GASTROINTESTINAL

PHARMACOLOGY

Common GIT disorders include;

• Gastro-eosophageal reflux disease (GERD)

• Peptic Ulcer Diseases (PUD)

• Vomiting

• Diarrhea

• Constipation

Drugs for PUD and GERD (ACID-PEPTIC DISEASES)

Peptic Ulcer Disease (PUD)

• PUD- characterized by ulcer formation in the

esophagus, stomach, or duodenum areas of the GI

mucosa that are exposed to gastric acid and pepsin

• PUD can be;

 Gastric
 Duodenal

• Causes;

 Stress
 Drugs (NSAIDs)
 H. pylori

• Pathophysiology; imbalance between cell destructive and cell protective effects

Aggressive Factors
• H. pylori , Drugs (NSAIDs), Acid , bile,Pepsin

Protective Factors

 Mucus,Bicarbonate,Blood flow, Cell renewal, Prostaglandins, Somatostatin

Protecting factors
• Mucus- thin protective layer

• Bicarbonate- secreted by the surface epithelial cells

Prostaglandins- PGE2 & PGI2; produced by cells through out the GIT

inhibit acid secretion, increase mucosal blood flow

• Dilution of gastric acid by food and secretion

• Various growth factors- such as epidermal growth factor

and transforming growth factors

• A competent pyloric sphincter which prevents – the regurgitation of the aggressive factors
(bile acids and pancreatic enzymes) in to the stomach.
Aggressive Factors;
• H. pylori: colonize the mucus secreting epithelial cells

of the stomach mucosa

• Gastric Acid: activates pepsin and injures mucosa

• Decreased blood flow: causes decrease in mucus

production and bicarbonate synthesis

• NSAIDS: inhibit the production of prostaglandins

– ↓ Mucus, ↓ bicarbonate, ↓ blood flow, ↓ proliferation of

cells and ↑ gastric acid secretion

• Smoking: nicotine stimulates gastric acid production

• Pepsin: is a proteolytic enzyme that helps in digestion

of protein foods and – also can digest the stomach wall.

 Parietal Cell & Acid Regulation

Gastric acid secretion is regulated by three distinct and

interdependent pathways:

 Neuronal: Ach
 Endocrine: gastrin from antral G cells in response to food ingestion

and stretching of the stomach wall.

 Paracrine: histamine from Enterochromaffin like cells in gastric mucosa.

 Parietal cells contain H+-K+ ATPase which is responsible for exchange of H+ and K+.
 H+ is combine with Cl ions in the gastric lumen to form HCL.

Gastro esophageal Reflux Disease (GERD)

• Backflow of stomach acid into the esophagus

• Esophagus is not equipped to handle stomach acid => scaring

– Main symptoms are irritation and burning in chest or throat.

• More severe symptoms: difficulty swallowing, chest pain

• In some patients (~10%), the normal esophageal lining or epithelium may be replaced with
abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to
esophageal cancer.

DRUGS USED IN PUD and GERD:

 Antacids, H2 Receptor Blockers, Proton Pump
Inhibitors,Prostaglandin Analogs, Mucosal Protective Agents,
Anti-cholinergics, Eradicating the H. pylori infection with anti-
microbial agents
 Antacids
•Antacids are Weak bases in nature React with HCl in the stomach

 Produce less acidic and poorly absorbed salts

 Raise the PH of gastric secretions
 indirectly inhibiting activity of pepsin (pepsin is inactive above
pH=4)

Al compounds -Al(OH)3
•have low neutralizing capacity,Slow onset of action,Can cause constipation,Rarely used alone

•Used for patients with chronic renal failure and hyperphosphatemia.

 decreases the absorption of phosphate.

Mg compounds (Mg(OH)2, Magnesium tri silicate)

–High neutralizing capacity, –rapid onset of action

–Cause diarrhea and hypermagnesemia, –CI- renal failure

Ca compounds(Calcium Carbonate )
–Rapid onset of action,–May cause hypercalcemia

–Cause rebound acid secretion due to Gastrin release in large doses

 Rarely used in PUD

 Commonly used antacids are combinations of Al and Mg

compounds.

Therapeutic uses:
• To prevent and treat PUD & GERD

 To neutralize meal Stimulated acid secretion - Usually taken 1

hour after meal

• Antacids are cleared from the empty stomach in ~30 minutes. However, the presence of food is
sufficient to elevate gastric pH to ~5 for ~1 hour and to prolong the neutralizing effects of antacids for
~2-3 hours.
• 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

H2-receptor antagonists
 They competitively block the binding of histamine to H2

receptors,

 reduce the intracellular concentrations of cAMP and, thereby, secretio of gastric acid.
 in usual doses, all inhibit 60–70% of total 24-hour acid secretion.
 H2 antagonists are especially effective at inhibiting nocturnal acid secretion which depends
largely on histamine

• unlike antacids, they may not relieve symptoms for at least 45

Minutes. H2-receptor antagonists act by inhibiting acid secretion

General properties;
• Rapidly absorbed from the intestine

• Undergo first-pass hepatic metabolism (BA of approximately 50%)

• Nizatidine has little first-pass metabolism (BA of almost 100%)

• All H2 antagonists may reduce the efficacy of drugs that require an

acidic environment for absorption, such as ketoconazole.

