PHARMACOLOGY OF GASTROINTESTINAL DRUGS (PT 1)

Gastrointestinal Tract (GIT)/ Alimentary Canal

• Also known as the digestive system

• A complex organ system responsible for processing food into nutrients that the body can absorb. 

• Long muscular tube that extends from the mouth to the anus

Gastrointestinal Tract (GIT)/ Alimentary Canal

• It consist of several organs that work together to 

• break down food, 

• absorb nutrients, and 

• eliminate waste.

Major organs

• Mouth 

• Espohagus 

• Stomach 

• Small intestines 

• Large  intestines (colon)

• Rectum

• Anus

Accessory Organs

• Liver

• Gallbladder 

• Pancreas

The parietal cell contains receptors for:

• gastrin

• histamine

• acetylcholine 

gastrin

G/CCK-B receptor

histamine

H2

acetylcholine

M3

When ACh and gastrin bind to the parietal cell receptors, they cause 

an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from an H⁺/K⁺-ATPase (the proton pump) on the canalicular surface.

In close proximity to the parietal cells are gut endocrine cells called

enterochromaffin-like (ECL) cells.

enterochromaffin-like (ECL) cells

have receptors for gastrin and acetylcholine, which stimulate histamine release.

Histamine binds to H₂ receptor on the parietal cell, resulting in

activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+/K+-ATPase.

Parietal cells are stimulated to secrete acid by:

• Gastrin on gastrin CKKB receptors 

• Histamine on H2 receptors 

• ACh on M3 receptors

Parietal cells

(in the stomach lining) is responsible for secreting HCl

Gastrin

(released by G-cell) stimulate HCl release from parietal cells

Histamine release by Enterochromaffin-like (ECL)

stimulate parietal cells to release HCl

Vagus nerve

stimulating release of gastrin and activation of parietal cells

Somatostatin

hormone release by these cells for the inhibition of release of gastrin and histamine, decreasing HCl secretion

CONDITIONS AFFECTING THE GIT

• Gastroesophageal Reflux Disease (GERD)

• Barrett’s Esophagus

• Peptic Ulcer Disease (PUD)

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

• A chronic condition where stomach acid and pepsin flow back up into the esophagus, causing heartburn and other symptoms.

  • This backward flow is called acid reflux.

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

common cause 

• overproduction of acid/pepsin in the stomach 

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

complications if left untreated 

• severe chest pain

• bleeding

• Barrett's esophagus

BARRETT’S ESOPHAGUS

• A complication of GERD.

• A condition where the lining of the esophagus, normally made of squamous cells, is replaced by cells similar to those found in the intestine

BARRETT’S ESOPHAGUS

not cancerous, but 

increases the risk of developing esophageal adenocarcinoma

PEPTIC ULCER DISEASE (PUD)

A condition characterized by painful sores in the lining of the stomach or duodenum.

PEPTIC ULCER DISEASE (PUD)

• These sores can be caused by a variety of factors, including:

1. Helicobacter pylori (H. pylori) infection

2. NSAIDs

3. stress-induced (attributed to excessive acid production)

Estimates suggest that _ of the population will experience a peptic ulcer at some point in their lives.

around 10-15%

It is also estimated that over half of the world’s ulcer population is

infected with H. pylori infection.

WHO GETS PEPTIC ULCER?

• Men have twice the risk as women do

• genetic factors

• Increase acid production and/or decrease bicarbonate and prostaglandin production:

WHO GETS PEPTIC ULCER?

Genetic factors:

• high levels of acid production

• weakness in the mucosal layer 

• abnormal non-protective mucus production

WHO GETS PEPTIC ULCER?

Increase acid production and/or decrease bicarbonate and prostaglandin production:

• caffeine

• cigarettes

• alcohol

• fruit juices

• stress

Acid-peptic disorders involve

• mucosal cell erosion or ulceration from the caustic effects of aggressive factors like acids, pepsin or bile. 

• These aggressive factors overwhelm the gastrointestinal mucosa leading to gastroesophageal reflux, peptic ulcers, and stress induced mucosal injury

Agents that promote mucosal defense or mucosal protective agents

• Sucralfate

• prostaglandin analogs

• bismuth compounds

Agents that reduce intragastric acidity

• Antacids

• H2-receptor antagonists 

• PPI

DRUGS FOR ACID-PEPTIC DISORDERS

• ANTACIDS

• H2-RECEPTOR ANTAGONISTS

• PROTON-PUMP INHIBITORS

• MUCOSAL PROACTIVE AGENTS

ANTACIDS

drugs 

• Sodium Bicarbonate

• Calcium Carbonate

• Aluminum and Magnesium Hydroxide

ANTACIDS

description

• weak bases that react with gastric HCl to form salt and water.

