This group is among the leading pharmacological preparations, belongs to the means of choice in the treatment of peptic ulcers. The discovery of H2 histamine receptor blockers over the past two decades is considered the largest in medicine, helping to solve economic (affordable cost) and social problems. Thanks to H2-blockers, the results of therapy for peptic ulcers have improved significantly, surgical interventions have been used as rarely as possible, and the quality of life of patients has improved. "Cimetidine" was called the "gold standard" in the treatment of ulcers, "Ranitidine" in 1998 became the sales record holder in pharmacology. The big plus is the low cost and at the same time the effectiveness of drugs.
Use
H2 histamine receptor blockers are used to treat acid-dependent diseases of the gastrointestinal tract. The mechanism of action is the blocking of H2 receptors (otherwise theycalled histamine) cells of the gastric mucosa. For this reason, the production and entry into the lumen of the stomach of hydrochloric acid is reduced. This group of drugs belongs to antisecretory antiulcer drugs.
Most often, H2 histamine receptor blockers are used in cases of manifestations of peptic ulcer. H2 blockers not only reduce the production of hydrochloric acid, but also suppress pepsin, while gastric mucus increases, the synthesis of prostaglandins increases here, and the secretion of bicarbonates increases. The motor function of the stomach is normalized, microcirculation improves.
Indications for H2 blockers:
- gastroesophageal reflux;
- chronic and acute pancreatitis;
- dyspepsia;
- Zollinger-Ellison syndrome;
- respiratory reflux disease;
- chronic gastritis and duodenitis;
- Barrett's esophagus;
- lesions of ulcers of the esophageal mucosa;
- gastric ulcer;
- ulcers medicinal and symptomatic;
- chronic dyspepsia with retrosternal and epigastric pain;
- systemic mastocytosis;
- for the prevention of stress ulcers;
- Mendelssohn's syndrome;
- prevention of aspiration pneumonia;
- bleeding of the upper GI tract.
H2 histamine receptor blockers: classification of drugs
There is a classification of this group of drugs. They are divided by generation:
- To the I generationrefers to Cimetidine.
- "Ranitidine" is a blocker of H2 histamine receptors of the II generation.
- Famotidine belongs to the III generation.
- Nizatidin belongs to the IV generation.
- Roxatidin belongs to the V generation.
"Cimetidine" is the least hydrophilic, due to this, the half-life is very short, while liver metabolism is significant. The blocker interacts with cytochromes P-450 (a microsomal enzyme), while the rate of hepatic metabolism of the xenobiotic changes. "Cimetidine" is a universal inhibitor of hepatic metabolism among most drugs. In this regard, it is able to enter into pharmacokinetic interaction, therefore, cumulation and increased risks of side effects are possible.
Among all H2 blockers, "Cimetidine" penetrates tissues better, which also leads to increased side effects. It displaces endogenous testosterone from its connection with peripheral receptors, thereby causing sexual dysfunction, leads to a decrease in potency, develops impotence and gynecomastia. "Cimetidine" can cause headaches, diarrhea, transient myalgia and arthralgia, increased blood creatinine, hematological changes, CNS lesions, immunosuppressive effects, cardiotoxic effects. Blocker H2 histamine receptors III generation - "Famotidine" - less penetrates into tissues and organs, thereby reducing the number of side effects. Does not cause sexual dysfunctionpreparations of subsequent generations - "Ranitidine", "Nizatidin", "Roxatidin". All of them do not interact with androgens.
Comparative characteristics of drugs
Descriptions of H2 histamine receptor blockers (preparations of the extra-class generation) appeared, the name is "Ebrotidine", "Ranitidine bismuth citrate" is singled out, this is not a simple mixture, but a complex compound. Here the base - ranitidine - binds to trivalent bismus citrate.
Blocker H2 histamine receptors III generation "Famotidine" and II - "Ranitidine" - have greater selectivity than "Cimetidine". Selectivity is a dose-dependent and relative phenomenon. "Famotidine" and "Ranitidine" more selectively than "Cinitidine", affect H2 receptors. For comparison: "Famotidine" is eight times more powerful than "Ranitidine", "Cinitidine" - forty times. Differences in potency are determined by dose equivalence data of different H2 blockers that affect hydrochloric acid suppression. The strength of connections with receptors also determines the duration of exposure. If the drug is strongly bound to the receptor, dissociates slowly, the duration of the effect is determined. On the basal secretion "Famotidine" affects the longest. Studies show that "Cimetidine" provides a decrease in basal secretion for 5 hours, "Ranitidine" - 7-8 hours, 12 hours - "Famotidine".
