GIT PHARMACOLOGY

10/15/2017 1
 Introduction

 Common GIT disorders include:

Gastro-eosophageal reflux disease (GERD)
Peptic Ulcer Diseases (PUD)
Vomiting
 Diarrhea
Constipation

10/15/2017 2
 Peptic ulcer disease
• Several major causative factors are:
 Non steroidal anti-inflammatory drug (NSAID) use,
 Infection with gram-negative Helicobacter pylori,
 Increased hydrochloric acid secretion, and
 Inadequate mucosal defence against gastric acid.

 Note : There are three common forms of peptic ulcers.

 H. pylori induced PUD
 NSAID induced PUD
 Stress related mucosal damage

10/15/2017 3
 Pathogenesis of Ulcers

Aggressive Defensive
Factors Factors
• H. pylori 
Mucus
• Drugs (NSAIDs) 
Bicarbonate
• Acid layer
• Pepsin 
Blood flow
• Bile salts 
Cell renewal
•

Prostaglandi
ns

Phospholipid
10/15/2017

Somatostati 4
 Drugs Used In Peptic Ulcer Disease

10/15/2017 5
 Antiacids

• Weak bases react with acid to form salt & H2O

• Act locally in the stomach
• Neutralize the acid in the stomach and indirectly inhibiting activity of
pepsin (pepsin is inactive above pH 4)
• Antacids more quickly and efficiently neutralize stomach acid, but
their action is only temporary
• Note:
 Al (OH) 3+ Mg (OH) 2: 2 tsp TID
 Mg trisilcate (chewable): 2-4 tab PO, between meals
 Mg trisilcate + Al (OH)3 (Chewable): 2-4 tab PO between meal and
10/15/2017 6
 Antacids…

•Side effects:
–Constipation (Al3+),
–diarrhea (Mg2+ );
–rebound hyperacidity (CaCO3)
•Drug interaction
–↑ oral absorption of weak bases (e.g., quinidine)
–↓ oral absorption of weak acids (e.g., warfarin)
–↓ oral absorption of tetracyclines (via chelation)
–↓ oral absorption of iron products
–Can alter pH of urine and interfere with drug excretion
10/15/2017 7
 H2-receptor antagonists

 They competitively block the binding of histamine to H2 receptors,

these agents reduce the intracellular concentrations of cAMP and,

thereby, secretion of gastric acid.
 Inhibit (> 90%) basal, food-stimulated, and nocturnal secretion of
gastric acid after a single dose.
 They bring about symptomatic relief & ulcer healing

• H2-receptor antagonists act by stopping acid secretion.

• Therefore, they may not relieve symptoms for at least 45 minutes

10/15/2017 8
 H2-receptor antagonists

Used for
PUD (less effective than proton pump
inhibitors)
Gastroesophageal
10/15/2017 reflux disease (GERD) 9
 A. Cimetidine

• Inhibit stimulated acid secretion (histamine)

• Inhibit meal stimulated acid secretion
• Dose: - 400mg po bid, 200mg IV BID
• Adverse Effect
 Hepatotoxicity, diarrhea, dizziness and inhibit CYP450 enzymes

• It acts as a non-steroidal anti-androgen: Sexual dysfunction,

gynecomastia, galactorrhea and menstrual abnormality

10/15/2017 10
 A. Cimetidine...

10/15/2017 11
 B. Ranitidine
• More potent than cimetidine (5X)

• Action is more selective and long duration of action

• Dose: 150mg Bid or 300mg at bed time

• Advantage

– Doesn't produce sexual dysfunction

– Doesn't interfere with hepatic Metabolism

– Ranitidine binds 4-10 times less avidly than cimetidine to CYP 450.

C. Famotidine
• More potent than ranitidine, (40x cimetidine)

• Well tolerated and posses fewer side effect

• Doesn't interfere with Hepatic drug metabolism like nizatidine

• 10/15/2017
Doses: 20mg bid or 40mg once a day at bed time 12
 Proton Pump Inhibitors (PPIs)
•Six PPIs are available for clinical use: omeprazole, esomeprazole, lansoprazole,
dexlansoprazole, rabeprazole, and pantoprazole.
•Mechanism of action:
Omeprazole & related “–prazoles” are irreversible, direct inhibitors of the proton pump
(K+/H+ antiport) in the gastric parietal cell.
•Uses:
–More effective than H2 blockers in peptic ulcer disease (PUD).
–The PPIs are superior to the H2 antagonists in suppressing acid production and healing
ulcers.
–Also effective in GERD and Zollinger-Ellison syndrome.
–Eradication regimen for H. pylori.
–Half-life is about 1.5 hours; however, the duration of acid inhibition lasts up to 24 hours
10/15/2017 13
due to the irreversible inactivation of the proton pump.
 PPIs…

