GI Pharmacology

Question 1

What are some of the symptoms of GORD?

Answer 1

• Painful heart burn
• Cough
• Larygntitis
• Astha
• Dental erosion

Question 2

What are some of the complications of GORD?

Answer 2

• Oesophagitis
• Ulceration
• Haemorrhage (anaemia)
• Stricure formation
• Barret’s oesophagus

Question 3

What medications can exacerbate the symptoms of GORD?

Answer 3

Anything that relaxes smooth muscle

• alpha bockers
• anticholinergics
• benzodiazepines
• beta blockers
• CCBs
• NSAIDs
• Nitrates
• Theophylline
• TCAs

Question 4

What are some risk factors for developing GORD?

Answer 4

• Older age
• Hiatus hernia (lower oesophageal sphinter into thorax)
• Obesity
• Pregnancy
• Smoking
• Alcohol consumption

Question 5

What lifestyle changes would you recommend for someone experiencing GORD symptoms?

Answer 5

• Weight loss
• Avoid trigger food
• Eat smaller meals
• Eat earlier in the day
• Reduce alcohol/ caggeine intake
• Stop smoking (limited evidence)

Question 6

What are the pharmacological steps for treating GORD?

Answer 6

• Introduce proton pump inhibitor first line
• If unsuccessful- add in H₂ Receptor Antagonist

Question 7

Name 2 proton pump inhibitors

Answer 7

• Omeprazole
• Lansoprazole

Question 8

What is gastritis?

Answer 8

An inflammatory change in the gastric mucosa

Can be erosive/ non-erosive. Acute / chronic

Question 9

What are some of the symptoms of gastritis?

Answer 9

• Burning epigastric pain
  
  • Food may increase or decrease pain
• Nausea
• Vomiting

Question 10

What are some of the risk factors for developing gastritis?

Answer 10

• H. pylori infection
• Chronic NSAID use
• Bile reflux
• Chronic alcohol use

Question 11

How do you manage erosive gastritis?

Answer 11

• Remove irritant (NSAID, alcohol, bile)
• Add PPI or H₂ Receptor antagonist

Question 12

How do you eradicate H. pylori?

Answer 12

Triple therapy

1. PPI
2. • Amoxicillin
3. • Clarithromycin or Metronidazole (effectove but has side effects)

Question 13

How do PPIs work?

Answer 13

Question 14

How do H2 receptor antagonists work?

Answer 14

Question 15

Name a H2 receptor antagonist

Answer 15

Ranitidine

Question 16

What is peptic ulcer disease?

Answer 16

A defect in the gastric or dueodenal mucosa that exptends through the muscularis mucosa

Question 17

What are some the symptoms of peptic ulcer disease?

Answer 17

• Epigastric pain after meals
  
  • soon after meals (gastric ulcer)
  • 2-3 hours after (duodenal)

Question 18

What are some of the risk factors for developing peptic ulcer disease?

Answer 18

• H pylori infection
• NSAIDs

Question 19

How do manage peptic ulcer disease that is H.pylori negative?

Answer 19

• Stop NSAIDs
  
  • consider switching to COX-2 selective NSAID e.g. celecoxib
  • doesn’t effect COX-1 prostaglandin synthesis which is protective for the GI tract
• Add PPI (+ H₂ RA if unresponsive)

Question 20

How do you test for H.pylori?

Answer 20

• Carbon 13 urea breath test
• Or stool antigen test

Question 21

What are the 2 different isoforms of COX enzymes and where are they distributed throughout the body?

Answer 21

COX-1

• high concentration in platelets, vascular endothelial cells, stomach and kidney
• produces prostaglandings necessary to maintain endocrine, renal function, gastric mucosa integrity and haemostasis

COX-2

• normal conditions, very low levels
• rapdily increases at time of tissue damage

Question 22

What are the benefits and disadvantages of COX-2 inhibitors

Answer 22

Benefit:

• Gastric protection

Disadvantage:

• not good for CVS if given long term
• High levels of TXA₂ → pro-thrombotic

Question 23

What factors of the stomach offer protection against mucosal injury?

