Presented by,

ROSHNI ANN BABY

Pharm. Chemistry

M.Pharm Part I

*Drugs Acting on Gastro

Intestinal Tract

*CONTENTS

INTRODUCTION TO GI AGENTS

EMETICS

ANTIEMETICS

DIARRHOEA AND ANTIDIARRHOEALS

CONSTIPATION AND LAXATIVES

MISCELLANEOUS DRUGS

*GASTRO INTESTINAL AGENTS

Drugs acting on gastrointestinal tract gastrointestinal

agents/drugs.

Classified as –

Drugs for peptic ulcer – Cimetidine, ranitidine, omeprazole,

misoprostol, sucralfate etc.

Emetics and anti emetics.

Laxatives – lactulose, bisacodyl, liquid paraffin, castor oil etc.

Anti diarrhoeal drugs – Ispaghula, atropine, codeine,

loperamide, sulfasalazine etc.

Miscellaneous – Peppermint, cardamom, pepsin, papain,

ursodiol, chenodiol etc

*EMETICS

Emetics drugs used to evoke vomiting.

Vomiting undesirable substances are ingested.

At emergency powdered mustard suspension or strong salt

solution may be used.

CLASSIFICATION.

Act on Chemoreceptor Trigger Zone(CTZ).

eg: Apomorphine.

Act reflexly and on CTZ.

eg: Cephaeline.

*APOMORPHINE.

Mechanism of action(MOA)

Acts centrally by stimulating the

medullary CTZ connected with

vomiting centre

Uses

As emetic.

OHOH

N

CH3

H

*CEPHAELINE

MOA.

Locally by irritating the gastric mucosa & centrally by

stimulating the medullary CTZ to induce

vomiting.

Uses – as emetic.

Chemically it is an alkaloid found in ipecac.

CH3

H

H

CH3

CH3

O

O

N

NH

OH

O CH3

*ANTIEMETICS

Anti emetics drugs used to prevent or suppress

vomiting.

CLASSIFICATION OF ANTI EMETICS

Anticholinergics

eg: Hyoscine,Dicyclomine.

H1 antihistamines.

eg: Promethazine, Diphenhydramine, Dimenhydrinate,

Doxylamine, Cyclizine, Meclizine, Cinnarizine.

Neuroleptics or D2 blockers.

eg: Chlorpromazine, Prochlorperazine, Haloperidol.

Prokinetic drugs.

eg: Metoclopramide, Domperidone, Cisapride, Mosapride,

Tegaserod.

5HT3 antagonists.

eg: Ondansetron, Granisetron.

Adjuant antiemetics.

eg: Dexamethasone, Benzodiazepine, Cannabinoids.

*ANTICHOLINERGICS

HYOSCINE

MOA

Blocks conduction of

nerve impulses across a

cholinergic link in the pathway

leading from the vestibular

apparatus to the vomiting centre.

Uses

For motion sickness.

O

O

O

N OH

CH3

9-methyl-3-oxa-9-azatri

cyclo[3.3.1.02,4]non-7-yl

(2S)-3-hydroxy-2-phenylpropanoate

*DICYCLOMINE

MOA

Same as that of hyoscine.

2-(diethyl amino)ethyl(bicyclohexane)-

1- carboxylate.

Uses

As antiemetic, spasmolytic, in motion sickness, morning

sickness.

O

O N

CH3

CH3

*H1 ANTIHISTAMINES.

MOA OF ANTIHISTAMINES

Act by both relaxing the smooth muscles and also act

centrally to depress vomiting centres.

They diminish vestibular stimulation & depress labyrinthine

function.

H1 antagonism.

*PROMETHAZINE

Uses

Antihistaminic

Antiemetic

sedative

10-(2-(dimethylamino)propyl)

phenothiazine.

CH3

S

N

CH3

N

CH3

S

NH

PHENOTHAIZINE

S

N

NaNH2ClCH2CHN(CH3)2

S

N

CH3

N

CH3

CH3

+

*DIPHENHYDRAMINE

Uses

Antihistaminic

Antiemetic

Antitussive

2-(diphenylmethoxy)

Sedative N,N-dimethylethanamine.

CH3

O

N

CH3

*MECLIZINE

Uses

Antihistaminic

Antiemetic

1-(p-chlorophenylbenzyl)-4-

(m-methylbenzyl)piperazine.

Cl

NN

CH3

*CYCLIZINE

1-(diphenylmethyl)-4-methyl piperazine.

Uses

In postoperative and drug induced vomiting.

In motion sickness.

