GI Pharmacology

Question 1

What does the GI tract consist of?

Answer 1

The: mouth, pharynx, oesophagus, stomach, small intestine, large intestine, rectum/anus. Also, accessory glandular organs include the: salivary glands, liver, gallbladder, pancreas.
Insulin is secreted by the beta cells in the pancreas, glucagon secreted by the alpha cells.

Question 2

Functions of the GI tract include:

Answer 2

Secretion, absorption, and motility.

Digesting food: breakdown of large food into molecules.

Absorbing nutrients: from the intestines to the blood stream.

Eliminating waste: expulsion of food not digested/absorbed

Digestion is only controlled in the mouth, whereas the rest of the GI tract is controlled by sympathetic and parasympathetic nervous system.

No digestion takes place in the oesophagus.

Law of gut, food is always pushed down the path of the GI tract.

Question 3

Main functions of the stomach include:

Answer 3

Storage - (1-2L, 2-6 hours) – no need to eat constantly

Preparing the food which has been broken down by the teeth for digestion in the small intestine - Churns food, begins digestion, produces acid chyme

Absorption of water and lipid-soluble substances (alcohol and drugs)

Constrictions in opening and exit of the stomach: the gastroesophageal and pyloric sphincters respectively.

Side note: minimal absorption has taken place at this point from the mouth.

Question 4

Secretory and motor functions of the stomach:

Answer 4

Secretory:

• parietal cells secrete HCl
• chief cells secrete pepsinogen (activated by low pH forms pepsin – begins protein hydrolysis)
• mucus, bicarbonate, water – lubrication/protect stomach from injury
• Intrinsic factor (parietal cells) - cobalamin (vitamin B12) absorption, also iron.
• G cells produce gastrin.

Motor:

Regulates intake of food, mixing, reduction in particle size, emptying to duodenum

Question 5

What are the 3 receptors in parietal cell that stimulate acid secretion?
Hint: Neural, paracrine, and endocrine

Answer 5

Acetylcholine (neural - muscarinic type receptor): response to the sight, smell & presence of food in mouth - distension of the stomach. When food reaches the stomach, the wall distends and stretches, this causes nearby cells to start secreting. Influences IP3 and Ca ions secretion, therefore increasing secretion of H+.

Gastrin(paracrine): activated by the vagus nerve, gastrin related peptide and by peptides in the stomach lumen produced via protein digestion. Influences secretion of HCl

Histamine (endocrine - H2 type receptor) : released from enterochromaffin like cells in the stomach, binds toH2receptors, increases secretion of cAMP; increases activity of the H+/K+ ATPase pump. Signals other cells nearby to secrete.

Question 6

What is the exact mechanism for increasing stomach acidity via parietal cells?

Answer 6

Carbonic anhydrase contained in the cells break down water and aqueous carbon dioxide to form H2CO3, which dissociate to form H+ and bicarbonate ions (HCO3-).
The H+ stored in the parietal cells are pumped against a concentration gradient in exchange for K+ into the lumen of the gastric pit. The parietal cells leak potassium back into the lumen of the gastric pit however.
The pump requires energy to work as it uses active transport to pump the protons.
Cl ions are pumped into the lumen of the gastric pit to react with the protons to form HCl acid.
The chloride comes from the blood in exchange for the bicarbonate ions.
The strong acid in the stomach is for optimal enzyme activity such as pepsinogen, as well as protecting the body from bacteria.

Question 7

What are the protective mechanisms of the stomach?

Answer 7

The HCO3 ions form an alkaline lining along the cells of the inner-stomach lining to prevent the acid from burning through the stomach.
The mucus lining of the inner-stomach is also to protect from the acid, by neutralising the acid diffusing from the lumen.
Prostaglandins -

Question 8

What is pepsin, and in turn pepsinogen?

