Proton pump inhibitors: beware of long-term side effects

Pantoprazole, lansoprazole, omeprazole, esomeprazole and rabeprazole are among the most prescribed drugs in Italy. This article summarizes the main pharmacological effects of proton pump inhibitors and the possible side effects due to prolonged use..

The best known active ingredients belonging to the category of proton pump inhibitor drugs (IPP) I'm:

- pantoprazole (Pantecta®, Pantopan®, Pantorc® and Peptazol®),

- lansoprazole (Frilans®, Lansox®, Limpidex®, Zoton®),

- omeprazole (Antra®, Cletus®, Mepral®, Omeprazen®, Protect®),

- esomeprazole (Esopral®, Lucen®, Nexium®),

- rabeprazole (Pariet®).

These drugs are prescribed by the doctor to treat gastric disturbances, very common diseases related to the digestive system. These pathologies can present themselves as minor disorders that can be easily solved by following a correct lifestyle, avoiding coffee or foods that increase acid secretion such as red meat or alcohol, but there are cases in which it is necessary to intervene pharmacologically to avoid future complications.

Among the most common gastric disorders we find the gastroesophageal reflux, caused by the abnormal ascent towards the esophagus of the gastric juices produced by the stomach; there gastritis, an inflammation of the gastric mucosa; L'ulcer, a lesion of the gastric or duodenal mucosa, due to the corrosive action of gastric juices, which can cause perforation of the organ and the release of the contents into the abdominal cavities.

From the analysis in the first 9 months of 2015, conducted byOsMed (National Observatory on the Use of Medicines) it should be noted that that of proton pump inhibitors remains firmly in first place in terms of agreed spending in Italy (€ 11.40 spent per capita) and are by far the most prescribed drugs.

Just think that only the prescriptions of pantoprazole have an impact of 2.8% on the entire national pharmaceutical expenditure under agreement and always pantoprazole is in first place in the year 2015 among the drugs with the highest per capita expenditure (€ 3.70). Lansoprazole is in fourth place and accounts for 2.1% on the entire expenditure of the NHS; followed by omeprazole in sixth place (1.8% of the NHS expenditure) and esomeprazole in ninth place (1.5% of expenditure).

Overall, the NHS disbursed approximately 700 million euros in the first nine months of 2015 to reimburse the cost of these drugs (almost one billion euros per year).

Around the world, according to an estimated total expenditure in 2006, approximately $ 24 billion per year is spent on the purchase of proton pump inhibitor drugs.

PPIs are highly effective and have revolutionized the approach to treating gastric acid disorders over the past 20 years. Chronic use of PPIs appears to have a high safety margin, but doubts have been raised about possible risks associated with their long-term use. It is necessary to minimize the unnecessary and inappropriate use of these drugs to reduce the potential associated risks and health costs. The use of these drugs should always be considered with caution, especially in hospitalized patients. Indeed, the 50-60% of prescriptions in hospitalized patients has been shown to be inappropriate.

Gastric secretion and functioning of the proton pump

The stomach secretes an average of 2.5 liters of gastric juices per day. Gastric juices are composed of water, proenzymes such as prorenin and pepsinogen, hydrochloric acid (HCl) and intrinsic factor. The cells responsible for the secretion of gastric juice are the cells parietal which constitute the internal mucosa of the stomach, or the superficial wall that lines the lumen of the stomach.

The parietal cells also release bicarbonate ions, which remain trapped in the mucus, thus creating a pH gradient that varies from a value of 1-2 towards the lumen of the stomach to one of 6-7 at the level of the gastric surface. The mucus and bicarbonate form a gel, which does not mix with the acid liquids of the lumen, thus protecting the inner wall of the stomach from the corrosive action of the gastric juice. Some substances such as alcohol and bile can break down this layer, exposing the stomach wall to the corrosive action of gastric juices. Locally produced prostaglandins stimulate the secretion of both mucus and bicarbonate, and therefore have a protective role.

