pharmalogical basis for the treatment of GI disorders Flashcards
describe H2 receptor agonists - anti secretory drug
used to treat:
* Peptic ulcers → Reduce acid & pepsin, promote healing.
* Reflux oesophagitis → Decrease acid reflux & symptoms.
mechanism of action:
* Block H₂ receptors on parietal cells → ↓ Acid secretion.
* Inhibit histamine, ACh, & gastrin-stimulated acid release.
* Raise stomach pH, reducing pepsin activation.
* ↓ Basal & food-stimulated acid secretion by 90%.
Food & Acid Secretion:
* food stimulates acid secretion via 3 phases:
* Cephalic phase (30%) – Sight, smell, thought → Vagus nerve (ACh).
* Gastric phase (50-60%) – Stomach distension & gastrin release.
* Intestinal phase (5-10%) – Duodenal gastrin release.
* H₂ receptor antagonists inhibit all these pathways, reducing food-stimulated acid secretion by up to 90%.
side effects:
* Generally rare but there may be diarrhoea, muscle cramps, transient rashes, hypergastrinemia
* Cimetidine → gynaecomastia in men (↓ sexual function, but this is rare)
* Cimetidine also inhibits P450 enzymes → ↓ metabolism of a number of drugs metabolised by P450 enzymes, e.g. anticoagulants, tricyclic antidepressants
describe proton pump inhibitors - anti secretory drug
examples:
* Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole
used to treat:
* Peptic ulcers → Reduce acid, promote healing.
* Reflux oesophagitis (GERD) → Prevent acid reflux & damage.
* H. pylori eradication → Used with antibiotics.
* Zollinger-Ellison syndrome → Drug of choice for extreme acid hypersecretion.
mechanism of action:
* they are Weak bases, inactive at neutral pH.
* Become active in acidic parietal cells (pH < 4).
* Irreversibly inhibit H⁺/K⁺-ATPase (proton pump) → Block final step of acid secretion.
* Decreases basal & food-stimulated acid secretion → More effective than H₂ blockers.
* Long-lasting effect (24-48h) due to irreversible inhibition.
side effects:
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia; dizziness
describe metoclopramide
- prokinetic agent
- enhances gut motility by modulating neurotransmitter activity in the enteric nervous system (ENS) and central nervous system (CNS).
- enhances gastric emptying, increases gut motility, reduces nausea/vomiting, and prevents reflux, making it useful for conditions like gastroparesis, reflux disease (GERD), and nausea/vomiting.
How it works:
1. Normally, dopamine (D₂ receptors) inhibits ACh release, reducing gut motility. Metoclopramide blocks D₂ receptors, allowing more ACh release, which enhances smooth muscle contractions in the gut.
- Directly stimulates enteric neurons to release acetylcholine (ACh) and substance P, increasing gut contractions and motility.
- Stimulates 5-HT₄ receptors (prokinetic effect in ENS) → enhances ACh release, promoting motility. Inhibits 5-HT₃ receptors (CNS effect) → reduces nausea & vomiting by blocking signals in the brainstem.
- Activates nitric oxide (NO) release, which helps regulate relaxation-contraction cycles in the gut, improving coordinated movement.
- Enhances lower oesophageal sphincter (LOS) tone → reduces acid reflux. Increases gastric muscle contractions → improves gastric emptying.
- Synchronizes stomach and duodenum movements, preventing food stasis and improving digestion.
describe antispasmodic agents
- Examples: propantheline, dicloxerine (dicyclomine), mebeverine
- ↓ spasm in bowel. They have relaxant action on GIT (relax smooth muscle in GIT)
- Propantheline, dicyclomine, mebeverine = antimuscarinic agents - block Ach
- Muscarinic receptor antagonists: inhibit parasympathetic activity. This reduces spasm in the bowel (inhibit peristalsis)
- May be useful in irritable bowel syndrome and diverticular disease – a congenital lesion, may be a source of bacterial overgrowth.
