Teddy: First two lectures

what are the 2 sections of the stomach

corpus and antrum

what are the 4 sections of the corpus glands

pit (fovelus), isthmus, neck, and base

what are the 2 main types of cells unique to the corpus glands and what do they do

o   Have mucus neck cells that secrete mucus to protect the stomach from acid (MUC6, TFF2)

o   Have parietal cells that secrete acid (H/K-ATPase pump)

what do the "other" types of cells in the corpus and antrum glands do?

mainly play a role in parietal cell regulation

what are the 3 sections of the antral glands

pit, progenitor zone, and base

function of surface cells

produce mucus (protective)

D cell function

produce somatostatin which inhibits parietal cells

ECL cell function

produce histamine (positive regulation of paietal cells)

EC cells function

produce serotonin for mechanosensation

X cell function

produce ghrelin, the hunger hormone

chief cell function

produce pepsin (protease)

what are the 3 pathways and 3 cells that regulate parietal cells

neural, hormonal, and paracrine pathways

G, ECL, and parietal cells

neuron activation pathway of parietal cells

Neurons activate G cells using GRP. They then produce gastrin which goes into the bloodstream and can activate ECL cells to produce histamine or directly activate parietal cells

neuron secretion of ACh downstream effects

ACh secreted can activate parietal cells directly or activate ECL cells

ECL cells can then secrete histamine which activates parietal cells

what 4 molecules ca cause proton pump activation?

ACh, Histamine, Prostaglandin E2 inhibition, and gastrin can all cause proton pump activation by activating protein kinases

proton pump exchange (what comes in and what comes out?)

Proton pump in parietal cells causes H+ to come out of the cell in exchange for K+ going into the cell

histamine MOA in activation of the proton pump

Histamine binds to a Gs GPCR which converts ATP into cAMP using adenylyl cyclase

Protein kinases are then activated which then activate the proton pump

prostaglandin E2 MOA with proton pump

· Prostaglandin E2 can bind to a Gi GPCR which blocks protein kinase activation and doesn't allow the proton pump to be activated

what is the key cell type of the stomach wall that pumps proton into the lumen of the stomach to cerate an acid environment

parietal/oxyntic cells

which molecule is inhibitory of the proton pump (Gi)

PGE2

what happens if there is too much H+ (too acidic)

D cells secrete somatostatin which inhiibts the amount of gastrin released by G cells or directly inhibits parietal cells

The less gastrin being released, the less that parietal cells will be activated and secrete acid

what does PUD stand for?

peptic ulcer disease

acid peptic disorders

conditions that are the result of damage from acid and pepsin activity in the gastric mucosa

what are the 3 acid peptid diseases

o GERD

o Peptic ulcers (stomach and duodenal)

o Zollinger-Ellison syndrome

what 3 factors stimulate acid secretion

histamine, ACh, and gastrin

which 2 factors inhibit acid secretion

somatostatin and PGE2

whta are 3 reasons for GERD

o Weakened lower esophageal sphincter

o Hiatal hernia

o Pressure in the stomach

symptoms of GERD

heartburn, uncomfortable burning sensation behind the breastbone, MI can be mistaken for GERD episodes

severe: difficulty swallowing, chest pain

Complications of GERD

·      esophageal erosions, esophageal ulcers and narrowing of the esophagus (esophageal stricture)

what is Barrett's epithelium

when normal esophageal lining or epithelium is replaced with abnormal epithelium

what things can cause ulcers?

o H/ pylori infection

o Excess inflammation

o Excess acid

o Infection

o NSAIDs

o Lifestyle

what are 3 protective features/mucosal defenses against ulcers?

o Prostaglandins

o Mucosal regeneration

o Mucus and bicarbonate production

what ultimately causes ulcers

an imbalance between defenses and aggressive factors

factors that defend the stomach and duodenum from self-digestion

o Mucus: continually secreted for protective effect

o Bicarbonate secreted from endothelial cells

o Blood flow: proper flow maintains mucosal integrity

o Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid

what is H. pylori?

