GI Pharmacology

Dr. Alia Shatanawi

5/4/2018

• Drugs used in Peptic Ulcer Diseases.

• Drugs Stimulating Gastrointestinal Motility &Laxatives.

• Antidiarrheal Agents.

• Drugs used in Irritable Bowel Syndrome.

• Antiemetic Agents.

• Drugs used in Inflammatory Bowel Disease.

• Pancreatic Enzyme Supplements.

• Bile Acid Therapy for Gall stones.

• Drugs used in Variceal Hemorrhage.

Drugs Used in Gastrointestinal Diseases

Upper GI Drugs

Peptic ulcer is a defect in the lining of the stomach or

the duodenum

• The most common cause is infection of the

stomach by bacteria called Helicobacter pylori

(H.pylori).

• Ulcers can also be caused or worsened by drugs

such as aspirin, ibuprofen, and other NSAIDs

• Other factors: Smoking, Stress, Spices (diet) and

alcohol….

• Gastrinomas (Zollinger Ellison syndrome), rare

gastrin-secreting tumors

Causes of Peptic Ulcer

Treatment Approach

Peptic ulcer

1. Reduce acid secretion

from parietal cells

2. Neutralize acid in the

lumen

3. Protect the mucosa from

acid destruction

4. Antibiotics to eradicate

Helicobacter pylori

Physiology of gastric secretion

Gastrin

Histamine

Pepsin

HCl

Three pathways control parietal cell acid secretion

Acetylcholine receptor pathway

• Sight, smell, taste of food cause stimulation of vagal nerve to release acetylcholine.

• Ach binds to M3 receptor and Cai rises activating phosphokinases

• H+K+ATPase translocates to the secretory canaliculus.

• K+ in extracellular space exchanged for H+.

• Cl- diffuse across cell membrane to form HCl in canaliculus.

• Ach increases gastrin and histamine release.

Gastrin receptor pathway

• Digested food in stomach stimulates release of gastrin from G cells in antrum of stomach; distention releases Ach increasing gastrin levels.

• Gastrin binds to CCK-B receptor and Cai rises activating phosphokinases.

• H+K+ATPase translocates to the secretory canaliculus.

• K+ in extracellular space exchanged for H+.

• Cl- diffuse across cell membrane to form HCl in canaliculus.

• Gastrin increases histamine release.

Histamine receptor pathway

• Ach and gastrin release stimulates

ECL cells to release histamine.

• Histamine binds to H2 receptor and

Cai and cAMP rises activating

phosphokinases.

• H+K+ATPase translocates to the

secretory canaliculus.

• K+ in extracellular space

exchanged for H+.

• Cl- diffuse across cell membrane to

form HCl in canaliculus.

Were used long time ago, and were mainstay of treatment.

Nonprescription remedies.

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

Also stimulate mucosal prostaglandin production, therefore may promote mucosal defense mechanisms.

Antacids

Given after a meal, can neutralize acidity for up to

2 hours.

Efficacy varies according to rate of dissolution,

water solubility, rate of reaction with acid and the

rate of gastric emptying.

May affect the absorption of other medications by

binding to drugs or by changing ph, therefore,

dissolution.

Antacids

Sodium Bicarbonate (Baking Soda):

– Reacts rapidly with acid to produce NaCl

and CO2.

– CO2 leads to gastric distension and

belching.

– NaCl may exacerbate fluid retention.

– Systemic absorption leads to metabolic

alkalosis.

Antacids

Magnesium Hydroxide.

Aluminum Hydroxide.

– React slowly and without gas formation.

– Metabolic alkalosis is also uncommon.

– Mg salts cause diarrhea.

– Aluminum salts cause constipation.

– Usually given in combination.

– Contraindicated in renal insufficiency.

Antacids

Neutrolization of acid

Antacids

• Aluminum antacids absorb or chelate many drugs; most common used.

• Magnesium antacids have laxative action; diarrhea.

• Calcium antacids stimulates acid rebound by promoting gastrin release.

