Prokinetics

Prokinetics

Motor evacuation disorders (MED) of the esophagus, stomach, intestine and biliary tract often play a leading role in the genesis of the disease, determining the nature of clinical manifestations. MED serve as the main mechanism for the development of reflux esophagitis, postprandial and distress syndrome in functional dyspepsia, irritable bowel syndrome, peptic ulcer with impaired antroduodenal coordination, various types of gastroparesis, dysbiotic disorders, etc.

     For any MED, the local tissue blood flow changes, due to which the protective mechanisms weaken: mucus formation, excretion of bicarbonates, prostaglandin synthesis, regulating homeostasis and preventing normal damage to pepsin, bile and hydrochloric acids. First-line drugs in the treatment of MED are prokinetics, used as monotherapy or in combination with drugs from other pharmaceutical groups.

Prokinetics normalize peristalsis of the digestive tract, regulating the rhythm of contractions, thereby creating a favorable physiological background for the advancement of the digested food mass, which is adequate to the needs of the parietal digestion. In addition, prokinetics have antireflux action, increase the tone of the lower esophageal sphincter, effectively eliminate nausea, vomiting, heartburn, belching, discomfort in the epigastric region, in some cases atonic constipation.

Currently, several prokinetic groups are used. Nonselective dopamine receptor blockers type 2 (D2 receptors) (metoclopramide). 1st generation selective agents (domperidone) and 2nd generation selective blockers (itoprid).

Other groups of prokinetics that are not yet registered in our country, such as antagonists of 5-HT3 receptors. Prokinetic groups are being developed: 5-HT1 receptor agonists, motilin receptors, kappa-receptor opioid analogs of gonadotropin-releasing hormone, and others.

Metoclopramide has been used in practice for several decades and has long been the only drug of prokinetic action. Undesirable adverse neurological reactions have been identified due to the fact that the drug penetrates the blood-brain barrier. In 2013, the Medicines Control Committee (CHMP) of the European Medicines Agency (EMA) recommended changes to the wording of guidelines for the use of drugs containing metoclopramide. EMA recommends not using metoclopramide to correct any dysmotility, but to prescribe only for cancer patients with severe vomiting during chemotherapy. It is recommended to limit the use of metoclopramide for 5 days with a maximum daily dose of not more than 30 mg.

Domperidone (Domperidone) Motilium

Pharmacodynamics. The prokinetic effects of domperidone are associated with the blockade of peripheral dopamine D2 receptors and the removal of the inhibitory effect of dopamine on the gastrointestinal tract. Increases the duration of contractions of the antrum of the stomach and duodenum, improves the function of the stomach by accelerating its emptying while slowing down this process, increases the tone of the lower esophageal sphincter. The antiemetic property is possible due to a combination of blockade of chemoreceptors of the trigger zone in the emetic center and peripheral action. Domperidone prevents the development or reduces the severity of vomiting and nausea. Increases the content of prolactin in blood.

Pharmacokinetics. When ingested, it is absorbed quickly (reduced acidity of gastric juice or food intake reduce and inhibit absorption). The maximum concentration in the blood is usually reached in 0.5–1 hours. Due to the “first pass” effect through the liver, bioavailability is 15%. 91–93% bound to plasma proteins. It passes through the blood-brain barrier poorly; it can be found in small amounts in breast milk.

Pharmacokinetics. In the liver and intestinal wall it undergoes intensive metabolism. When taking a single dose, the half-life is 7 hours. 31% is excreted by kidneys, 66% - by intestines. In patients with liver disorders the drug may get accumulated.

Indications

Dyspepsia in case of gastroesophageal reflux disease and slow gastric emptying: feeling of bloating, feeling of fullness in the epigastrium, pain in the upper abdomen, flatulence, belching, heartburn without throwing or with throwing the contents of the stomach into the oral cavity; vomiting and nausea of ​​various origins (including organic and functional diseases, infections, radiation therapy, toxemia, dietary disorders, medication, X-ray and endoscopic studies of the gastrointestinal tract); atony of the gastrointestinal tract; hiccups; the need to accelerate peristalsis to conduct (when conducting) X-ray studies of the gastrointestinal tract.

Administration method and dose

Domperidone is taken orally, 15-30 minutes before meals. 10 mg 3 to 4 times a day for adults, with possible increase to 60 mg / day.

Not recommended for use as a prophylaxis of postoperative vomiting.

Contraindications

Hypersensitivity, mechanical intestinal obstruction, gastrointestinal bleeding, intestinal or gastric perforation, prolactinoma, hyperprolactinemia, age under 5 years, and children weighing under 20 kg – for tablets.

Usage restrictions:

Pregnancy, liver or / and kidney failure, breastfeeding.

Side Effects of Domperidone:

Sense organs and nervous system: extrapyramidal disorders, headache, irritability, asthenia, nervousness, leg cramps, drowsiness, lethargy, conjunctivitis (itching, pain, redness, swelling of the eyes);

digestive system: dry mouth, smooth muscle spasm of the gastrointestinal tract, stomatitis, heartburn, thirst, change in appetite, diarrhea / constipation;

allergic reactions: itching, skin rash, urticaria, swelling (hands, feet or legs, face);

other: an increase in the content of prolactin in the blood plasma, gynecomastia, galactorrhea, menstrual disorders, changes in the frequency of urination, mastalgia, palpitations, dysuria (burning, soreness and difficulty during urination).