C

H

C6H5

N N CH3

*

NH NH + CH3COCl N NHCH3

O

CH3I

-HIN N CH3

CH3

O

HCl

NH N CH3+

Cl

N N CH3-HCl

*NEUROLEPTICS

MOA – They block D2 receptors in the CTZ.

CHLORPROMAZINE.Uses

Antipsychotic

Antiemetic

Antitussive

2-chloro-10-(3-(dimethylamino)

propyl)phenothiazine.

CH3

CH3N

N

S

Cl

*HALOPERIDOL

4-(4-(p-chlorophenyl)-4-hydroxy

piperidone)-4-N-fluorobutyrophenone

Uses

Antipsychotic

antiemetic

CCH 2CH2CH2

O

F N

Cl

OH

*PROCHLORPERAZINE

2-chloro-10-[3-(4-methyl-1-piperazinyl) propyl ] phenothiazine

Uses

antiemetic

S

N Cl

(CH2)3 N N CH3

*

S

NH

Cl

2 CHLORO PHENOTHAIZINE

+ N NCH3 Cl-HCl

NaNH2/TOLUENE

NNCH3

S

N Cl

*PROKINETIC DRUGS

METOCLOPRAMIDEMOA

D2 antagonism,

5HT3 antagonism,

5HT4 agonism in CTZ

or NTS.

Uses

Antiemetic 4-amino-5-chloro-N-(2-(diethyl-

aminoethyl)-2-methoxy benzamide

NH2

Cl

O

NHN

CH3

CH3

O

CH3

*DOMPERIDONE

5-chloro-1-(1-(3-(2-oxo2,3-dihydro-1H-benzo

imidazol-1-yl)propyl)piperidin-4-yl)-1H-benzo

imidazol-2(3H)-one.

MOA – D2 antagonism in CTZ.

Uses

Antiemetic

ONH

N

O

N

N

NH

Cl

*5HT3 ANTAGONISTS

ONDANSETRONAct via CTZ or NTS

Uses

In chemotherapy induced vomiting.

In post operative vomiting.

CH3O

N

N N

CH3

9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one

*GRANISETRON

Has long half life compared to

ondansetron.

Uses

In chemotherapy induced vomiting

In post operative vomiting

O

N

CH3

NH

N

N

CH3

1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide

DIARRHOEA

Loose bowel movements resulting into the frequent

passage of watery,uniformed stools with or without

mucous and blood.

Classification

Osmotic diarrhoea

Something in the bowel draws water from the body into the

bowel.

Eg;Sorbitol is not absorbed by the body but draws water from

the body into the bowel, resulting in diarrhoea.

Secretory diarrhoea

Occurs when the body is releasing water into the bowel,

many infections, drugs causes secretory diarrhoea.

Exudative diarrhoea

Diarrhoea with the presence of blood and pus in the stool.

This occurs with inflammatory bowels disease (IBD), such as

Crohn’s disease or ulcerative colitis etc.

Acute diarrhoea

Sudden onset in a previously healthy person

Lasts from 3 days to 2 weeks

Self-limiting

Resolves without sequels

Chronic diarrhoea

Lasts for more than 3 weeks.

Associated with recurring passage of diarrhoeal stools, fever,

loss of appetite, nausea, vomiting, weight loss, and chronic

weakness

CAUSES OF DIARRHOEA

Acute Diarrhoea

Microbes

Drug induced

Nutritional

Chronic Diarrhoea

Tumours

Diabetes

Addison’s disease

Hyperthyroidism

Irritable bowel syndrome

E. Coli bacteria Rotavirus

DRUG THERAPY

i. Specific antimicrobial drugs

ii. Non specific antidiarrhoeal drugs

ORAL REHYDRATION

THERAPY

Specific anti microbial drugs

A. Antimicrobials are of no value

Due to non infective causes such as

Irritable bowel syndrome

Colic disease

Pancreatic enzyme deficiency etc

Rota virus causes acute diarrhoea, specially in children

B. Antimicrobials are regularly useful

choleraTetracyclines,

chloramphenicoletc

Clostridium difficile

Vancomycin, metronidazole etc

amoebiasisMetronidazole,

dioxonidfuroate

NON SPECIFIC ANTIDIARROEALS

1.Adsorbents

Eg; kaolin, pectin, calcium carbonate. Etc

2.Anti secretory drugs

Eg; sulphasalazine, bismuth sub salicylate,

atropine etc.

3.Antimotility drugs

Eg: codeine, loperamide, diphenoxylate etc

Functions of Antidiarrhoeal Drugs

Decrease irritation to the intestinal wall

Block GI muscle activity to decrease movement

Affect CNS activity that cause GI spasm and stop

movement

Relief of symptoms and compensation of fluid &

electrolyte loss

Non Specific Antidiarrhoeal Drugs

Adsorbents

Coat the walls of the GI tract

Bind to the causative bacteria or toxin, which is then

eliminated through the stool

Examples: bismuth subsalicylate, kaolin-pectin, activated

charcoal.

