GI Exam 2 Part 2: Pharmacology of peptic Acid Diseases

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

where can H. pylori be found

found in the antrum of the stomach in a significant number of patients with duodenal and gastric ulcers

how does H. pylori survive in the acidic conditions of the stomach and thrive

because it produces ammonia from urea by urease enzymes

the ammonia neutralizes the gastric acid and allows the bacteria to escape digestion

it can then proliferate, migrate, and form infection

destroys mucosa and causes immune-mediated inflammation and mucosal cell death

what does H. pylori prevalence correlate with

socio-economic status and older age

what are the 5 types of treatmets for H. pylori?

· antibiotics

· antisecretory agents

· mucosal protectants

· antisecretory agents that enhance mucosal defenses

· antacids

antibiotic ulcer therapy

A. Combinations must be used:

Bismuth:- disrupts cell wall of H. pylori

Clarithromycin- inhibits protein synthesis

Amoxicillin- disrupts cell wall

Tetracyclin- inhibits protein synthesis

Metronidazole

- used for bacterial resistance

clarithromycin function in combination antibiotic ulcer therapy

inhibits protein synthesis

amoxicillin function in combination antibiotic ulcer therapy

disrupts bacteria cell wall

tetracycline function in combination antibiotic ulcer therapy

inhibits protein synthesis

metronidazole function in combination antibiotic ulcer therapy

bacterial resistance

bismuth (pepto bismol) function in combination antibiotic ulcer therapy

disrupts cell wall of H. pyrlori; coating agent

what do PCABs (potassium competitive acid blockers) target?

target the proton pump in gastric parietal cells (the cells responsible for secreting peptic acid into the stomach

what is an example of a PCAB

vonoprazan

what does PCAB stand for?

potassium competitive acid blockers

MOA of PCABs

bind to proton pumps like PPIs but non-covalently (reversible)

potassium-dependent

benefit of PCABs

they don't irreversibly bind so they can be controlled by the timing of the dosing strategy

PPIs depend on the half-life of the proton pumps

vonoprazan brand name

Voquesna