This group is one of the leading pharmacological drugs; it 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, helps in solving economic (affordable cost) and social problems. Thanks to the H2-blocker drugs, the results of the treatment of peptic ulcers have significantly improved, surgical interventions have been applied 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 record holder for sales in pharmacology. A big plus is the low cost and the effectiveness of the drugs.
Using
H2 histamine receptor blockers are used to treat acid-dependent gastrointestinal diseases. The mechanism of action is the blocking of H2 receptors (otherwise they are called histamine) of the gastric mucosa cells. For this reason, the production and entry of hydrochloric acid into the lumen of the stomach is reduced. This group of drugs refers to antisecretory anti-ulcer drugs.
Most often, H2 histamine receptor blockers are used in cases of peptic ulcer manifestations. H2 blockers not only reduce the production of hydrochloric acid, but also suppress pepsin, while gastric mucus increases, the synthesis of prostagladins increases here, and the secretion of bicarbonates increases. The motor function of the stomach is normalized, microcirculation improves.
Indications for use of H2 blockers:
- gastroesophageal reflux;
- chronic and acute pancreatitis;
- dyspepsia;
- Zollinger-Ellison syndrome;
- respiratory reflux induced diseases;
- chronic gastritis and duodenitis;
- Barrett's esophagus;
- lesions of the esophagus mucosa;
- stomach ulcer;
- ulcers medicinal and symptomatic;
- chronic dyspepsia with sternal and epigastric pain;
- systemic mastocytosis;
- for the prevention of stress ulcers;
- Mendelssohn syndrome;
- prevention of aspiration pneumonia;
- bleeding of the upper gastrointestinal tract.
H2 histamine receptor blockers: drug classification
There is a classification of this group of drugs. They are divided by generation:
- "Cimetidine" belongs to the first generation.
- "Ranitidine" - a blocker of H2 histamine receptors of the II generation.
- The III generation includes Famotidine.
- The fourth generation includes "Nizatidine."
- The fifth generation includes Roxatidine.
"Cimetidine" is least hydrophilic, due to this the half-life is very short, and liver metabolism is significant. The blocker interacts with P-450 cytochromes (a microsomal enzyme), with a change in the rate of xenobiotic hepatic metabolism. "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 risk of side effects are possible.
Among all H2 blockers, Cimetidine penetrates better into tissues, which also leads to increased side effects. It displaces endogenous testosterone from the connection with peripheral receptors, thereby causing sexual dysfunction, leads to a decrease in potency, and develops impotence and gynecomastia. "Cimetidine" can cause headaches, diarrhea, transient myalgia and arthralgia, increased blood creatinine, hematological changes, central nervous system lesions, immunosuppressive effects, cardiotoxic effects. The blocker of H2 histamine receptors of the third generation - “Famotidine” - penetrates less into tissues and organs, thereby reducing the number of side effects. Subsequent generations of drugs do not cause sexual dysfunctions - Ranitidine, Nizatidine, Roxatidine. All of them do not interact with androgens.
Comparative characteristics of drugs
Descriptions of H2 histamine receptor blockers appeared (extra-class generation drugs), the name is “Ebrotidine”, “Ranitidine bismuth citrate” is highlighted, it is not a simple mixture, but a complex compound. Here the base - ranitidine - binds to trivalent bismus citrate.
The H2 blocker of histamine III generation receptors 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, and forty times more powerful than Cinitidine. Differences in strength are determined by the equivalence of doses of various H2-blockers that affect the suppression of hydrochloric acid. The strength of the bonds with the receptors also determines the duration of exposure. If the drug is strongly associated with the receptor, it dissociates slowly, and the duration of the effect is determined. “Famotidine” acts on the basal secretion for the longest time. As studies show, "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 him the possibility of easy penetration into various organs, exposure to H2 receptors, which leads to many side effects. “Famotidine” and “Ranitidine” are considered highly hydrophilic, they penetrate poorly through tissues, their primary effect on the H2 receptors of parietal cells.
The maximum number of side effects of "Cimetidine". "Famotidine" and "Ranitidine", due to changes in the chemical structure, do not affect metabolizing liver enzymes and give fewer side effects.
Story
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. After safe compounds were identified, they were referred to clinical trials. The very first blocker buriamide was not entirely effective. Its structure was changed, methiamide was obtained. Clinical studies have shown greater efficacy, but there has been greater toxicity, which manifested itself in the form of granulocytopenia. Further work led to the discovery of Cimetidine (1st generation of drugs). The drug passed successful clinical trials, in 1974 it was approved. At that time, H2 blockers of histamine receptors began to be used in clinical practice, it was a revolution in gastroenterology. James Black received the Nobel Prize for this discovery in 1988.
Science does not stand still. Due to the numerous side effects of Cimetidine, pharmacologists have begun to maintain a guide to the search for more effective compounds. Thus, other new histamine H2 receptor blockers were discovered. Drugs reduce secretion, but do not affect its stimulants (acetylcholine, gastrin). Side effects, the "acid rebound" are orienting scientists to search for new drugs to reduce acidity.
Outdated medicine
There is a more modern class of drugs - proton pump inhibitors. They are superior in acid suppression, in minimizing side effects, in terms of exposure to histamine H2 receptor blockers. The drugs whose names are listed above are still used in clinical practice quite often 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) and histamine H2 receptor blockers. The latter drugs are characterized by the effect of tachyphylaxis, when repeated administration causes a decrease in the therapeutic effect. IPPs do not have such a drawback, so they, unlike H2 blockers, are recommended for long-term therapy.
