Pharmacology Ii - 3/22/10

Front 1

What pump within parietal cells is responsible for proton secretion into the stomach?

Back 1

H-K ATPase
Exchanges H for K

Front 2

What are the 3 neurohormonal secretagogues that regulate this process?

Back 2

Histamine
Gastrin
Acetylcholine

Front 3

What type of cell is Histamine released by? What receptor do they bind? What biochemical reaction does binding cause?

Back 3

Enterochromaffin-like cells and mast cells
H-2
Increased cAMP which activates PKA which phosphorylates H/K ATPase.

Front 4

What type of cell secretes Gastrin?
What type of cell secretes Acetylcholine?

Back 4

G-cells
Post-ganglionic nerves

Front 5

What receptor types do these compounds bind to?
What does this binding cause?

Back 5

CCK-2
M-3
Increased intracellular Calcium - Protein Kinase C - H ion efflux

Front 6

Describe the regulation of gastric acid secretion.

Back 6

Gastric acid secretion is regulated by somatostatin-secreting D cells and prostaglandins which limit the extent of excretion.

This occurs by 3 main mechanisms:
(1) Inhibition of gastrin release
(2) Inhibition of histamine release
(3) Direct inhibition of gastric acid secretion

Front 7

What is the function of Prostaglandin E-2?
What 2 mechanisms facilitate this action?

Back 7

To enhance mucosal resistance to tissue injury
(1) Reducing basal and stimulated gastric acid secretion
(2) Enhancing epithelial cell bicarbonate secretion, mucus production, cell turnover and local blood flow

Front 8

What are the 3 phases of gastric acid secretion following a meal?

Back 8

Cephalic phase - Response to sight, taste, smell and thought of food

Gastric phase - Mechanical distention of the stomach and ingestion of amino acids and peptides

Intestinal phase - digested protein in the intestine

Front 9

Mucus, Bicarbonate, prostaglandins, restitution, and blood flow all help to protect the lining of the stomach. What is restitution? How does this occur?

Back 9

The ability of the gastric mucosa to undergo repair.
Damage is repaired through migration of undamaged epithelial cells along the basement membrane to fill defects created by the sloughing of injured cells.

Front 10

How does blood flow act as a protective factor?

Back 10

By removing acid that has diffused across a damaged mucus layer.

Front 11

How does the urea breath test work?

Back 11

Radioactive urea is ingested and converted to radioactive CO2, which is then exhaled and detected.

Front 12

What pathologic mechanism accounts for local gastrointestinal injury?

Back 12

NSAIDs are weak organic acids that are neutral in the stomach. They then cross the plasma membrane of parietal cells, re-ionize and are trapped causing local injury.

Front 13

What accounts for their harmful systemic effects?

Back 13

COX-1 is constitutively expressed and produces gastric prostaglandins.
COX-2 is induced by inflammation
Inhibition of COX-1 by NSAIDs inhibits prostaglandin E-2 synthesis removing one of the protective factors

Front 14

What are two disease states that lead to hypersecretion of gastric acid?

Back 14

Zollinger-Ellison Syndrome - gastrin secreting tumor in the pancreas
Cushing's ulcers

Front 15

What are the risk factors for Peptic Ulcer Disease?

Back 15

Cigarette smoking - impaired mucosal blood flow, healing, and inhibited pancreatic bicarb secretion
Alcoholic cirrhosis, glucocorticoid use, stress, genetics

Front 16

Name the agents that decrease acid secretion.

Back 16

H-2 Antagonists
Proton Pump Inhibitors
Anti-cholinergics

Front 17

H-2 antagonists reversibly and competitively inhibit histamine binding to H-2 receptors. They also indirectly decrease gastrin and acetylcholine induced acid secretion.

Back 17

Cimetidine - Inhibits CYP enzymes - crosses the placenta and is secreted into breast milk - not recommended during pregnancy or lactation.
Ranitidine
Famotidine
Nizatidine
Are all tolerated well

Front 18

How do proton pump inhibitors work?

Back 18

They block the parietal cell H/K ATPase.
Superior at suppressing acid secretion
Omeprazole and other drugs that end with -zole.

Front 19

How are these drugs activated?
Once activated, describe their action.

Back 19

They are all pro-drugs that are activated by acidic environment.

They are converted into sulfenamide and react with the H/K ATPase inhibiting it irreversibly.
For acid secretion to resume, the parietal cell must synthesize new H/K ATPase. This takes approximately 18 hours.
Esomeprazole seems to be the most effective PPI at therapeutic doses.

Front 20

What are the clinical indications of PPIs?

Back 20

H Pylori associated ulcers - PPIs contribute to eradication of the infection by inhibiting growth.
To allow NSAIDs in a patient with known peptic ulcer
Hemorrhagic Ulcers - PPIs allow pH to be raised enough to promote clot formation.

Front 21

PPIs are generally more effective. However, there are instances where H-2 antagonists would be preferred. What are these?

Back 21

(1) H-2 antagonists are better studied and are proven safe in pregnancy
(2) H-2 antagonists are also less expensive

When there is H Pylori present, give a PPI, if not give H-2 antagonist because it is more affordable.

Front 22

What are some general concerns with PPIs?

Back 22

Adverse effects - HA, Nausea, Disturbed bowel function, abdominal pain
Such a large decrease in acid secretion that enteric infections occur such as salmonella because the ingested bacteria are not killed by the stomach acid.
Increased gastrin release due to constantly lowered gastric secretion.

Front 23

Discuss a particular anti-cholinergic drug and why it works to decrease acid secretion.

Back 23

Dicyclomine - antagonize muscarinic receptors on parietal cells decreasing gastric acid secretion. Generally not used because they are less effective than H-2 antagonists and PPI's.

Front 24

What are the most widely used antacids?

Back 24

Aluminum hydroxide and magnesium hydroxide - react with acid to form water and salts

Front 25

Magnesium commonly causes
Aluminum commonly causes

Back 25

Diarrhea
Constipation

Front 26

Patients with CKD should avoid this

Back 26

Magnesium - can lead to hypermagnesemia

Front 27

Agents that promote mucosal defense include

Back 27

Sucralfate
Colloidal Bismuth
Misoprostol

Front 28

Sucralfate and Colloidal Bismuth are considered this type of agent

Back 28

Coating agents

Front 29

Sucralfate has little ability to alter gastric pH. What does it do instead?

Back 29

Sucralfate forms a viscous gel that binds to positively charged proteins and thereby adheres to gastric epithelial cells