Medicinal Chemistry III Gi System: Emetics & Anti-Emetics: Pharm. Chem. PH.D

Medicinal Chemistry III GI SYSTEM: EMETICS & ANTI-EMETICS
UNIT: AGENTS USED IN THE TREATMENT OF GASTROINTESTINAL DISORDERS

CHAPTER 1:
EMETICS AND ANTI-EMETICS
Sam Dawbaa, Pharm. Chem. Ph.D.
I. BACKGROUND
Vomiting (or emesis) is an involuntary expulsion of the stomach content upward through the mouth.
Vomiting begins with stimulation of the chemoreceptor trigger zone (CTZ) in the postrema region of
the medulla oblongata or stimuli from the upper part of the gastrointestinal tract to the vomiting center
via vestibular stimulation. CTZ has dopaminergic (D2), cholinergic, serotonergic (5-HT3), opioid
receptors, in addition to receptors for substance P, whereas the vestibular system is rich in muscarinic
and histaminic H1 receptors.
Persistent vomiting in severe cases may cause disruption of water and electrolyte balance. As a
result, hypochloremic alkalosis, oliguria, dry mouth, fever, and coma can be seen. Vomiting is the main
symptom of motion sickness. In addition, vomiting occurs in the morning, the early stages of pregnancy,
after administration of cytostatic drugs, and following radiation therapy.
II. EMETIC AGENTS
Emetic agents are drugs that induce vomiting. They are especially used in poisoning and the effects
are increased when taken with plenty of water. It is undesirable to use emetics in cases of
unconsciousness or semi-coma, cognitive loss, alcohol intoxication, and poisoning with caustic
compounds, petroleum products or essential oils.
A. Peripherally Acting Emetics
1. Ipecac syrup
One of the most used compounds is ipecac syrup. It is a rapid acting emetic whose constituents
(plant alkaloids mainly cephaeline, and methyl-cephaeline (emetine)) act locally by irritating the gastric
mucosa and centrally by stimulating the medullary chemoreceptor trigger zone to induce vomiting.
However, ipecac syrup should not be confused with ipecac extract. Ipecac extract is fourteen times more
concentrated than syrup and can cause death.
2. Copper sulfate (CuSO4, 1% solution)
Copper sulfate has been advocated as a rapidly acting emetic for use in the immediate treatment of
poisoning by ingestion. It is also used as a water-algicide, agricultural fungicide, and herbicide.
3. Zinc sulfate (ZnSO4, 1% solution)
It is a rapid emetic. It is also as a dietary supplement in cases of zinc deficiency.
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4. Potassium antimony tartrate
It is an emetic that directly achieve its action directly on the GIT. It is still used
as a diaphoretic or expectorant in cough mixtures.
B. Centrally Acting Emetics
1. Apomorphine
• It is used as a hydrochloride hemihydrate salt.

• It is obtained from morphine heating at 140°C with 35% HCl under pressure.
• It acts directly on the chemoreceptor trigger zone.
• It causes euphoria, tremors and constant movement, in
which case naloxone is used as an antidote.
• It is ineffective orally and is used subcutaneously.
• (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-
dibenzo[de,g]quinoline-10,11-diol
III. ANTIEMETIC AGENTS
Antiemetics are drugs that suppress nausea and vomiting.
A. Tropane Alkaloids
They exert their effects by blocking the neuronal pathways from the inner ear to the vestibular
nuclei and the vomiting center in the reticular formation.
1. Hyoscine
• (1R,2R,4S,5S,7S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-
yl(2S)-3-hydroxy-2-phenylpropanoate
• Because inner ear impulses are mediated by acetylcholine, hyoscine
exerts a potent antiemetic effect in motion sickness.
• It is not the right choice for the treatment of nausea and vomiting
other than motion sickness.
2. Hyoscyamine
• [(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl](2S)-3-hydroxy-2-
phenylpropanoate
• It the levorotatory (L) enantiomer of atropine (atropine is a racemic mixture).
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B. H1-Antagonists
• They are benzhydryl derivatives & used in the prophylaxis and treatment of motion
sickness.
• They are taken an hour and a half before the trip. The dose is repeated every 4 hours.
• These compounds are thought to exert their effects in the inner ear.
1. Dimenhydrinate
• 2-(Diphenylmethoxy)-N,N-dimethylethylamine 8-
chlorotheophyllinate
• It is an 8-chlorotheophylline salt of diphenhydramine.
• H1-antagonism in the vestibular system → antiemetic &
antivertigo properties. Its antimuscarinic properties enhance
its efficacy.
• 8-chlorotheophylline → excitatory effects (adenosine
receptor blockade) e.g., hallucinations & excitements.
2. Meclizine
• 1-(p-Chlorobenzhydryl)-4-(m-methylbenzyl)piperazine
3. Chlorphenoxamine
• {2-[1-(4-Chlorophenyl)-1-phenylethoxy]ethyl}dimethylamine
C. Phenothiazines
• Piperazine-substituted phenothiazine derivatives such as perphenazine are antiemetic.

