Garopride

Training Manual

EVA PHARMA
Marketing Department

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 Understanding digestion

Food passes down the oesophagus into

the stomach.

The stomach makes acid which helps to

digest food.

Food then passes gradually into the

duodenum (the first part of the small
intestine).

In the duodenum and the rest of the small

intestine, food mixes with enzymes.

The enzymes come from the pancreas

and from cells lining the intestine.

The enzymes break down (digest) the food. Digested food is then
absorbed into the body from the small intestine.

GIT Motility Disorders

I. Dyspepsia

Popularly known as indigestion, meaning hard or difficult digestion

Definitions:

 Recurrent or persistent abdominal pain or abdominal discomfort

centered in the upper abdomen.

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 The "discomfort" is an uncomfortable feeling but does not reach the
level of pain.

Causes:

1. Excessive acid secretion.

2. Inflammations of the stomach or duodenum.
3. Food allergies, lifestyle and diet influences.
4. Psychological factors.
5. Medication side effects (drugs such as NSAIDs, aspirin, calcium
antagonists, nitrates, theophylline and corticosteroids.
6. Helicobacter pylori infection.

Types of dyspepsia:

 "Functional" dyspepsia refers to the dyspepsia that occurs with no

identifiable abnormality in the digestive tract (such as an ulcer).

 "Organic" or "non-functional" dyspepsia refers to conditions that have

a visible abnormality in the digestive tract.

DIAGNOSIS

A medical history and physical examination is performed to narrow the

possible list of causes.

Testing recommendations:

 People older than 55 or with serious symptoms, such as repeated

vomiting, weight loss or difficulty swallowing should have an upper
endoscopy.

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 People younger than 55 and who do not have serious symptoms are
generally offered noninvasive testing to detect infection with H. pylori (eg,
stool or breath testing).

Functional dyspepsia

FD is a chronic sensory and peristalsis problem of the digestive tract.

This disorder is called ‘functional’ because there are no observable or

measurable structural abnormalities found to explain persistent symptoms.
FD does not lead to cancer or other serious illness.

Other terms can be used to describe this condition such as non-ulcer

dyspepsia, pseudo-ulcer syndrome, pyloroduodenal irritability, nervous
dyspepsia.

Symptoms:

The disturbed motility leads to uncoordinated and even ineffectual

emptying of the upper gut, with resulting symptoms of:
Epigastric pain.
Post-meal fullness and bloating.
- Inability to finish meals, early satiation.
- Heartburn, sour taste in mouth, excessive burping.
- Nausea and sometimes vomiting.

Characteristically, these complaints are sporadic, poorly localized, and

without consistent aggravating or relieving factors.

The majority of patients experience more than one symptom.

FD may come and go, and symptoms could present with increased
severity for several weeks or months and then decrease or disappear
entirely for some time.

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Causes of functional dyspepsia?
The cause of FD is unknown; however, several hypotheses exist to explain
this condition:

 Sensation in the stomach or duodenum may be altered in some way - an

'irritable stomach'.
About 30% of non-ulcer dyspepsia patients also have 'irritable bowel
syndrome' and have additional symptoms of lower abdominal pain.
 A delay in emptying the stomach contents into the duodenum, the
muscles in the stomach wall may not work as well as they should.
 Infection with H. pylori. This bacterium is found in the stomach in some
people with non-ulcer dyspepsia. However, many people are 'carriers' of
this bacterium, and it causes no symptoms in most people.
 Certain foods and drinks may cause the symptoms or make them
worse. It is difficult to prove this. eg.: peppermint, tomatoes, chocolate,
spicy foods, hot drinks, coffee, and alcoholic drinks. However, food is not
thought to be a major factor in most cases.
 Anxiety, depression, or stress are thought to make symptoms worse in
some cases.
 A side-effect of some drugs can cause dyspepsia. The most common
culprits are anti-inflammatory drugs such as ibuprofen and aspirin,
antibiotics, steroids, iron, calcium antagonists, nitrates, theophyllines.

Diagnosis of functional dyspepsia:

Normal result on x-ray or endoscopy (means that no evidence of structural

disease)

With at least three months, of one or more of the symptoms.

