Thiazide
As a thiazide diuretic substances is called a group, which can be seen as a development of carbonic anhydrase inhibitors on the type of acetazolamide. Chemically, it is the one to further developments of the sulfonamide chlorothiazide, one of the first developed in the laboratory diuretics, and a number of other substances, but they are all based on the same principle of action. The inhibition of a transport protein in the renal tubules leads to reduced re-uptake of ions from the primary, and thus due to the variation of the osmotic pressure for increased water excretion.
- 4.1 Literature
- 4.2 Notes and references
Representatives and chemical composition
The thiazide diuretics include two chemically distinct groups: firstly, all those substances which contain a benzothiadiazine ring and are referred to as thiazides, and secondly those without benzothiadiazine ring, referred to as thiazide analogues. All require a chlorine atom or a CF3 group in close proximity to the sulfonamide group for their effect. This sulfonamide group is indeed responsible for the inhibition of carbonic anhydrase (see carbonic anhydrase inhibitors ), the effect of thiazide diuretics is not based on this effect.
As a lead compound is considered hydrochlorothiazide (brand name Disalunil ® or Esidrix ®), a benzothiadiazine derivative. Other substances in this group are benzthiazide, chlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide and trichlormethiazide. Bendroflumethiazide is hardly used. The Thiazidanaloga however, include chlorthalidone ( Hygroton ®), clopamide ( Briserin ®), indapamide ( Natrilix ®), mefruside, metolazone and xipamide.
Pharmacology
Mechanism of Action
In the kidney, metabolic waste products are filtered from the blood and excreted in the urine. Here, about 180 to 200 liters of primary urine are first produced daily. The following tubules, this amount is reduced by various resorption, remain until only about 1 to 1.5 liters of final urine. Furthermore, important substances such as glucose, amino acids and electrolytes are absorbed. Thiazide diuretics act in the proximal part of the distal tubule in the nephron. Here about six to eight percent of the sodium ions are precipitated resumed. This recovery is performed using a transport protein, the sodium - chloride symporter ( cotransporter ). It is located on the luminal ( urine -facing ) side of the tubule cells and transported in addition to sodium and chloride ions in the tubule. Driving force is the active transport of sodium out of the cell into the blood by the sodium - potassium pump, as this builds up a concentration gradient (gradient ) between the tubule and the urine within the renal tubule. This decreased sodium concentration in the cell is also used as a driving force for the 3 Na / Ca2 antiport carrier containing sodium into the cell and pumping out of calcium. Due to the lower concentration of calcium in the cell the calcium ions can be incorporated passively from the urine of special channels. Chloride ions and potassium ions are delivered passively through ion channels in the blood.
Thiazide diuretics act now, where they reversibly inhibit these sodium - chloride cotransport. Sodium and chloride can not be zurückabsorbiert why the urine is concentrated. This leads to increased excretion of water by osmosis. The increased sodium concentration in the urine leads to increased excretion of potassium ions in the collecting duct. This effect is caused by the collecting duct luminal constant potassium ion channels, which in the by the Na / K -ATPase activity ( Na / K -ATPase is basolateral, ie directed blood down) in the cell cumulative potassium ions lumen passes. Furthermore, thiazide diuretics in high doses inhibit the enzyme carbonic anhydrase. This is attributable to the sulfonamide group.
Treatment with thiazide diuretics, in addition to the increased sodium excretion also decreased calcium excretion result. Since the Na -Cl - no sodium symporter transported into the cell, the sodium concentration is reduced in the cell. This stimulates the 3 Na / Ca2 antiport Carrier to more sodium into the cell and simultaneously pump out more calcium in the cell. The low calcium concentration in the cell leads to an increased absorption of calcium. Therefore, they can be used in the treatment of kidney stones as a result of increased calcium concentration in the urine ( hypercalciuria ).
In patients with renal diabetes insipidus, the kidneys do not respond adequately to the antidiuretic hormone ( ADH), which is why large amounts of highly diluted urine are excreted. Since thiazide diuretics a more concentrated urine is produced, they can be used therapeutically here.
Areas of application
The main 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 in the treatment of kidney stones, which occur at elevated concentration of calcium in the urine, are used. Another possible application is the treatment of nephrogenic ( verursachtem of the kidney ) diabetes insipidus. In patients whose vasopressin levels in the blood is normal, but whose kidneys do not respond to the hormone, thiazide diuretics can help reduce the formation of urine and increase the osmolarity.
Limited, they can be used for a short time to support compression therapy at the start of therapy of chronic venous insufficiency, to reduce existing edema. For the exclusive treatment without compression they are not suitable.
Contraindications
Thiazide diuretics may not (<30 ml / min, serum creatinine > 2.0 mg / dl glomerular filtration rate ) to be applied in patients with impaired renal function because the kidney function continued to deteriorate as a result. An exception is the Thiazidanalogon xipamide, which, as well as loop diuretics, can be used in higher grade renal impairment. In severe hepatic impairment is a risk of azotemia with accumulation of ammonia and development of hepatic encephalopathy. Likewise caution to existing hypovolemia, severe potassium deficiency, sodium deficiency and hypercalcemia.
Pharmacokinetics
Thiazides may be administered orally ( in tablet form ) and are relatively rapidly absorbed in the digestive tract. Chlorothiazide is not very lipophilic and can therefore only representative, also be administered parenterally ( infusion). Since there are organic acids, they are not filtered in the kidney in the renal corpuscles, but actively secreted in the proximal tubule. In addition, some bile and faeces excreted.
Side effects
Due to the increased loss of potassium and sodium ions can lead to hypokalemia (potassium deficiency) and hyponatremia (sodium deficiency ) may occur. Also chloride and magnesium ions are excreted in increased numbers. The former can lead to hypochloraemic alkalosis. Therefore a regular review of the electrolyte concentration in the serum is necessary.
By inhibiting calcium excretion may lead to hypercalcemia, particularly in older women or if a deferred primary hyperparathyroidism is.
Decreased glucose tolerance may occur. Furthermore Thiazides affect the fat metabolism. After several weeks of use dose-dependent triglycerides and LDL cholesterol can be increased, but the return to normal levels after discontinuation of the medication.
Thiazide diuretics are excreted in the proximal tubule of the anion. This is otherwise responsible among others for the excretion of uric acid, which can cause the blood to the accumulation of uric acid. This results in hyperuricemia and gout in severe cases. In rare cases of pancreatitis occur.
Since thiazide diuretics contain a sulfonamide, can cause allergic reactions, characterized by rash, eosinophilia and interstitial nephritis in rare cases in patients with hypersensitivity to sulfonamides.
Interactions
Since they are excreted in the proximal tubule of the anion transporter, they influence the action of a number of other drugs that are also excreted in this way. These include nonsteroidal anti-inflammatory drugs (such as aspirin or ibuprofen ), lithium, digoxin, dofetilide, or fluconazole.
History
Chlorothiazide was synthesized in 1955 by researchers at MSD Sharp & Dohme, which were for 1975 awarded the Special Award of the Lasker Foundation Public Health. In 1957 the launch, and although it was originally intended for the treatment of edema, the effectiveness of high blood pressure was discovered relatively quickly.