The Pharmacological Basis of the Treatment of GI Disorders Flashcards
State the areas of the GI tract that are pharmacologically important
- Gastric acid secretion - 2.5L of gastric juice secreted a day
- Vomiting
- Gut motility
- Bile formation and excretion
State some examples of H2 receptor antagonists and what they are used for
H2 receptor antagonists (ranitidine, cimetidine, famotidine, nizatidine)
Clinical uses of H2 receptor antagonists - peptic ulcers, reflux oesophagitis
State the mechanism of action of H2 receptor antagonists
- They inhibit histamine, acetylcholine and gastrin stimulated acid secretion on parietal cells
- Reduce gastric acid secretion and as a consequence reduce pepsin secretion
- Can decrease basal and food stimulated acid secretion by 90%
- Promote the healing of duodenal ulcers but if treatment stops there is relapse
What are some unwanted effects H2 receptor antagonists produce
- Generally rare but may be diarrhoea, muscle cramps, transient rashed and hypergastrinemia
- Cimetidine - gynaecomastia in men - decreased sexual function
- Cimetidine also inhibits P450 enzymes - decreased metabolism of a number of drugs metabolised by P450 enzymes e.g. anticoagulants, tricyclic antidepressants e.g. imipramine, dosulepin and amitriptyline
Compare the effects of ranitidine and cimetidine on inhibition of acid secretion
- Graph shows that as serum concentration of ranitidine and cimetidine increases the % of acid inhibition also increases
- But ranitidine is more potent than cimetidine as it needs a lesser serum concentration to produce maximum % of acid inhibition
- IC50 for ranitidine is 0.07 mcg/ml while IC50 for cimetidine is 0.44 mcg/ml - the lower the IC50 the more active the drug
Give examples of proton pump inhibitor drugs
Omeprazole, lansoprazole, pantoprazole, rabeprazole
Describe what proton pump inhibitors are used for
- Peptic ulcers, reflux oesophagitis, as a component of therapy for H pylori
- Can also be used in the treatment of zollinger ellison syndrome
- Drugs of choice especially if hyper secretion of acid occurs
Describe the mechanism of action of proton pump inhibitors
- They are weak bases that are inactive at a neutral pH and irreversibly inhibit the H+/K+ ATPase pump
- Decreases the basal and food stimulated gastric acid secretion
What are the unwanted effects of proton pump inhibitors
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia, dizziness
What type of drugs protect the gastric mucosa?
Prostaglandins are gastroprotective
Describe what misoprostol does
- Inhibits basal and food stimulated gastric acid secretion
- Inhibits histamine and caffeine induced gastric acid secretion
- Inhibits the activity of parietal cells
- Increases the mucosal blood flow and can augment the secretion of HCO3- and mucus
Describe the effects of metoclopramide on gastric motility/emptying
- Metoclopramide has mixed effects - inhibits pre and postsynaptic dopamine receptors as well as 5HT3 receptors - inhibits vomiting
- Also stimulates 5HT4 - prokinetic
Describe the effects of dopamine
- Dopamine acts on different dopamine receptors
- Dopamine has relaxant effects on the gut by deactivating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum)
- Overall dopamine has mixed effects on the gut - may induce contraction of the proximal small intestine but relaxation in the distal small intestine
- Dopamine inhibits the release of acetylcholine from intrinsic myenteric cholinergic neurons by activating presynaptic D2 receptors
Explain what inhibition of dopamine by metoclopramide does in the GI tract
- Increases the release of acetylcholine which increases peristalsis of the duodenum, jejunum and ileum
- The increased acetylcholine leads to increased intragastric pressure due to increased lower oesophageal sphincter tone and increased tone of gastric contractions
- These improve antroduodenal coordination which accelerates gastric emptying and relaxes the pyloric sphincter
- Through additional prokinetic effects it stimulates the presynaptic excitatory 5HT receptors and inhibitory nitrergic neurons which leads to coordinated gastric motility
What other areas does metoclopramide have use in?
- Metoclopramide has some antiemetic properties via central effects
- Metoclopramide relieves headaches via its central effects
State some conditions in which metoclopramide may be used
- Antiemetic - nausea due to surgery or cancer
- Gastro-oesophageal reflux disease (GORD)
- Relieve symptoms of gastroparesis - promotes gastric emptying by stimulating gastric motility
Summarise the effects of metoclopramide
- Inhibits presynaptic and postsynaptic D2 receptors
- Stimulates the release of acetylcholine/SP from enteric neurons
- Elicits mixed 5HT agonist and antagonist effects e.g. stimulates excitatory 5HT4 receptors and inhibits 5HT3 receptors
- Stimulates inhibitory nitrergic neurons - mediate NO release
- Increases intragastric pressure - increased lower oesophageal sphincter and gastric tone
- Motility stimulant - improves antroduodenal coordination and accelerated gastric emptying
State some examples of antispasmodic drugs and what they do
- Examples - propantheline, dicloxerine, mebeverine
- Decrease the spasm of the bowel - they have a relaxant action of the GI tract (relax the smooth muscle of the GI tract)
What type of drug is propantheline and what is it useful in as a treatment?
- Propantheline is an antimuscarinic agent (muscarinic receptor antagonists inhibit parasympathetic activity to reduce spasm of the bowel)
- May be useful in irritable bowel syndrome and diverticular disease - a congenital lesion may be a source of bacterial overgrowth
State the goals of pharmacological treatment of gastric ulcers
- Reduce acid secretion with H2 receptor antagonists e.g. ranitidine
- Neutralise secreted acid with antacids e.g. gaviscon
- Attempt to eradicate H pylori
Drugs that inhibit or neutralise acid secretion can be used to treat what?