· gram negative bacteria that can live in the stomach and duodenum

what does H. pylori do to the stomach?

o   Breakdown mucus layer due to inflammatory response by the presence of bacteria

o   Produces urease which forms CO2 and ammonia which can damage the mucosal integrity

what must be present for an ulcer to form

gastric acid

gastric acid MOA in ulcers

Activates pepsin which acts with HCL in the injury of the mucosa (causes crater)

Decrease blood flow, causes decrease mucus production and bicarbonate synthesis and promotes gastric acid secretion

what does chronic use of NSAIDs cause

inhibits production of prostaglandins

what does smoking do to the GIT

nicotine stimulates gastric acid production

MOA of metaplastic transformation of esophageal lining

o Repeated injury and inflammation will break down the normal squamous epithelial layer of the esophagus

o Will grow back as columnar epithelium--> intestinal metaplasia (with goblet cells)

what is Zollinger-ellison syndrome (ZES)?

·      Condition associated with one or more tumors in the duodenum or the pancreas

o   Tumors are known as gastrinomas and secrete lots of Gastrin

what type of tumors are gastrinomas

neuroendocrine tumors

cause of Zollinger-ellison syndrome/gastrinomas

· Cause not fully understood but 25-30% of all gastrinomas are caused by inherited genetic disorder called multiple endocrine neoplasia type 1 (MEN1)

wermer syndrome (MEN1 mutation)

a rare disorder that causes tumors in the endocrine glands and parts of the small intestine and stomach

what levels should be tested if ZES is suspected?

blood gastrin levels

effect of excess gastrin production in ZES

·      Excess gastrin production leads to extreme production of acid in the stomach eventually causing peptic ulcers. There are usually many ulcers in the affected area

symptoms other than ulcers seen with ZES

diarrhea, bloating, burping, nausea, vomiting, weight loss, poor appetite

prevalence of ZES

Extremely rare condition that can start at anytime but usually isn't diagnosed until ~50 years old

4 categories of action of drugs for peptic diseases

o Neutralizing gastric acid

o Reduce gastric acid secretion

o Enhance mucosal defenses/ "cytoprotectants"

o Antimicrobial activity

what are the 3 goals of treating peptic ulcer disease

-pain relief

-ulcer healing

-prevention of complications and ulcer recurrence

MOA of antacids

·      Simply work by neutralizing hydrochloric acid

·      They are weak bases that react with hydrochloric acid to form salts and water

·      By increasing the pH of the stomach, antacids also inactivate pepsin (known to contribute to ulcer formation by digesting proteins in the stomach wall)

what pH level is pepsin activity significantly reduced?

pH>4

common antacid ingredients

o Aluminum hydroxide

o Magnesium hydroxide

o Calcium carbonate

o Sodium bicarbonate

3 parts of normal response to acid neutralization

o Increase gastrin release

o Increase acid output

o Increase volume of secretion

what is acid rebound

overproduction of HCl after stopping antacids

which ingredient in antacids are more likley to cause acid rebound

o   Calcium carbonate is more likely to induce rebound vs Mg and Al-containing antacids

o   Rapid vs slow acting antacids

what 2 factors determine the net buffering capacity of antacids

o Their ability to neutralize acid

o Time of residency in the stomach

aluminum hydroxide vs calcium carbonate antacids

aluminum hydroxide: act very gradually and their effects continue for several hours

calcium carbonate: act quickly and increase pH a lot so more likley to cause acid rebound

3 factors that affect how well a patient respond to antacids

o How much acid the patient secretes (hypersecretion)

o Rate at which antacids are emptied from the stomach

o Potency of the acid (ANC/ acid neutralizing capacity)

effect of aluminum-based antacids on GI motility

produce constipation

effect of Mg-containing antacids on GI motility

produce diarrhea

what is a possible consequence of absorption of un-neutralized sodium bicarbonate

can produce metabolic alkalosis

why should you be cautious with using antacids in patients with renal sufficiency

can cause some absorption of cations like Ca, Mg, Al, and Na

DDI of antacids

May chelate other drugs (avoid concomitant administration of other drugs such as tetracyclines, digoxin, propranolol)

what are the 3 histamine-2 receptor antagonists

famotidine, cimetidine, and nizatidine

MOA of histamine-2 receptor antagonists

·      Are competitive inhibitors of H2 receptor in parietal cells

·      H2 blockers also decrease (indirectly) gastrin and ACh-induced gastric acid secretion

3 effects of H2 antagonism

reduction in...

