Pharamacological Basis of Treatment of GI disease Flashcards
How much gastric acid is secreted a day?
Gastric acid secretion → 2.5L of gastric juice secreted/day
Describe the mechanism of action of acid secretion
Gastrin can engage ECL cells causing Histamine release. Histamine binds to specific H₂ receptors on parietal cells which invariably leads to acid secretion via the activation of Na/K pump
List H₂ Receptor Antagonists used to inhibit acid secretion
Ranitidine
Cimetidine
Famotidine
Nizatidine
What are the clinical uses of H₂ Receptor Antagonists ?
Peptic ulcer and Reflex oesophagitis
Explain how H₂ Receptor Antagonists inhibit acid secretion
Inhibit histamine-, ACh- and gastrin-stimulated acid secretion on parietal cells
Reduce gastric acid secretion ∴ reduce pepsin secretion as there’s no hyperacidity to convert pepsinogen → pepsin
What potential side effects may occur when using H₂ Receptor Antagonists?
Generally rare but may be diarrhoea, muscle cramps, transient rashes, hypergastrinemia
Cimetidine → gynaecomastia in men (↓ sexual function, but this is rare)
What effect does cimetidine have on drug metabolism?
Cimetidine also inhibits P450 enzymes leading to ↓ metabolism of a number of drugs metabolised by P450 enzymes, e.g. anticoagulants, tricyclic antidepressants (e.g. imipramine, dosulepin, amitriptyline, etc.)
Compare the effects of cimetidine and ranitidine on acid secretion inhibition
Ranitidine is more potent than cimetidine:
IC50 for ranitidine = 0.07mcg/ml
IC50 for cimetidine = 0.44mcg/ml
What is the IC50 of a drug?
IC50 - [ ] that inhibits 50% of the drug
The lower the IC50, the more active the drug
What is the function of proton pump inhibitors?
treat gastric ulcers
Name some examples of proton pump inhibitors
omeprazole, lanzoprazole, pantoprazole, rabeprazole
What are the clinical uses of proton pump inhibitors?
Peptic ulcer, reflux oesophagitis; as a component of therapy for H. pylori
Can also be used in the treatment of Zollinger-Ellison syndrome
Explain the mechanism of proton pump inhibitor action
Weak bases; inactive at neutral pH and irreversibly inhibit the H+/K+-ATPase pump
Decreases basal and food-stimulated gastric acid secretion
What are the side effects of using proton pump inhibitors?
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia; dizziness
What are gastroprotective drugs?
Prostaglandins (PGE2 and PGI2) are gastroprotective as they protect the gastric mucosa by promoting mucus secretion, blood flow, bicarbonate secretion and negatively regulate acid secretion by parietal cells
What is a stable analogue of PGE1?
Misoprostol (a stable analogue of PGE1)
Explain the mechanism 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
What cautions must be taken into considerations before using misoprostol?
Induces labour/abortion
What effect does metoclopramide have on gastric motility and emptying?
Metoclopramide inhibits pre- and postsynaptic dopamine (D2) receptors as well as 5-HT3 receptors (CNS) –
inhibits vomiting
Stimulates 5-HT4 (ENS) - prokinetic (promotes kinesis)
How does dopamine inhibit the release of ACh?
Dopamine inhibits the release of ACh from intrinsic myenteric cholinergic neurons by activating prejunctional D2 receptors
What effect does dopamine have on the gut?
Dopamine has relaxant effects on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum)
How does dopamine produce different effects in the gut?
dopamine has mixed effects on the gut – may induce contraction in the proximal, but relaxation in the distal small intestine as it acts on different dopamine receptors
What is the effect of inhibition of dopamine at D2 receptors?
↑ ACh (↑ peristalsis of duodenum, jejunum + ileum)
↑ ACh = ↑intragastric pressure (due ↑ LOS tone + ↑ tone of gastric contractions)
these improve antroduodenal coordination accelerating gastric emptying; relaxes pyloric sphincter
What is the role of metoclopramide prokinetic effects?
It stimulates presynaptic excitatory 5-HT receptors and inhibitory nitrergic neurons → coordinated gastric motility
What other effects areas is metoclopramide useful in?