10/15/2017 14
 IV) Antimicrobial Agents
Triple Therapy (14 days)
Drug #1 Drug #2 Drug #3
Omeprazole 20mg BID Clarithromycin Amoxicillin 1 g BID
Or 500 mg BID or
lansoprazole 30mg BID Metronidazole 500 mg
Or BID
pantoprazole 40mg BID
or
esomeprazole 40 mg
daily
or
rabeprazole 20 mg daily

10/15/2017 15
 V) Anti-Muscarinic agents

a) Pirenzepine

• MOA: M1- receptor antagonist

• Effect: Beneficial in treatment of duodenal ulcer than gastric ulcer

• SE: dryness of mouth, dizziness, headache

b) Librax: Chlordiazepoxide + Clindium (5mg, 2.5mg)

– MOA: chlorediazepoxide, decreases the acid secretion by reducing vagal
activity that result from response to stress

– Clindium bromide has a direct M1 - receptor antagonist effects.

– Therapeutic use: - Treatment of peptic ulcer

-Antispasmodic agent
– Dosage: 1-2capsule 3-4 times/day, before meals
10/15/2017 16
 VI) Mucosal Protective Agents
• Misoprostol (Prostaglandin E Analogue)
 Misoprostol has both acid inhibitory and mucosal protective properties.
 Believed to stimulate mucus and bicarbonate secretion and enhance mucosal
blood flow.
 In addition, it binds to a prostaglandin receptor on parietal cells, causing modest
acid inhibition.
• Approved for prevention of gastric ulcers induced by NSAIDs.
• Like other prostaglandins, misoprostol produces uterine contractions and is
contraindicated during pregnancy.
• Dose-related diarrhea and nausea are the most common adverse effects and limit the
use of this agent.
– Misoprostol, 200 mcg orally four times per day
10/15/2017 17
– A fixed combination of misoprostol 200 mcg and diclofenac (50 mg or 75 mg)
 Anti-Emetics

10/15/2017 18
 Anti-Emetics

• Nausea refers to the feeling of an imminent desire to vomit

• Vomiting; refers to the forceful oral expulsion of gastric content
• Anti-emetics are drugs which oppose or counter act nausea and
vomiting
• Vomiting center is located in the lateral medullary reticular
formation and coordinates the complex act of vomiting through
interactions with cranial nerves
• High concentrations of muscarinic, histamine H1 and serotonin 5-
HT3 receptors have been identified in the vomiting center
10/15/2017 19
 Stimuli

• Pain
• Pregnancy (specially multiple pregnancy)
• Post operative vomiting
• Bad taste
• Bad sight
• Anticancer drug, emetic substance (ipecac)
• Rotation
• Electrolyte disturbance

10/15/2017 20
 Management

• Non-drug treatment of N/V

 Correction of the underlying cause
 Hydration

10/15/2017 21
 Anti-Emetics...

H1-receptor antagonists
 Promethazine
 Dimenhydrnate
 Meclizine (less anti cholinergic & sedation)
– These have little or no effect against vomiting produced by
substance acting directly on the CTZ but are effective in motion
sickness & against vomiting caused by substances which act locally
in the stomach.

10/15/2017 22
 Anti-Emetics...

Muscarinic receptor antagonist

Hyoscine
• Use: motion sickness, spasm
• Hyosine is the most potent agent available for prevention of
motion sickness, though it is less useful once sickness occurs
• Should be taken before meal
• MOA: block the action of acetylcholine at parasymphatetic sites
• Dosage: adults 10mg 2 tab prn

10/15/2017 23
 5-HT3 Receptor Antagonists

 Drugs: Ondansetron, Granisetron, Dolasetron, tropisetron and

Palonosetron (IV only)
 Potent antagonists of 5-HT3 Rs, on peripheral vagal nerve terminals and

centrally in the CTZ.

 During chemotherapy that induces vomiting, mucosal enterochromaffin

cells in the GIT release serotonin, which stimulates 5-HT3 Rs.

