Potassium-sparing diuretics
Potassium-sparing diuretics are a group of active substances that stimulate urine production ( diuretics ) without leading to a loss of potassium . They were developed because the body - v. a. in states of hunger - is less well protected against potassium loss than against sodium loss. Some potassium-sparing diuretics compete with aldosterone for binding to its receptor and thus prevent the incorporation of the epithelial sodium channel into the collecting ducts of the kidney ; others block this channel directly.
Representative and chemical structure
The potassium-sparing diuretics belong to two different groups of active substances with different chemical structures and different mechanisms of action.
The active ingredients amiloride (drug name Midamor ® ) and triamterene (Dyrenium ® ) inhibit the resorption of sodium and the secretion of potassium in the distal tubule . Amiloride is a pyrazine derivative with a guanidino group . Triamterene is a pteridine derivative .
Spironolactone (Aldactone ® , Osyrol ® ) is a synthetic steroid and prodrug . Its active metabolite is canrenone , the antagonistic to the receptor for aldosterone acts and thus locking in the renin-angiotensin system is engaged. Canrenon is also available as a drug, either in its pure form or as its salt, potassium canrenoate (Aldactone pro Injectione ® ). Eplerenone (Inspra ® ) is a spironolactone analogue with increased selectivity for aldosterone.
pharmacology
Mechanism of action
In the kidney , metabolic end products are filtered out of the blood and excreted with the urine . At first around 180 to 200 liters of primary urine are produced daily , which is then concentrated in the subsequent system of tubules , Henle's loop and collecting ducts by reabsorption of water until only around 1 to 1.5 liters of terminal urine or secondary urine remain. Important substances such as glucose , amino acids and electrolytes are also absorbed .
The collecting tube is at the end of the nephron. Here, under the influence of the hormones aldosterone and vasopressin , about five percent of the sodium and water absorption takes place. There are two different types of cells in the wall of the collecting tube: In the main cells , sodium and water are absorbed and potassium is excreted. The switching cells are responsible for the resorption or excretion of protons and therefore play an important role in the acid-base balance .
The resorption of the sodium ions in the main cells takes place passively through the so-called epithelial sodium channel ( ENaC for short ). This is made possible by the higher concentration of sodium ions in the urine in relation to the inside of the cell (sodium concentration gradient ). Responsible for this is the sodium-potassium pump on the basal side (facing the blood), which pumps sodium ions out of the cell and potassium ions into the cell using ATP . Since water osmosis follows sodium, the urine becomes concentrated. Since the concentration of potassium in the cell is increased relative to the urine, the potassium ions flow through channels into the urine.
Spironolactone and its analogues are structurally similar to aldosterone . Aldosterone works by attaching to an intracellular receptor. The aldosterone receptor complex causes an increased synthesis of sodium and potassium channels. Aldosterone antagonists now block this intracellular aldosterone receptor . As a result, the number of ducts decreases, sodium and water remain in the urine, and ultimately there is a small increase in sodium and water excretion. Since the channels can only work if aldosterone is present, these diuretics are ineffective in patients after surgical removal of the adrenal glands ( adrenalectomy ).
Triamterene and amiloride, on the other hand, work by blocking the epithelial sodium channel regardless of the presence of aldosterone . This stops the uptake of sodium ions in the tubular cell. As a result, the urine remains concentrated, which leads to increased water excretion through osmosis. Since the sodium-potassium pump cannot absorb potassium ions into the tubular cell due to the lack of sodium , the passive excretion of potassium ions comes to an almost complete standstill. Furthermore, the excretion of magnesium ions decreases significantly, as does the active removal of hydrogen ions ( protons ), although the underlying mechanism is still unknown.
Potassium-sparing diuretics are only moderately effective, as the reabsorption of the primarily filtered sodium ions is only reduced by 2-3%. They are therefore unsuitable for monotherapy of heart failure .
Indications
Amiloride and triamterene have only a limited effectiveness, since only a small proportion of the sodium absorption takes place in the collecting tube. They are therefore mainly used in conjunction with other diuretics, especially thiazides and loop diuretics , to treat or prevent potassium deficiency . Triamteren can be used to treat heart failure , cirrhosis of the liver, and edema caused by secondary hyperaldosteronism . Amiloride can be used in combination with thiazides to treat high blood pressure .
Aldosterone antagonists are used particularly frequently in patients with primary ( Conn syndrome ) and secondary hyperaldosteronism , as they block the aldosterone receptor. Further areas of application are potassium deficiency, high blood pressure, heart failure, liver cirrhosis and nephrotic syndrome.
Another indication are diseases of the cardiovascular system . These lead to an increased aldosterone level, which plays a role in the formation of connective tissue (fibrosis) in the heart muscles and blood vessels, the programmed cell death of myocardial cells, the reduced availability of the vasodilating nitric oxide (NO) and, under certain circumstances, the hypertrophy of the heart chambers . Aldosterone antagonists have been shown to reduce these complications.