Answer 23

• Acid - innate defence against bacterial invasion
• Mucus - lubricates, traps bacteria, barrier against pepsin (protease that can auto-digest stomach)
• Epthelial replaced 2-4 days
• Good mucosal blood flow- if epithelium damaged rapid repair can occur

Question 24

What are the two types of gastric prostalandins and what are their effects?

Answer 24

PGE₂ & PGI₂

• Potent vasodilators
• Decrease acid secretion (at high levels)
• Stimulate mucus and bicarb secretion in stomach
• Reduce permeability of epithelium to backflow of acid
• Reduce release of inflammatory mediators
• Promote ulcer healing

Question 25

Explain how parietal cells change from non-secreting state to secreting states

Answer 25

* **Non-secreting state:** Proton pumps are in membrane bound compartments (**tubovesicles)** * **​**lack K⁺ permeability blocking H-K ATPase activity * **Apical membrane** of parietal cell has involutions called **canaliculi** - v. acidic, have K⁺ channels * **Secreting state:** tubulovesicles **fuse** with canalicular membrane * proton pumps move to a position where they can exchange H⁺ for K⁺ * Requires a lot of **energy**

Question 26

Proton pump inhibitors are pro-drugs. Explain how they are activated

Answer 26

* Activated by the **acidic conditions** of the parietal cell canaliculus * PPIs are **weak bases** so accumulate in the acidic space of secreteory canaliculi * Gives them a high concentration in the luminal surface of parietal cell

Question 27

Explain the MoA of proton pump inhibitors

Answer 27

* Bind **covalently** to the gastric H⁺/K⁺ ATPase to irreversibly block function * Prolonged and nearly complete suppression of acid secretion * Have long effect- takes time for de novo synthesis to produce more enzyme

Question 28

What are some of the side effects of proton pump inhibitors?

Answer 28

* Generally well tolerated * Headache, nausea, GI tract issues, abdo pain * May decrease effectiveness of clopidogrel (anti-platelet) * Increased risk of infections if used in hosptials * Leads to an increased production of **gastrin** due to parietal cell and ECL hyperplasia

Question 29

Explain how H₂ receptor antagonists work

Answer 29

* Competitively and reversibly inhibit the binding of histamine to H₂ receptors on patietal cells * Indirectly block the effects of gastrin and ACh on the parietal cell * Activate PKA to change **shape** of parietal cell → create cannaliculi

Question 30

What are some of the side effects of H₂ receptor antagonists?

Answer 30

* Diarrhoea * Constipation * Musche ache and fatigue

Question 31

Why is the H₂ receptor antagonists Cimetidine not used as frequently?

Answer 31

* Inhibitis several Cytochrome P450s * Decreases metabolism of lidocaine, phenytoin theophylline and warfarin * Potentially results in toxic levels

Question 32

Give an example of prostaglandin analogue

Answer 32

Misoprostol

Question 33

Explain how misoprostol works

Answer 33

* Prostaglandin analgoue * Acts on PGE₂ affecting similar pathway to H₂ RA * Eventually inhibits PKA so there is **no conformational change** of parietal cell

Question 34

What are some of the side effects and contraindications of misoprostol?

Answer 34

**Side effect:** * Diarrhoea * Abdominal pain * Often result in non-compliance **Contra-indicated:** * Pregnant women * Causes uterine contractions * useful in post-partum haemorrhage

Question 35

How to antacids work?

Answer 35

* Neutralise HCl in stomach * React with acid to form water and salt

Question 36

Name 2 commonly used antacid preparations

Answer 36

Alginic acid Aluminium hydroxide

Question 37

What is step up vs step down therapy for treating GORD?

Answer 37

**Step up:** Start on H₂ RA then progress to PPI if necessary (more economical) **Step down:** start on PPI and lower to H₂ RA to see if they can maintain symptoms Continuous PPI therapy is the most effective

Question 38

What properties of helicobacter pylori mean it thrives in the upper GI tract?

Answer 38

* Microaerophillic (stomach has perfect amount of O₂) * Has flagellae- allows movement through mucus layer * Can attach to gastric epithelia * Produces urease. Converts urea→ ammonia + CO₂

Question 39

How does helicobacter pylori damage the gastric epithelium

Answer 39

* Promotes strong immune response * Ammonium hydroxide is toxic to gastric epthelia * Produces endotoxins