• Sodium antacids should be avoided; aggravate CHF and counteracts diuretic therapy for HBP, short duration of action, followed by acid rebound, highly absorbed.

Cimetidine, prototype, many problems.

Ranitidine.

Famotidine.

Nizatidine.

– Were the most commonly prescribed

drugs in the world.

H2- Receptor Antagonists(1970s-1990s)

Selective competitive inhibitors of the parietal

cell H2 receptors and suppress basal and

meal-stimulated acid secretion in a dose-

dependent manner.

Also decrease volume of secretion and pepsin

concentration.

Decrease secretion stimulated by:

– Histamine.

– Gastrin.

– Acetylcholine.

H2- Receptor Antagonists(1970s-1990s)

• Duration of action: 12 hours.

Inhibit 60-70% of total 24-h acid secretion.

– 90% of nocturnal acid.

– 60% of day-time and meal- stimulated acid..

H2- Receptor Antagonists(1970s-1990s)

H2 Receptor Antagonists

• Competitively inhibit the interaction of histamine with H2 receptors.

• Selective for H2 over H1 receptors; appear to only interfere with H2 physiological functions on gastric acid secretion.

• Well-absorbed orally and reach peak serum concentration in 1-3 hours.

• Found in cerebrospinal fluid, cross placental barrier, and excreted in breast milk.

H2 Receptor Antagonists

• Developed in 1970’s.

• Inhibit basal (fasting) and nocturnal acid secretion.

• Decreases volume of gastric “juice” and [H+].

• Decreases acid secretion stimulation by food, distention, and pharmacological agents.

• Used for Zollinger-Ellison syndrome, ulcers, GERD.

• OTC preparations advertised for “heartburn”.

Histamine

Cimetidine

(many side-effects)

Ranitidine

Famotidine

(Most potent)

Nizatidine

Cimetidine (Tagamet)

• Inhibits cytochrome P450 activity; will slow down metabolism of other drugs.

• Anti-androgen activity; loss of libido, impotence

• Increases plasma estradiol in men; increases secretion of prolactin.

• CNS effects in elderly with systemic illnesses; confusion, agitation, lethargy.

H2- Receptor Antagonists

Duration of action: 12 hours.

Inhibit 60-70% of total 24-h acid secretion.

– 90% of nocturnal acid.

– 60% of day-time and meal- stimulated acid.

H2- Receptor Antagonists

Clinical Uses:

Gastroesophageal Reflux:

– Prophylactically, before meals.

– Afford healing for erosive esophgitis in less

than 50% of patients.

– Proton pump inhibitors are preferred.

Non Ulcer Dyspepsia.

Stress- Related Gastritis:

– Can prevent bleeding, usually given IV.

H2- Receptor Antagonists

Peptic Ulcer Disease:

– Replaced by PPI.

– Healing rate greater than 80-90% after 6-8

weeks.

– Not effective in the presence of H. pylori

infection.

– Not effective if NSAID is continued.

H2- Receptor Antagonists

Adverse Effects:

Extremely safe drugs, but can (in 3%

of patients) cause diarrhea, headache,

fatigue, myalgia and constipation.

CNS:

– Confusion, hallucinations and agitation

occur only with IV cimetidine to elderly

patients in ICU.

H2- Receptor Antagonists

Adverse Effects:

Endocrine Effects:

– Again only with cimetidine, can inhibit DHT

binding to its receptor, estradiole metabolism,

and can increase prolactin serum levels.

Pregnancy and Nursing Mothers:

– Can cross placental barrier and appear in breast

milk.

Other Effects:

– Rarely can cause blood dyscrasias, bradycardia

and hypotension.

H2- Receptor Antagonists

Drug Interactions:

Cimetidine can inhibit

cytochrome P450

enzymes(CYP1A2, CYP2C9,

CYP2D6, and CYP3A4), so can

increase half life of many drugs.

Ranitidine binds 4-10 times less.

Nizatidine and famotidine binding

is negligible.