Anti-ulcer drugs / dyspepsia

Question 1

What is dyspepsia?

Answer 1

Indigestion

Upper abdominal pain (above the naval)
Belching
Nausea (with or without vomiting)
Abdominal bloating (sensation of abdominal fullness without objective distention)
Early satiety
Possible abdominal distention (swelling)

Most often provoked by eating

Question 2

What are the causes/epidemiolgoy of gastric/duodenal ulcers?

Answer 2

Benign ulcer disease of the upper GI tract common entity

• ratio of duodenal:gastric ulcer is 4:1
• there is a wide age distribution with peak incidence in middle age
• male:female is 1.5:1
• acid and bacterial factors can lead to ulcers

Stomach ulcers (gastric) may become malignant

- mucus secretion and acid secretion - Duodenal ulcers (most common) usually benign - Both are peptic ulcers

Question 3

What are the goals of ulcer therapy?

Answer 3

Relieve symptoms - antacids, prostaglandins, gel formers
Repair damage - PPI, H2 antagonists
Eradicate bacteria

• Prostaglandins involved in acid secretion (involves COX)
• NSAIDs = increased risk of ulcer

Symptom relievers only work for short time period
To repair damage - need to block acid secretion (PPI, H₂ antagonists)
- parietal cell expresses histamine type 2 receptor
- histamine binds to cause acid secretion

Eradicate bacteria - inflammation causes acid secretion

Question 4

Risks for developing an ulcer?

Answer 4

H. pylori, smoking, predisposition & stress –> acid
NSAIDS, smoking, predisposition & stress –> impaired mucosal defence

H. pylori biggest risk but half of population infected

• CAG-A1 strain - more likely to cause cancer complication
• Less CAG-A strain in Europe - less cancer associated

Question 5

Symptoms of peptic ulcer?

Answer 5

Duodenal

• often associated with weight gain
• relieved by: milk, eating, rest, antacids

In stomach, quite often eating stimulates acid and causes more pain

Gastric:

• upper abdominal pain
• vomiting
• blood in stools (black = upper GI)
• appetite loss
• weight loss
• anaemia

Question 6

What are the consequences of a stomach ulcer?

Answer 6

Nerve agitation - pain
Erosion of blood vessels - haemorrhages
Stomach or intestine wall tear - peritonitis
Spasm or swelling - obstruction

Question 7

What is GORD?

Answer 7

5-7% of global population

• Total time acid is in contact with oesophageal sphincter
• Acid reflux can reflux back up oesophagus
• Can cause pain, changes in enamel, throat/voice changes
• Retrosternal chest pain most likely to be description of GORD

Hiatal hernia keeps acid close to lower oesophageal sphincter –> irritation

Question 8

Goals of treatment of GORD?

Answer 8

Relieve symptoms
Repair oesophagus (in oesophagitis)
Prevent relapse and complications - Barrett’s oesophagus

Question 9

GORD symptoms?

Answer 9

• Chronic sore throat
• Belching
• Pain on swallowing
• Waterbrash
• Throat irritation
• Morning hoarseness
• Sour taste
• Bad breath
• Enamel erosion
• Gum inflammation
• Laryngitis

Question 10

Risk factors in GORD?

Answer 10

• Spicy foods
• Tomato based foods
• Alcohol
• Fatty/fried foods
• Overweight
• Pregnancy
• Smoking
• Citrus fruits
• Chocolate
• Caffeine
• Garlic/onions
• Mint flavouring

Question 11

What are proton pump inhibitors

Answer 11

Omeprazole, pantoprazole, lansoprazole (inhibit acid secretion)

Omeprazole and pantoprazole may enhance warfarin effect - inhibition of Cyt P450 - lansoprazole OK
NICE - combination (PPI + warfarin) can be used with caution

Short half life but are prodrugs converted to active sulfenamide

Irreversible, require PP synthesis - 1 dose lasts 24 hours

Only 90% inhibition- pH can rise above 4 - some bacterial colonisation may occur

Use with caution in liver disease - can mask gastric cancer

Question 12

What are cytochrome P450 enzymes?