H2-blockers belong to the group of hydrophilic drugs. Among all generations, Cimetidine is less hydrophilic than others, while moderately lipophilic. This gives it the ability to easily penetrate into various organs, affect H2 receptors, which leads to many side effects. "Famotidine" and "Ranitidine" are considered highly hydrophilic, they penetrate poorly through tissues, their predominant effect on the H2 receptors of parietal cells.
The maximum number of side effects in "Cimetidine". "Famotidine" and "Ranitidine", due to changes in the chemical structure, do not affect the metabolizing liver enzymes and give fewer side effects.
History
The history of this group of H2-blockers began in 1972. An English company in the laboratory under the leadership of James Black investigated and synthesized a huge number of compounds that were similar in structure to the histamine molecule. Once safe compounds were identified, they were transferred to clinical trials. The very first buriamid blocker was not entirely effective. Its structure was changed, methiamide turned out. Clinical studies have shown greater efficacy, but greater toxicity has manifested itself in the form of granulocytopenia. Further work led to the discovery of "Cimetidine" (I generation of drugs). The drug passed successful clinical trials, in 1974 it was approved. Then they becameto use histamine H2 receptor blockers in clinical practice, it was a revolution in gastroenterology. James Black received the Nobel Prize in 1988 for this discovery.
Science does not stand still. Due to the multiple side effects of Cimetidine, pharmacologists began to focus on finding more effective compounds. So other new H2 blockers of histamine receptors were discovered. Drugs reduce secretion, but do not affect its stimulants (acetylcholine, gastrin). Side effects, "acid rebound" orient scientists to search for new means to reduce acidity.
Obsolete medicine
There is a more modern class of drugs called proton pump inhibitors. They are superior in acid suppression, in the minimum of side effects, in the time of exposure to histamine H2 receptor blockers. The drugs whose names are listed above are still used quite often in clinical practice due to genetics, for economic reasons (more often it is "Famotidine" or "Ranitidine").
Modern antisecretory drugs used to reduce the amount of hydrochloric acid are divided into two large classes: proton pump inhibitors (PPIs), as well as H2 histamine receptor blockers. The latter drugs are characterized by the effect of tachyphylaxis, when repeated administration causes a decrease in the therapeutic effect. PPIs do not have this disadvantage, so they are recommended for long-term therapy, unlike H2 blockers.
The phenomenon of the development of tachyphylaxis when taking H2-blockers is observed from the beginning of therapy within 42 hours. In the treatment of gastroduodenal ulcer bleeding, it is not recommended to use H2-blockers, preference is given to proton pump inhibitors.
Resistance
Histamine H2 receptor blockers (classified above) and PPIs sometimes cause resistance in some cases. When monitoring the pH of the gastric environment in such patients, no changes in the level of intragastric acidity are detected. Sometimes cases of resistance to any group of H2 blockers of the 2nd or 3rd generation or to proton pump inhibitors are detected. Moreover, increasing the dose in such cases does not give a result, it is necessary to choose a different type of drug. The study of some H2-blockers, as well as omeprazole (PPI) shows that from 1 to 5% of cases have no changes in daily pH-metry. With dynamic monitoring of the process of treatment of acid dependence, the most rational scheme is considered, where daily pH-metry is studied on the first, and then on the fifth and seventh days of therapy. The presence of patients with complete resistance indicates that in medical practice there is no drug that would have absolute effectiveness.
Side effects
H2 histamine receptor blockers cause side effects with varying frequency. The use of "Cimetidine" causes them in 3, 2% of cases. "Famotidine - 1.3%,"Ranitidine" - 2.7%. Side effects include:
- Dizziness, headaches, anxiety, fatigue, drowsiness, confusion, depression, agitation, hallucinations, involuntary movements, visual disturbances.
- Arrhythmia, including bradycardia, tachycardia, extrasystole, asystole.
- Diarrhea or constipation, abdominal pain, vomiting, nausea.
- Acute pancreatitis.
- Hypersensitivity (fever, rash, myalgia, anaphylactic shock, arthralgia, erythema multiforme, angioedema).
- Changes in liver function tests, mixed or holistic hepatitis with or without jaundice.
- Elevated creatinine.
- Hematopoietic disorders (leukopenia, pancytopenia, granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia and cerebral hypoplasia, hemolytic immune anemia.
- Impotence.
- Gynecomastia.
- Alopecia.
- Decreased libido.