Metoclopramide has some antiemetic properties via centra effects
Metoclopramide relieves headache via central effects
What effects does metoclopramide have on gastric motility and emptying?
Useful for reflux [but useless in paralytic ileus; causes moderate to diffuse abdominal discomfort e.g. → abdominal distension, nausea/vomiting especially after meals, lack of bowel movement/flatulence]
Stimulates gastric motility
Accelerates gastric emptying
What is teh clinical utility of metoclopramide?
Symptoms of gastroparesis
Promotes gastric emptying
Antiemetic effects via central pathways
GORD; nausea due to surgery or cancer
Summarise how metoclopramide promotes gut motility
Inhibits pre/postsynaptic D2 receptors,
Stimulates ACh / SP release from enteric neurons
Elicits mixed 5-HT ant/agonist effects
- stimulates excitatory 5-HT4 receptors (ENS), but inhibits
5-HT3 receptors (CNS);
Stimulates inhibitory nitrergic neurons – mediate NO release
Increases intragastric pressure -↑ LOS + gastric tones
Motility stimulant - improves antroduodenal coordination + accelerated gastric emptying
Name some antispasmodic agents
propantheline, dicloxerine (dicyclomine), mebeverine
What are the effects of antispasmodic agents?
↓ spasm in bowel. They have relaxant action on GIT (relax smooth muscle in GIT)
May be useful in irritable bowel syndrome + diverticular disease – a congenital lesion, may be source of bacterial overgrowth
What is the role of muscarinic receptor antagonists?
inhibit parasympathetic activity. This reduces spasm in the bowel
What are the goals of pharmacological intervention in gastric ulcers?
Reduce acid secretion with H2 receptor antagonists
Neutralise secreted acid with antacids
Attempt to eradicate H. pylori
What effect does inhibition of acid secretion have on gastric ulcers?
Inhibition of acid secretion, removes the constant irritation and allows the ulcer to heal
Which conditions are drugs used to inhibit / neutralise gastric acid secretion for?
Peptic ulcer
Reflux oesophagitis: gastric acid secretion can damage oesophagus
Zollinger-Ellison syndrome: gastrin-producing tumour
What is a major risk factor for gastric ulcer?
H. pylori infection is a risk factor
H. pylori: a Gram negative bacillus→ chronic gastritis → duodenal ulcer
What antacids are used for heartburn?
Sodium alginate
Sodium bicarbonate
Calcium carbonate
How do antacids work to neutralise gastric acid?
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.
Which antacids have cytoprotective effects?
Bismuth chelate Protects gastric mucosa Forms base over crater of ulcer Adsorbs pepsin ↑ HCO3- + PG secretion Toxic against H. pylori – used as part of triple therapy to eradicate it
What is the side effects of bismuth chelate?
Blackens stool and tongue
Suspected GORD or heartburn must be investigated
What is the pharmacological management of gastric ulcers?
Prostaglandins protect the stomach mucus against damage by:
Stimulating bicarbonate secretion
Reducing H+ secretion
Promoting vasodilation
What is the advantage of PGs?
PGs protect the stomach against damage
Why do NSAIDS (e.g. aspirin) cause gastric bleeding?
Inhibit PG synthesis
Celecoxib, rofecoxib (selective COX-2 inhibitors) → less bleeding
Which antibiotics can be used to treat a H.Pylori infection?
Omeprazole, amoxicillin and metronidazole, clarythromycin, tetracycline,bismuth chelates
What cytoprotective effects do bismuth chelates have?
Provide physical barrier (coat) over surface/base of ulcer
Enhances local synthesis of PGs
Promote bicarbonate secretion
What are the toxic effects of bismuth chelate?
Bismuth chelate has toxic effects on the bacillus: it prevents the adherence of H. pylori to the mucosa or inhibit its proteolytic activity; stimulates bicarbonate secretion; ↑ PG synthesis; adsorbs pepsin
What caution must be taken before administering bismuth chelate to patients with renal failure?
If patient has renal impairment, [bismuth chelate]plasma may rise causing encephalopathy
What are the unwanted side effects of bismuth chelate?
nausea, vomiting, blackening of tongue and faeces
What advice is given to patients when taking bismuth chelate?