Side Effects

Increased bleeding time

Constipation, dark stools

Confusion

Hearing loss, metallic taste, blue gums

Anti secretory drugs

Agents which reduce the secretion

Decrease intestinal muscle tone and peristalsis of GI tract

Result: slowing the movement of faecal matter through the

GI tract

Examples: belladonna alkaloids, atropine, sulphasalazine,

hyoscyamine

Side effects

Urinary retention, impotence

Headache, dizziness, confusion, anxiety, drowsiness

Dry skin, rash, flushing

Blurred vision, photophobia, increased intraocular

pressure

Hypotension, hypertension, bradycardia, tachycardia

Antimotility drugs

Decrease bowel motility and relieve rectal spasms

Decrease transit time through the bowel, allowing more

time for water and electrolytes to be absorbed

Examples: codeine, loperamide, diphenoxylate

Side effects

Drowsiness, sedation, dizziness, lethargy

Nausea, vomiting, anorexia, constipation

Respiratory depression

Bradycardia, palpitations, hypotension

Urinary retention

Flushing, rash, urticaria

O

N

N

C CH2

CH2C

C

O

CH2

CH3

Diphenoxylate HCl

CH2

CH3

NHO

O

+ OCH2

CH2

CH2

CH3

NO

O

CH2

CH2OH

CH2

CH3

NO

O

CH2

CH2Cl

CCH3H +

N

N

C CH2

CH2 O

O

CH2

CH3

C

ethyl 4-phenylpiperidine-4-carboxylate ethyl 1-(2-hydroxyethyl)-4-phenylpiperidine-4-carboxylate

ethylene oxide

SYNTHESIS OF DIPHENOXYLATE HCL

N

N

C CH2

CH2

OH

C

Cl

O

CH3CH3

LOPERAMIDE

N

NH

OS

N

N

OH

O

OH

O

SULPHASALAZINE

O

OH

OH

NH2

Cl

N O

OH

OH

N

+

H

S

O

O

N N

NH2

H

N

N

O

S

N

N

OH

O

OH

O

5-amino-2-hydroxybenzoic acid

NaNO2/HCl

5-[(Z)-chlorodiazenyl]-2-hydroxybenzoic acid

4-amino-N-(pyridin-2-yl)benzenesulfonamide

2-hydroxy-5-{(E)-[4-(pyridin-2-ylsulfamoyl)phenyl]diazenyl}benzoic acid

Synthesis of Sulphasalazine

Metabolism of Sulphasalazine

Sulphasalazine[H]

Gut

NH2

OH

O

OH

5- Amino salicylic acid

+

HO

SN

NO

N-(pyridin-2-yl)benzenesulfonamide

Prodrug, having low solubility and poorly absorbed from

ileum.

The azo bond split by colon bacteria into Sulfapyridine and

5-amino salicylic acid.

Blocks cyclooxgenase and lipooxygenase pathway and

reduce mucosal secretion.

Laxatives

CONSTIPATION

Constipation is the infrequent and/or unsatisfactory

defecation fewer than 3 times per week.

Abnormally infrequent and difficult passage of faeces through

the lower GI tract

Symptom, not a disease

Disorder of movement through the colon and/or rectum

CAUSES OF CONSTIPATION

Diet

Lack of exercise

Irregular bowel habits

Drug induced

Disease States/Conditions

Spasm of colon

Dysfunction of myenteric plexus

SYMPTOMS OF CONSTIPATION

Infrequent defecation

Nausea

Vomiting

Anorexia

Feeling full quickly

Stools that are small, hard, and/or difficult

to evacuate

Rectal bleeding

Weight loss (in chronic constipation)

• Mild action, elimination of soft stools but formed stools.

Laxative or aperients

• Stronger action resulting in more fluid evacuation.

Purgative or cathartic

LAXATIVES

Drugs that promote evacuation of bowels.

Based on intensity of action

Classification

• Methyl cellulose, ispaghula,Agar, Psyllium seeds

1. Bulk forming

• Liquid paraffin, Glycerine, Olive oil

2. Stool softener

Diphenylmethanes

• Bisacodyl, phenolphthalein, sodium

picosulphate.