Famotidine has the most side effects on the gastrointestinal tract, with diarrhea often developing, in rare cases, on the contrary, constipation occurs. Diarrhea occurs due to antisecretory effects. Due to the fact that the amount of hydrochloric acid in the stomach decreases, the pH level rises. In this case, pepsinogen is more slowly converted to pepsin, which helps break down proteins. Digestion is disturbed, and most often diarrhea develops.
Contraindications
To H2 blockershistamine receptors include a number of drugs that have the following contraindications for use:
- Disturbances in the work of the kidneys and liver.
- Cirrhosis of the liver (history of portosystemic encephalopathy).
- Lactation.
- Hypersensitivity to any drug in this group.
- Pregnancy.
- Children under the age of 14.
Interaction with other tools
H2 blockers of histamine receptors, the mechanism of action of which is now understood, have certain pharmacokinetic drug interactions.
Absorption in the stomach. Due to the antisecretory effects of H2 blockers, they are able to influence the absorption of those electrolyte drugs where there is a dependence on pH, since the degree of diffusion and ionization may decrease in drugs. "Cimetidine" is able to reduce the absorption of drugs such as "Antipyrine", "Ketoconazole", "Aminazin" and various iron preparations. To avoid such malabsorption, drugs should be taken 1-2 hours before using H2 blockers.
Hepatic metabolism. Blockers of H2 histamine receptors (preparations of the first generation especially) actively interact with cytochrome P-450, which is the main oxidizer of the liver. At the same time, the half-life increases, the effect may be prolonged and an overdose of the drug, which is metabolized by more than 74%, may occur. Cimetidine reacts most strongly with cytochrome P-450, 10 times more than Ranitidine. Interaction with "Famotidine" does not occur at all. For this reason, when using Ranitidine and Famotidine, there is no violation of the hepatic metabolism of drugs, or it manifests itself to a small extent. When using Cimetidine, the clearance of drugs is reduced by about 40%, and this is clinically significant.
Hepatic blood flow rate. It is possible to reduce the rate of hepatic blood flow up to 40% when using Cimetidine, as well as Ranitidine, it is possible to reduce the systemic metabolism of high-clearance drugs. "Famotidine" in these cases does not change the rate of portal blood flow.
Tubular excretion of the kidneys. H2-blockers are excreted with active secretion of the tubules of the kidneys. In these cases, interactions with concurrent drugs are possible if they are excreted by the same mechanisms. "Imetidine" and "Ranitidine" are able to reduce renal excretion to 35% of novocainamide, quinidine, acetylnovocainamide. "Famotidine" does not affect the excretion of these drugs. In addition, its therapeutic dose is able to provide a low plasma concentration that will not significantly compete with other agents in terms of calcium secretion.
Pharmacodynamic interactions. The interaction of H2-blockers with groups of other antisecretory drugs can increasetherapeutic efficacy (for example, with anticholinergics). The combination with drugs that act on Helicobacter (drugs of metronidazole, bismuth, tetracycline, clarithromycin, amoxicillin) accelerates the tightening of peptic ulcers.
Pharmacodynamic adverse interactions have been established when combined with drugs containing testosterone. "Cimetidine" hormone is displaced from its connection with receptors by 20%, while the concentration in the blood plasma increases. Famotidine and Ranitidine have no such effect.
Trade names
The following drugs of H2-blockers are registered and allowed for sale in our country:
"Cimetidine"
Trade names: Altramet, Belomet, Apo-cimetidine, Yenametidine, Histodil, Novo-cimetine, Neutronorm, Tagamet, Simesan, Primamet ", "Cemidin", "Ulcometin", "Ulkuzal", "Cymet", "Cimehexal", "Cygamet", "Cimetidin-Rivopharm", "Cimetidin Lannacher".
"Ranitidine"
Trade names: "Acilok", "Ranitidine Vramed", "Acidex", "Asitek", "Histak", "Vero-ranitidine", "Zoran", "Zantin", "Ranitidine Sediko", "Zantak ", "Ranigast", "Raniberl 150", "Ranitidine", "Ranison",Ranisan, Ranitidin Akos, Ranitidin BMS, Ranitin, Rantak, Renks, Rantag, Yazitin, Ulran, Ulkodin.
"Famotidine"
Trade names: "Gasterogen", "Blokatsid", "Antodin", "Kvamatel", "Gastrosidin", "Lecedil", "Ulfamid", "Pepsidin", "Famonit", "Famotel", "Famosan" ", "Famopsin", "Famotidine Akos", "Famocide", "Famotidine Apo", "Famotidine Akri".
"Nizatidin". Trade name "Axid".
"Roxatidine". Trade name "Roxan".
"Ranitidine bismuth citrate ". Trade name "Pylorid".
