W3.3_Upper GI Therapeutics

Question 1

Explain what dyspepsia and functional dyspepsia are.

Answer 1

• Dyspepsia: umbrella term of group of upper GI symptoms/diseases
• Functional dyspepsia: persistent, bothersome epigastric pain/burning, early satiation and/or postprandial fullness with no specific cause (structural abnormality) identified
• can be a disorder of gut-brain interaction

Question 2

What are the factors of functional dyspepsia (7)?

Answer 2

• Abnormalities in GI motility
• Altered visceral sensitivity (physical/chemical stimuli)
• Central nervous system processing
• Psychology (stress/anxiety/depression)
• Immune function, inflammation, epithelial permeability
• Changes in microbiome
• Genetics

Question 3

For Gastro-oesophageal reflux disease (GORD), how does it occur? Explain the other symptoms (4), complications (3), most common cause, and factors (7) of GORD.

Answer 3

• Reflux of gastric contents into oesophagus/oral cavity/lungs -> chronic cough/laryngitis
• Other symptoms: retrosternal heartburn, bloating, belching, night-time/after-meal cough
• Complications: stricture, Barrett’s oesophagus, esophageal carcinoma
• Causes: weakening of lower esophageal sphincter allows stomach acid to pass up into the oesophagus
• Factors: obesity, genetic, diet, medication, age, pregnancy, psychological

Question 4

What is severe oesophagitis? Explain the symptoms of it (6).

Answer 4

• Inflammation of oesophagus (commonly caused by GORD), scarring of esophageal tissues and ulcers development, increased likelihood of cancer
• Symptoms: dysphagia, acid regurgitation, heartburn, chest pain, nausea, vomiting

Question 5

Describe the formation of peptic ulcer disease (PUD). How is the location of PUD distinguished? What are the common causes (2) and initial symptoms (8) of PUD?

Answer 5

• Open sores/localised erosions that develop in inside lining (mucous membrane) of stomach/duodenum, caused by imbalance between agents that protect the epithelium and those which attack (excessive gastric acid) -> complications such as upper GI bleed can occur
• By location: gastric ulcer/duodenal ulcer
• Common cause: infection with H. pylori bacteria, taking NSAIDs for long time/at high doses
• Initial symptoms: upper abdominal discomfort, heartburn, bloating, early satiety, heaviness, flatulence, nausea, vomiting

Question 6

How are upper GI diseases usually diagnosed? What is the responsibility of pharmacists in primary care in dealing with upper GI symptoms? Explain the alarms and red flags relating to upper GI system that requires referral (6/4).

Answer 6

• Most people self-treat, majority present to community pharmacy initially and managed in primary care (GP/community pharmacy)
• Initial assessment to check for risk factors (ex. age, nature of pain, other symptoms, factors, red flags, history)
• ALARMS: Anaemia (tiredness/shortness of breath), Loss of weight (unintentional), Anorexia (unexplained appetite loss), Recent onset of progressive symptoms/recurrent problems (particularly age >55 with unexplained/persistent/treatment-resistant dyspepsia), Melaena/ haematemesis (blood in stools/vomit), Swallowing problems (dysphagia) -> refer to GP
• Red flags: severe and debilitating pain, persistent vomiting, pain awakens person at night, radiating pain to jaw/neck/arm (heart attack)

Question 7

What are the possible further investiagations needed when diagnosis is not clear (4)? How are FD, GORD, and PUD usually diagnosed?

Answer 7

• Investigations: FBC tests, specific tests for H. pylori and coeliac, endoscopy, gastroscopy
• FD: in absence of upper GI alarms symptoms, FD is diagnosed when symptoms persist for >8 weeks
• GORD: based on symptoms, endoscopy can prove erosive oesophagitis when esophageal inflammation and mucosal erosions are observed
• PUD: Well-localised, sharp and stabbing pain (pain in empty stomach for gastric ulcer, pain 2-3 hours after meal for duodenal ulcer), endoscopy can be used to observe breach in epithelium

Question 8

List out the lifestyle measures to manage FD and GORD (8).

