CPPS 306 GI pharmacology

What are the major GI disorders

1. Acidity

2. Nausea

3. Diarrhea

4. Constipation

5. Irritation

6. Inflammation

What are the two main acid-related GI disorders

Ulcers and Gastro-esophageal reflux disease (GERD)

Breifly explain what happens in Gastro-esophageal reflux

Acid from stomach refluxes into esophagus

This burns the esophagus (what we feel as “heartburn”)

What two factors contribute to GERD

Mechanical dysfunciton + excess acid production

What stimulates acid secretion in parietal cells?

1. Ach (M3)

2. Gastrin (CCK2)

3. Histamine (H2)

which all stimulate the H/K ATPase

What is the final common effector of acid secretion

H+/K+ ATPase (proton pump)

Describe the roles of Ach, Gastrin, and histamine in acid secretion

1. Ach + Gastrin bind to their receptors and activates PLC which converts PIP2 → IP3 and triggers release of Ca from the sarcoplasmic reticulum.

2. Histamine binds to the H2 receptor to activate AC and activation of PKA

What are the classes of drugs for stomach problems

1. Buffering agents

2. Agents that decrease acid secretion

3. Mucosal defense

What are the two types of drugs for agents that decrease acid secretion

H2 antagonists

Proton pump inhibitors

What are the two drugs used under the class of mucosal defense for stomach problems

Prostaglandins

Coating agents

What is the prototype for buffering agents and what is the mechanism

Ca Carbonate, Mg, Al hydroxide

• Neutralize acid

What are the side effects for buffering agents

1. Diarrhea: Mg

2. Constipation: Ca, Al

What is the prototype for H2 antagonists? AND what is the mechanism of these drugs? and key limitation of H2 drugs

Ran-iti-dine

• Reversible antagonists at H2 receptors → decrease acid secretion

• Tolerance develops

Which H2 antagonist is a potent CYP450 inhibitor

Cime-ti-dine

Ran-iti-dine and famo-ti-dine are generally well tolerated H2 antagonists, but what are the side effects specific to cimetidine

1. Gynecomastia (man boobs)

2. Galactorrhea (milk production unrelated to pregnancy or lactation)

What is the prototype for proton pump inhibitors? and its mechanisms

Ome-pra-zole

• Binds + inhibits active proton pumps irreversibly

  • Potent acid suppression when used correctly

When intaking proton pump inhibitors, what is one thing to keep in mind

Pharmacokinetics is complicated!!!

Proton pumps must be active for inhibitors to work → food commonly activates proton pumps → therefore proton pump inhibitors shoulf be given prior to a meal

What are side effects of proton pump inhibitors

1. Reduced absorption of nutrients → INCREASED fracture risk

2. Alteration in GI flora → infections like clostridium difficile

3. Increased Gastrin secretion (hypergastrinemia) → increased gastrin stimulates tumour growth

What is the prototype for Anticholinergics and problems with it

Pi-renza-pine

BUT!!!! its rarely used

• Poor efficacy

• Many side effects

Prostaglandins are used for mucosal defense agents, what is the specific PG used

Miso-pro-stol

Coating agents are used for mucosal defense agents, what are the specific medications used

1. Sucral-fate (PROTOTYPE!!)

2. Bismuth subsalicylate

What is the mechanism of misoprostol (Prostaglandin)

↑ mucus + bicarbonate → ↓ acid secretion

What are side effects with Mosoprostol (PG)

1. Diarrhea

2. Abdominal cramping

3. Induces abortion!!! contraindicated in pregnancy

Prototype for mucosal defense coating agents, what its made of, and mechanism

Sucral-fate

• Made from Aluminum hydroxide + sucrose sulfate

• Forms paste + increase mucus/bicarbonate secretion

What are side effects of Sucral-fate

1. Acts locally

2. Al causes consitpation

What is the prototype for bismuth salts mucosal defense agents and mechanism

Bismuth Sub-sali-cylate

• Forms protective barrier on ulcer

• Enhances mucous + bicarbonate secretion

• Inhibits growth of H Pylori and adherence to mucosa

What are the two main causes of ulcer

• H pylori

• NSAIDs

Infections with H pylori is one of the two causes of ulcers, specifically, what happens with H Pylori infections

1. Produces inflammatory changes in mucosa

2. Impairs mucosal defense

3. Increases acid secretion

What are the common antibiotics used to eradicate H pylori in ulcers

1. Amoxicillin

2. Clarithromycin

3. Tetracycline

4. Metronidazole

5. Bismuth

What are future directions for treating GI diseases

• Potassium competitive acid blockers (PCAB)

• Target the acid “pocket” (alginic acid and buffers)

• New motility agents for GERD

  • GABA agonists

  • Glutamate antagonist