nierentubuli ausüben. Der zeitliche Verlauf der zur Verfügungstellung des Pharmakons wie auch die Gesamtmenge des in das Lumen transportierten Pharmakons bestimmen die kumulierte Pharmakareaktion. Ausnahmen bilden Muolimin und die Aldosteron-Antagonisten, die an der peritubulären Membran angreifen. Bestimmte stereospezifische Effekte auf den luminal tubulären Ionentransport treten mit Indacrinon und Etozolin auf.

Die klinische Verwendung der Diuretika erfolgt oft mit der gleichzeitigen Verabreichung anderer Pharmaka. Die beteiligten Mechanismen bei einer Anzahl von resultierenden pharmakodynamischen und pharmakokinetischen Interaktionen sind für die Behandlung der Patienten von beträchtlicher Relevanz. Bemerkenswerte Beispiele dieser Interaktionen sind die Aufhebung der diuretischen Wirkung durch nicht-steroidale, antiinflammatorische Medikamente und die Diuretika-induzierte Verminderung der renalen Clearance von Lithiumsalzen.

Resumen

Los diuréticos orales son uno de los grupos de medicamentos más usados en lapráctica clínica. Su aparición hace treinta años marcó un hito en el progreso terapéutico. Aunque destinados en principio a tratar la insuficiencia cardiaca, en todo el mundo los diuréticos se prescriben más frecuentemente para tratar la hipertensión que para aliviar el edema. Desde la introducción de la clorotiacida, el desarrollo de los diuréticos ha pasado por una série de etapas. La época de las tiacidas fue seguida por la de los diuréticos de ‘alto techo’, la de los anticaliuréticos y mas recientemente, la de los medicamentos polivalentes que producen saluresis y uricosuria. Junto con estos logros sintéticos se han conseguido grandes avances en el conocimiento de la función de la nefrona y de los mecanismos del transporte iónico; tales hallazgos han supuesto un estimulo para el diseño de nuevas categorías de diuréticos.

El clínico tiene, pues, a su disposición, una amplia gama de diuréticos. La apropiada eleccion de un fármaco destinado al alivio de los síntomas, con minimos efectos secundarios, requiere conocer dóndey cómo actuan los diuréticos en el interior de su principal órgano efector, el riñón. Aunque se han utilizado diversos procedimientos experimentales, desde la micropunción al estudio de las vesículas de membrana de borde en escobilla, la investigación del modo de actuación y de los lugares de acción de los diuréticos en el hombre depende en gran parte de la aplicación de la metodología del aclaramiento. El perfeccionamiento de las técnicas de la química analítica ha estimulado el estudio del objetivo farmacocinético y metabólico de los diuréticos. En conjunto, los datos de los que se dispone indican que la mayoría de los diuréticos ejercen su acción salurética desde la superficie intraluminal de los túbulos renales. El curso temporal de la liberación del medicamento y la cantidad total de fármaco transportado a la luz determinan la respuesta acumulativa al medicamento. Son excepciones la muzolimina y los antagonistas de la aldosterona que actúan en la membrana peritubular. Al administrar indacrinona o etozolina se producen efectos estereospecíficos sobre el transporte luminal tubular de iones.

El uso clínico de los diuréticos suele comportar la administración concomitante de otros medicamentos. Los mecanismos implicados en varias de las interacciones farmacodinámicas y farmacocinéticas resultantes tienen una considerable importancia en el tratamien to de los pacientes. Notables ejemplos de estas interacciones son la reducción de la acción diurética como consecuencia de la administración de antiinflamatorios no esteroidesy la disminución del aclaramiento renal de sales de litio inducida por los diuréticos.

Resumo

Os diuréticos orais estão entre os medicamentos mais amplamente utilizados na prática clínica atualmente. A sua descoberta há cerca de trinta anos, constitui um dos pontos altos dos progressos terapêuticos. Embora tenham sido originalmente planejados para o tratamento de insuficiências cardíacas, os diuréticos são mais usados mundialmente para tratar a hipertensão que para aliviar edemas. Desde que se introduziu a clorotiazida, o desenvolvimento dos diuréticos passou por uma série de estágios diferentes. À era da tiazida seguiram-se os diuréticos de alta potência, os antipotassioréticos, e, mais recentemente, os agentes polivalentes que causam tanto saliurese como uricosuria. Paralelamente a estes sucessos na síntese, ocorreram avanços importantes no conhecimento dafunção do néfron e dos mecanismos de transporte de íons. Estes atuaram como estimulo para o desenvolvimento de novas categorias de diuréticos.