Dosage forms. Coated tablets. 1 tablet contains 0,01 g (10 mg) of domperidon.

Currently, domperidone continues to be widely used in clinical practice, because for a long time it is considered an effective and safe stimulator of motility. However, hormonal disorders, extrapyramidal disorders and, most dangerously, increased risk of severe ventricular arrhythmias and sudden cardiac death, especially when used in people over 60 years of age at a daily dosage of more than 30 mg, have been observed with the use of domperidone. If the patient has chronic heart failure or signs of significant electrolyte abnormalities and prolonged QT intervals on the ECG, especially if these people are over 60 years old or if the daily dose of the drug exceeds 30 mg, you need to exercise considerable alertness.

     In 2009, itoprid hydrochloride is called the “prokinetic of choice”. Itopride hydrochloride is distinguished by a dual mechanism of prokinetic action. Increasing the level of acetylcholine in the intermuscular plexuses of the smooth muscles of the gastrointestinal tract due to inhibition of acetylcholinesterase and the blockade of D2 receptors, itopride has a positive effect on the tone of the lower esophageal sphincter, it enhances the motor-evacuation function of the stomach, it helps eliminate the duodeno-gastric reflux, improves the tone of the gastric sphincter, enhances the motor-evacuation function of the stomach, motor activity and muscle tone of the small and large intestine. This makes its use advisable for IBS with a predominance of both constipation and when IBS is combined with the functional dyspepsia. The effect of itoprid on the motor-evacuation function of the stomach is very significant, it improves the contractile function of the antrum of the stomach and, thus, suppresses gastric reflux more strongly.

Itopride (Itopride) Itopra. Ganaton

Pharmacodynamics. A drug that stimulates GI motility. Itopride enhances GI motility due to antagonism of dopamine D2 receptors and inhibition of acetylcholinesterase. Itopride activates the release of acetylcholine and inhibits its destruction. Itoprid has an anti-emetic effect due to interaction with D2-receptors located in the trigger zone. Causes dose-dependent suppression of vomiting caused by apomorphine.

Itopide activates the propulsion motility of the stomach due to antagonism with D2-receptors and dose-dependent inhibition of acetylcholinesterase activity.

Itoprid has a specific effect on the upper GI tract, it accelerates transit through the stomach, and improves its emptying.

Pharmacokinetics

Itopride hydrochloride is rapidly and well absorbed in the gastrointestinal tract. The relative bioavailability is 60%. The maximum plasma concentration (Stax) is 0.28 micron / ml. The period of reaching the maximum plasma concentration (TC) is 0.5-0.75 hours after taking 50 mg of the drug. Cumulation of the drug is minimal. Binding with proteins is 96%. Itoprid hydrochloride is distributed in the kidneys, small intestine, liver, adrenal glands, stomach. The volume of distribution (Vd) is 6.1 l / kg. At therapeutic doses of itoprid, hydrochloride slightly penetrates the brain and also into breast milk. The drug is metabolized in the liver. Itopride hydrochloride and its metabolites are excreted mainly by the kidneys. The half-life period (T1 / 2) is 6 hours.

Indications. Symptomatic treatment of functional non-ulcer dyspepsia (chronic gastritis), including: bloating (flatulence); pain or discomfort in the epigastric region (gastralgia); anorexia; heartburn; nausea, vomiting; feeling of quick saturation.

Contraindications. Increased sensitivity to itoprid or any excipient of the drug; gastrointestinal bleeding; mechanical obstruction and perforation of the digestive tract; children's age under 16 years; pregnancy; lactation period (breastfeeding).

Adverse reactions

Hematopoietic system: leukopenia, thrombocytopenia.

Allergic reactions: skin hyperemia, pruritus, rash, anaphylactic shock.

Endocrine system: gynecomastia, increased prolactin levels.

Digestive system: increased salivation, nausea, diarrhea, constipation, abdominal pain, jaundice.

Nervous system: headache, dizziness, tremor.

Laboratory indicators: increased activity of ACT, ALT, GGT, ALP,

Dosing regimen. For adults and children under the age of 16, itopride is administered as 1 tablet (50 mg) 3 times a day 15–30 minutes before meals. The average daily dose is 150 mg. The recommended course of treatment is for 2-3 weeks.

Itopride has the highest safety profile, almost does not penetrate the blood-brain barrier and therefore does not cause side effects in the central nervous system, does not adversely affect the cardiovascular system. It has not yet displayed any side effects typical for other prokinetics.

Sulpiride - D2-dopamine and serotonin receptor blocker, besides its central action (neuroleptic), it has properties of prokinetics. It is prescribed in a dose of up to 200 mg / day.

     In the treatment of inert colon, the priority belongs to enterokinetic drugs — stimulants of colon propulsive motility, which include serotonergic enterokinetics, agonists of 5-HT4 receptors and activators of chlorine channels. Serotonin (5-hydroxy-tryptamine; 5-HT) is synthesized in the mucous membrane of the gastrointestinal tract by enterochromaffin cells. There are 14 known subtypes of the 5-HT receptor family. The most studied are 5-HT3-and 5-HT4-receptors of serotonin. They enhance peristalsis by stimulating secondary messengers (acetylcholine and calcitonin). 5-HT3 receptors also promote water secretion via the cAMP mechanism and increase visceral sensitivity. 5-HT3 receptor antagonists reduce postprandial colonic motility and retard colonic transit. The most well-known 5-HT4 receptor agonist is prucalopride.