• traditionally used for acid peptic disorders

ANTACIDS

moa 

Reduction of intragastric acidity by neutralization.

ANTACIDS

doa

Short-lived; 1-2  hours

ANTACIDS

clinical implications/ precautions 

• These agents may affect the absorption of other medications by binding to the drug or by increasing intragastric pH, thus affecting the drug’s dissolution or solubility (esp. weakly basic or acidic drugs).

Antacids should not be given within 2 hrs of doses of:

• tetracycline, 

• fluoroquinolones, 

• Itraconazole

• iron.

SODIUM BICARBONATE
other name/ brand name

baking soda, Alka Seltzer®

SODIUM BICARBONATE

moa

• Reacts rapidly with HCl to produce carbon dioxide and sodium chloride.

SODIUM BICARBONATE

s/e

• belching (burp)

• metabolic alkalosis (high doses)

• may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency.

CALCIUM CARBONATE

brand name 

• Tums®

• Os-Cal®

CALCIUM CARBONATE

moa 

• Less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride.

CALCIUM CARBONATE

s/e 

• belching or metabolic alkalosis.

• High doses may lead to renal insufficiency and hypercalcemia

ALUMINUM AND MAGNESIUM HYDROXIDE

moa 

• Reacts slowly with HCl to form magnesium chloride or aluminum chloride with water.

ALUMINUM AND MAGNESIUM HYDROXIDE

• Belching and metabolic alkalosis is

• uncommon due to the efficiency of neutralization reaction. 

Unabsorbed Mg salts may cause

osmotic diarrhea

Al salts may cause

constipation. 

Al and Mg are commonly administered together in proprietary formulations (e.g. Maalox) to

minimize the impact on bowel function.

ALUMINUM AND MAGNESIUM HYDROXIDE

brand name 

Maalox 

ALUMINUM AND MAGNESIUM HYDROXIDE

pharmacokinetics 

• absorbed and excreted by the kidneys, therefore, renal insufficiency patients should not take this long term

H₂-RECEPTOR ANTAGONISTS

drugs 

• Cimetidine

• Ranitidine

• Famotidine

• Nizatidine

H₂-RECEPTOR ANTAGONISTS

pk 

Rapidly absorbed from the intestine

H₂-RECEPTOR ANTAGONISTS

pk : Cimetidine, ranitidine, and famotidine 

• undergo first-pass effect, resulting in a bioavailability of approximately 50%.

H₂-RECEPTOR ANTAGONISTS

pk : Nizatidine 

• has little first-pass metabolism.

H₂-RECEPTOR ANTAGONISTS

pk: H₂ blockers are cleared by a combination of:

• hepatic metabolism

• glomerular filtration

• renal tubular secretion

H₂-RECEPTOR ANTAGONISTS

pd 

• Exhibits competitive inhibition at the parietal cell H₂ receptor and suppresses basal (fasting) and meal-stimulated acid secretion in a linear, dose-dependent manner.

• Highly selective and does not affect H₁ or H₃ receptors

H₂-RECEPTOR ANTAGONISTS

moa 

1. Blocks histamine release from ECL cells by gastrin or vagal stimulation.

2. Can diminish acid secretion effect of gastrin and acetylcholine.

H₂-RECEPTOR ANTAGONISTS

doa

6-10 hours

H₂-RECEPTOR ANTAGONISTS

clinical uses 

• GERD

• PUD

• BLEEDING FROM STRESS-RELATED GASTRITIS

H₂-RECEPTOR ANTAGONISTS

clinical uses : gerd

May be taken prophylactically before meals in an effort to reduce the likelihood of heartburn.

H₂-RECEPTOR ANTAGONISTS

clinical uses : pud

• PPIs have largely replaced H2 blockers in the treatment of acute PUD.  (still used sometimes) 

• Nocturnal acid suppression affords effective ulcer healing in most patients with uncomplicated gastric or duodenal ulcers.

H₂-RECEPTOR ANTAGONISTS

clinical uses : BLEEDING FROM STRESS-RELATED GASTRITIS

• The increase in intragastric pH by H2 blockers reduces the incidence of critically significant bleeding and should be administered to patients who are at high risk of GIT bleeding.

 CIMETIDINE

BRAND NAME 

 CIMETIDINE

• Interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by:

  • CYP1A2

  • CYP2C9

  • CYP2D6

  • CYP3A4

• enzyme inhibitor.

RANITIDINE

BRAND NAME 

zantac 

RANITIDINE

• Binds 4-10x less avidly than cimetidine to CYP450.