Answer 8

Pepsin is a highly active protein enzyme, which is pepsinogen in the chief cells as pepsin would break down the stomach, that’s why it’s stored as pepsinogen. It is only converted from pepsinogen in a highly acidic medium as the stomach when digestion starts.

Question 9

Which nerve causes distension of the stomach?

Answer 9

The enteric nervous system acting upon the VAGUS nerve.

Question 10

What can cause injury to the stomach?

Answer 10

H.pylori infection
NSAIDs
Aspirin
Cigarettes
Alcohol
Gastric hyperacidity
Duodenal-gastric reflux

Ischaemia
Shock
Delayed gastric emptying
Host factors

Question 11

What is GORD (Gastroesophageal reflux disease)?

Answer 11

A condition where there is backflow of acid and stomach contents into the oesophagus. If there is damage to the oesophageal sphincter, too much food, or emptying is delayed – can lead to inflammation of the walls and cause oesaphagitis.

Someone can have it with or without oesophagitis and symptoms.

Question 12

What kind of patients is GORD the most common in?

Answer 12

Often occurs in patients with hernia or patients who are pregnant.
Increased abdominal pressure to cause delayed gastric emptying leads to influx in the oesophagus, less mucus there, less bicarbonate ions so can lead to damage to the oesophageal lining and burning and inflammation.

Question 13

What can cause GORD?

Answer 13

NSAIDS and excessive coffee can cause this.
Tobacco and alcohol can lead to inflammation in the stomach – gastritis or chronic gastritis.
Chronic gastric can also be caused by infection of Helicobacter pylori.
Gastritis, initial part of the duodenal lining can lead to peptic ulcers:
Duodenal ulcer, gastric ulcer.
Ulcer means erosion in the lining – a hole in the lining.

Question 14

What is acute gastritis?

Answer 14

Transient mucosal inflammatory process.
Caused by irritants such as drugs (NSAIDs), excessive coffee, tobacco, alcohol, or by an infection.
Often erosive and can be haemorrhagic.

Question 15

What is Chronic gastritis?

Answer 15

Chronic inflammation of the gastric mucosa
Common, often asymptomatic (80%)

Types (Aetiology):
Type A: Autoimmune
Type B: H. pylori infection (85-90%) - Gram negative, produces Ammonia which erodes the stomach lining.

Question 16

The main symptoms of peptic ulcers

Answer 16

Main symptoms:

• Epigastric tenderness (pain or discomfort right below your ribs in the area of your upper abdomen)
• sharp, burning, aching, and or gnawing pain
• Dyspepsia (indigestion)
• Nausea/vomiting
• Belching

Question 17

What is the science behind peptic ulcers caused by H.pylori?

Answer 17

H.pylori is found deep in the mucosa as pH 7 is the optimum growth pH; it invades the epithelium, produces toxins and ammonia, damages cells and causes persisten gastritis for years/life. Sustained, exaggerated release of gastrin causes acid to damage the mucosa and causes ulcers.

First line treatment: (MOST IMPORTANT BIT)
Triple therapy of - PPI e.g., Lansoprazole
Abx combination of clarithromycin/metronidazole and amoxicillin (or tetracycline for KDA)

Question 18

What is the standard for peptic ulcer diagnosis?

Answer 18

Currently the gold standard is oesophagogastroduodenoscopy –
(OGD) and H. pylori infection screen.

• H. pylori detection
  
  • 13C-Urea Breath Test:
  • Non-invasive test for H. pylori
  • H. pylori produce the enzyme urease, splits urea to CO2 and H2O
  • Patients swallow 13C urea: 13CO2 is detected in the breath, and shows presence of H Pylori
  • Diagnostic accuracy >95%
  • Isotope-labelled urea solution, excreted isotope-labelled carbon dioxide is then measured
• Faecal Antigen Test
• Rapid urease test (CLOtest = Campylobacter-like organism)
• Serology (i.e. blood tests) - NB: problem here is cannot differentiate between past and present infection.

