Module 5 Section 1 (Drugs for Ulcers)

Question 1

What is the stomach? Where is it located? And what is its role?

Answer 1

The stomach is a muscular, hollow organ in the gastrointestinal (GI) tract.

It is located between the esophagus and the small intestine.

It plays a vital role in digestion.
- Specifically, the cells of the stomach produce a number of chemicals, factors, and proteins that aid in the breakdown of many foods.

Question 2

What occurs when the cells of the stomach don’t function properly?

Answer 2

When these cells do not function properly, an excess of acid occurs and can lead to acid-related diseases, such as peptic ulcer disease.

• A peptic ulcer occurs when acid in the digestive tract eats away at the inner surface of the stomach or small intestine.
• The acid can create a painful open sore that may bleed.

Question 3

A number of cells are involved in acid secretion of stomach acid and in protecting the stomach lining against this acid. In response to food, stomach distension, or CNS stimuli, the antral cells of the stomach release the peptide hormone gastrin. Gastrin has at least two actions. What are they?

Answer 3

1) It can stimulate the enterochromaffin like cells to secrete histamine, which then acts on the histamine receptors (H2) on parietal cells to secrete acid.
2) It can act directly on the parietal cells, by binding to gastrin receptors and stimulating acid secretion.

Question 4

How does the stomach receive input from the stomach?

Answer 4

The stomach also receives input from the CNS, by way of the vagus nerve.
- The vagus nerve interacts with the nervous system of the gastrointestinal tract (called the enteric nervous system) by releasing acetylcholine, which then binds to muscarinic receptors to stimulate acid secretion.

Question 5

What is the enteric nervous system?

Answer 5

The enteric nervous system is a network of ganglion cells and neurons between the mucosal and muscle layers of the gastrointestinal tract.

• The enteric nervous system is influenced by sympathetic and parasympathetic nerves, but the enteric nervous system can act independently to initiate gastrointestinal muscle contraction and secretion.
• Several neurotransmitter systems are found in these nerves, including acetylcholine, norepinephrine, serotonin, and dopamine.

Question 6

Explain the process of acid secretion.

Answer 6

Acid secretion is an active process where protons (H+) are transferred into the stomach in exchange for potassium (K+).

• This process is carried out by the proton pump (also known as the H+,K+ ATPase) found in the parietal cells.
• One of the functions of acid in the stomach is to convert the protein digesting enzyme pepsinogen into pepsin.
• Pepsin and acid can cause an ulcer if the protective barriers of the stomach are reduced.

Question 7

A number of natural defenses exist to protect the esophagus and stomach mucosa from the effects of acid and pepsin. What are they?

Answer 7

1) The lower esophageal sphincter prevents acid from refluxing back up into the esophagus
2) Mucous neck cells secrete a mucous that forms a protective layer on the surface of the stomach lining, as well as secrete bicarbonate to neutralize acid near the mucosal surface

3) Prostaglandins can also inhibit acid secretion by acting on prostaglandin receptors in the lining of the stomach.
- Nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis can inhibit this protective mechanism and thus cause peptic ulcers.

Question 8

Drugs can act in several places to neutralize acid and control acid secretion. What are some of these drug classes?

Answer 8

• Antacids: neutralize acid in the stomach
• Histamine-2 (H2) receptor antagonists: prevent acid stimulation by histamine
• Muscarinic receptor antagonists: inhibit acid secretion induced by the nervous system (vagus)
• Proton pump inhibitors: block the actual acid secretory process

Question 9

What are antacids? What do they do?

Answer 9

Antacids are alkaline substances, usually calcium, aluminum, or magnesium salts.

These alkali compounds react with the acid in the stomach, neutralizing the acid, and thereby reducing the irritation of the gastric mucosa.

• By decreasing the amount of acid in the stomach, antacids also reduce the activity of pepsin.
• This equation demonstrates the chemistry of neutralization: 2 HCL + MgOH2 —> 2 H2O + MgCl2

Question 10

What is stomach acid composed of?

Answer 10

Stomach acid, or gastric acid, is composed of hydrochloric acid (HCl), potassium chloride, and sodium chloride.