Treatment of functional dyspepsia:

1. Diet & Lifestyle:

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- Avoiding excessive amounts of milk, alcohol, caffeine, fatty or fried
foods, mint, tomatoes, citrus fruits, and spices.
- After meals, it helps to avoid lying down for at least two hours. When
the patient lies down, it would be best to raise the head by about six to
eight inches.
- Regular eating times with avoidance of large meals and rapid eating are
important to normalize upper gut motility.
- Weight reduction and giving up smoking.

2. Neutralize acid:
Antacids can provide quick, temporary, and/or partial relief.

3. Block acid production:

a. Histamine receptor antagonists (H2RAs) work by blocking the effect of

histamine, which stimulates certain cells in the stomach to produce acid.
These include ranitidine and famotidine.

b. Proton pump inhibitors (PPIs) are a newer class that works by blocking
an enzyme necessary for acid secretion. These include omeprazole
(Losec®), lansoprazole(Lanzor), pantoprazole (Pantoloc®), esomeprazole
(Nexium®), and rabeprazole (Pariet™).

4. Prokinetics: promote downward emptying of the esophagus and

stomach.

II. Gastroparesis

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Gastroparesis, delayed gastric emptying, is a disorder in which the
stomach takes too long to empty its contents.

Normally, the stomach contracts to move food down into the small
intestine for digestion, the vagus nerve controls the movement of food
from the stomach through the digestive tract.

Gastroparesis occurs when the vagus nerve is damaged and the muscles
of the stomach and intestines do not work normally resulting in:

- Nausea, vomiting of undigested food, sometimes several hours

after the meal.

- Feeling of fullness after only a few bites of food.

- Vague stomach pain.
- Weight loss due to a decreased appetite.

Gastroparesis is idiopathic but the most common known causes are:

- Longstanding diabetes mellitus.

- Stomach surgery (Vagus nerve may be affected).

- Nervous systems disease; e.g: parkinson's disease.
- Anorexia nervosa or bulimia.
- Medications that slow intestine contractions; narcotics, anticholinergics.
- Metabolic disorders; eg: hypothyrodism.

Gastroparesis Mechanisms:

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 1. The outlet of the stomach may be obstructed by an ulcer or
tumor, or by something large and indigestible that was
swallowed.
2. The pyloric sphincter may not open enough or at the right times.
This sphincter is controlled by neurological reflexes to regulate
the passage of food and drinks.
3. The normally rhythmic (3 per minute) contractions of the lower
part of the stomach can become disorganized so that the
contents of the stomach are not pushed towards the pyloric
sphincter. This also usually has a neurological basis.

Gastroparesis Complications:

 Bacterial overgrowth from the fermentation of food that stays too long
in the stomach
 Also, the food can harden into solid masses that may cause nausea,
vomiting, and obstruction in the stomach.
 Gastroparesis can make diabetes worse by making blood glucose
control more difficult, Since gastroparesis makes stomach emptying
unpredictable.

Gastroparesis Treatment:
 Medications; eg: antiemetics, prokinetics.
 Dietary changes to liquids and pureed food and avoiding high
protein or fat diets.
 Feeding tube that is inserted through the skin of the abdomen
into the small intestine.
 Parenteral nutrition delivering nutrients directly into the bloodstream,
bypassing the digestive system.
 Gastric Electrical Stimulation:
A surgically implanted device that releases mild electrical pulses to
help control nausea and vomiting, available for people whose nausea
and vomiting do not improve with medications.

In case of Diabetic gastroparesis:

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 Dietary Changes.
 Insulin for Blood Glucose Control.

GERD
III.
(Gastroesophageal Reflux Disease)

Occasional GER is common and does not necessarily mean

one has GERD. Persistent reflux that occurs more than twice a
week is considered GERD
Occurs when:
- (LES) lower esophageal sphincter ,opens spontaneously, for
varying periods of time, or does not close properly
- Stomach contents rise up into the esophagus. (acid reflux or
acid regurgitation,)
- Digestive juices rise up with food to the esophagus
- Food or fluid can be tasted in the back of the mouth.
- Burning sensation in the chest or throat called heartburn or
acid indigestion.

Other factors that may contribute to GERD:

o Obesity.
o Pregnancy.
o Smoking.

