Thiazide diuretics

Thiazide diuretics are a group of water tablets (diuretics) . They inhibit a transport protein of the early distal tubular cells so that they recover less common salt from the primary urine . The resulting increased osmotic pressure of the urine leads to increased water excretion.

Representative and chemical structure

Benzothiadiazine

Chemical structure of various thiazide diuretics

Thiazide diuretics are to be seen as a further development of the carbonic anhydrase inhibitors of the acetazolamide type . From a chemical point of view, it is a further development of the sulfonamide chlorothiazide , one of the first diuretics developed in the laboratory, and a number of other substances, which are all based on the same principle of action.

The thiazide diuretics belong to two chemically different groups: on the one hand, all substances that contain a benzothiadiazine ring and are known as thiazides, and secondly, those without a benzothiadiazine ring, which are called thiazide analogues. All of them require a chlorine atom or a CF ₃ group in close proximity to the sulfonamide group for their effect . Although this sulfonamide group is responsible for the inhibition of carbonic anhydrase (cf. carbonic anhydrase inhibitors ), the effect of the thiazide diuretics is not based on this effect.

The lead substance is hydrochlorothiazide (HCT, brand names Disalunil ^® or Esidrix ^® ), a benzothiadiazine derivative. Other substances in this group are benzthiazide , chlorothiazide , hydroflumethiazide , methyclothiazide , polythiazide and trichloromethiazide . Bendroflumethiazide is rarely used. On the other hand, the thiazide analogues include chlortalidone (Hygroton ^® ), clopamid (Briserin ^® ), indapamide (Natrilix ^® ), mefruside , metolazone and xipamide .

pharmacology

Mechanism of action

Transport processes in the distal convolute of the nephron

In the kidney , metabolic end products are filtered out of the blood and excreted with the urine . Initially, around 180 to 200 liters of primary urine are produced daily. In the subsequent tubule system , this amount is reduced through various resorption processes until only about 1 to 1.5 liters of terminal urine remain. Important substances such as glucose , amino acids and electrolytes are also absorbed . Thiazide diuretics act in the proximal part of the distal tubule in the nephron . About six to eight percent of the excreted sodium ions are reabsorbed here . This resumption takes place with the help of a transport protein , the sodium chloride symporter (cotransporter). It is located on the luminal side (facing the urine) of the tubular cells and transports a chloride ion into the tubular cell with each sodium ion . The driving force is the active transport of sodium out of the cell into the blood by the basolateral sodium-potassium pump (facing the blood) , as this creates a concentration gradient between the tubular cell and the urine within the tubule. This reduced sodium concentration within the cell also acts as a driving force for the basolateral 3 Na ⁺ / Ca ²⁺ antiport carrier, which pumps sodium into the cell and calcium out. Due to the lower calcium concentration in the cell, calcium ions can be absorbed passively from the urine via the luminal calcium channel TRPV5 . Chloride and potassium ions are passively released into the blood through ion channels.

Thiazide diuretics now work by reversibly inhibiting this sodium chloride transport. Sodium and chloride cannot be reabsorbed, which is why a lower osmotic pressure difference builds up between urine and blood . This means that less water diffuses from the urine into the blood (the cells have a high level of water permeability due to water channels ). The increased sodium concentration in the urine compensatory increases the sodium absorption in the collecting tube . Since sodium is absorbed there in exchange for potassium , thiazide diuretics lead indirectly to a loss of potassium. Because of their sulfonamide group, thiazide diuretics also inhibit the enzyme carbonic anhydrase in high doses .

Treatment with thiazide diuretics results in increased sodium excretion and decreased calcium excretion. Since the Na ⁺ -Cl ^- symporter no longer transports sodium into the cell, the sodium concentration in the cell is reduced. This stimulates the 3 Na ⁺ / Ca ²⁺ antiport carrier to pump more sodium into the cell and at the same time more calcium out of the cell. The low calcium concentration in the cell leads to increased absorption of calcium. Therefore, they can be used in the treatment of kidney stones due to increased calcium concentration in the urine ( hypercalciuria ).

In patients with diabetes insipidus renalis , the kidneys do not respond adequately to the antidiuretic hormone (ADH), which is why large amounts of very dilute urine are excreted. Since more concentrated urine is produced with thiazide diuretics, these can be used therapeutically here.

application areas

The most important indications for thiazide diuretics are high blood pressure and chronic heart failure . They are also used in the treatment of chronic renal , cardiac and hepatogenic edema . Due to the increased absorption of calcium, they are used in the treatment of kidney stones that occur when the concentration of calcium in the urine is increased. Another possible use is the treatment of nephrogenic (kidney-caused) diabetes insipidus . In patients whose blood vasopressin levels are normal but whose kidneys do not respond to the hormone , thiazide diuretics can help reduce urination and increase osmolarity .