The phenomenon of tachyphylaxis when taking H2 blockers has been observed since the start of therapy for 42 hours. In the treatment of ulcerative gastroduodenal bleeding , H2-blockers are not recommended, proton pump inhibitors are preferred.
Resistance
In some cases, histamine H2 receptor blockers (classification above), as well as PPI drugs, sometimes cause resistance. When conducting such monitoring of the pH of the stomach 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 do not have changes in the daily pH meter. When dynamically monitoring the process of acid dependence treatment, the most rational scheme is considered where the daily pH-metry is examined on the first, and then on the fifth and seventh day 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 blockers of histamine receptors cause side effects at different frequencies. 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, confused consciousness, depression, agitation, hallucinations, involuntary movements, visual impairment.
- 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 functional liver tests, mixed or holistic hepatitis with or without jaundice.
- Increased creatinine.
- Hemopoiesis disorders (leukopenia, pancytopenia, granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia and hypoplasia of the brain, hemolytic immune anemia.
- Impotence.
- Gynecomastia
- Alopecia.
- Decreased libido.
Famotidine has the most side effects on the gastrointestinal tract, while diarrhea often develops, 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. At the same time, pepsinogen is more slowly converted to pepsin, which helps the breakdown of proteins. Digestion is impaired, and most often diarrhea develops.
Contraindications
Histamine receptor H2 blockers include a number of drugs that have the following contraindications:
- Violations of the kidneys and liver.
- Cirrhosis of the liver (history of portosystemic encephalopathy).
- Lactation.
- Hypersensitivity to any drug in this group.
- Pregnancy.
- Children under 14 years old.
Interaction with other means
H2 histamine receptor blockers, the mechanism of action of which is now understood, have certain pharmacokinetic drug interactions.
Absorption in the stomach. Due to antisecretory effects, H2-blockers are able to affect the absorption of those electrolyte drugs where there is a pH dependence, since the degree of diffusion and ionization can decrease. "Cimetidine" is able to reduce the absorption of drugs such as "Antipyrine", "Ketoconazole", "Aminazine" and various iron preparations. To avoid such malabsorption, medications must be taken 1-2 hours before the use of H2 blockers.
Hepatic metabolism. H2 histamine receptor blockers (drugs of the first generation especially) actively interact with cytochrome P-450, which is the main oxidizing agent of the liver. At the same time, the half-life is increased, the effect may be prolonged and an overdose of the drug may occur, which is metabolized by more than 74%. The most reactive with cytochrome P-450 is Cimetidine, 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 appears to a small extent. When using "Cimetidine" clearance in drugs is reduced by about 40%, and this is clinically significant.
The rate of hepatic blood flow . It is possible to reduce hepatic blood flow to 40% when using "Cimetidine", as well as "Ranitidine", it is possible to reduce the subsystem 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 during active secretion of the renal tubules. In these cases, interactions with parallel drugs are possible if their excretion is carried out by the same mechanisms. "Imetidine" and "Ranitidine" are able to reduce renal excretion up to 35% of procainamide, quinidine, acetylnovocainamide. "Famotidine" has no effect on the removal of these drugs. In addition, its therapeutic dose is able to provide a low concentration in plasma, which will not substantially compete with other agents at the levels of calcium secretion.
Pharmacodynamic interactions. The interaction of H2 blockers with groups of other antisecretory drugs can increase therapeutic efficacy (for example, with anticholinergic drugs). The combination with agents that act on Helicobacter (preparations of metronidazole, bismuth, tetracycline, clarithromycin, amoxicillin) accelerates the healing of peptic ulcers.
Pharmacodynamic adverse interactions have been established when combined with drugs that include testosterone. “Cimetidine” hormone is displaced from communication with receptors by 20%, while the concentration in the blood plasma increases. "Famotidine" and "Ranitidine" do not have this effect.
Trade Names
In our country, the following H2 blockers have been registered and are eligible for sale:
"Cimetidine"
Trade names: Altramet, Belomet, Apo-cimetidine, Yenametidine, Histodyl, Novo-cimetin, Neutronorm, Tagamet, Simesan, Primamet, Cemidine , "Ulcometin", "Ulkuzal", "Tsimet", "Tsimegeksal", "Tsigamet", "Tsimetidin-Rivofarm", "Tsimetidin Lannacher".
"Ranitidine"
Trade names: “Atzilok”, “Ranitidin Vramed”, “Acidex”, “Asitek”, “Histak”, “Vero-ranitidine”, “Zoran”, “Zantin”, “Ranitidin Sediko”, “Zantak”, “Ranigast” , "Raniberl 150", "Ranitidine", "Ranison", "Ranisan", "Ranitidine Akos", "Ranitidine BMS", "Ranitin", "Rantak", "Ranks", "Rantag", "Yazitin", "Ulran "," Ulkodin. "
"Famotidine"
Trade names: "Gasterogen", "Blockacid", "Antodyne", "Kvamatel", "Gastrosidin", "Letsedil", "Ulfamide", "Pepsidin", "Famonite", "Famotel", "Famosan", "Famopsin" , Famotidine Akos, Famocide, Famotidine Apo, Famotidine Acre.
Nizatidine Trade name "Acid".
"Roxatidine ." Trade name "Roxane".
"Ranitidine Bismuth Citrate ." Trade name "Pilorid".