Common foods that can worsen reflux symptoms:

o Citrus fruits.
o Chocolate.
o Caffeine or alcohol.
o Fatty and fried foods.
o Garlic and onions.
o Spicy foods.

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 GERD Symptoms:
o Indigestion
o Burning-type pain in the lower part of the mid-chest
o Dry cough
o Asthma symptoms
o Trouble swallowing.
GERD Treatment:
1- Antacids
2- H2 blocker
3- PPI
4- Prokinetics.

Itopride

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Itopride (INN) is a prokinetic benzamide derivative unlike
metoclopramide or domperidone.

N-[[4-(2-Dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide

Mode of action

Acetylcholine (ACh) is a neurotransmitter released from enteric nerve

endings stimulates the contraction of smooth muscle through M3 receptors
that exist on the smooth muscle layer throughout the gut.

The enzyme AChE hydrolyses the released ACh, inactivates it and thus
inhibits the gastric motility leading to various digestive disorders.

Dopamine is another neurotransmitter present in significant amounts in

the GIT and has several inhibitory effects on gastrointestinal motility,
including reduction of lower esophageal sphincter and intragastric
pressure. These effects are mediated by the D2 subtype of dopamine
receptors.

Itopride inhibits dopamine D2 receptors and acetylcholinesterase, resulting

in higher acetylcholine concentrations in the GIT:

- increases GI peristalsis

- increases the lower esophageal sphincter pressure.

- stimulates gastric motility.

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- accelerates gastric emptying.

- improves gastro-duodenal coordination.

Pharmacokinetics

- After oral administration, Itopride is rapidly and extensively absorbed.

- Tmax = 30-40 minutes

- Relative bioavailability = 60%.

- Food does not affect its bioavailability.

- T ½ is about 6 hours.

- 96% is bound to plasma proteins.

- Metabolized in the liver by N-oxidation to inactive metabolites by the

enzyme flavin-containing monooxygenase (FMO).

- Excreted mainly by the kidneys as metabolites and unchanged drug.

Indications:

Itopride is indicated in the treatment of GI symptoms caused by reduced

GI motility, functional dyspepsia and diabetic gastroparesis.

improve symptoms in patients with motility disorders:

 anorexia
 heartburn
 regurgitation
 bloating
 nausea and vomiting

Dosage:

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Typical adult dosage is 50mg 3 times daily taken on an empty stomach
about 30 minutes before meals.

Drug Interactions
Unlike cisapride and mosapride citrate, itopride is metabolized by the
enzyme flavin containing monooxygenase and not by the cytochrome P450
enzyme system.
It is thus devoid of the risk of significant pharmacokinetic drug interaction
with cytochrome P450 enzyme inhibitors such as macrolides and azole
antifungal agents.

Anticholinergic agents reduce the action of itopride.

Adverse drug reactions

Rash, diarrhoea, constipation, abdominal pain, increased salivation.

Exhaustion, back or chest pain, headache, sleeping disorders, dizziness.

- Endocrine disorders Increased prolactin level and gynecomastia

- Other side-effects may also be present: Leukopenia, a reduction in the

normal level of white blood cells, can be a potentially life-threatening
reaction.

Precautions:
- The young and the elderly population.
- During pregnancy.

“Safety has not been established in the pregnant females although no

abnormalities in the organogenesis and foetal developments were observed in
animal studies”.

Contraindications:

- Hypersensitivity to itopride or benzamides.

- Lactation.
- GI hemorrhage, obstruction or perforation.

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- Patients suffering from conditions involving dopamine regulation
issues;eg: Parkinson's disease.

Overdose:
There have been no reported cases of overdose in humans.
In case of excessive overdose the usual measures of gastric lavage and
symptomatic therapy should be applied.

Cardiac studies

Itopride is devoid of the potential to cause prolongation of the QT interval

and posed no risk of cardiac arrhythmias, this due to:

- The lack of interaction and metabolism via the CP450 enzyme

pathway.
- The lack of effect on certain potassium mechanisms that may have
been affected by cisapride or mosapride.

- No affinity for the 5-HT4 receptors unlike other benzamides 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.