Answer 12

Metabolism of ingested compounds
Can be induced or inhibited

Cytochrome P450 ‘A’ -metabolises omeprazole, warfarin
Cytochrome P450 ‘B’- metabolises Lansoprazole

Question 13

What are histamine receptor antagonists? (H2)

Answer 13

Cimetidine, ranitidine

• Competitively at receptor on parietal cell
• Reduce basal acid secretion and secretin - reduces acid by ~60% (cf PPI)
• Both available as OTC

Side effects:

• cimetidine inhibits P450 so potential for drug interactions (warfarin, theophylline)
• used with caution in renal impairment
• mask gastric cancer

Question 14

What are drugs which neutralise acid secretion?

Answer 14

Antacids

aluminium hydroxide, magnesium trisilicate, calcium and sodium bicarbonates
acid-base chemistry H+ and OH- = H2O neutralise acid

Fast acting (lasts longer after food due to slower gastric emptying) ~1h
High doses needed for ulcer healing (only last 1h)

Side effects

• Constipation with AI salts
• Diarrhoea with Mg (therefore combination of salts)
• not taken with other drugs due to risk of malabsorption e.g. ketoconazole (antifungal)
• calcium - hypercalcaemia, alkalosis

Question 15

What are drugs which protect the mucosa?

Answer 15

Prostaglandin analogues, gel formers

MISOPROSTOL (synthetic PGE1)
PGE2
Increased mucus formation and blood flow (helps with buffering)

BISMUTH SUBSALICYLATE (PEPTO-BISMOL)
coats, antinflammatory?

SUCRALFATE
forms a gel at low pH and buffers acid
given before food - sticks to gut wall, used for duodenal ulcers

Side effects:

• Bismuth - greying of teeth enamel, blackening of stools
• Reye’s syndrome (rare) - flu like and use of aspirin (salicylates) Pepto-bismol

Question 16

What are pro kinetics?

Answer 16

Prokinetics: dopamine antagonists

Block central dopamine receptors in the chemoreceptor trigger zone
ncrease contractility in the stomach to reduce residence times (pro kinetic) - can increase drug absorption

METOCLOPRAMIDE
- neurological movement disorder - dystonia (rare), (central and peripheral)

DOMPERIDONE - non sedative (BBB) (peripheral)

Question 17

Drugs used in indigestion?

Answer 17

OTC antacids and alginates
Initial PPI
Test for and treat H. pylori

2 week wash out of PPI before H. pylori test, also stool or breath test
Plus lifestyle changes - avoidance of triggers…

Question 18

Ulcer treatment if H pylori positive?

Answer 18

1) Antibiotics
2) PPI
3) H2 antagonists

Antacids (OTC)

Non treatment may lead to anaemia, perforation, stomach cancer, recurrence of ulcers within one year if H. pylori not eradicated

Question 19

Ulcer treatment if H pylori negative?

Answer 19

If NSAID dependent stop NSAID

1) PPI
2) H2 antagonists
Antacids (OTC)

Non treatment may lead to anaemia, perforation, stomach cancer

Question 20

What is triple therapy?

Answer 20

7-14 days of 2 types of antibiotics + PPI initially
- (H₂ antagonist can be used as well, third type of antibiotic, if really bad - quadruple therapy: three antibiotics plus acid suppression)

AMOXICILLIN + CLARITHROMYCIN / METRONIDAZOLE
(from different areas, target different targets - multiple drugs designed to have fewer side effects ?)
+ OMEPRAZOLE

Question 21

Why are two different antibiotics used in triple therapy?

Answer 21

H. pylori - some strains resistant to some antibiotics

• single antibiotic can be very effective but in some cases can become resistant and stops working
• multiple drugs targeting different areas reduces risk of resistance

Question 22

When is triple therapy given?

Answer 22

After positive H. pylori diagnostic test

• Breath test, clothe test (?), endoscopy etc.
• Otherwise, probably guess that every other patient coming in is H. pylori positive (half world infected)
• So easier to send everyone away with antibiotics and PPI
• Still go through initial PPI to hopefully reduce some of infection

Question 23

Side effects of triple therapy?

Answer 23

Transient candidiasis possible

Yeast-like fungal infection, opportunistic infection
(more nutrients available)

Candida alvicans - commencal fungi, live on all of our skins, most don’t have problem with it - unless have niche created - get rid of bacteria and fungi move on (or immune system compromised in some way, start to feel run down → thrush infection)

Candidiasis and thrush infection really quite common especially if eradicated lots of bacteria - transient and can be treated

Question 24

Clarithromycin and omeprazole used together?