describe the pharmalogical management of heartburn or ulcers
goal:
* Reduce acid secretion with H2 receptor antagonists, e.g., famotidine
* Neutralise secreted acid with antacids, e.g. gaviscon
* Attempt to eradicate H. pylori
* Inhibition of acid secretion, removes the constant irritation and allows the ulcer to heal
Drugs can be used to inhibit or neutralise gastric acid secretion for the following conditions:
* Peptic ulcer
* Reflux oesophagitis: gastric acid secretion can damage oesophagus
* Zollinger-Ellison syndrome: gastrin-producing tumour
describe antacids
- treats heartburn
- Neutralise gastric acid
- ↑ the pH of gastric acid (peptic activity stops at pH 5)
- Prolonged dosing can lead to healing of duodenal ulcers; less effective for gastric ulcers
describe antacids with cytoprotective effects
- Bismuth chelate (Pepto Bismol)
- Decreases fluid secretion in bowel
- Protects gastric mucosa
- Forms a base over crater of the ulcer
- Adsorbs pepsin
- ↑ HCO3- and prostaglandin secretion
- Toxic against H. pylori – used as part of triple therapy
to eradicate it - Blackens stool and tongue
- Suitable for children (12 years and over). BUT DO NOT use in children with chicken pox or flu-like symptoms as can cause Reye syndrome- brain & liver affected
describe prostaglandins
- Prostaglandins (PGs) protect the epithelial cells of the stomach against damage by:
- Stimulating the secretion of HCO3- which neutralises gastric acid
- Reducing H+ secretion
- Stimulating mucus production
- Promoting vasodilation
- PGs protect the stomach against damage
Why do NSAIDS (e.g. aspirin) cause gastric bleeding?
Aspirin inhibits COX which inhibits the synthesis of Prostaglandins
what is misoprostol ?
- a stable analogue of PGE1
Mode of action of misoprostol:
* Inhibits basal- and food-stimulated gastric acid secretion
* Inhibits histamine-, and caffeine-induced gastric acid secretion
* Inhibits the activity of parietal cells
* Increases mucosal blood flow and can augment the secretion of HCO3- and mucus
Caution:
Induces labour/abortion
describe the treatment of H. pylori infection
H. Pylori & Risks:
* Increases gastric acid production.
* Risk factor for gastric cancer.
Combination Therapy for H. pylori Eradication:
* Omeprazole + Amoxicillin + Metronidazole
* Omeprazole + Clarithromycin + Amoxicillin
* Tetracycline + Metronidazole + Bismuth Chelates
* Lansoprazole + Clarithromycin + Tinidazole + Bismuth Chelates
Gastric Mucosal Protection (Bismuth Chelate):
* Forms protective barrier over ulcers.
* Enhances PG synthesis & bicarbonate secretion.
* Toxic to H. pylori → prevents adherence, inhibits proteolytic activity.
* Adsorbs pepsin, reducing damage.
Unwanted Effects of Bismuth Chelate:
* Nausea, vomiting.
* Black tongue & stools.
* Warning: In renal impairment, bismuth can accumulate → encephalopathy.
Metronidazole Precautions:
* Adhere to treatment → resistance risk.
* No alcohol → Disulfiram-like reaction (flushing, nausea).
* Avoid in 1st trimester of pregnancy.
describe constipation
- Subjective complaint
- Obstruction → constipation; investigate
Is your frequency of bowel movement normal?
* Normal bowel opening = 1-3x per day, but hugely varies between people
* One does not have to be regular to be physiologically adequate/normal
* No toxic substances accumulate upon prolonged constipation*
Consequences of constipation as a result of rectal distension:
* Headache
* Loss of appetite
* Nausea
* Abdominal distension and stomach pain
- Holding of faecal matter → ↑ water loss and dryer faeces (*painful and harder to defecate)
what are the causes of constipation ?
- decreased motility of large intestine
- Old age
- Damage to enteric nervous system of colon (-may affect the initiation of vago-vagal reflex)
Factors that can increase colonic motility (↑ distension of large intestine) and improve symptoms of constipation:
* ↑ fibre, cellulose and complex polysaccharides
Bran, some fruits and vegetables with high fibre
* Laxatives, but excessive use → ↓ responsiveness
* Mineral oil – lubricates faeces
* Castor oil – stimulates motility of colon
what are the causes , alarm signs and management of constipation ?
Causes of constipation (elderly):
* Diet
* Inactivity
* Drugs (polypharmacy)
Alarm signs and symptoms of patients with chronic constipation:
* Acute onset constipation in older individuals
* Weight loss (10lb)
* Blood in the stool
* Anaemia
* Family history of colon cancer or inflammatory bowel disease
Management of constipation:
* Lifestyle changes
* Diet, fluid intake and exercise and their effects on constipation (appealing?)
* ↑ fibre intake → bloating and flatulence (not appealing)
* ↑ water intake??
what are the treatments of constipation ?
Purgatives:
* Purgatives can modulate/hasten food transit in the intestine
- Laxatives, faecal softeners & stimulant.