• It is a weak enzyme inhibitor.

FAMOTIDINE

brand name 

H2-BLOC 

FAMOTIDINE

• Most potent agent, has the longest duration of action, and fewest side effects among H2 blockers.

NIZATIDINE

BRAND NAME 

(AXID^Ⓡ)

NIZATIDINE

• Moderately potent than cimetidine, but generally less potent than famotidine.

PROTON-PUMP INHIBITORS

DRUGS 

• Omeprazole

• Esomeprazole

• Lansoprazole

• Dexlansoprazole

• Rabeprazole

• Pantoprazole

PROTON-PUMP INHIBITORS

NOTES 

• More commonly prescribed than H2 antagonists for most clinical indications. 

  • But the OTC preparations of the H2 antagonists are heavily used by the public.

PPIs are among the

most widely prescribed drugs worldwide.

PPIs are administered as

• inactive prodrugs.

PPIs

• All are substituted _

• benzimidazoles that resemble H2 antagonists in structure but have a completely different MOA.

PROTON-PUMP INHIBITORS

To protect the acid-labile prodrug from rapid destruction within the stomach,

• oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets.

PROTON-PUMP INHIBITORS

the bioavailability is _

• decreased approximately 50% by food.

PPIs have a short serum half-life of about

• 1.5 hrs, but acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump.

PROTON-PUMP INHIBITORS

undergo __ 

• rapid first-pass and systemic metabolism and have negligible renal clearance.

PROTON-PUMP INHIBITORS

pd

• Inhibits both fasting and meal-stimulated secretion due to the blockade of the final pathway of acid secretion.

• can inhibit 90-98% of 24-hour acid secretion.

PROTON-PUMP INHIBITORS

moa 

• Suppresses gastric acid secretion by inhibiting the H+/K+-ATPase pump (proton pump).

PROTON-PUMP INHIBITORS

clinical use

• GERD

• STRESS-RELATED MUCOSAL BLEEDING

• GASTRINOMA AND OTHER HYPERSENSITIVITIES

• PUD

PROTON-PUMP INHIBITORS

clinical use: GERD

• Most effective agent for the treatment of:

  • erosive reflux disease

  • esophageal complications of reflux disease 

    • (Barrett’s esophagus)

  • extraesophageal manifestations of reflux disease

PROTON-PUMP INHIBITORS

clinical use: STRESS-RELATED MUCOSAL BLEEDING

The only PPI approved by the USFDA for this indication is

an oral immediate-release omeprazole.

PROTON-PUMP INHIBITORS

clinical use: GASTRINOMA AND OTHER HYPERSENSITIVITIES

Best treated with surgical resection. With PPIs, excellent acid suppression can be achieved in all patients.

PROTON-PUMP INHIBITORS

clinical use: pud

• PPIs afford 

  • more rapid symptom relief and faster ulcer healing for duodenal ulcers and, 

  • to a lesser extent, gastric ulcers.

H.PYLORI-ASSOCIATED ULCERS

• The most effective regimen for H. pylori eradication is

• a combination of two antibiotics and a PPI (14-day regimen of “triple therapy”)

“triple therapy”

PPI (bid, except omeprazole) + Clarithromycin 500mg BID  + Amoxicillin 1g BID

Due to rising treatment failures due to clarithromycin resistance, “quadruple therapy” is now recommended as  

• first-line treatment for patients with antibiotic resistance to clarithromycin.

• Two 14-day treatments.

HELIDAC

• bismuth subsalicylate, 525 mg (two 262.4 mg-chewable tablets)

• metronidazole, 250 mg (one 250-mg tablet)

• tetracycline hydrochloride, 500 mg (one 500-mg capsule)

  • taken four times daily for 14 days plus an H2 antagonist

HELIDAC

dosing schedule: 

PYLERA

• 140 mg of bismuth subcitrate potassium

• 125 mg of metronidazole

• 125 mg of tetracycline hydrochloride.

  • take 3 pills QID + PPI 

NSAID-ASSOCIATED ULCERS

• For patients who require continued NSAID therapy,

• treatment with PPI promotes ulcer healing. 

  • Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications develop in 1-2% of persons per year.

Asymptomatic peptic ulceration develops in 10-20% of people taking

frequent NSAIDs, and ulcer-related complications develop in 1-2% of persons per year.

OMPERAZOLE

brand name 

(PRILOSEC^Ⓡ)

OMPERAZOLE

• Contains racemic mixtures of R and S isomers.

• R isomer accounts for the side effects, while the S isomer accounts for the therapeutic effect of omeprazole.