Answer 8

• Smoking cessation (causes irritation and changes to GI tract)
• Healthy eating
• Avoid known precipitants that cause dyspepsia (fatty/acidic/fried/chocolate/alcohol/caffeine)
• Avoid eating late in the evening
• Weight reduction, reduce stress, raising head of bed/extra pillows, regular aerobic exercise

Question 9

Explain the different types of pharmacological treatments to manage FD and GORD (6).

Answer 9

• Reduce dose/stop/switch potential causative medications (ex. antimuscarinics and anticholinergics, aspirin, benzodiazepines, bisphosphonates, corticosteroids, NSAIDs
• Antacids: neutralises hydrochloric acid in stomach to increase pH -> suppress action of pepsin to prevent exacerbation of mucosal ulceration (ex. aluminium hydroxide, magnesium trisilicate)
• Alginate: reacts with stomach acid to form a floating physical layer of gel on gastric acid, neutral pH, act as mechanical barrier to acid reflux
• Gaviscon advance: sodium alginate with potassium bicarbonate, individual actions with the carbon dioxide released from antacids is trapped within the gel precipitate to form a foam layer and sodium ions in alginate can enhance precipitation of alginate
• H2 receptor antagonist: act as inverse agonist by reversibly binding to H2Rs on gastric parietal cells to inhibit binding and activity of endogenous ligand histamine -> prevents histamine from binding to cause gastric acid release (ex. famotidine, nizatidine, cimetidine)
• Proton pump inhibitor: acts through systemic circulation by re-exposure to stomach from blood, bind irreversibly to opening of ion channel in H+, K+-ATPase channel on parietal cells -> reacts with Cys813 to form covalent bonds -> prevents the pumping of H+ ions into the stomach (ex. lansoprazole, omeprazole, pantoprazole, rabeprazole)

Question 10

Explain the pharmacological difference between omeprazole and esomeprazole. What is the caution of long PPI treatment?

Answer 10

• Omeprazole is used as a racemate due to chiral centre on sulphur, S-omeprazole (esomeprazole) is metabolised more slowly -> less clearance and higher exposure, halved-dose can achieve same effect of full-dose omeprazole
• PPIs are generally well tolerated in short term, but long term use (few months) can cause achlorhydria with increased risk of gastric cancer, H. pylori infection, pneumonia, C. diff. infection, reduced calcium absorption resulting in hip fracture -> lowest effective dose for shorter period of time with regular review to prevent side effects, over 8 weeks use is discouraged and non-pharmacological management should be considered

Question 11

What are the properties of H. pylori? State the risk factors for NSAID induced GI injuries. Explain the direct and indirect mechanisms of causing PUD.

Answer 11

• H. pylori is a gram-negative bacteria and causes persistent infection in gastroduodenal mucosa (90% of DU and 70% of GU are found to be infected)
• Risk factors for NSAID induced GI injures: >65 age, high dose, concurrent other medicines that increase risk of GI adverse-effects, serious comorbidity, heavy smoker, excessive alcohol consumption
• Direct mechanisms: inhibition of prostaglandin synthesis impairs mucosal defences -> erosive breach of epithelial barrier, acid attack deppens break into ulceration, low pH encourages passive absorption of NSAID trapped in mucosa
• Indirect mechanisms: reduce gastric blood flow, reduce mucus and bicarbonate production, decreased cell repair

Question 12

For NSAID-induced PUD, what are the general management guidelines?

Answer 12

• Stop NSAID if possible, test for H. pylori, treat with full dose PPI for 8 weeks and eradication therapy after
• If NSAID need to be continued: discuss potential harm, regular review, reduce dose or switch to safer NSAID such as ibuprofen, prescribe gastroprotection of PPI/misoprostol as prostaglandin analogue

Question 13

Explain the drug development cycle. What are the models/methods used to prove the efficacy and safety of a drug?

Answer 13

• All properties of drugs: determined by molecular structure
• Understanding of structure activity relationships (SAR) is developed through a cycle
• Design of compounds -> synthesis of compounds -> testing of compounds -> analysis of data -> repeat
• Pre-clinical animal trials: X-species animal toxicology, dose-effect relationships in animal models
• Methods: rodent toxicology, human/animal tissue models, efficacy in animal models, X-species PK (blood levels)