GASTRO INTESTINAL TRACT PHARMACOLOGY - 1

LECTURE 7

The Gastrointestinal Tract

•Gastroesophageal Reflux Disease (GERD)

•Peptic Ulcer Disease (PUD)

•Duodenal Ulcer

•Nausea

•Emesis

•IBS

•Diarrhea

•Constipation

Gastroesophageal Reflux Disease (GERD)

GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn;

1) Overproduction of acid/pepsin

2) Over relaxation of the Lower Esophageal Sphincter (LES);

Complications; if not treated - severe chest pains, bleeding or a pre-malignant change in the lining of the esophagus called Barrett’s esophagus – can result in adenocarcinoma

General Considerations- Backflow of stomach acid into the esophagus

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

- Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !)

- More severe symptoms: difficulty swallowing, chest pain

- Reflux into the throat can cause sore throat

- Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture)

- 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 cancer of the esophagus.

- Treatment : Generally antacids

PEPTIC ULCER

– A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin;

– 1) Excess acid production– 2) Intrinsic defect in the mucosal defense barrier

– Average size ¼ and ½ inch in diameter•Peptic Ulcer Disease Affects All Age Groups•Men Have Twice The Risk as Women Do•Genetic Factors•Increase Acid Production and/or Decrease in Bicarbonate and PG Production

Pathophysiological Processes Involved in Duodenal and Gastric Ulcers

HP

NSAID

Cancer (ZE)

Other

Duodenal Ulcer Gastric Ulcer

Strategies for Inhibiting Parietal Cell Acid Secretion

GastrinAntagonists

H+HistamineAntagonists

MuscarinicAntagonists

CCK2

H2

M3

↓ Ca +2

↓cAMP

↓ Ca+2

PP

GastricLumen

Cyclooxygenase Pathway

Arachidonic Acid

COX-1

Prostaglandin H2Prostaglandin G2

ProstacyclineSynthase

Prostacycline PG12

Prostacycline E2, F2Prostacycline G2

ProstaglandinSynthase

ThromboxaneSynthase

Thromboxane A2Thromboxane B2

RESULT = DECREASED ACID SECRETION & INCREASED MUCUS PRODUCTION

PPI- Omeprazole• Prototype H+, K+-ATPase inhibitor; A prodrug that needs a

low pH to be active;

• Irreversible (forms a covalent bond with the proton pump) - long lasting inhibition of acid production;

• Profound reduction of gastric acid - elevates gastric pH significantly (20mg/day for 7days will decrease acid by 95%);

• Highly protein bound; Metabolized by CYP2C & CYP3A; plasma half life of 1 to2 hours but long duration of action; Should be taken just prior to a meal and should NOT be taken with other acid-suppressing agents.

• Others: esomeprazole, lansoprazole and pantoprazole

Histamine H2 Antagonists Decrease Acid Output

Histamine

ProteinKinase

ATP

cAMP

K+

H+

HistamineAntagonist

Acid

Out

put

(mEq

/hr)

Time (hr) 1 2 3 4 5

H2 antagonist administered orally at arrow

10

20

30

PP

Cimetidine (Tagamet)Ranitidine (Zantac)Famotidine (Pepcid)Nizatidine (Axid)

Strategies for Inhibiting Parietal Cell Acid Secretion

Gastrin

Histamine

Acetylcholine Ca2+

ProteinKinase

ATP

cAMP

ProstaglandinAgonists (-)

K+

H+

PP

H2

M3

CCK 2

EP3

Ca2+

Drugs for Acid-Peptic Disorders - Anticholinergics

• Blockade of acetylcholine at muscarinic (M3/M1) receptors– Effectively blocks acid secretion (30 to 40%)– Limited by side-effects

• Side-effects are typical of anticholinergics such as atropine– Dry mouth– Tachycardia– Blurred vision– Bowel discomfort (constipation)– Difficulty in urination

Drugs for Acid-Peptic Disorders - Anticholinergics

• General muscarinic receptor antagonists (block all types of muscarinic receptors)– Atropine– Propantheline (Pro-Banthine)– Dicyclomine (Bentyl)

• Selective M1 receptor antagonists– Pirenzepine– Telenzepine

Drugs for Acid-Peptic Disorders – Prostaglandins (PGE2 & PGI2 )

Inhibits:– Acid secretion– Gastrin release– Pepsin secretion

Stimulates:

– Mucus secretion– Bicarbonate

secretion– Mucosal blood

flowThese compounds act by both inhibition of acid

production and by increasing defense mechanisms

• Act at prostaglandin EP3 receptors on parietal cells & on epithelial cells

• These compounds are also effective against direct damage produced by alcohol, aspirin and NSAIDs, and are therefore termed “cytoprotective”

Drugs for Acid-Peptic Disorders - Prostaglandins

Misoprostol (Cytotec):• Synthetic Analog of Prostaglandin E1

• Anti-acid secretory• 0.1 to 0.2 mg results in 85% to 95% acid reduction• Prevention of NSAID gastric ulcers

Side Effects• Diarrhea• Abortion• Exacerbate IBD and should not be given

Drugs for Acid-Peptic Disorders - Antacids

• Antacids are weak bases that neutralize HCl in the stomach;

• They do not decrease the secretion of acid, and in some cases increase secretion;

• They do not suppress nocturnal acid secretion

1. Neutralize acid2. Decrease acid load to duodenum3. Diminish pepsin activity

Drugs for Acid-Peptic Disorders - Antacids

• Magnesium hydroxide

• Magnesium trisilicate

• Magnesium-aluminum mixtures

• Calcium carbonate

• Sodium bicarbonate

Drugs for Acid-Peptic Disorders – Sucralfate (Carafate)

• Sucralfate is a basic aluminum salt of sucrose octasulfate;

• In the presence of acid (pH < 3-4) some of the aluminum ions dissociate and the resulting negatively charged molecule polymerizes to form a viscous paste-like substance;

• This substance adheres strongly to gastric and duodenum mucosa and adheres even more strongly to partially denatured proteins such as those found at the base of the ulcer.

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

Treatment Pooled Eradication Rate

Dual Therapy 72%

Triple Therapy 85%

Quad Therapy 90%

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

GENERIC NAME DOSING DURATION CURE RATE (%)

Dual therapies

omeprazole 500 mg TID 14 days 70-80 amoxycillin 1,000 mg TID 14 days

ranitidine 400 mg BID 28 days 73-84

clarithromycin 500 mg TID 14 days lansoprazole 30 mg TID 14 days 66-77 amoxycillin 1,000 mg TID 14 days

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

GENERIC NAME DOSING DURATION CURE RATE (%)

Triple therapies lansoprazole 30 mg BID 14 days 86-92 amoxycillin 1,000 mg BID 14 day clarithromycin 500 mg BID 14 days

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

GENERIC NAME DOSING DURATION CURE RATE (%)

Quad therapies bismuth subsalicylate Two tablets 7 days 85-95 525 mg QID metronidazole 250 mg QID 7 days tetracycline 500 mg QID 7 days

omeprazole 20 mg BID 7 days or lansoprazole 30 mg BID 7 days

NEXT LECTURE•Nausea

•Emesis

•IBS

•Diarrhea

•Constipation

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