Adhere to treatment
Resistance to metronidazole
Do not give metronidazole in first trimester
Disulfiram-like reaction results if metronidazole is taken with alcohol
Which proton pump inhibitors treat gastric ulcers?
omeprazole, lanzoprazole, rabeprazole
What are the consequences of constipation upon rectal distension?
Headache
Loss of appetite
Nausea
Abdominal distension and stomach pain
What is constipation?
Holding of faecal matter → ↑ water loss and dryer faeces (*painful and harder to defecate)
Causes of Constipation
What are the causes of constipation?
↓ motility of large intestine Old age Damage to enteric nervous system of colon Diet Inactivity Drugs (polypharmacy)
Which factors increase colon 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 signs indicate 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
How do we manage 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 purgatives?
laxatives, faecal softeners & stimulant purgatives can modulate/hasten food transit in the intestine
Name examples of bulk laxatives
Bulk laxatives: methylcellulose, Plant gums (e.g. sterculia, agar, linseed, bran, ispaghula husk- are polysaccharide polymers)
What is the function of bulk-forming and osmotic laxatives ?
They retain water in gut lumen → promotion of peristalsis, but take a few days to work
Increase the stool’s solid content
What is the side effect of bulk-forming use?
Bloating and flatulence
How does the osmotic laxative (lactulose) maintain water in faeces?
↑s and maintains volume of fluid in the lumen of bowel by osmosis
How does lactulose aid the movement of contents through the gut?
↑s transfer of gut contents into the intestine
WHat effect does lactulose (osmotic laxative) have on defecation?
Increases volume of gut content entering the colon → distension and purgation in 1hr
What is the consequence of taking high doses of osmotic laxatives?
High doses → flatulence, cramps, diarrhoea, vomiting and tolerance
What is the role of anti-diarrhoeal agents?
Maintain body fluids and electrolytes
Identify causal organism and if possible treat with antibiotics e.g. erythromycin for Campylobacter jejuni
Modify secretion/ absorption balance
What are the causes of diarrhoea?
Infectious agents
Toxins
Anxiety
Drugs
What are the consequences of diarrhoea?
↑ motility of GIT, with ↑ secretion and ↓ absorption of fluid → ↓ electrolyte (Na+) and H2O
What is the effect of diarrhoea due to cholera?
loss of gut contents
How can we maintain fluid and electrolyte balance in patients with diarrhoea?
Maintain fluid and electrolyte balance: Oral rehydration therapy
Why may anti-infectives be used to tackle diarrhoea?
Diarrhoea could be due to bacteria
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
*don’t use if viral in nature
What drugs are used to decrease motility through the gut?
Use of anti-motility drugs: adsorbents and agents that modify fluid and electrolyte transport
How can we mediate the movement of substances in the gut?
The movement of substances in the gut can be modulated by:
Purgatives: ↑ passage of food through the intestine
Which agents increase motility without leading to purgation?
Antidiarrhoeal drugs → ↓ movement
Antispasmodic drugs → ↓ movement; relax smooth muscles in GIT
Explain the effects pf loperamide on travellers diarrhoea
Selective on GIT, decreases passage of faeces; Decreases duration of illness Anti-secretory action; ↓ intestinal motility *codeine has same effects
What are the effects of bismuth subsalicylate on travellers diarrhoea?
Decreases fluid secretion in bowel;
Safe for young children;
May cause tinnitus and blackening of stool
Describe the mechanism of action of loperamide?
An opioid receptor agonist
A spasmolytic agent ↓ smooth muscle activity in GIT ∴reduces passage of faeces
↓ force + speed of colonic movement
↑ haustral mixing of the proximal colon
Inhibits propulsive mass movement of the distal colon
Explain the advantage of using loperamide to treat diarrhoea?
Doesn’t cross blood brain barrier; no CNS effects
*Controls motility + secretion of GIT
Stimulation of μ-opioid receptor by loperamide inhibits gastric emptying, ↑ sphincter tone, induces stationary motor patterns + blocks peristalsis
