GASTROINTESTINAL

DRUGS
• Drugs for Peptic Ulcer and GERD
• Antiemetic, Prokinetic and Digestant Drugs
• Drugs for Constipation and Diarrhoea
 PEPTIC ULCER
• occurs in gastrointestinal tract exposed to gastric acid and pepsin -
stomach and duodenum
• Etiology is not clearly known
• A variety of psychosomatic, humoral and vascular derangements
• Helicobacter pylori - contributor to ulcer formation and recurrence

Defensive factors
gastric mucus and
bicarbonate secretion, Aggressive factors
prostaglandins, nitric oxide, Imbalance acid, pepsin, bile and
high mucosal blood flow, H. pylori
innate resistance of the
mucosal cells
Regulation of gastric acid secretion
 Goals of therapy
• Peptic ulcer is a chronic remitting and relapsing disease
lasting several years.
The goals of antiulcer therapy are:
✓ Relief of pain
✓ Ulcerhealing
✓ Prevention of complications(bleeding, perforation)
✓ Prevention of relapse.
Approaches for the treatment of
peptic ulcer
1. Reduction of gastric acid secretion
(a) H2 antihistamines: Cimetidine,Ranitidine,
Famotidine, Roxatidine
(b) Proton pump inhibitors: Omeprazole,
Esomeprazole, Lansoprazole, Pantoprazole,
Rabeprazole,
(c)Anticholinergic drugs:
Pirenzepine,Propantheline, Oxyphenonium
(d) Prostaglandin analogue: Misoprostol
2. Neutralization of gastric acid (Antacids)
(a) Systemic: Sodium bicarbonate,Sod. citrate
(b)Nonsystemic: Magnesium hydroxide, Mag.
trisilicate, Aluminium hydroxide gel, Magaldrate,
Calcium carbonate

3.Ulcer protectives: Sucralfate, Colloidal

bismuth subcitrate (CBS)

4.Anti-H. pylori drugs: Amoxicillin, Clarithromycin,

Metronidazole, Tinidazole,Tetracycline
 DRUG USED FOR PEPTIC ULCER
Based on KD Tripathi Classification

Reduction of Neutralization of Ulcer Protective Anti H Pylori

Gastric acid Secretion Gastric acid Drugs

H2 Antihistaminic Systemic Example Example

Cimetidine, Ranitidine, Famotidine,
Roxatidine
Proton Pump Inhibitor
Omeprazole, Esomeprazole,
Lansoprazole, Pantoprazole,
Rabeprazole, Dexrabeprazole
Sodium bicarbonate, Sodium citrate Sucralfate, Colloidal bismuth sub
Amoxicillin, Clarithromycin
citrate
Metronidazole, Tinidazole
Tetracycline
No systemic
MgOH, Magnesium trisilicate, Aluminum
hydroxide gel, Magaldrate, Calcium carbonate
NaHCO3+HCL NaCl+H2O+CO2 Base

Anticholinergic Drugs Pylori

Pirenzepine, Propantheline, Antibiotics
Oxyphenonium

Acid + Base
Prostaglandin Analogue
Misoprostol
Anti Pylori
Ulcer
Coating
Neutralization

Key point- Peptic ulcer is result of imbalance between attacking gastric acid and protective bicarbonate system. Gastric
acid secretion is regulated by cholinergic system, Histaminic system, stress, Hyperacidity, Microorganism and somehow
smoking and spicy diet. The first attempt towards treatment is neutralization of hyper acidity by using antacids which are
chemically base and they give their action by neutralizing acid. Protective drug are not the treatment they can mask the
pain or irritation signal arising from the ulcer. Anti microbial drug may only be effective in case of infection.
H2 ANTAGONISTS
• Marked inhibition of gastric secretion (all phases) due to
competitive H2 blockade
• Four H2 antagonists cimetidine, ranitidine, famotidine and
roxatidine are available in India

❑ CIMETIDINE - first H2 blocker to be introduced.