A magnesium salt (MgOH2) reacts with hydrochloric acid to produce water and magnesium chloride, effectively neutralizing acid in the stomach.

Question 11

How long do antacids act for?

Answer 11

Antacids are rapid acting, relieving acid induced gastric pain within 15 minutes. But, as acid secretion continues, the duration of pain relief is usually two hours or less.

Question 12

What are antacids used for?

Answer 12

They are widely used by the general public for the treatment of minor gastric irritation due to excess acid often caused by over eating and drinking.

Once widely used in the treatment of peptic ulcer disease, antacids are now predominantly used as an over the counter treatment for acute heartburn.

Question 13

What are the 2 general classes of antacids?

Answer 13

Systemic antacids: these antacids are absorbed into the body.

• Ex: sodium bicarbonate increases sodium intake for the individual and as excess sodium contributes to high blood pressure, it should not be used.
• Ex: calcium carbonate can cause constipation as an adverse effect.

Non-systemic antacids: these antacids are not absorbed into the body.

• Non-systemic antacids are safer than systemic antacids, as they are not absorbed.
• Ex: magnesium hydroxide (also known as milk of magnesia) rapidly neutralizes stomach acid but is a laxative and causes diarrhea.
• Ex: aluminum hydroxide slowly neutralizes acid and causes constipation.
• The two compounds are usually combined to give rapid and slow acid neutralizing effects and to balance the incidence of diarrhea and constipation.

Question 14

What are muscarinic antagonists?

Answer 14

Blocking the muscarinic receptors on parietal cells reduces the influence of the vagus nerve on acid secretion.

Antimuscarinic drugs can reduce acid secretion by only about 40%, as gastrin and histamine play greater roles in stimulating acid secretion.
- As more effective and less toxic drugs are available for suppressing acid, muscarinic antagonists have a limited role in acid suppression.

Question 15

What are H2 antagonists?

Answer 15

These agents block the histamine (H2) receptors on the parietal acid secreting cells.

• As histamine has a major role in acid secretion, H2-antagonists suppress acid secretion by about 70%.
• More importantly, they suppress acid that is secreted at night.

Question 16

True or false: acid secretion varies throughout the day.

Answer 16

True

It’s high before meals and overnight while we are sleeping. It is believed that the suppression of overnight acid secretion is important in ulcer healing.

Question 17

How long does suppression of acid secretion occur?

Answer 17

Suppression of acid secretion with this class of drugs occurs within one to two hours, and can last up to 12 hours.

Question 18

What is a common drug in the H2 antagonists class?

Answer 18

Cimetidine, is an inhibitor of some of the cytochrome P450s (CYPs) resulting in reduction in the rate of biotransformation of other drugs administered at the same time.

• These drug interactions have limited the clinical use of cimetidine.
• Other H2 antagonists do not inhibit the CYPs, and thus have far fewer drug interactions.

Question 19

What are proton pump inhibitors?

Answer 19

Proton pump inhibitors are the most effective drugs currently available for the suppression of acid secretion.

Question 20

How do proton pump inhibitors work?

Answer 20

These drugs permanently bind to the proton pump.

• Therefore, the activity of the pump can only be restored with synthesis of new proteins for the proton pump.
• As these drugs are inhibiting the final step in acid secretion, they are more effective than H2 antagonists and can block acid secretion from all stimulating factors.
• Thus, the proton pump inhibitors reduce acid secretion by 90% or more.

Question 21

All drugs in the proton pump inhibitors class end in “__”? How can these drugs be effective?

Answer 21

All drugs in this class end in “prazole” and an example drug is omeprazole.

For these drugs to be effective, the proton pumps must be actively secreting acid, which usually occurs just prior to a meal.
- Therefore, these drugs are administered one hour before a meal to ensure the drug concentrations in the body are highest when acid is being actively secreted.

Question 22

When are proton pump inhibitors used?

Answer 22

The proton pump inhibitors are the drugs most commonly used in gastric ulcer disease, reflux disease, stress related ulcers, NSAID-induced ulcers, and most conditions where gastric acid suppression is required.