Answer 24

Plasma concentrations of both drugs is raised when used in combination
- both metabolised by same CYP450

Omeprazole contraindicated with warfarin etc. (metabolised by same CYP450) - rate at which lost from body is slowed so conc stays relatively high for longer - can be useful for PPI but not for warfarin because you bleed

Same applies to clarithromycin and omeprazole - both metabolised by same one - dose of each drug must be careful as MAY BE SLIGHTLY OVERDOSING from what is actually required
- If an issue - can change combination - replace with METRONIDAZOLE

(However - metronidazole - lots of resistance- in some cases 70% of a certain area of H. pylori shows resistance - despite combination therapy which is supposed to be reduced)

Question 25

How do the antibiotics of triple therapy work?

Answer 25

Amoxycillin prevents cross linking of cell wall proteoglycans and disrupts proliferation - cell wall specific bacteria has cell wall that we don’t have - gets combined with bacterial cell wall, they become very leaky - can’t keep insides in - blow apart Metronidazole is reduced in the bacteria by nitroreductase enzymes and the toxic products disrupt DNA - nucleic acid inhibitor - stops DNA being formed - start to fall apart - by causing strand breaks in DNA - long piece of DNA has to be replicated by bacteria to make more bacteria - If break DNA - bacteria has to go back and repair it - takes awful lot of energy - Bacteria eventually runs out of energy and has to repair itself - Metronidazole (nitrate - nitromedazoles) used by bacteria as energy substrate- especially for bacteria that like low oxygen environments like H. pylori - tend to use these for metabolism instead of oxygen/nitrates - because no oxygen around Clarithromycin inhibits mRNA and protein formation - protein specific inhibitor Ribosomes in bacteria are sufficiently different to ours that you can target them specifically, - block protein formation, bacteria can't function Combo: target different areas so reduce risk of resistance

Question 26

What happens if fail to eradicate H. pylori after two rounds of treatment?

Answer 26

Possible resistant H. pylori - From endoscopy and biopsy test for bacterial resistance, chose appropriate antibiotics - Trial one antibiotic to see if it works or not E.g. metronidazole very resistant, in presence of clarithromycin instead get killing of bacteria Failure to eradicate H. pylori leads to recurrence of duodenal ulcer in ~80% of patients - Important as if don’t eradicate the bacteria - go on to relapse and have more ulceration - can go on to bleed, perforate, or cancer If don’t fully eradicate, after 1 year, 80% patients go on to have further ulceration - eradication: only about 20% go on to have further ulceration

Question 27

If triple therapy doesn't work?

Answer 27

Multidrug resistance? Quadruple drug regime - PPI + metronidazole + amoxicillin + clarithromycin - May go to ‘quintuple’ - H₂ antagonist on top of that (just incase, because of possible hyperacidaemia you may get, as been suppressing acid for so long)

Question 28

Should there be an eradication process for H. pylori?

Answer 28

Possible use of vaccination - immunisation with urease (not found in humans) - immune system not really doing it as once infected, infected for life Human milk secretory IgA confers protection to neonates to H. pylori infection T cell effect on mucin secretion reduces protection of H. pylori However, different geographical location may need different targets - CagA strains more prevalent in some parts of world - South East Asia - more CagA bacteria than Western countries → more cancer associated with those H. pylori gives some protection against IBD - not everyone benefits from eradication therapy?

Question 29

Important aspects of eradication regimes?

Answer 29

Patient compliance very important (antibiotics - tend to feel better in a couple of days, especially children/young siblings) - have to finish course - less resistance associated with this and bacteria don’t come back and redevelop GI upsets - increase in campylobacter jejuni (especially small intestine)- clearing out lots bacteria from lower intestine - CLOSTRIDIUM difficile - associated with AMOXYCILLIN, C. diff can cause diarrhoeal disease - can be big problem especially where patients are ill - loss of bodily fluid - real emergency need to deal with if get C. diff: metronidazole would be drug of choice - which is also a problem (resistance) Resistance to metronidazole is increasing (70% in some areas) and clarithromycin - Less resistance to amoxicillin in the community Metronidazole interacts with alcohol (if ill not necessarily a problem, but PPI ? issue but may not be aware) - of all antibiotics mentioned thats the one that really causes a problem - rest usually OK Clarithromycin and omeprazole interfere with cytochrome P450 enzymes- be careful with their dosing (for each one!)