Pharmaceutical presentation:
- Itopride Hcl 50mg Tablets: pack of 30 F.C.Tablets (24.00 L.E)

Itopride vs competition:

Itopride is a better and safer prokinetic agent.

Metoclopramide causes extra pyramidal symptoms such as dystonic

reactions.
Dystonic reactions are characterized by intermittent spasmodic or
sustained involuntary contractions of muscles in the face, neck, trunk,
pelvis, and extremities.

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 Domperidone, is associated with galactorrhoea or gynaecomastia and
hyperprolactinaemia.

Cisapride has the potential to cause QT prolongation on ECG, thus

predisposing to cardiac arrhythmias and its use has been restricted.

Mosapride belongs to the same group, although its side effects are not
well documented, it has drug interaction potential similar to that of
cisapride.

Also, itopride has a rapid onset of action, unlike cisapride and mosapride,
(which take around 60 minutes to reach peak plasma concentrations).

Features & Benefits:

Feature Benefits

1. Dual mode of action Patient will feel with fast relief of dyspepsia sympto
( anti- Dopaminergic and Acetyl (trusted efficacy).
cholinesterase inhibitor )

2- T max is 40 minutes Fast onset of action (patient relief).

3- Metabolized by FMO (Flavine Mono- Devoid of drug interactions (can be

oxygenase) but not Cytochrome P450 taken with macrolides and azoles).

4- No affinity for 5HT4 receptors The safest prokinetic on the CVS

unlike Cisapride and Mosapride without arrhythmia risk

5- Devoid of extra pyramidal side The safest prokinetic without

effects that seen in metoclopramide significant CNS side effects.

6- No reported cases for overdose High safety margin.

7- High clinical success rates that High efficacy that relief all the
make it superior over other prokinetics. dyspeptic symptoms

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 Product Price AC. Co.
MOTILIUM DOMPERIDONE JOHNSON E JOHN*
FILM C.TABS 10 MG 30 14.7
SUSP ORAL 1 MG /ML 1 100 ML 8.5
SUSP .10 % 1 200 ML 9.9
SUPP 60 MG ADLT 6 14.9
SUPP 10 MG BABY 6 6.1
SUPP 30 MG PAED 6 9.3
MOTINORM DOMPERIDONE GLAXOSMITHKLINE*
TABS 10 MG 30 12.8
SUSP 5 MG 1 120 ML 6.0
SUPP 60 MG 5 9.0
SUPP 10 MG ADLT 5 2.5
SUPP 30 MG ADLT 5 5.0
TABS 10 MG 20 6.5
FILM C.TABS 10 MG 10 3.3
PRIMPERAN METOCLOPRAMIDE SANOFI AVENTIS
AMP. 10 MG 12 2 ML 15.0
TABS 10 MG 20 5.0
DROPS 1 15 ML 3.5
SYRUP 5 MG /5ML 1 120 ML 3.5
SYRUP 5 MG /5ML 1 100 ML 3.5
SYRUP 1 120 ML 2.4
TABS STRIPS 10 MG 20 5.0
GANATON ITOPRIDE ABBOTT*
FILM C.TABS 50 MG 30 34.5
GASTROMOTIL DOMPERIDONE EIPICO*
SUSP 5 MG /5ML 1 200 ML 5.5
TABS 10 MG 20 6.0
SUPP ADULT 60 MG 5 8.0
SUPP INFANT 10 MG 5 2.5
SUPP CHILD 30 MG 5 4.5
FARCOTILIUM DOMPERIDONE PHARCO*
SUSP ORAL 5 MG /5ML 1 120 ML 4.3
CAPS 10 MG 24 5.8
SUPP 60 MG ADLT 5 9.0
MOSAPRIDE MOSAPRIDE WESTERN PH*
FILM C.TABS 5 MG 10 10.0
FILM C.TABS 2.50 MG 10 7.0
MOTIL FAST DOMPERIDONE AMOUN PHARM.CO.
SACHETS 10 MG 5 5 G 3.3
DOMPERIDONE DOMPERIDONE SEDICO
TABS 10 MG 20 6.0
SUPP 60 MG 6 11.0
SUPP 10 MG 6 3.0
SUPP 30 MG 6 6.0

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