Question 23

What are the adverse effects of proton pump inhibitors?

Answer 23

The frequency of adverse effects with proton pump inhibitors is low, with 2 to 5% of patients reporting diarrhea, headache, and abdominal pain.

Muscle soreness and skin rashes have also been reported.

Overall, these drugs are considered to be one of the safest classes of drugs available for inhibiting acid secretion.

Question 24

True or false: over 60% of the cases of peptic ulcer disease are caused by an infection with the organism Helicobacter pylori.

Answer 24

True

Eradication of the organism with antibiotics in the presence of a H2antagonist or proton pump inhibitor usually results in cure of the ulcer.

Question 25

Describe the mechanism of action of proton pump inhibitors for the treatment of ulcer.

Answer 25

Proton pump inhibitors permanently bind to and antagonize the proton pump in the stomach lumen, effectively blocking the final step in acid secretion and protecting the stomach from further damage.

Question 26

Describe the mechanism of action of antacids for the treatment of ulcers.

Answer 26

Antacids are basic substances. When they enter the acidic stomach, they undergo a neutralization reaction with the acid to produce water and a salt.

Question 27

Describe the mechanism of action of muscarinic receptor antagonists for the treatment of ulcers.

Answer 27

Muscarinic receptor antagonists block the muscarinic receptors on parietal cells, thereby reducing acid secretion from these cells.

Question 28

Describe the mechanism of action of histamine-2 receptor antagonists for the treatment of ulcers.

Answer 28

Histamine-2 receptor antagonists block the histamine-2 receptors on the parietal cells, inhibiting the secretion of stomach acid.

Question 29

What are the consequences for decreasing stomach acids to allow ulcers to heal?

Answer 29

1) Acid is needed to release vitamin B12 from food.
- Therefore, people who are chronically reducing the amount of acid in their stomach may become anemic and require B12 supplements.

2) Gastric acid is also important in preventing the colonization and infection of the stomach with bacteria.
- As such, patients with decreased acid are at increased risk for salmonella and shigellainfections.

3) Lowered gastric acid decreases the absorption of some drugs, such as the cardiac glycoside digoxin.

Question 30

The GI mucosa has several mechanisms to protect it against the corrosive insult of acid. A few drugs attempt to augment these protective processes, however, these drugs are not as effective as the proton pump inhibitors, and therefore are not commonly used clinically. What are 2 examples of drugs that protect the mucosa?

Answer 30

Sucralfate: this drug is a complex of sucrose and modified aluminum hydroxide.

• In water and acidic solutions, such as found in the stomach, sucralfate forms a viscous gel that coats the mucosal lining of the stomach.
• The drug is not absorbed to any appreciable extent, and thus the toxicities are few.
• The clinical usefulness of sucralfate is limited to conditions where H2 antagonists and proton pump inhibitors are contraindicated.

Misoprostol: misoprostol is a prostaglandin derivative that is approved for the prevention of non-steroidal anti-inflammatory drug (NSAID) induced ulcers.

• NSAIDs inhibit the production of prostaglandins in the gastric mucosa, thereby reducing mucus and bicarbonate production and increasing acid secretion, which can result in an ulcer.
• When co-administered with a NSAID, misoprostol reduces the incidence of NSAID-induced ulcers.
• Unfortunately, it also causes diarrhea and must be taken frequently, limiting its use.
• Proton pump inhibitors are as effective as misoprostol in preventing NSAID-induced ulcers and have less adverse effects.

Question 31

Which one of the drug classes listed has limited therapeutic efficacy in suppressing acidity?

a) Antacids
b) Proton-pump inhibitors
c) Muscarinic receptor antagonists
d) Histamine-2 receptor antagonists

Answer 31

c) Muscarinic receptor antagonists

Although blocking the muscarinic receptors on parietal cells reduces the influence of the vagus nerve on acid secretion, these drugs can reduce acid secretion by only about 40%. Gastrin and histamine play greater roles in stimulating acid secretion than do muscarinic targets, demonstrating why drugs targeting these other mechanisms are more effective