Endoscopy after Isotopic carbon test
How to treat:
   - Diet
   - Antibiotics
   - Proton pump inhibitor – stop release of protons in stomach to decrease HCl production – ultimately lowers ph

Question 19

What does treatment with antacids involve?

Answer 19

Neutralise acid and prevent formation of pepsin

MECHANISM OF ACTION : Antacids are weak bases, react with gastric hydrochloric acid to form salt and water and reduce intragastric acidity.

Types of antacids:
– Systemic: sodium bicarbonate and sodium citrate

It reacts rapidly with hydrochloric acid to produce carbon dioxide and sodium chloride.

Formation of CO2 results in gastric distention, bloating, belching, flatulence. Unreacted alkali is readily absorbed and can cause metabolic alkalosis, damaging to the kidneys. Sodium chloride absorption may exacerbate the fluid retention in certain patients

Question 20

What are the types of antacids used?

Answer 20

Types of antacids:

Non systemic: magnesium hydroxide, magnesium trisilicate, aluminum hydroxide gel and calcium carbonate.

Formulations containing magnesium hydroxide or aluminium hydroxide react slowly with HCl to form magnesium chloride, aluminium chloride & water; no gas is generated (Belching & metabolic alkalosis does not occur).
Unabsorbed magnesium causes water to come into GIT and causes osmotic diarrhoea, while aluminium causes constipation. Both are given together to minimize the impact on bowel function.

Ideal antacids: Insoluble and neutralize acid, should not liberate CO2, non-absorbable, should not disturb acid-base balance

Question 21

What is the function of H2-receptor antagonists?

Answer 21

Block histamine-stimulated gastric secretion (most common drugs are Cimetidine, Ranitidine, famotidine)

• MECHANISM OF ACTION: Competitively block H2 receptors on parietal cells.
  
  • Suppress basal and meal stimulated acid secretion in a linear dose dependent fashion.
  • Most effective in suppressing nocturnal acid secretion.
• Less potent than PPIs.
• SIDE EFFECTS: Diarrhoea, headache, myalgia (muscle pain), constipation, fatigue, confusion, hallucination

Question 22

How do anticholinergic agents work?

Answer 22

• Block acetylcholine-stimulated gastric secretion (Pirenzepine, Telenzepine)
• MECHANISM OF ACTION: Competitively and selectively block
  M1-receptors on parietal cells.
  
  • Inhibit acid secretion
  • Delay gastric emptying. However, food remains for longer time – patient feels uncomfortable; not first line.
• Not commonly used because of their low efficacy and anticholinergic effects

Question 23

How do PPIs work?

Answer 23

• Irreversibly inhibits H+/K+-ATPase, suppressing gastric acid production (Omeprazole, Esomeprazole (s-omeprazole), Lansoprazole)
• H+/K+-ATPase membrane bound enzyme plays an important role in the final step of gastric acid secretion (basal and stimulated).
• Omeprazole is the prototype drug
• Prodrugs: activated to sulfonamide at acidic pH. Activated form binds covalently with SH group of H+ pump and irreversibly inactivates it.

Adverse effects:

• Headache, diarrhoea and abdominal pain.
• Skin rashes and arthralgia.
• May decrease vit B12 absorption
• Increase rate of infection and fracture of bones.
• Drug interactions: omeprazole can inhibit metabolism of phenytoin, warfarin, diazepam. PPIs decreases bioavailability of itraconazole, iron salts, etc

Question 24

PPIs more in-depth:

Answer 24

• PPIs administered orally when fasted / 30 min. before meal. Once there is a meal, will delay gastric emptying – prevents acid from the initial part. Acid should be only secreted when food reaches the stomach, as even the sight smell and sound of food can activate the stomach’s system.
• Half life short (1.5 hr), acid secretion suppressed for up to 24
  hr. 18 hours are required to synthesize the new H+/K+ ATPase.
• Enteric coated form or powder containing sodium bicarbonate.
• i.v. formulations available for esomeprazole, lansoprazole, pantoprazole and rabeprazole.
• They are highly bound to plasma proteins; extensively metabolized in liver and metabolites secreted in urine.