Atualmente, o médico dispõe, portanto, de uma ampla gama de diuréticos. A escolha mais apropriada de um agente que alivie os sintomas com um mínimo de efeitos adversos requer a compreensão de como e onde os diuréticos atuam no órgão a que se destinam, a saber, os rins. Enquanto que diversos procedimentos —variando da micropunção ao estudo das vesículas com membrana com borda em escova —tenham sido utilizados experimentalmente, a pesquisa do modo e dos locals de ação dos diuréticos no hörnern dependeu em grande parte da aplicação da metodologia da depuração. A crescente sofisticação da química analitica estimulou o estudo do destino farmacocinético e metabólico dos diuréticos. Tais avanços evidenciam que a maioria dos diuréticos exercem a sua ação salurética a partir da face intraluminal dos túbulos renais. A demora do transporte da droga, bem como a quantidade total de droga transportada para o lúmen, determinam a resposta cumulativa da droga. Exceções constituem os antagonistas de muzolimina e de aldosterona, que atuam na membrana peritubular. Com indacrinona e etozolina, ocorrem efeitos estereospecíficos distintos no transporte lúmino-tubular de íons.

O uso clínico dos diuréticos envolve muitas vezes a administração concomitante de outras drogas. Os mecanismos envolvidos em várias das interações farmacodinâmicas e farmacocinéticas resultantes são de consideràvel relevância no contróle do paciente. Algumas exceções notàveis a estas interações são a atenuação da ação dos diuréticos por parte dos agentes anti-inflamatórios não-esteróides e a diminuição da depuração renal de sais de lítio.

Riassunto

I diuretici sono oggi tra i farmaci più largamente usati nella pratica clinica. La loro scoperta avvenuta circa 30 anni fa rimane una pietra miliare nel progresso terapeutico. Sebbene originariamente destinati al trattamento dello scompenso cardiaco, oggi i diuretici sono in tutto il mondo più largamente presenta nel trattamento dell’ipertensione piuttosto che dell’edema. Dall’introduzione della clorotiazide, lo sviluppo dei diuretici è passato attraverso una serie di fasi distinte. I tiazidici furono seguiti dai diuretici dell’ansa, dai risparmiatori di potassio e, più recentemente, da sostanze polivalenti saluretiche e uricosuriche. Insieme alla sintesi di nuove sostanze, si sono registrati grandi progressi nella conoscenza della funzione del nefrone e dei meccanismi di trasporto ionico. Questo è servito da stimolo nella progettazione di nuovi tipi di diuretici.

Il medico pratico ha così una vasta gamma di diuretici tra cui scegliere. La scella più appropriata di un farmaco, al fine di ottenere la regressione dei sintomi con minimi effetti indesiderati, richiede la conoscenza della sede e del meccanismo d’azione della sostanza usata a livello dell’organo bersaglio principale, il rene.

Mentre varie tecniche sono state usate sperimentalmente, dalle microiniezioni allo studio delle vescicole dell’orletto a spazzola, le ricerche nell’uomo su meccanismo e sede d’azione dei diuretici sono in larga misura fondate su studi di clearance. I progressi della chimica analitica hanno incoraggiato lo studio della farmacocinetica e del metabolismo dei diuretici. Nell’insieme i dati disponibili dimostrano che la maggior parte dei diuretici esercita l’effetto saluretico dall’interno del lume dei tubuli renali. La liberazione del farmaco nel tempo e la quantità totale di farmaco trasportato nel lume determinano l’effetto farmacologico complessivo. Fanno eccezione la muzolimina e gli antialdosteronici che agiscono a livello della membrana peritubulare. Indacrinone ed etozolina esercitano effetti stereospecifici particolari sul trasporto ionico nel lume tubulare. In clinica i diuretici sono spesso associati ad altri farmaci. Gli effetti secondari alle numerose interazioni farmacodinamiche e farmacocinetiche risultanti, hanno una notevole importanza nel trattamento del paziente. Esempi significativi di queste interazioni sono la soppressione dell’effetto diuretico da parte di farmaci anti—infiammatori non steroidei e la diminuzione indotta dai diuretici della clearance renale dei sali di litio.

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Copyright information

© ADIS Press Limited 1986

Authors and Affiliations

  • Ariel Lant
    • 1
  1. 1.Department of Clinical Pharmacology and TherapeuticsCharing Cross and Westminster Medical School, Westminster HospitalLondonEngland

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