• Cleared by a combination of hepatic metabolism, glomerular

filtration, and renal tubular secretion.

• Dose reduction is required in patients with moderate to severe

renal (and possibly severe hepatic) insufficiency.

• Cimetidine, ranitidine, and famotidine are also available in iv

formulations.

A. Cimetidine
• Crosses placenta and reaches milk

 Caution for pregnant and lactating mothers!

Adverse Effect;
• Cimetidine is well tolerated by most patients.

• Headache, dizziness, bowel upset, dry mouth, rashes.

• Cimetidine (but not other H2 blockers)

– inhibits binding of dihydrotestosterone to androgen receptors

(gynecomastia or impotence in men).

– increases plasma prolactin (galactorrhea in women) and inhibits

degradation of estradiol by liver (menstrual abnormality).

• Cimetidine inhibit cytochrome P450 enzymes .

– CYP1A2, CYP2C9, CYP2D6, and CYP3A4

B. Ranitidine
• More potent than cimetidine (5X) .

• Action is more selective and posses long duration of action .

• Advantage
– Doesn't produce sexual dysfunction .

– Doesn't interfere with hepatic Metabolism Ranitidine binds 4-10 times less avidly than
cimetidine to CYP.

C. Famotidine
• More potent than ranitidine, (40x cimetidine),Well tolerated and posses fewer side effect

• Doesn't interfere with Hepatic drug metabolism like nizatidine .

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).

– Also effective in GERD and Zollinger-Ellison syndrome.

– Eradication regimen for H. pylori, – Px and Tx of NSAID induced ulcer.

• In contrast to H2 antagonists, PPIs inhibit both fasting and meal stimulated secretion because
they block the final common pathway

• PPIs inhibit 90–98% of 24-hour acid secretion. When administered at equivalent doses, the
different agents show little difference in clinical efficacy.

• Omeprazole and esomeprazole, have been shown to decrease the effectiveness of clopidogrel
due to inhibition of CYP2C19.
• Administered as inactive prodrugs

• In the alkaline intestinal lumen, the enteric coatings dissolve

and the prodrug is absorbed. Are lipophilic weak bases, therefore diffuse readily across

lipid membranes into acidified compartments such as

 Canaliculi of the parietal cells.

• There, they rapidly undergo molecular conversion to the active, reactive thiophilic
sulfenamide cation.

• Sulfenamide reacts with the H+/K+ ATPase, forms acovalent disulfide linkage, and irreversibly
inactivates the enzyme.

• All of the PPIs are effective orally. Esomeprazole, lansoprazole and pantoprazole

(ivformulation).

• Bioavailability of all PPIs is reduced by food; they should be taken in empty stomach, followed
1 hour later by a meal to activate the H+/K+ ATPase and make it more susceptible to the PPI.

• In a fasting state, only 10% of proton pumps are actively secreting acid and susceptible to
inhibition. Should be administered approximately 30 to 60 minutes before a meal (usually
breakfast or dinner), so that the peak serum concentration coincides with the maximal activity
of proton pump secretion.

• Dexlansoprazole has a dual delayed release formulation and can be taken without regard to
food.

• Half-life is about 1.5 hours; however, the duration of acid inhibition lasts up to 24 hours due
to the irreversible inactivation of the proton pump. At least 18 hours are required for synthesis
of new H+/K+ ATPase.

• Because not all proton pumps are inactivated with the first dose of medication, up to 3-4 days
of daily medication are required before the full acid-inhibiting potential is reached.

Therapeutic uses:
• The PPIs are superior to the H2 antagonists in

 suppressing acid production and healing ulcers.

• for stress ulcer, for prophylaxis and for the treatment of GERD, for esophagitis,
• for active duodenal ulcer, for Zollinger-Ellison syndrome, used with antimicrobial regimens to
eradicate H. pylori

Omeprazole
• MOA: inhibit H+/K+- ATPase enzyme
• An oral product containing omeprazole combined with sodium

bicarbonate for faster absorption

• Effect

 More potent & has longer duration of action than H2 – blocker

 No rebound increase in gastric acid secretion
 Reduce the risk of bleeding from an ulcer caused by aspirin and other NSAIDs. Used for
GERD.

• should be taken 30-60 minutes before meal

• In combination with antibiotics, it can be used in the treatment of H. pylori induced PUD .