Question 25

What is the function of prostaglandin analogs?

Answer 25

• Reduce gastric acid secretion
• Increase mucosa blood flow
• Augment the secretion of mucus and bicarbonate, and prostaglandins (they increase the formation of the barrier)
• Misoprostol - Synthetic PGE1 (prostoglandin E1)
• Common side effects: Diarrhoea and abdominal cramps.

Question 26

What are the mucosal barrier fortifiers?

Answer 26

Form a complex gel with the mucus, creating a protective coat

• Sucralfate: it is a complex of aluminium hydroxide and sulphated sucrose.
  
  • In acidic solutions it polymerises to form sticky gel that adheres to the ulcer base and protects it (for up to 6h).
  • Form barrier against acid-pepsin
• Bismuth salicylates and colloidal bismuth subcitrate.
  
  • React with proteins in the base of ulcer and protect it from peptic digestion.
  • Stimulates secretion of PGE2, mucus and bicarbonate.
  • Anti-microbial effects against H. pylori.
  • Binds to enterotoxins, used in travelers diarrhoea

Question 27

H. Pylori peptic ulcer treatment: Combination therapy - learn this (comes very frequently as a question)

Answer 27

Aim to: Promote rapid ulcer healing, eradicate H. pylori infection, and prevent relapse

• TRIPLE THERAPY (7 days) –
  Lansoprazole + Amoxicillin/metronidazole + clarithromycin
  (1st & 2nd line, alternative 2nd line tetracycline)
• Quadruple therapy (10 days) – 3rd line treatment
  Lansoprazole + bismuth subsalicylate + 2 antibiotics

Question 28

Why do NSAIDs cause ulcers with association with COX-1/2 and epithelial damage?

Answer 28

All of the following lead to mucosal injury and bleeding
Inhibit COX-1 -> prostoglandins not stimulated to secrete mucus and bicarbonates:
- Reduced mucosal blood flow -> Impaired defence
- Reduced mucus & bicarbonate secretion -> impaired defence
- Impaired platelet aggregation
Epithelial damage - due to aspirin and salicyclic acid removing epithelium -> acid back-diffusion:
- Impaired platelet aggregation
- Impaired healing
Inhibit COX-2:
- Reduced angiogenesis -> impaired healing
- Increased leukocute adherence -> leukocyte activation

Question 29

Why are peptic ulcers so worrying?

Answer 29

Even though stomach lining is thick, the pits in the stomach can be eroded. As there is a lot of acid produced as well as pepsinogen, if the barrier is not there and a peptic ulcer is formed – leads to bleeding, sepsis, infection, and clots - as it goes into the blood to clot; can lead to strokes, heart attack, and ischaemia.

Question 30

Why is NSAID toxicity a problem?

Answer 30

Important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe.
Linked to GI toxicities
While endoscopic ulcers can be documented in up to 40% of chronic NSAID users, it is estimated that as many as 85% of these never become clinically apparent.
Serious NSAID induced GI complications such as haemorrhage, perforation or death are much less common, occurring collectively with an incidence of about 1.5% per year.

Question 31

What is done if NSAID needs to be continued?

Answer 31

-Consider:
- reducing the dose of the NSAID OR
- Change NSAID to one of the following: Acetaminophen (AKA paracetamol), a nonacetylated salicylate (salsalate, trisalicylate)
- A partially selective COX-2 inhibitor (etodalac, nabumetone, meloxicam, diclofenac, celecoxib)
-Could also use a PPI to treat the ulcer:
- When an NSAID needs to be continued, PPIs are the drugs of choice to treat and heal the ulcer OR switch to misprostol (PGE1 analogue maintains mucosal defence (increases mucus secretion mucus blood flow) but at clinical doses is an acid suppressant)) for maintenance therapy.
Also bismuth preps: e.g., tripotassium dicitratobismuthate.
Switching to an alternative acid suppression therapy, e.g. H2-receptor antagonists may be beneficial if the response to proton pump inhibitor therapy is inadequate.