- Peptic ulcers
- Reflux oesophagitis - gastric acid secretion can damage the oesophagus
- Zollinger ellison syndrome - gastrin producing tumour
What is the general mechanism of antacids?
- Neutralise gastric acids
- Increase the pH of gastric acid
- Prolonged dosage can lead to healing of duodenal ulcers but is less effective for gastric ulcers
Describe what bismuth chelate does
- Protects the gastric mucosa
- Forms a base over crater of the ulcer
- Absorbs pepsin
- Increases HCO3- and PG secretion
- Toxic against H pylori
- Blackens the stool and tongue
How to prostaglandins protect epithelial cells of the stomach against damage?
- Stimulating the secretion of HCO3- which neutralises gastric acid
- Reducing H+ secretion
- Stimulating mucus production
- Promoting vasodilation
How is H pylori treated?
- Omeprazole, amoxicillin and metronidazole
- Omeprazole, clarithromycin and amoxicillin or tetracycline, metronidazole and bismuth chelates
- Lansoprazole, clarithromycin, tinidazole and bismuth chelates
Describe how bismuth chelate has cytoprotective effects
- Provides a physical barrier over the surface/base of the ulcer
- Enhances local synthesis of prostaglandins
- Promotes bicarbonate secretion
- 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 - increases prostaglandin synthesis and absorbs pepsin
State some unwanted effects of bismuth chelate
Nausea vomiting blackening of the tongue and faeces
What is the patient advice when taking metronidazole?
- Adhere to the treatment
- Disulfiram like reaction if metronidazole is taken with alcohol - patient will feel severely ill and may stop taking the drug
What is normal bowel movement in a day?
Normal bowel opening is 1-3 x a day but hugely varies
What symptoms can constipation produce?
Constipation causes rectal distension which can lead to - headache, loss of appetite, nausea and abdominal distension/stomach pain
What are the causes of constipation?
Decreased motility of large intestine due to old age or damage to enteric nervous system of the colon
What are some factors that increase colonic motility and increase constipation symptoms
- Increases fibre cellulose and complex polysaccharides
- Bran some fruits and vegetables with high fibre
- Laxatives
- Mineral oil - it lubricates the faeces
- Castor oil - stimulates motility of colon
State the causes, alarm signs and management of constipation
Causes -
- Diet
- Inactivity
- Drugs
Alarm signs -
- Acute onset constipation in older individuals
- Weight loss
- Blood in the stool
- Anaemia
- Family history of colon cancer or inflammatory bowel disease
Management of constipation -
- Diet, fluid intake and exercise
- Increased fibre intake and increased water intake
Describe the drug treatments available for constipation
Purgatives -
- Can modulate/hasten food transit in the intestines
- Laxatives, stool softeners and stimulants
Describe what bulk and osmotic laxatives do
Bulk -
- Bulk laxatives = methylcellulose
- Plant gums e.g. agar, linseed, bran are polysaccharide polymers
- They retain water in the gut lumen to promote peristalsis
- Increase the stools solid content
Osmotic laxatives - e.g. lactulose
- Increases and maintains the volume of fluid in the lumen of bowel by osmosis
- Increases transfer of gut contents into the intestine
- Increases volume of gut content entering the colon - distension and purgation in 1hr
- High doses cause flatulence, cramps, diarrhoea, vomiting and tolerance
Describe the mode of action of lactulose in constipation
- The unchaged lactulose reaches the colon
- The colonic bacteria breaks it down into short fatty acid chains
- This increases osmotic pressure and increases biomass
- There is then softening of the faeces/volume of the stool increases
- Peristalsis is stimulated
- Colonic transit time is shortened
How is diarrhoea treated?
- Maintain body fluid and electrolytes
- Identify causal organism and if possible treat with antibiotics
- Modify secretion/absorption balance
What are the causes of diarrhoea?
Infectious agents
Toxins
Anxiety
Drugs
What does diarrhoea do to fluid balance?
- Diarrhoea increases the motility of the GI tract
- This increases secretion and decreases the absorption of fluid
- This decreases electrolytes and water
State 2 types of drugs used to treat diarrhoea
- Antidiarrhoeal drugs - decreases movement
- Antispasmodic drugs - decrease movement - relax smooth muscle in GI tract
State the main therapeutic strategies to diarrhoea treatment
- Maintain fluid and electrolyte balance through oral rehydration therapy
- Use of anti-infectives as bacterial infections can resolve with time - if viral these may not be needed
- Use of non microbial antidiarrheal agents
- Use of anti motility drugs - absorbents an agents that modify fluid and electrolyte transport
Describe what drugs are used to treat travellers diarrhoea
- Most develop diarrhoea while travelling
- Loperamide- selective on GI tract - decreases passage of faeces and decreases duration of illness
- Codeine and loperamide - antisecretory action - Decreases intestinal motility
Describe the mechanism of action of loperamide
- Mechanism of action of loperamide -
- An opioid receptor agonist
- Binds to the u-opioid receptor of the myenteric plexus of the large intestine which inhibits bowel function
- Controls motility and secretion of GI tract
- Stimulation of the u-opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone and induces stationary motor patterns and blocks peristalsis
- Antispasmolytic agent which reduces smooth muscle activity in the GI tract and reduces passage of faeces
- Reduce force and speed of colonic movement by:
- Increasing haustral mixing in proximal colon
- Inhibits propulsive mass movement in distal colon
