Carbonic anhydrase inhibitor
Carbonic anhydrase inhibitors are a group of drugs that inhibit the enzyme carbonic anhydrase. Although it was originally developed as a diuretic drugs, today they are mostly used in the treatment of other diseases, mostly against glaucoma ( glaucoma), but also against epileptic seizures. The carbonic anhydrase inhibitors are structurally to the group of sulfonamides.
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Representatives and chemical composition
Chemically, it is in the carbonic anhydrase inhibitors to unsubstituted sulfonamide derivatives. Prototype of the carbonic anhydrase inhibitor acetazolamide is the active ingredient. Methazolamide and diclofenamide are further developments of acetazolamide.
Dorzolamide and brinzolamide be used in the surface treatment of glaucoma.
Other drugs with an inhibitory activity on carbonic anhydrase are the anticonvulsants sulthiame, topiramate and zonisamide.
Pharmacology
Mechanism of Action
Carboanhydrases occur in the proximal tubule cells of the kidney. They are responsible for the excretion of protons ( H ). Inhibition of these excretion leads to a lower recovery of bicarbonate ( HCO3-) and sodium ions (Na ) and thus a decreased reabsorption of water. As a result, water is increasingly excreted.
Since this mechanism but especially occurs in the proximal tubule, the distal tubule increases the resulting water is absorbed compensatingly increased, which reduces the effect of carbonic anhydrase inhibitors.
In addition, the increased loss of sodium ions leads to increased retention of Cl - and increased secretion of K . This results in hypokalemia (too little potassium in the blood ) and a hyperchloremic metabolic acidosis, which lowers the pH in the kidney and thus dramatically reduces the effect of carbonic anhydrase.
Areas of application
Since carbonic anhydrase inhibitors have little diuretic effect and effective alternatives are available, they are now no longer used as such. My main application is in the treatment of glaucoma.
They can be used to increase the pH of the urine, as it increases the solubility, and thus elimination of uric acid, cysteine and other weak bases. But this can only be maintained with the concomitant use of bicarbonate for a long time. In metabolic alkalosis as a result of the use of diuretics carbonic anhydrase inhibitors may help normalize the pH of the blood again.
Increased intracranial pressure with altitude sickness can be treated with acetazolamide, as this inhibits the formation of new Liquors and also lowers the pH thereof. In addition, carbonic anhydrase inhibitors are used to increase phosphate excretion in hyperphosphataemia.
The inhibition of carbonic anhydrase is used in the treatment of epileptic seizures. The best-known anticonvulsant from this group of substances is sulthiame. Acetazolamide is relatively rarely used, mostly as an adjunct in difficult to treat seizures or status epilepticus during. Even the newer anticonvulsants topiramate and zonisamide have - among other mechanisms - also an inhibitory effect on carbonic anhydrase. This inhibitory effect results in a Gewebsübersäuerung, in turn, can reduce the excitability of nerve cells.
Contraindications
In cases of renal or hepatic carbonic anhydrase inhibitors may not be applied because the decreased excretion of ammonium in the kidney could lead to hyperammonemia and hepatic encephalopathy.
Caution is advised when allergies to the sulfone group, in pulmonary emphysema and in pregnancy. During long- term use must be taken by the resulting loss of potassium on sufficient potassium intake.
Pharmacokinetics
Carbonanhydrasehemmer are well absorbed after oral administration ( tablets). After half an hour, their effect is visible in the form of urine alkalinisation. This effect reaches its peak after two hours and lasts up to twelve hours. Be Eliminated carbonic anhydrase in the proximal tubule of the kidney.
In the glaucoma treatment applied carbonic anhydrase inhibitors (such as dorzolamide ) topically ( superficially ) applied.
History
In the late 1930s, the Notes multiplied that in patients who were treated with sulfonamides against bacterial infections, an increased urine output occurred. It was found that this effect is due to an inhibition of carbonic anhydrase in the kidney. Starting from sulfanilamide therefore began the search for substances that could be used as diuretics. With acetazolamide one was even find it. Due to the greater effectiveness of thiazide diuretics in the 1960s began to displace carbonic anhydrase inhibitors as diuretic drug of choice.