Question 31

How can mucosal resistance be increased to an acid-pepsin attack?

Answer 31

“Mucosal strengtheners”

Sticky gel coats base of ulcer, gives physical protection, HCO3- secretion restores pH gradient

Question 32

What is the function of the small intestine?

Answer 32

Small intestine has a lot villi – highly absorptive organ. A lot of peristalsis takes places. Following law of gut, whatever isn’t absorbed (mainly fats due to alkalinic environment) is passed into the large intestine – where water and minerals are absorbed.

Question 33

What causes problems with motility?

Answer 33

Any damage to the muscles or nerves in the intestines reduces peristalsis, which reduces the movement of bulk in the intestines.

Question 34

What is constipation?

Answer 34

Generally defined hard stools with infrequent and/or unsatisfactory defecation fewer than 3 times per week. Patients may define constipation as passing hard stools or straining, incomplete or painful defecation. Constipation is a symptom, NOT a disease.

Symptoms: painful bowel movements, bloated, uncomfortable, and sluggish
Complications: haemorrhoids, and fissures

Question 35

Constipation risk factors and causes:

Answer 35

Female gender - Pregnancy
Over 65 years of age
Low caloric intake (eating less food)
Greater number of medications used
Sedentary lifestyle (lack of exercise)
Ignoring the urge to defecate
Smoking – Tobacco addiction
Eating too little fibre
Not drinking enough liquids
Change in routine – travel
Frequent use of laxatives
Certain diseases or conditions

Medications:
Pain (narcotics)
Antacids containing aluminum
Antidepressants
Iron supplements
Diuretics

Question 36

How to prevent Constipation?

Answer 36

High fibre diet
Minimum fluid consumption of 1500mL daily
Regular, private toilet routine
Heed the urge to defecate – allow time
Become more physically active
Use of a laxative if using constipating medication or in presence of diseases associated with constipation

Question 37

How to treat constipation with bulk forming agents?

Answer 37

Bulk-Forming Agents - Absorb water into the intestine increasing faecal bulk and stimulating peristalsis. The drug of choice for prevention, not for immediate relief:
Dietary fibers
Bran
Ispaghula husk (seeds of Plantago ovata) – increases water – forms a bulk
Methylcellulose
Sterculia

Not absorbed from the intestines, safe for long-term use. Safe for elderly patients. Helpful in patients with irritable bowel syndrome, diverticulosis, and colostomies. Onset of action: 8-24 hours up to 72h

Question 38

What are the disadvantages of senna?

Answer 38

Damages epithelium, causes melanosis coli and apoptosis – inflammatory response, fluid secretion, diarrhoea
Not recommended for chronic use
Melanosis coli (epithelial cells migrating toward the submucose in the process of apoptosis obtain a black colour from anthaquinone and are then phagocytosed. The macrophages take on the black pigment and then migrate away by way of lymphatic vessels) may be harmless or linked to a possible increased risk of colon cancer.

Question 39

How do stool softeners work?

Answer 39

Prevent hardening of the faeces by adding moisture to the stool. Become emulsified with stool, decreasing surface tension of the faecal mass to allow water to penetrate into the stool:
Docusate (DOSS) – Di Octyl
Sodium Sulfosuccinate
Glycerol
Liquid Paraffin
Arachis oil (ground-nut oil, peanut oil)

Patients who should avoid straining while defecating: Patients recovering from abdominal, pelvic, or rectal surgery, childbirth, or a heart attack.
Patients with severe high blood pressure or abdominal hernias
patients with painful hemorrhoids and/or anal fissures.

Question 40

How do osmotics work?