o Volume of gastric juices secreted

o Gastrin secretion

o H+ concentration

what are the 4 uses of histamine-2 receptor antagonists

o Duodenal ulcers, gastric ulcers, ZES, and GERD

adverse effects of H2RAs

usually well-tolerated

D, HA, muscle pain, constipation, fatigue

cimetidine DDI

inhibits CYP450-mediated drug metabolism

cimetidine effects other than on histamine

anti-androgenic effects by antagonizing the androgen receptor and increases estrogen levels by inhibiting its CYP-mediated metabolic inactivation

o gynecomastia in men

o galactorrhea in women

dicyclomine brand name

Bentyl

MOA of dicyclomine (lentil)

antagonizes the muscarinic ACh-R on parietal cells therby decreasing gastric acid secretion

why are anticholinergic agents rarely used?

because they're less effective and have less desirable side effects

ADEs of anticholinergic agents

o Dry mouth

o Blurred vision

o Cardiac arrythmias

o Urinary retention

what are PPIs

substituted benzimidazole prodrugs that block the activity of this transport protein for proton (H+) molecules

what cell type are proton pumps unique to?

parietal cells

what facilitates the MOA of PPIs

the pH of the stomach

PPI MOA

Irreversibly inhibit the H+/K+-ATPase in gastric parietal cells

o   Produces dose-dependent inhibition of gastric acid secretion that persists even after the drug disappears from the plasma

what environemnt are PPIs active vs inactive

PPIs are inactive at neutral pH, but they are weak bases so in acidic stomach they’re activated

how are PPIs activated from their prodrug form?

require activation from the parietal cell canaliculus (side of cell that faces the acidic lumen of the stomach)

o PPIs are activated only when bound to the proton pump and exposed to the acid of the stomach

describe the release path of PPIs

·      PPIs need to pass intact through the stomach into the intestines where the drug is released from its enteric coating formulation for absorption into the blood

·      The pro-drug reaches the parietal cells via blood

·      The pro-drug then diffuses into the canaliculi of parietal cels facing the lumen where the acidic environment converts the pro-drug into a sulfonamide reactive intermediate

·      The active drug then binds to sulfhydryl groups of cysteine residues in the pump, leading to irreversible activation

PPI and infections

increase in pH may mean other bacteria may be able to tolerate the environment (C. diff, salmonella, E. coli)

DDI of PPIs

competition with clopidogrel for CYP2C19

both these drugs need to be activated by this enzyme

PPI possible side effects?

osteoporosis and bone fractures from decreased absorption of Ca in higher pH

kidney disease and dementia associations

how does mucosal erosion and ulceration occur in peptic acid diseases

pepsin-mediated hydrolysis of mucosal proteins

MOA of mucosal protective agents

create a barier in stomach and intestinal mucosa that prevents damaging effects of HCl and pepsin

they also bind pepsin and bile salts

misoprostol brand name

cytotec

what is mistoprostol and when is it used

o Prostaglandin E1 analog (PG stimulate mucus and bicarbonate production)

o Used when treatment with NSAIDs inhibits endogenous PG synthesis

when should mistoprostol not be used

in women of child-bearing potential

sulcralfate brand name

carafate

what is sucralfate made of

Complex of aluminum hydroxide and sulfated sucrose

MOA of sucralfate

o Undergoes polymerization and cross linking at low pH of stomach

o Binds tightly to the necrotic/ulcerated tissue

o Forms complex gel with mucus; mucus stabilized; diffusion of HCL and pepsin to mucosa is impaired

why does sucralfate have little side effects

not absorbed into the blood

duodenum and sucralfate

Although the pH of duodenum is >4, sucralfate retains its viscosity and binds tightly to the ulcerated intestine as well

colloidal bismuth compounds MOA

o Second coating agent (not mucus-like)

o Bismuth salts combine with mucus glycoproteins to form a barrier that protects the ulcer from further damage by acid and pepsin

o Bismuth is also known to stimulate secretion of bicarbonate, PG, and mucus

colloidal bismuth effect on H. pylori

o Colloidal bismuth has been shown to impede the growth of H. pylori

§ used in combination with antimicrobial agents and PPIs in patients that are H. pylori positive

what is H. pylori

gram-negative, spiral shaped bacterium that is flagellated

what is the most common cause of non-NSAID associated peptic ulcer disease?

H. pylori