• They show their antiemetic effects by blocking dopamine receptors in the postrema region.
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D. Benzamide and Benzimidazolone Derivatives
• Benzamide and benzimidazolone derivatives act by inhibiting dopaminergic receptors in

the postrema region, especially D2 subtype.
• This group of antiemetics is not effective enough in motion sickness.
• They are used for movement changes in the stomach as peristaltic stimulants and anti-
emetic agents for dyspepsia, indigestion, epigastric pain, nausea, and vomiting.
• The benzamide derivatives include metoclopramide, bromopride, and trimethobenzamide.

• Domperidone is a benzimidazolone derivative.
1. Metoclopramide
• It is a gastroprokinetic agent used in the treatment of gastroesophageal reflux disease,

prevention of nausea and vomiting (e.g., diabetic gastroparesis), and to stimulate gastric
emptying.
• It does not increase gastric acid secretion.
• >90% orally absorbed, t1/2 is 2.5-5.5 hours, about 40% is bound to plasma proteins.
2. Domperidone
• It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic

and tool in the study of dopaminergic mechanisms.
• For management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting.
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• 93% orally absorbed, t1/2 is 7.5 hours, about 91-93% is bound to plasma proteins.
E. 5-Hydroxytryptamine Antagonists
5-Hydroxytryptamine (5-HT3) antagonists are very useful and effective in treatment of cytostatic
or radiation induced vomiting.
1. Ondansetron
• Ondansetron is used to prevent nausea and vomiting associated with cancer chemotherapy
and radiation therapy.
• It shows central and peripheral activity.
• Vomiting that occurs during radiation and chemotherapy appears to be due to serotonin
released from enterochromaffin cells in the intestines. ondansetron acts by blocking the
nerve endings in the intestines, interrupting the flow of impulses to the central nervous
system.
F. Vitamin B6 (Pyridoxine hydrochloride)
• 5-Hydroxy-6-methyl-3,4-pyridindimetanol hydrochloride.
• Drug of choice to treat pregnancy related nausea and vomiting.
Dr. Sam Dawbaa, Pharm. Chem. Ph.D.

References: 1. Akgün et al. Farmasotik Kimya;
2. Drugbank.com;
3. Pubchem https://pubchem.ncbi.nlm.nih.gov;
4. Wilson & Gisvold’s, Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th edn.
Software: 1. ChemDraw 12;
2. ChemSketch
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Medicinal Chemistry III GI SYSTEM: EMETICS & ANTI-EMETICS

UNIT: AGENTS USED IN THE TREATMENT OF GASTROINTESTINAL DISORDERS

II. EMETIC AGENTS

A. Peripherally Acting Emetics

2. Copper sulfate (CuSO4, 1% solution)

3. Zinc sulfate (ZnSO4, 1% solution)

It is a rapid emetic. It is also as a dietary supplement in cases of zinc deficiency.

4. Potassium antimony tartrate

B. Centrally Acting Emetics

• It is used as a hydrochloride hemihydrate salt.

III. ANTIEMETIC AGENTS

Antiemetics are drugs that suppress nausea and vomiting.

• Piperazine-substituted phenothiazine derivatives such as perphenazine are antiemetic.

D. Benzamide and Benzimidazolone Derivatives

• Benzamide and benzimidazolone derivatives act by inhibiting dopaminergic receptors in

• The benzamide derivatives include metoclopramide, bromopride, and trimethobenzamide.

• It is a gastroprokinetic agent used in the treatment of gastroesophageal reflux disease,

• It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic

F. Vitamin B6 (Pyridoxine hydrochloride)

Dr. Sam Dawbaa, Pharm. Chem. Ph.D.

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