• Adverse effect

 Inhibit drug metabolizing enzyme

 Hyper-gastremia, Prolonged complete suppression of the acid barrier to bacteria entry
into the body.

Misoprostol
• A congener of prostaglandin E1

• Misoprostol has both acid inhibitory and mucosal protective properties.

• stimulate mucus and bicarbonate secretion and enhance mucosal blood flow.

• In addition, it binds to a prostaglandin receptor on parietal cells, reducing histamine-

stimulated acid secretion.

• Approved for prevention of gastric ulcers induced by NSAIDs especially at anti-inflammatory

doses.

• It is less effective than H2 antagonists and the PPIs for acute treatment of peptic ulcers.
• Cytoprotective actions are clinically observed only at higher doses

 Routine prophylactic use of misoprostol may not be justified

except in patients who are taking NSAIDs and are at high risk of NSAID-induced ulcers, such as

the elderly or patients with ulcer complications.

• Contraindication- pregnancy

 induce abortion, premature birth or birth defects.

• Dose-related diarrhea (10 to 40%) and nausea – are the most common AEs and limit the use of this
agent.

Mucosal Protective Agents.

• Agents that enhance mucosal defense Also known as cytoprotective compounds

• Have several actions that enhance mucosal protection mechanisms, thereby;

 preventing mucosal injury, reducing inflammation, and healing existing ulcers.

1) Sucralfate
• A preparation of sulfated sucrose and Al(OH)3 Can be used to prevent & treat PUD

• It requires an acid PH to be activated Forms sticky polymer in acidic environment and adheres to

the ulcer site, forming a barrier.

• May bind with other drugs and interfere with absorption

• Take on an empty stomach before meals

2) Chelated Bismuth (Bismuth subsalicylate)

• In addition to its antimicrobial actions, it;

 inhibits the activity of pepsin, increases secretion of mucus, and interacts with glycoproteins in
necrotic mucosal tissue to coat and protect the ulcer .
 Helicobacter pylori
• Optimal therapy for patients with PUD who are infected with H. pylori requires antimicrobial
treatment.

• H. pylori are bacteria able to attach to the epithelial cells of the stomach and duodenum
which stops them from being washed out.

• Once attached, the bacteria start to cause damage to the cells by secreting degradative
enzymes, toxins and initiating a selfdestructive immune response.

• Eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence
rates.

 Less than 15% compared with 60-100% per year for patients with initial ulcers healed by
traditional anti-secretory therapy.

• Successful eradication of H. pylori (80-90%) is possible with various combinations of

antimicrobial drugs.

Therapy of H. pylori-positive PUD

Triple Therapy - 14 day treatment - Effective 80-85%

• Proton pump inhibitor + amoxicillin (metronidazole in pencillin

allergy) + clarithomycin

Quadruple Therapy - 7 day treatment (PPI based) = as efficacious

as triple therapy

• bismuth salicylate + metronidazole + tetracycline + either a PPI

or H2RA

SEQUENTIAL THERAPY- PPI(1-10)+ amoxicillin(1-5) + metronidazole

(6-10) + clarithromycin(6-10).
• a meta-analysis indicated that quadruple therapy with a PPI provides greater efficacy and
permits a shorter treatment duration (7 days) when compared with the H2RA-based regimens
(10 to 14 days).

 However, a 10- to 14-day duration is recommended as it

generally provides higher eradication.

 When treating an active ulcer, the antisecretory drug is usually continued for 2 (PPI) to 4
(H2RA) weeks after stopping bismuth and antibiotics.

• switching of antibiotics is also not recommended, do not substitute

– ampicillin for amoxicillin or

– erythromycin for clarithromycin

Anti-Muscarinic agent
Pirenzepine;
• MOA:- M1- receptor antagonist

• reduce gastric acid secretion at doses that do not antagonize other systems

• About as effective as H2 blockers.Rarely used, primarily as adjunct therapy

• Anticholinergic side effects (anorexia, blurry vision,

constipation, dry mouth, sedation).

Anti-Emetics
• Nausea refers to the feeling of an imminent desire to vomit

• Vomiting refers to the forceful oral expulsion of gastric content

• N & V are generally viewed as protective reflexes – that serve to rid the stomach and intestine
of toxic substances and prevent their further ingestion.

• Anti-emetics are drugs which oppose or counter act nausea and vomiting

• Vomiting range from the physiologic state of pregnancy to serious pathology.

• Vomiting can be triggered by a variety of stimuli:

 stimulation of the sensory nerve endings in the GI tract and

pharynx;

 drugs; endogenous emetic substances produced as a result of radiation or disease;

 disturbance of vestibular appratus;
 stimuli to the sensory nerves of the heart and visera; endocrine factors
 a rise in ICP; nauseating smells; repulsive sights; disgusting experience.