Proton pump inhibitors, H+/K+-ATPase inhibitors

Omeprazole was the first proton pump inhibitor, followed by lansoprazole and more recently pantoprazole and rabeprazole. Esomeprazole is the S-isomer of omeprazole.

Effects

Omeprazole, lansoprazole, pantoprazole and rabeprazole, irreversible inhibitors of proton pump, do not act directly by contact with the gastric mucosa but after intestinal absorption, distribution throughout the body in not ionized form and secretion into the microchannel of the gastric parietal cells.

In the microchannel where the pH is low, close to 2, these inhibitors are ionized and transformed into active molecules which establish covalent bonds with HS group of cystein of the alpha subunit of the pump. The pump is thus inhibited in an irreversible way. The renewal of activity of pumping requires the synthesis of new pumps. As the half-life of renewal of the pumps is about 18 to 24 hours, a single intake allows an inhibition of almost 24 hours.

The fact that the blockers are active only in acid medium, after protonation, explains why they have little effects on extra-gastric H+/K+-ATPase of the kidney and of the colon.

If these inhibitors were given in non enteric coated form, they would be transformed into active metabolite in the stomach, but without reaching in the microchannel a concentration sufficient to inhibit the proton pump.

The Cl- secretion which is concomitant with that of H+ to give HCl is not directly modified by the inhibitors of H+/K+-ATPase. The mechanism of the Cl- secretion remains poorly understood. It appears coupled to that of potassium, which is recycled.

A consequence of the gastric inhibition of H+/+-ATPase is the reactional rise in gastrin plasma level, very important in rats, but weak in humans. The hypergastrinemy could induce a hyperplasia of the enterochromaffin cells.

Pharmacokinetic features

Proton pump inhibitors are given by oral route in acid-resistant enteric coated forms, with intestinal gradual release. There is also a presentation of omeprazole for intravenous route.

Administered by oral route, they are absorbed from the intestine and are distributed throughout the body. Their plasma half-life is approximately an hour but, as they inhibit the H+/K+-ATPase enzyme in an irreversible way, their action lasts the time of the renewal of enzyme, i.e. nearly 24 hours.

Therapeutic uses

Proton pump inhibitors are indicated in the treatment of gastric and duodenal ulcers, the gastroesophageal reflux and the Zollinger-Ellison syndrome. They are also used to prevent the gastroduodenal damage elicited by nonsteroidal anti-inflammatory drugs. The clinical effectiveness of these products is documented.

Adverse effects

The decrease of gastric acidity could facilitate the development of certain bacteria.

Proton pump inhibitors can cause some digestive disorders, constipation or diarrhea, headache, seldom mental confusion or blood disorders. Eye and hearing disorders were reported after omeprazole parenteral administration. The mechanisms at the origin of adverse effects remain poorly understood.

Omeprazole and lansoprazole are metabolized by the P-450 cytochrome and metabolic interactions with other drugs are possible but not clearly documented.

Although they did not show a teratogenic effect in animal experiments, their prescription, like that of many recent drugs, is disadvised during pregnancy, in particular during the first trimester.

Remarks

An acid secretion by the stomach is necessary for the development of an ulcer but gastric acidity is not the direct cause of the disease, which is related to the presence of Helicobacter pylori. The inhibition of gastric acid secretion makes it possible to cure the ulcer but, in absence of eradication of Helicobacter pylori, there is a relapse at discontinuation of the antisecretory medication.
The eradication of Helicobacter pylori by a treatment associating two antibiotics (or an antibiotic and metronidazole or a salt of bismuth) during approximately two weeks constitutes the etiologic treatment.
Antacids neutralize gastric acidity and gastrointestinal topics protect the gastric and duodenal mucosa by covering it and by acting on mucus. The same drug can have antacid and topical properties. The principal gastroduodenal topics are aluminum and magnesium compounds.
Prothontherapy is a technique of radiotherapy which uses the protons produced by ionization of the hydrogen atom and accelerated by powerful machines of the cyclotron type towards the tumor to treat. Prothontherapy is used in the treatment of ocular melanoma and certain brain neoplasms.
There are proton pump H+/K+-ATPase, localized in osteoclast vacuoles. This pump creates by secretion of protons an acid environment which dissolves the mineral part of the bone and permit to collagenases to alter the protein matrix. Research to find specific inhibitors of this pump is ongoing in order to slow bone breakdown and osteoporosis aggravation.