✓ Well absorbed orally
✓ Well tolerated .
✓ Common side effects
headache, diarrhoea/constipation,dizziness
✓ Inhibitor of several Cytochrome P-450
✓ Use has declined due to incidence of male sexual
dysfunction and several drug interactions
• Ranitidine- 5 times more potent than cimetidine
Longer duration of action with greater 24 hr acid
suppression
No antiandrogenic action
Overall incidence of side effects is lower
• Famotidine- binds tightly to H2 receptors and
exhibits longer duration of action despite an
elimination t½ of 2.5–3.5 hr
5–8 times more potent than ranitidine
• Roxatidine- pharmacodynamic, pharmacokinetic
and side effect profile is similar to ranitidine, but
twice as potent and longer acting
PROTON PUMP INHIBITORS (PPIs)
❑ Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole,
Rabeprazole
• have overtaken H2 blockers for acid-peptic disorders
• Most powerful inhibitor of gastric acid secretion.
• Inhibit resting as well as that stimulated by food or any of the
secretagogues
• react covalently with H+K+ATPase enzyme
• inactivate it irreversibly
• have high degree of selectivity of action
• Minimal adverse effects. Nausea, loose stools, headache,
abdominal pain, muscle and joint pain
• All PPIs are administered orally in enteric coated form
• Omeprazole: It is the prototype member
dose dependent suppression of gastric acid secretion;
without anticholinergic or H2 blocking action
bioavailability is reduced by food should be taken in empty
stomach 1 hr before meal

Esomeprazole : It is the S-enantiomer of omeprazole; have

higher oral bioavailability
• Pantoprazole: It is similar in potency and clinical efficacy to
omeprazole, but is more acid stable and has higher oral
bioavailability
• Rabeprazole : cause fastest acid suppression
 USES
• Peptic ulcer: Gastric and duodenal-
prophylaxis, treatment, relapse
• Bleeding peptic ulcer
• Stress ulcers
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Aspiration pneumonia
PROSTAGLANDIN ANALOGUE
• PGE2 and PGI2 serve cytoprotective role
• inhibit acid secretion
• promote mucus and HCO3¯ secretion
• Misoprostol (methyl-PGE1 ester) is a longer acting
synthetic PGE1 derivative
• inhibits acid output dose dependently.
• side effects and multiple daily dosing - Patient
acceptability is poor
• primary indication - prevention and treatment of
NSAID associated gastrointestinal injury and blood
loss
 ANTACIDS
• basic substances
• Neutralize gastric acid and raise pH of gastric contents
• Peptic activity is indirectly reduced
• potency of is expressed in terms of acid neutralizing capacity
(ANC): defined as number of mEq of 1N HCl that are brought to pH 3.5 in
15 min by a unit dose of the antacid preparation
• Systemic antacids: potent, rapidly acting but
infrequently used due to systemic side effect
• Nonsystemic antacids : salts of magnesium and
aluminium used in combination for better tolerabilty
and reduced side effects.
ULCER PROTECTIVES
• Sucralfate: basic aluminium salt of sulfated sucrose
• polymerizes at pH < 4 by cross linking of molecules, assuming
a sticky gel-like consistency.
• strongly adheres to ulcer base
• acts as a physical barrier preventing acid, pepsin and bile from
coming in contact with the ulcer base

• Colloidal bismuth subcitrate: a colloidal bismuth

compound; water soluble but precipitates at pH < 5
• mechanism of action is not clear: probably increase gastric
mucosal PGE2, mucus and HCO3¯ production. detach and
inhibit H.pylori directly
ANTI-HELICOBACTER PYLORI DRUGS
• is a gram negative bacillus
• attaches to surface epithelium beneath the mucus
• maintains a neutral microenvironment around the
bacteria
• promotes back diffusion of H+ ions
• causation of chronic gastritis, dyspepsia, peptic
ulcer, gastric lymphoma and gastric carcinoma
• Antimicrobials against H. pylori are:
amoxicillin, clarithromycin, tetracycline and
metronidazole/tinidazole
• Eradication of H. pylori concurrently with PPI therapy
of peptic ulcer: faster ulcer healing, prevents ulcer
relapse
• US-FDA approved regimen is: Lansoprazole 30 mg + Amoxicillin 1000 mg+
clarithromycin 500 mg, all given twice daily for 2 weeks.
• National Formulary of India (NFI, 2010): 1 week consisting of:
Omeprazole 40 mg OD + Metronidazole 400 mg TDS + Amoxicillin 500
mg TDS.
• Quadruple therapy: CBS 120 mg QID +tetracycline 500 mg QID +
metronidazole 400mg TDS + omeprazole 20 mg BD for failure cases.
GERD
• Reflux of acid gastric contents into lower 1/3rd of esophagus
• Functional disorder: relaxation of lower esophageal sphincter
(LES) in the absence of swallowing

• causes esophagitis, erosions, ulcers, pain on swallowing,

dysphagia, strictures, and increases the risk of esophageal
carcinoma.