Anthraquinones

• Senna, cascara sagrada

5HT4 agonist • Tegaserod

Fixed oil • Castor oil

3. Stimulant purgative

4. Osmotic purgativeMagnesium salts, lactulose

etc

Bulk Forming Laxatives

Improve stool consistency and frequency with regular use

Ensure good fluid intake to prevent faecal impaction

Onset of action 2-3 days

Side Effects may include bloating, flatulence, distension

Stool Softeners

May be useful with anal fissures of haemorrhoids

Liquid paraffin is not recommended for treatment of

constipation

- risk of aspiration and lipoid pneumonia

- long term use may result in depletion of Vitamins

A, D, E and K

Stimulant Laxatives

Increase intestinal motility by stimulating colonic nerves

Useful with opioids

Onset of action 8-12 hours

May develop tolerance

2nd line therapy in elderly due to risk of electrolyte

disturbances

Cramping, diarrhoea, dehydration

Osmotic Laxatives

Increase fecal water content

Result: bowel distention, increased peristalsis, and

evacuation

Improving stool frequency

Onset of action – up to 48 hours

Metabolized by bacteria flatulence

OO

N

OOCH3 CH3

Bisacodyl

ON

CH + 2C6H5OH

H2SO

4

(CH3CO)

2O

N

O

O

C

CH3

C

CH3

O

O

pyridine-2-carbaldehyde

(pyridin-2-ylmethanediyl)dibenzene-3,1-diyl diacetate

Synthesis of Bisacodyl

O

O

OH

OH

O

O

O

+

OH

OH

H2SO

4

O

O

OH

OH

phathalic anhydride

phenol

phenolphthalein

3,3-bis(4-hydroxyphenyl)-2-benzofuran-1(3H)-one

Synthesis of phenolphthalein

Phenolphthalein

Na Na

N

OOSS

O-

O-

O

O O

O

sodium picosulphate

-{(pyridin-2-ylmethanediyl)dibenzene-4,1-diyl bis[hydrogenato(2-)-O sulfate]}disodate(2-)

OH

NHN NH

NH

CH3Tegaserod

3-[(E)-{2-[(pentylamino)methyl]hydrazinylidene}methyl]-1H-indol-5-ol

It is 5HT4 agonist used for the management of

irritable bowel syndrome and constipation

*Contract stomach muscles and stimulate hunger

N

N

3-phenyl-3,4-dihydroquinazoline( Orexin)

Bitters – secretion of gastric juice

Eg: Quassins

*

*Disturbance of appestat – weight regulating

mechanism in hypothalamus

Eg: Dextro amphetamine

CH3

NH2

CH3

NH2

CH3

Aptrol

**HCl

*Pepsin

O

O

CH3

O

CH3

O

OH

CH3

Florantyrone

Si O

CH3

O

CH3

Si CH3

CH3

CH3

Si

CH3

CH3

CH3

n

Simethicone

*

*Protect sensitive surface from irritation

*Lozenges or gargles

*Cohesive substances like colloids, dextrins, sugar, starches

*Eg: Acacia

Tragacanth

Liquorice

*

*PPI

*H2 blockers

*Sodium alginate

*Prokinetic drugs

*Antacids

*

*Expulsion of gases

*Eg: Sodium bicarbonate

Peppermint oil

Tincture of cardamom

Oil of dill

Tincture of ginger

*

*Anticholinergics

O O CH3

CH3

NH

N

CH3

CH3

Camylofin

NH

O

CH3

O

CH3

OCH3

OCH3

Dicycloverine

Liver protectants*Chenodiol ( chenodeoxy cholic acid)

*Ursodiol ( Ursodeoxy cholic acid)

Gall stone dissolving drugs *Metadoxine

*L-Ornithine

*L- Aspartase

*Silymarin

*

Proton pump inhibitor

IL – YANG pharmaceuticals

NH

NH

N

S

O

N

CH3 O CH3

Ilaprazole

Anti diarroheal

HIV Assosiated

NAPO pharmaceuticals

O

O

OHOH

OH

OHOH

OH

OH

OH

OH

OH

O

OH

OH

OH

OH

OH

Crofelimer

Antiemetic drug

Neurokinin receptor antagonist

N

N

N

F

CH3

O

CH3

N

O

CH3

CH3

CF 3

CF 3

Casopirant

REFERENCE

1.Text Book of Medicinal Chemistry by V. Alagarsamy,

1st edition volume-II, page no:1137

2.Bently and Driver’s Text book of Pharmaceutical Chemistry

8th edition, page No. 724, 625.

3.Essentials of Medicinal Pharmacology by K D TRIPATHI,

6th edition page No. 651

4.Clinical Pharmacy and Therapeutics, by Roger Walker,

Cate Whitelsia, 4th edition, Page No: 824- 832

5. Foye’s principles of Medicinal Chemistry, 5th edition,

page No: 474-475