 This causes vagal afferent discharge, inducing vomiting

 Are the most widely used drugs for chemotherapy-induced emesis(longer

duration of action and superior efficacy)
 Also used to prevent or treat post-operative/radiation nausea and vomiting
10/15/2017 24
 Dopamine antagonists…

Metoclopramide (substituted benzamide)

• MOA: block the dopamine receptor in chemo receptor trigger
zone of the CNS
• Prokinetic agent (increases motility)
• SE: disorder of movement, drowsiness, fatigue, disorder of
galactorrhea, menstruation(due to prolactin release)
• Dosage:
– Adults:- 10-15mg/dose up to four times a day 30 minute
before meal
– Children: - 0.1-0.2mg/kg/dose up to four times a day
10/15/2017 25
 Others antiemetic drugs….
 Corticosteroids
– Mechanism of action not clear
– May be related to blockage of PGs
• Dexamethasone, Prednisone
 Benzodiazepines
– Good for anticipatory nausea and vomiting before cancer
therapy
• Diazepam- typical dose is 2-5mg, once or twice/day
• Lorazepam- typical dose is 0.5mg BID

10/15/2017 26
 Efficacy of antiemetic drugs

10/15/2017 27
 Effectiveness of combinations

10/15/2017 28
 Drugs for Constipation

10/15/2017 29
 Drug for Constipation

• In general, it may be defined as infrequent or seemingly

incomplete evacuation.
• Cause; change in diet, exercise, GI motility
• Laxative: drug which produce soft formed stool
• They usually eases defecation by softening faces
• Cathartic : Produce severe action, watery stool or liquid/semi
liquid stool . They accelerate defecation
• Non - drug treatment:
– Removal of underlying cause
10/15/2017 30
– More fiber diet intake and increase fluid intake
 Stimulant or irritant laxatives

• Castor Oil
– Castor Oil is obtained from seed of ricinus communis
– By itself, it is not irritant
MOA: when ingested
– Castor Oil Pancreatic Lipase Ricinoleic acid
– Ricinoleic acid causes stimulation of small intestine and thereby
increases peristalsis and result in laxative action.
– Dose: 5-30ml - Effect quickly seen in 2-3 hr
• CI; pancreatic disease
• Castor oil is used less frequently;
– it is pregnancy category X and is associated with uterine
10/15/2017 31
contractions and rupture.
 Stimulant or irritant laxatives

• Bisacodyl
– Can be used orally or rectally
– Stimulate the large intestine
– Dose 10mg in the night, 10mg rectally in the morning
• Children: 5mg rectally in the morning (4yrs)
 Anthraquinone Laxatives
 Derivatives of plants aloe, cascara, and senna

10/15/2017 32
 Osmotic Laxatives
• Salt: Mg SO4, Mg citrate
MOA: when given orally, not absorbed from GIT.
• They exert osmotic effect on the GIT there by holding considerable
amount of water.
• Increase in bulk which exert mechanical effect thereby ses motility
and facilitating evacuation of faces.
• Onset of action is fast and hence given before meals (breakfast) in the
morning.
• Patient should be advised to take plenty of water
• Small amount of these drugs which are absorbed may produce toxic
effect especially in renal insufficiency. Mg - Marked CNS depression33
10/15/2017
 ANTIDIARRHEAL AGENTS

• Diarrhea is the frequent passage of liquid faeces

• Cause - infectious agents, toxins, drugs
• It is characterized by
– ↑ed stool frequency (usually >3x daily), stool weight, liquidity
– ↓ed consistency of stools compared with an individual’s usual
pattern.
• Diarrhea is classified as
– Acute: lasting for ≤ 14 days (mostly caused by infections)
– Persistent: 15 to 30 days
– Chronic: >30 days
10/15/2017 34
 Management
• They are different approach in the treatment of diarrhea.

1. Maintenance of fluid with electrolyte balance

 ORS (oral rehydration salt)

• Glucose, Nacl, Kcl

• One Sachet in 1 lit of H2O

2. Anti-infective agent
 Depending on the problem (i.e. type of infectious agent), d/t antibiotics can

be given.

3. Anti motility agents

 The main pharmacological agent which decrease motility are opiates like

codeine, diphenoxylate and loperamide.

10/15/2017 35
 Anti motility agents

Loperamide
• Loperamide is an opiate analogue with major peripheral opioid
agonist
• Dosage: 4mg initially, followed by 2mg after each loose stool (max
16mg/day)
• Advantage: no abuse potential
• But in overdose it may occur

10/15/2017 36
 Anti motility agents...

Diphenoxylate (2.5mg)+ atropine (0.25mg)=Lomotil

- It is an opiod chemically related to pethidine
• Constipating agent
• Action: is similar to codeine
• Antidiarheal is most prominent
• Can cross BBB-CNS effect
• Atropine is added in non-pharmacologic doses to discourage
abuse
• Dose:10mg followed by 2.5-5mg 6 hourly.

10/15/2017 37