Itopride (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

; brand name Ganaton) is a

prokinetic A prokinetic agent (also prokineticin, gastroprokinetic agent, gastrokinetic agent or propulsive) is a type of drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhyt ...

benzamide Benzamide is an organic compound with the chemical formula of C7H7NO. It is the simplest amide derivative of benzoic acid. In powdered form, it appears as a white solid, while in crystalline form, it appears as colourless crystals. It is slightly ...

derivative. These drugs inhibit

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and acetylcholine esterase enzyme and have a

gastrokinetic A prokinetic agent (also prokineticin, gastroprokinetic agent, gastrokinetic agent or propulsive) is a type of drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhyth ...

effect. Itopride is indicated for the treatment of

functional dyspepsia Functional dyspepsia (FD) is a common gastrointestinal disorder defined by symptoms arising from the gastroduodenal region in the absence of an underlying organic disease that could easily explain the symptoms. Characteristic symptoms include ep ...

and other gastrointestinal conditions. It is a combined D₂ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...

. Itopride is the dimethoxy analog of

trimethobenzamide Trimethobenzamide (trade names Tebamide, Tigan) is an antiemetic used to prevent nausea and vomiting. Mechanism of action Trimethobenzamide is an antagonist of the D2 receptor. It is believed to affect the chemoreceptor trigger zone (CTZ) of ...

Medical uses

Typically, itopride is indicated in the treatment of GI symptoms caused by reduced GI motility: *

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

of a non-ulcer/dysmotility type (gastric "fullness", discomfort, and possible pain) * gastroparesis (delayed gastric emptying) *

anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...

heartburn Heartburn is a burning sensation felt behind the breastbone. It is a symptom that is commonly linked to acid reflux and is often triggered by food, particularly fatty, sugary, spicy, chocolate, citrus, onion-based and tomato-based products. Ly ...

*regurgitation *bloating *nausea and vomiting *other possible gastric, prolactin, or dopamine related conditions Itopride was shown to significantly improve symptoms in patients with functional dyspepsia and motility disorders in placebo-controlled trials. These studies concluded that the reduction in the severity of symptoms of

after 8 weeks of treatment with itopride indicated that itopride was significantly superior to placebo and that itopride yielded a greater rate of response than placebo in significantly reducing pain and fullness.

Adverse drug reactions

Central nervous system adverse effects do not tend to occur due to poor penetration across the blood brain barrier, although a slight raising of prolactin levels may occur. Raising of prolactin levels is more common with high dose regimes of itopride.

Cardiac studies

Itopride belongs to the same

group as

cisapride Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors incr ...

, a drug found to affect

QT interval The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...

and possibly predispose those using it to cardiac

arrhythmias Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...

. However, itopride does not have any adverse effect on the QT interval. Later, in a study conducted with healthy adult volunteers, itopride was shown as unlikely to cause cardiac arrhythmias or ECG changes in part to the lack of significant interaction and metabolism via the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme pathway, unlike

and

mosapride Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates emptying throughout the whole of the gastrointestinal ...

, as it is metabolized by a different enzyme set. New molecular studies on guinea pig ventricular

myocytes A muscle cell, also known as a myocyte, is a mature contractile cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal, smooth, and cardiac (cardiomyocytes). A skeletal muscle cell is long and threadli ...

also supported the cardiac safety profile of itopride, as it did not affect certain potassium mechanisms that may have been affected by cisapride or mosapride. Moreover, itopride has no affinity for the 5-HT₄ receptors, unlike other

benzamides Benzamide is an organic compound with the chemical formula of C7H7NO. It is the simplest amide derivative of benzoic acid. In powdered form, it appears as a white solid, while in crystalline form, it appears as colourless crystals. It is slightly ...

such as cisapride and mosapride, which are 5-HT₄ agonists. The affinity of cisapride for 5-HT₄ receptors in the heart has been implicated in the undesirable cardiac effects of cisapride itself. The conclusion of this study revealed that itopride is devoid of any abnormal effect on

. Therefore, it may be possible that itopride could be considered as a better and certainly safer prokinetic agent than either

, and itopride should also be considered a welcome treatment addition for symptomatic nonulcer dyspepsia and other gastric motility disorders.

Pharmacology

Itopride acts as a selective dual D₂ receptor

. There is evidence that itopride may have prokinetic effects throughout the gastrointestinal tract from the stomach to the end of the colon. The pharmacokinetics of itopride appear to differ between Asian and Caucasian populations, with Caucasians having 30-50 percent lower blood levels of itopride after oral administration. Itopride poorly penetrates across the blood brain barrier because of its high polarity and thus itopride does not tend to cause any

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

adverse effects. Itopride has no effect on

potassium channels Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ...

. Similarly to other D₂ receptor antagonists, itopride has been found to dose-dependently increase

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

levels.

Pharmacokinetics

After oral administration itopride undergoes rapid and extensive absorption with levels of itopride peaking in the blood plasma after only 35 minutes. Itopride is primarily eliminated via the kidneys having an

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of approximately 6 hours.

Mechanism of action

Itopride increases

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

concentrations by inhibiting dopamine D2 receptors and

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

. Higher acetylcholine increases GI

peristalsis Peristalsis ( , ) is a type of intestinal motility, characterized by symmetry in biology#Radial symmetry, radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an wikt:anterograde, anterograde dir ...

, increases the lower esophageal sphincter pressure, stimulates gastric motility, accelerates gastric emptying, and improves gastro-duodenal coordination. Itopride given as a single dose study found that it also raises levels of

motilin Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the ''MLN'' gene. Motilin is secreted by endocrine Mo cells (also referred to as M cells, which are not the same as the M cells, or microfold ...

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...

and lowers levels of

cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat a ...

, as well as

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

. These effects may also contribute to itopride's pharmacology.

Society and culture

Names

Itopride is available under various brand names including Ganaton (Japan, India, Czech Republic, Russian Federation), Itoprid PMCS (Czech Republic, Slovakia), Itomed (Kyrgyzstan, Kazakhstan, Moldova, Russia, Ukraine, Uzbekistan), Prokit (Poland), and Itogard (Nepal). In Mexico, itopride is sold by Takeda Laboratories under the brand name Dagla. In Bulgaria and other countries of East Europe itopride is sold by Zentiva under the brand name Zirid

References

External links

* {{Authority control Acetylcholinesterase inhibitors Benzamides D2 antagonists Drugs developed by AbbVie Drugs developed by Takeda Pharmaceutical Company Motility stimulants Catechol ethers Peripherally selective drugs de:Prokinetikum es:Procinético ja:イトプリド塩酸塩 pl:Leki prokinetyczne