Proton pump function: proton pumps are located on the surface of the parietal cells in contact with the gastric lumen. This pump acts as a transmembrane transporter of ions, and to distinguish it from other membrane transporters it is called pump H⁺, K⁺-ATPase.

The function of the proton pump is to introduce H ions into the lumen of the stomach⁺, lowering the pH of the gastric juice up to values of 1-2, generating a strongly acidic environment, essential for activating the digestive enzymatic processes.

The concentration of the H ions⁺ in the stomach it exceeds the concentration of H by a million times⁺ in the blood.

The H⁺, K⁺-ATPase consumes energy in the form of ATP to pump H ions⁺ into the gastric lumen and at the same time carry the K ions⁺ inside the cell, which are in turn exchanged with Cl ions^–(chloride), to form hydrochloric acid (HCl) in the stomach.
 

How do IPP drugs work?

PPIs work by irreversibly blocking the proton pump H.⁺, K⁺-ATPase, significantly inhibiting both basal acid secretion and that stimulated by the presence of food in the stomach. Thanks to their chemical characteristics, these drugs accumulate specifically in the acidic environment of the canaliculi of the gastric parietal cells, which constitute the internal wall of the stomach.

The effect of a single dose affects the secretion for 2-3 days, thanks to the accumulation in the canaliculi of the drug. Daily administrations determine a progressive increase in the antisecretory effect until the fifth day of administration, after which the therapeutic plateau is reached.

Proton pumps can be released by the drug's action of glutathione, but it is generally necessary for the parietal cells to synthesize new ones.

Proton pump inhibitors, to carry out their function, when taken orally, are absorbed by the intestine and distributed in body fluids and blood. In fact, they need a latency period before generating an antacid response. IPP drugs are therefore prodrugs, ie molecules that must undergo a chemical reaction in order to be activated in drugs by the body.

From a chemical point of view they are weak bases, so they easily concentrate in the canaliculi that surround the parietal cells of the stomach, where they meet the most acidic environment of the whole organism. In these locations they can react and turn into active drugs. This mechanism underlies the selectivity of PPIs for the stomach and the reduced systemic side effects caused by these drugs.

Side effects

Side effects are quite rare and usually manifest as headache, nausea or skin rashes.

However, prolonged or chronic use of proton pump inhibitors can cause bone damage and important intestinal disorders. In recent years, potential adverse events such as increased respiratory infections, infections fromClostridium difficile and bone fractures have been associated with prolonged use of these drugs.

The acidic pH of the stomach facilitates the release of ionized calcium from minerals consumed in the diet, which are insoluble in water. The increase in gastric pH caused by chronic use of PPI, associated with hypochlorhydria, causes long-term calcium malabsorption, resulting in decreased bone density and increased incidence of fractures, especially in the elderly.

Gastric acidity constitutes an important selective step towards the bacteria ingested with food that will colonize the intestine. The reduction of gastric acidity could allow certain pathogenic bacterial strains, normally killed by the low pH value, to reach the intestine and colonize it, preventing the growth of "good" bacteria. Among the pathogenic ones we can include the Clostridium difficile, a bacterial species that causes diarrhea and respiratory infections and is very resistant to the action of antibiotics. It may be useful, for those who take proton pump inhibitor drugs (or antacids), to take supplements based on lactic ferments, to enhance the intestinal bacterial flora and counter the proliferation of harmful bacteria that cause swelling, constipation or intestinal disorders of various types.

Finally, there is clinical evidence, according to which the chronic use of PPI can lead to a deficiency of vitamin B12 in the blood, which is essential for haematopoietic functions. However, there are no large-scale studies to fully demonstrate this theory. Intrinsic factor secretion is the only gastric function that is essential for human life. Intrinsic factor is a glycoprotein secreted by the parietal cells of the stomach, in response to the same stimuli that determine the secretion of acid, which is essential for the normal intestinal absorption of vitamin B12.