Week 8: Peptic Ulcer related Drugs

Question 1

What is the cause of most acid-peptic disease (PUD, GERD and mucosal injury)?

Answer 1

Mucosal erosion or ulceration

Question 2

An imbalance of what two factors causes erosion or ulcerations?

Answer 2

Acid, pepsin or bile overwhelm the defensive factors of the GI mucosa – an imbalance between aggressive and defensive factors

Question 3

What are the two primary causes of an imbalance between aggressive and defensive factors?

Answer 3

H.pylori (causes 90% of peptic ulcers)

NSAIDS (inhibit prostaglandins)

Question 4

What are two general ways in which drugs can treat acid-peptic disorders?

Answer 4

Drugs that reduce intragastric acidity

Drugs that promote mucosal defens

Question 5

What are the 3 drug classes that reduce gastric acidity?

Answer 5

Antacids, H2-Receptor Antagonists, PPIs

Question 6

List some agents that promote mucosal defense

Answer 6

Sucralfate, Prostaglandin analogs, bismuth compounds

Question 7

How do antacids work?

Answer 7

Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water

Question 8

What are some antacid options?

Answer 8

Sodium bicarbonate

Calcium carbonate

Magnesium hydroxide

Aluminum hydroxide

Question 9

What are some side effects of the different antacid options?

Answer 9

Sodium bicarbonate – reacts rapidly with HCl to produce carbon dioxide and sodium chloride = gastric distention and belching

Calcium carbonate – slower reaction, may cause belching or metabolic alkalosis

**excessive doses of either sodium bicarb or calcium bicarb products with dairy products can lead to hypercalcemia, renal insufficiency and metabolic alkalosis (milk-alkali syndrome)
Magnesium hydroxide – can cause osmotic diarrhea

Aluminum hydroxide – can cause constipation

** both drugs react slowly with HCl to create magnesium chloride or aluminum chloride and water. Often given together to counteract GI side effects

Question 10

What are the pros and cons of antacid use?

Answer 10

Rapid acid neutralization

Short duration – usually 1-2 hours

Doesn’t solve the root of the problem, provides short term relief

Question 11

Name some H2 receptor antagonists

Answer 11

There are 4: cimetidine, ranitidine, famotidine, nizatidine

Question 12

True or false: H2 receptor antagonists are poorly absorbed

Answer 12

False: all four drugs are rapidly absorbed from the intestine. Nizatidine has minimal first-pass metabolism, the other 3 drugs undergo first-pass metabolism with a bioavailability of 50%

Question 13

How do H2 receptor antagonists work?

Answer 13

By competitively inhibiting the parietal cell H2 receptor and suppressing basal and meal stimulated acid secretion

Reduce acid secretion stimulated by histamine and by gastrin and cholinomimetic agents – histamine release is blocked by binding to the parietal cell H2 receptor and direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2 receptor blockade

Question 14

T/F: H2 receptor antagonists are highly selective for only gut H receptors

Answer 14

True, do not effect H1 or H3 receptors

Question 15

At usual prescribed doses, what percentage of acid-secretion is inhibited by H2 receptor antagonists?

Answer 15

60-70% of total 24 hour acid secretion is inhibited

Question 16

True or false: dose reduction of H2 receptor antagonists is required in renal insufficiency

Answer 16

True: cleared by a combination of hepatic metabolism, glomerular filtration and renal tubular secretion

Question 17

T/F: H2 receptor antagonists are typically prescribed once daily

Answer 17

False: acid inhibition typically lasts for 10 hours, so H2 receptor antagonists are generally prescribed BID

Fun fact: H2 receptor antagonists are specifically effective for inhibiting nocturnal acid secretion which depends largely on histamine, not as useful for meal stimulated acid secretion

Question 18

T/F: PPIs are inactive prodrugs

Answer 18

True

Question 19

T/F:PPIs are absorbed in the acidic environment of the stomach

Answer 19

False: Oral meds are acid-resistant delayed release enteric-coated formulations. After passing through the stomach to the alkaline intestinal lumen the enteric coatings dissolve and the prodrug is absorbed

Question 20

Describe the chemical properties and distribution of PPIs

Answer 20

PPIs are lipophilic weak bases. After intestinal absorption, they diffuse readily across lipid membranes into acidified compartments. Prodrug rapidly undergoes molecular conversion to the active form – a reactive thiophilic sulfenaminde cation

Question 21

What is the action of PPIs (what does their binding cause)?