They can also be used to a limited extent at the start of therapy for chronic venous insufficiency for a short time to support compression therapy in order to reduce existing edema. They are not suitable for treatment only without compression.

Contraindications

Thiazide diuretics must not be used in cases of impaired kidney function ( glomerular filtration rate <30 ml / min, serum creatinine > 2.0 mg / dl), as this further deteriorates kidney performance. An exception is the thiazide analog xipamide , which, like loop diuretics , can be used for severely impaired kidney function. In severe liver dysfunction, there is a risk of azotemia with accumulation of ammonia and the development of hepatic encephalopathy . Caution should also be exercised with pre-existing hypovolemia , severe potassium deficiency , sodium deficiency and hypercalcaemia .

Pharmacokinetics

Thiazides can be given orally (in tablet form) and are absorbed relatively quickly in the digestive tract . Chlorothiazide is not very lipophilic and can therefore, as the only representative, also be administered parenterally (as an infusion ). Since these are organic acids , they are not filtered in the kidney corpuscle , but actively excreted in the proximal tubule . In addition, some is excreted in the bile and stool .

Side effects

The increased loss of potassium and sodium ions can lead to hypokalaemia (potassium deficiency) and hyponatraemia (sodium deficiency). An increased number of chloride and magnesium ions are also excreted. The former can lead to hypochloremic alkalosis . It is therefore necessary to regularly check the electrolyte concentration in the serum .

Inhibition of calcium excretion can lead to hypercalcaemia , especially in older women or if there is latent primary hyperparathyroidism .

Decreased glucose tolerance can occur. Furthermore, thiazide diuretics influence lipid metabolism . After several weeks of use can dose-dependently triglycerides and LDL - cholesterol be increased, but return after stopping the drugs to normal levels.

Thiazide diuretics are excreted by the anion transporter in the proximal tubule . This is otherwise responsible, among other things, for the excretion of uric acid , which can lead to an accumulation of uric acid in the blood. The result is hyperuricemia and, in severe cases, gout . In rare cases, pancreatitis can occur.

Because thiazide diuretics contain a group of sulfonamides, allergic reactions such as rash, eosinophilia and, in rare cases, interstitial nephritis may occur in patients with hypersensitivity to sulfonamides .

Interactions

Since they are excreted by the anion transporter in the proximal tubule, they influence the effects of a number of other drugs that are also excreted in this way. These include nonsteroidal anti-inflammatory drugs (e.g. acetylsalicylic acid or ibuprofen ), lithium , digoxin , dofetilide or fluconazole .

White skin cancer and hydrochlorothiazide

It has been known for more than 50 years that chlorothiazides increase the photosensitivity of the skin.

Two studies from Denmark, published in 2017 and 2018, now seem to clearly show a link between hydrochlorothiazide and white skin cancer. The effect occurred in patients with long-term use. Other chlorothiazides do not appear to be affected.

history

Chlorothiazide was synthesized in 1955 by researchers at MSD Sharp & Dohme , who received the Lasker Foundation's Special Public Health Award in 1975 . It was launched in 1957, and although it was originally intended to treat edema , its effectiveness against high blood pressure was discovered relatively quickly.

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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 , pp. 3 ff. Chapter 3 A history of diuretics.
• Charles R. Craig, Robert E. Stitzel (Eds.): Modern Pharmacology with Clinical Applications. 6th edition. Lippincott Raven, 2003, ISBN 0-7817-3762-1 , pp. 249 ff. Chapter 21 Diuretic Drugs.

Individual evidence

1. ^ RA Wermers et al .: Incidence and clinical spectrum of thiazide-associated hypercalcemia . In: Am J Med . No. 120 (10) , 2007, pp. 911.e9-15 , PMID 17904464 .
2. ^ AB Magil, HS Ballon, EC Cameron, A. Rae: Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathologic observations in three cases. In: Am J Med. 69 (6), Dec 1980, pp. 939-943. PMID 7446559
3. ↑ Deutsches Ärzteblatt: Hydrochlorothiazide: Skin cancer risk from frequently used diuretics. In: Deutsches Ärzteblatt. Deutscher Ärzteverlag GmbH, Berlin, accessed on April 16, 2019 . 
4. ↑ Anton Pottegard: Hydrochlorothiazide use is strongly associated with risk of lip cancer . Ed .: Journal of Internal Medicine. tape 282 , 2017, p. 322-331 .
5. ↑ Sidsel Pedersen: Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark . Ed .: Journal of the American Academy of Dermatology. tape 78 , 2018, p. 673-81 .
6. ^ The Lasker Foundation Awards , accessed June 2, 2008.

Web links

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This article was added to the list of articles worth reading on June 16, 2008 in this version .

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