Sequential nephron block

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The sequential (according to the old spelling also: sequential ) nephron blockade is a pharmacological concept known since about 1985 in the treatment of acute edema with diuretics (water tablets), especially in intensive care medicine . A nephron is the functional subunit of the kidneys; it consists of kidney corpuscles (glomeruli) for filtration and an equal number of kidney tubules (tubules) for reabsorption . All diuretics basically reduce the tubular reabsorption rate , which without treatment is around 99 percent of the primary urine . With regard to the place of action of all diuretics, a distinction is made between the proximal and the distal tubule. And in the case of the distal tubule, a distinction is made between the early distal and the late distal tubular segment . The early distal tubular segment is also called the pars convoluta or distal convolute ; the late distal section is also called tubule reuniens or connecting tubule . Edema is almost always caused by renal sodium retention.

The usual monotherapy with a single loop diuretic is occasionally ineffective, despite intravenous administration and high dosage. The cause of this so-called diuretic resistance of loop diuretics is a compensatory increased reabsorption of sodium and water in the late distal section ( i.e. the site of action of the thiazides ) ( induced by their diuretic effect on the early distal tubule ). However, this view is controversial with regard to the site of action and thus the active principle, since the specialist books specify the early distal tubule as the site of blockage by thiazides. With this compensation, the organism tries to increase the intravascular blood volume and the arterial blood pressure and thus also the cardiac output . When a loop diuretic is used, the resorption rate tends to increase instead of decreasing. Thiazides are now supposed to inhibit or block reabsorption in the late distal tubule . The tubular reabsorption rate is reduced again, the cardiac output also reduced, the blood pressure lowered, the urine volume increased and the edema flushed out.

With the sequential nephron blockade , the glomeruli are not blocked. And the proximal sections are not blocked by the tubules either; and of the distal tubular sections , only the late distal and not the early distal sections are restricted in their function. The word blockade refers to the actual effect of all diuretics, namely the iatrogenic intended reduction of the tubular reabsorption. This blockage is called sequential (Latin: sequentia = succession, sequens = following) because it takes place gradually (in contrast to monotherapy , i.e. with two or three different active substances ) on subsequent tubular sections .

According to the current recommendation, the combination of the loop diuretic with a thiazide diuretic (attacking the last part of the renal tubules where the above compensation takes place) is temporarily beneficial, even in patients with advanced renal insufficiency , for whom thiazides are otherwise contraindicated . The current German and international guidelines give a corresponding recommendation. Such a combination therapy for renal insufficiency requires a lot of experience as well as close monitoring (especially of creatinine , magnesium and potassium in the blood) and should therefore be reserved for experts, especially if aldosterone antagonists are also prescribed to increase the diuresis (they also act on the late distal tubular segment). Several contraindications should be noted.

Since a diuretic only ever attacks part of the tubular system and therefore increased reabsorption can occur in more distal sections, the sequential nephron blockade by two (or more) diuretics with different attack sites is a pathophysiologically plausible concept. Its clinical relevance becomes clear , for example, in the treatment of renal insufficiency with the combination of a loop diuretic with a thiazide (e.g. hydrochlorothiazide (HCT; controversial because of undesirable drug side effects), chlorthalidone or xipamide , which is related to the benzothiadiazine derivatives): lower doses of the combination are more effective and at the same time fewer side effects than the high-dose monotherapy with a loop diuretic (which is sometimes still carried out).

In this respect, the sequential nephron blockade, as with any diuretic therapy, is only a tubular blockage. Since different diuretics have different sites of action, a combination of several preparations makes sense for this reason alone. This is called synergism . It is obvious that this sequence treatment simultaneously prevents compensatory counter-regulation (avoidance of resistance). This is called synergism with a super-additive effect . Only this avoidance of compensation distinguishes the principle of sequential nephron blockade from other combination therapies in pharmacology . In almost all main groups in the Red List you can even find related combination tablets (combination tablet , multiple combination , fixed combination , polypharmacotherapy , polypill ); these are also prescribed in the outpatient area and outside of inpatient intensive care medicine.

literature

Individual evidence

  1. ^ H. Knauf, Ernst Mutschler : Diuretika , 2nd edition, Urban & Schwarzenberg , Munich, Vienna, Baltimore 1992, ISBN 3-541-11392-8 , p. 224.
  2. In the specialist literature, however, the pars recta of the tubules is specified as the site of action of the loop diuretics. The pars recta lies in front of the pars convoluta .
  3. See for example: Gerd Herold : Innere Medizin , Eigenverlag, Cologne 2019, ISBN 978-3-9814660-8-9 , p. 218. Current books circumvent this problem by only referring to the distal tubular section, for example: Andreas Ruß: Arzneimittel pocket , special edition of the 23rd edition, Grünwald in December 2018, ISBN 978-3-89862-790-0 , p. 56.
  4. Willibald Pschyrembel: Clinical Dictionary , 267th edition, de Gruyter , Berlin, Boston 2017, ISBN 978-3-11-049497-6 , p. 1956.
  5. Kurt Kochsiek , H. Gillmann, A. Schrey: Diuretics for Hypertension and Heart Failure , Urban & Schwarzenberg , Munich, Vienna, Baltimore 1984, ISBN 3-541-10891-6 , p. 23.

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