Answer 40

Hyperosmolar salts or saline products: Insoluble, remain in lumen pulling water into colon, increasing water in the faeces and increasing bulk – increase peristalsis:

Magnesium citrate, hydroxide, oxide, sulphate
Sodium biphospahte, phosphate
Lactulose: Draws water into intestine and promotes water and electrolytes retention
Glycerin: Acts like Lactulose, increasing water in the faeces

Therapeutic Uses: Preparation of bowel for colonoscopy, sigmoidoscopy, and barium enema. Lactulose: liver disease (Hepatic encephalopathy)

Question 41

How to treat constipation with stimulants?

Answer 41

Stimulants - Increase water and electrolyte secretion by the mucosa. Stimulate sensory nerve endings in GI mucosa → Increasing peristalsis. The faeces are moved through the bowel too rapidly to allow colonic absorption of faecal water so a watery stool is eliminated. Usually given at bedtime and they usually provide overnight relief (work within 8-12 hours):

Phenolphthalein
Diphenyl Methanes
Bisacodyl (Dulcolax)
Sodium Picosulfate (Dulcolax liquid)
Anthraquinones (glycosides)
Senna (Cassia ssp), aloes (emodin)
Danthron (limited indications, carcinogenic)
Cascara sargada
5-HT4 agonist – Prucalopride
Fixed oil – Castor Oil emulsion
Colax: Stimulant laxative/probiotic: Aloe Vera concentrate, Lactobacillus Acidophilus, and a herbal blend

Therapeutic Use - Cleansing the colon for colonoscopies, barium enemas, and intestinal surgeries. Precaution - Chronic, long-term use of stimulant laxatives can lead to loss of colon function. Consequently, constipation becomes increasingly worse and unresponsive to laxatives. Too much use can also cause diarrhea short-term.

Question 42

How to treat constipation with laxatives?

Answer 42

Laxatives:

Macrogol (polyethylene glycol)
Stimulant laxatives - Anthraquinones
Bulk-forming laxatives Sterculia
Stool softeners - Docusate
OTHERS - Bowel cleansing preparations, Peripheral opioid-receptor antagonists

Question 43

Other treatments for constipation?

Answer 43

Bowel cleansing preparations: Used before colonic surgery, colonoscopy or radiological examination to ensure the bowel is free of solid contents

Peripheral opioid-receptor antagonists: Block / Decrease the gastro-intestinal (constipating) effects of opioids without altering their central analgesic effects.
Recommended for the treatment of opioid-induced constipation when response to other laxatives is inadequate. Naloxegol, Methylnaltrexone bromide

Question 44

Describe diarrhoea

Answer 44

Abnormal passing of loose or liquid stools, with increased frequency, increased volume, or both.
Pathophysiology: Increased active anion secretion, decreased absorption of water and electrolytes.
Overall weight and volume of stool is increased to >200mg or ml/day, and water content of stool is increased to 60-90%. Causes can be Infectious: Mostly faeco-oral route Bacterial, Viral, Parasitic, and Non-infectious: Normal mucosa: Osmotic diarrhoea Mal-absorption Abnormal mucosa: Inflammatory Bowel disease Celiac disease, microscopic colitis, eosinophilic and allergic Gastroenteritis, radiation enteritis.

Question 45

What is the treatment for diarrhoea?

Answer 45

Oral rehydration therapy (ORT):
-Mainstay of treatment for acute diarrhoea to prevent or correct diarrhoea dehydration and to maintain the appropriate fluid intake once rehydration is achieved

• Disodium hydrogen citrate with glucose, potassium chloride and sodium chloride
• Potassium chloride with sodium chloride
• Potassium chloride with rice powder, sodium chloride and sodium citrate
• Intravenous rehydration fluid:
  - In patients with severe dehydration and in those unable to drink
• Antimotility drugs: Loperamide
  - Mu-Opioid-receptor agonist, decreases the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall.
• Antibiotics if necessary