- Bulk-forming and osmotic laxatives
- Bulk laxatives: methylcellulose,
- Plant gums (e.g. sterculia, agar agar, linseed, bran, ispaghula husk) are polysaccharide polymers
- They retain water in gut lumen → promotion of peristalsis, but take a few days to elicit their effects
- Increase the stool’s solid content
- Other effects: bloating and flatulence
Osmotic laxatives: lactulose
* ↑ and maintains volume of fluid in the lumen of bowel by osmosis
* ↑ transfer of gut contents into the intestine
* Increases volume of gut content entering the colon → distension and purgation in 1hr
* High doses → flatulence, cramps, diarrhoea, vomiting and tolerance
what is the mode of actions of osmotic laxatives ?
what are therapeutic strategies to treat diarrhoea ?
- Maintain fluid and electrolyte balance: Oral rehydration therapy
- Use of anti-infectives: Bacterial infections may resolve with time
Campylobacter sp: cause of gastroenteritis in the UK - Use erythromycin or ciprofloxacin in severe infections
- If viral in nature, may not need to use anti-infectives
- Use of non-microbial anti-diarrhoeal agents
- Use of anti-motility drugs: adsorbents and agents that modify fluid and electrolyte transport
- Loperamide: Selective on GIT, decreases passage of faeces;
Decreases duration of illness - Codeine & loperamide: Anti-secretory action
↓ intestinal motility
describe the mechanism of action for loperamide
- An opioid receptor agonist
- Binds to the opioid receptor of the myenteric plexus* of the large intestine – inhibition of bowel function
*Controls motility and to a very minor extent GI secretion - Stimulation of the -opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone, induces stationary motor patterns (i.e., blocks peristalsis)
- A spasmolytic agent which reduces smooth muscle activity in the GIT and thus reduces the passage of stool
- Reduces force and speed of colonic movement by:
- Increasing haustral mixing of the proximal colon
- Inhibiting propulsive mass movement of the distal colon
- No CNS effects, as does not cross the blood-brain barrier
What is the mode of action of metoclopramide?
It stimulates 5-HT4 receptors, inhibits D2 receptors, and increases ACh release, promoting gastric emptying.
Metoclopramide acts on the gut to enhance motility and reduce nausea.
Name two conditions in which metoclopramide can be used.
- Gastrointestinal reflux (GORD)
- Nausea/vomiting after surgery or due to cancer chemotherapy
Which of the following is an antispasmodic agent? a) Propantheline b) Acetylcholine c) Carbachol d) CCK e) Lansoprazole
a) Propantheline
What is one way to treat gastric ulcers pharmacologically aside from H. pylori eradication?
Reduce acid secretion with H2 receptor antagonists (e.g., cimetidine, famotidine)
H2 receptor antagonists block multiple pathways of acid secretion.
List two other treatment options for gastric ulcers along with an example of an agent for each.
- Neutralize secreted acid with antacids (e.g., magnesium carbonate)
- Use proton-pump inhibitors (e.g., omeprazole)
List five points of advice for someone with gastro-oesophageal reflux disease (GORD).
- Avoid large meals
- Lose weight (if overweight)
- Avoid foods that increase gastric acidity
- Avoid lying down after meals
- Avoid some drugs and smoking
What are the receptors that modulate the response of parietal cells to gastric secretagogues?
- A1: muscarinic (M2/3) receptor
- A2: cholecystokinin receptor (CCK-B)
- A3: histamine receptor (H2)
What is the name of the pump that pumps protons into the gastric lumen?
K+/H+ ATPase pump or proton pump
What is the overall effect of the three molecules on the parietal cell?
They cause gastric acid secretion and synergize to cause hypersecretion of gastric acid.
Name two drug classes that can inhibit the effects of the molecules on the parietal cell.
- H2 receptor antagonists (e.g., cimetidine)
- Proton pump inhibitors (e.g., lansoprazole)
Which paracrine mediator can block the effects of the molecules on the parietal cell?
Somatostatin
What are the causes of constipation in the elderly?
- Diet – lack of fruits and vegetables
- Inactivity – lack of exercise
- Drugs – polypharmacy
Which drug is useful for decreasing colonic mass movement?
c) Loperamide
List three lifestyle changes that may help manage constipation.
- Increase fibre intake
- Regular exercise
- Improve water intake
List two ways to improve colonic motility.
- Eat bran and high-fibre fruits/vegetables
- Use agents that soften/lubricate faeces (e.g., mineral oil)
How does loperamide help to decrease bowel frequency?
It acts on µ-opioid receptors, decreasing muscle tone, increasing colonic retention time, and enhancing water absorption.