Answer 21

Irreversibly inactivate H+K+ATPase

Question 22

What is the result of inactivation of H+K+ATPase?

Answer 22

Inhibits both fasting and meal-stimulated secretion by blocking the final common pathway of acid secretion, the proton pump

Question 23

Name some PPIs

Answer 23

Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole

Few clinical differences between drugs

Question 24

What are some conditions that PPIs are indicated for?

Answer 24

GERD, PUD (h.pylori and NSAID associated ulcers), non-ulcer dyspepsia, prevention of stress-related mucosal bleeding, gastrinona and other hypersecretory conditions

Question 25

What are some adverse effects of PPIs

Answer 25

Diarrhea, headache, abdominal pain, acute interstitial nephritis, B12 deficiency, increased risk of fracture related to calcium absorption interruption, gastric bacterial or fungal infection

Question 26

What about PPIs might cause drug reactions?

Answer 26

Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability

Drugs this may effect: ketoconazole, itraconazole, digoxin, atazanavir

Also – PPIs are metabolized by hepatic P450 cytochromes so have potential to be inhibitors of other substances or enhance their metabolism.

Question 27

What does sucralfate do?

Answer 27

In water or acidic solutions sucralfate forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours

Breaks down into sucrose sulfate and an aluminum salt

Used to reduce the incidence of clinically significant upper GI bleeding in critically ill patients

Question 28

What about sucralfate might cause drug reactions?

Answer 28

May bind to other medications and impair their absorption

Question 29

What is an example of a prostaglandin analog drug?

Answer 29

Misoprostol

Question 30

What is misoprostol used for (in GI)?

Answer 30

Can reduce the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%

Question 31

What are the GI effects of misoprostol?

Answer 31

Has acid inhibitory and mucosal protective properties – stimulates mucous and bicarbonate secretion and enhances mucosal blood flow

Question 32

Pharmacokinetic specifics of misoprostol

Answer 32

With oral administration, rapidly absorbed and metabolized to a metabolically active free acid

Half life less than 30 mins – so dosed 3-4 times/day

Excreted in urine, but dose reduction not needed in renal insufficiency

Question 33

T/F: Bismuth compounds are available in two forms, both are OTC medications

Answer 33

False: bismuth subsalicylate is non-prescription/OTC, bismuth subcitrate potassium is prescription

Question 34

bismuth subcitrate potassium is available in a combination prescription format which also includes metronidazole and tetracycline for the treatment of which condition?

Answer 34

H.pylori infection

Question 35

Bismuth subsalicyclate undergoes rapid dissociation in the stomach – what happens to the components?

Answer 35

The salicylate is absorbed, 99% of the bismuth appears in the stool, but it can be stored in many tissues and has slow renal excretion

Question 36

What are the effects of bismuth?

Answer 36

Coats ulcers and erosion, creating a protective layer against acid and pepsin

May also stimulate mucus and bicarbonate secretion – MOA not known

Also has direct antimicrobial activity against H.pylori (How?)

Question 37

What are some names of bismuth compounds?

Answer 37

Pepto-bismol

Kaopectate

Question 38

What are some uses of bismuth compounds?

Answer 38

Nonspecific treatment of dyspepsia and acute diarrhea

Preventing traveler’s diarrhea

Used in four-drug regimens for eradication of H. pylori

Question 39

What are bismuth side effects?

Answer 39

Excellent safety profile

Harmless blackening of stool

Liquid formulation can cause harmless darkening of the tongue

Prolonged use may lead to toxicity resulting in encephalopathy