• Treatment: Proton pump inhibitors (PPIs)

H2 blockers
Antacids
Sodium alginate
Prokinetic drugs: Metoclopramide,
cisapride
Antiemetic Drugs
Physiology of Emesis
➢ stimulation of the emetic centre situated in the
medulla oblongata- Vomiting
➢ Multiple pathways are involved
• chemoreceptor trigger zone (CTZ) and
• nucleus tractus solitarius (NTS) : relay areas for afferent
impulses arising in the g.i.t, throat and other viscera
• CTZ is also accessible to blood borne drugs, mediators,
hormones, toxins
• Emetics like Apomorphine, Ipecacuanha are used when a
poison has been ingested
• CTZ and NTS express a variety of receptors: histamine H1,
dopamine D2, serotonin 5-
HT3, cholinergic M,
neurokinin NK1 , cannabinoid
CB1 and opioid μ receptors
• Through which the emetic signals are relayed and are targets
of antiemetic drug action.
CLASSIFICATION
1. Anticholinergics : Hyoscine, Dicyclomine
2. H1 antihistaminics: Promethazine, Diphenhydramine,
Dimenhydrinate, Cinnarizine.
3. Neuroleptics: Chlorpromazine(D2 blockers), Triflupromazine
4.Prokinetic drugs: Metoclopramide, Domperidone, Cisapride,
Mosapride, Itopride
5.5-HT3 antagonists: Ondansetron, Granisetron, Palonosetron,
Ramosetron
6. NK1 receptor antagonists : Aprepitant, Fosaprepitant
7. Adjuvant antiemetics: Dexamethasone, Benzodiazepines,
Dronabinol
• ANTICHOLINERGICS:
Hyoscine - most effective drug for motion sickness.
by blocking conduction of nerve impulses across acholinergic
link in the pathway leading from the vestibular apparatus to
the vomiting centre

• H1 ANTIHISTAMINICS:
useful mainly in motion sickness and to a lesser extent in
morning sickness, postoperative and some other forms of
vomiting

• NEUROLEPTICS:
act by blocking D2 receptors in the CTZ
useful in drug induced and postoperative nausea and vomiting
(PONV). Disease induced vomiting: gastroenteritis, uraemia,
liver disease, migraine
 PROKINETIC DRUGS
• promote gastrointestinal transit and speed gastric emptying
by enhancing coordinated propulsive motility
• Metoclopramide
Introduced as a ‘gastric hurrying’ agent, a commonly used
antiemetic
MOA involves- a) D2 antagonism
b) 5-HT4 agonism
c) 5-HT3 antagonism
generally well tolerated but Long-term use can cause
parkinsonism, galactorrhoea and gynaecomastia
• Effective and popular drug for many types of vomiting— postoperative,
drug induced, disease associated (especially migraine)
• Also used as a gastrokinetic, in Dyspepsia and other functional
g.i. disorders, GERD
• Domperidone: D2 receptor antagonist
antiemetic and prokinetic actions have a lower ceiling
extrapyramidal side effects are rare
Side effects Are much less than metoclopramide

• Cisapride: prokinetic with little antiemetic property

restores and facilitates motility throughout the g.i.t.,
including colon however predisposes to torsades de
pointes/ventricular fibrillation. Subsequently withdrawn
from the market
5-HT3 ANTAGONISTS
• Ondansetron, Granisetron, Palonosetron, Ramosetron
• Distinct class - developed to control cancer chemotherapy
/radiotherapy induced vomiting
• effective in PONV and disease/drug associated vomiting
• Blocks 5-HT3 receptors on vagal afferents in the g.i.t. as well as
in NTS and CTZ
• generally well tolerated except headache and dizziness
• superiority in terms of efficacy as well as lack of side effects
and drug interactions has been demonstrated over
metoclopramide and phenothiazines
NK1 RECEPTOR ANTAGONISTS
• Aprepitant, Fosaprepitant
• high affinity NK1 receptor antagonist blocks the emetic action
of substance P at CTZ
• Oral aprepitant combined with standard i.v. ondansetron+
dexamethasone regimen significantly enhanced the
antiemetic efficacy against high emetogenic cisplatin based
chemotherapy
• Effective against acute as well as delayed phase of vomiting
• Particularly useful in patients undergoing multiple cycles of
chemotherapy