Contraindications
Because they inhibit the excretion of potassium, potassium-sparing diuretics should not be used in patients with hyperkalemia (increased levels of potassium in the blood). This risk is particularly high in patients with chronic kidney failure , which is why they should generally not be treated with potassium-sparing diuretics.
Liver disease can hinder the metabolism of triamterene and spironolactone.
Pharmacokinetics
Both amiloride and triamterene can be administered orally (in tablet form). 50% of amiloride is absorbed from the digestive tract and is not metabolized in the liver . Its plasma half-life is 16-20 hours. It is excreted unchanged via the kidneys with the urine. 80% of the administered triamterene is absorbed from the digestive tract. Due to a strong first-pass effect in the liver, where it is metabolized into less effective end products, the absolute oral bioavailability is only 50%. 80% of the originally administered dose is excreted in the form of metabolic products mainly with the urine, as is the unchanged portion. Because of this high level of metabolism, its plasma half-life of around three hours is much shorter than that of amiloride, which is why it has to be administered more frequently.
About 72% of spironolactone is absorbed in the digestive tract. It takes more time before it becomes active than with amiloride or triamterene; It may take several days for the maximum effect to be achieved. It is metabolized in the liver to its active metabolite, canrenone. The plasma half-life of spironolactone is one to two hours, whereas that of canrenone is around 18 to 32 hours. The metabolic end products of spironolactone are excreted in both the urine and the bile in the stool . The proportion of unchanged spironolactone is low. The absolute bioavailability of eplerenone is unknown. Its plasma half-life is three to five hours. In the liver, it is metabolized into inactive metabolites that are excreted in urine and feces. The proportion of eplerenone excreted unchanged is only five percent.
Side effects
Since potassium-sparing diuretics inhibit the excretion of potassium, the blood concentration of potassium must be closely monitored and, if necessary, the potassium intake limited in order to counteract potentially life-threatening hyperkalaemia . Since the excretion of protons is also inhibited, metabolic acidosis can occur with long-term use .
A folic acid deficiency can occur with triamterene sometimes after treatment. Since triamterene is also poorly soluble in water, kidney stones can be the result.
Because synthetic steroids like spironolactone also have little effect on other steroid receptors , endocrine abnormalities can occur. These include gynecomastia , impotence, and benign prostatic hyperplasia . However, these side effects do not occur with eplerenone.
Interactions
Simultaneous use of potassium-sparing diuretics and other drugs that affect the renin-angiotensin-aldosterone system , particularly beta blockers and ACE inhibitors , increases the risk of hyperkalemia.
Strong inhibitors of the enzyme CYP3A4 , which metabolizes eplerenone (for example ketoconazole and itraconazole ), can greatly increase its plasma concentration.
The combination of triamterene with indomethacin can lead to acute kidney failure .
history
All diuretics that had been developed into the 1960s had in common that the increased sodium concentration in the distal tubule resulted in an increased excretion of potassium. And although this loss of potassium could be counteracted clinically by administering potassium, the search for diuretics that did not have this effect began. In 1959, Hollander and Chobanian described that spironolactone had an additional antihypertensive effect when administered simultaneously with hydrochlorothiazide . In 1961, GD Searle launched spironolactone . Triamterene was developed by researchers at SmithKline & French (now part of GlaxoSmithKline ) and amiloride at MSD Sharp & Dohme .
swell
literature
- Bertram G. Katzung: Basic and Clinical Pharmacology. 9th edition. Mcgraw-Hill Professional, 2004, ISBN 0-07-141092-9 , Chapter 15: Diuretic agents .
- Donald W. Seldin, Gerhard Giebisch (Ed.): Diuretic Agents: Clinical Physiology and Pharmacology. 1st edition. Academic Press, 1997, ISBN 0-12-635690-4 , p. 3 ff.
- Charles R Craig, Robert E Stitzel: Modern Pharmacology with Clinical Applications . 6th edition. Lippincott Raven, 2003, ISBN 0-7817-3762-1 , p. 246 ff.
- W. Hollander, AF Chobanian, RW Wilkins: The antihypertensive action of mercurial, thiazide, and spironolactone diuretics. In: E. Buchborn, KD Bock (Ed.): Diuresis and Diuretics, International Symposium. Springer Verlag, Berlin 1959, p. 297.
Individual evidence
- ↑ Jörg Korrell: Aldosterone and aldosterone antagonists and their significance in chronic heart failure. In: Small Animal Medicine . 11, 2008, pp. 1-3.
- ↑ Technical information on amiloride
- ↑ Technical information on triamteres
- ↑ Specialist information on spironolactone
- ↑ Specialist information on eplerenone
