Pharmacological Basis for Treatment of GI disorders Flashcards
What are the areas of the GI tract of pharmacological importance
- Gastric acid secretion → 2.5L gastric juice secreted/day
- Vomiting
- Gut motility
- Bile formation and excretion
- Pancreatic secretions
Describe the mechanism of action of metoclopramide and its effects on gastric motility and emptying
Has mixed effects:
- Inhibits pre-and post synaptic dopamine (D2) receptors as well as 5-HT3 receptors (CNS) - inhibits vomiting
- Stimulates 5-HT4 (ENS) - pro kinetic - It stimulates presynaptic 5-HT receptors and inhibitory nitregeric neurones → coordinated gastric motility
- Increased Ach release leads to increase peristalsis and increased intragastric pressure (due to increase LOS tone and increase tone of gastric contractions)
Dopamine inhibits the release of Ach from intrinsic myenteric cholinergic neurones by activating pre-synaptic D2 receptors, leads to indirect inhibition of musculature
Dopamine has relaxant effects on gut by activating D2 receptors in LOS and stomach (fundus and antrum). Dopamine acts on different dopamine receptors
Dopamine has mixed effects on gut - may induce contraction in proximal, but relaxation in distal small intestine
- 2 D1-like receptor subtypes (D1 and D5) couple to the G protein Gs, activate adenylyl cyclase. Other receptor subtypes are D2-like (D2, D3, D4) and are prototypic GPCR that inhibit adenylyl cyclase (they’re Gi) and activate K+ channels.
Describe the clinical use of metoclopramide
- Anti-emetic effects (nausea due to surgery or cancer) pharmacological effects via central pathways
- Relieves symptoms of gastroparesis - Promotes gastric emptying
- Stimulates gastric emptying - Accelerates it
- Pain killing effects
Describe the mechanism of action of antispasmodic agents
Examples: Propantheline, dicloxerine (dicyclomine), mebeverine
- Decrease spasms in bowel, have relaxant action on GIT (release smooth muscle)
- Propantheline = Antimuscarinic agent
- Can be useful in IBS and diverticular disease - Congenital lesion may be source of bacterial overgrowth
- Muscuarinic receptor antagonists - Inhibit parasympathetic activity - reduces spasm in bowel
Describe constipation
- Constipation is defined as having fewer bowel movements than you ordinarily would
- Consquences of constipations as a result of rectal distension:
- Headache
- Loss of appetite
- Nausea
- Abdominal distension and stomach pain
- No toxic substances accumulate upon prolonged constipation
- Holding of faecal matter → Increased water loss and dryer faeces (painful and harder to defecate)
What are causes of constipation? What are factors that can increase colonic motility?
- Decreased motility of large intestine
- Old age
- Damage to ENS of colon (may affect initiation of vago-vagal reflex)
- Diet, inactivity and drugs (polypharmacy) can also cause consitpation
Factors that can increase colonic motility (increase distension of large intestine) and improve symptoms of constipation:
- Increased fibre, cellulose, complex polysaccharides
- Bran, some fruits + veg high in fibre
- Laxatives, but excessive use can lead to decreased responsiveness
- Mineral oil - Lubricates faeces
- Castor oil - Stimulates motility of colon
What alarming signs alongside constipation need flagging, and how can conspitation be managed?
Alarming signs and symptoms of patients with chronic constipation:
- Acute onset constipation in older individuals
- Weight loss (10lbs)
- Blood in stool
- Aneamia
- Family history of colon cancer or IBD
Management of constipation:
- Lifestyle changes:
- Diet, fluid intake and exercise and their effects on constipation (appealing)
- Increase fibre intake → bloating and flatulence
- Increase water intake
What do purgatives do?
Modulate/hasten food transit in intestine:
- Laxatives, faecal softeners and stimulant
Describe the 4 main types of laxatives
- Bulk-forming laxatives: Methylcellulose etc
- Work by increasing ‘bulk’ or weight of stool by absorbing water, which in turn stimulates bowels by stimulating peristalsis, take 2/3 days to work.
- Side effects: Bloating and flatulence
- Osmotic laxatives: Lactulose
- Draw water from rest of body into bowel to soften stool, make it easier to pass. Take 2/3 days to work
- Increase and maintains volume of fluid in lumen of bowel by osmosis
- Increase transfer of gut contents into intestine
- Increases volume of gut content entering the colon → distension and purgation in 1hr
- High doses → flatulence, cramps, diarrhoea, vomiting and tolerance
- Stimulant laxatives:
- Stimulate the muscles that line gut, helping them move stool along to back passage. Take 6-12hrs to work
- Stool-softener laxatives:
- Lets water into stool to soften it, making it easier to pass
Describe the mode of action of lactulose
Unchanged lactulose reaches the colon, the colonic bacteria breaks it down into short chain FAs. Lactulose is a carb source for lactobacilli and bifidobactera, it increases the growth of colonic bacteria. Biomass increases and osmotic pressure increases. Water is able to be absorbed the stool, this leads to greater distension of the colon, which will induce/stimulate peristalsis and shorten the colonic transit time
Describe diarrhoea its causes and effects
Diarrhoea is when somebody is having far more bowel movements than they would ordinarily have, and the stool itself is far more liquidy than it should be. It can result in dehydration and loss of electrolytes, which can lead to a cascade of more significant events.
To treat:
- Maintain body fluids and electrolytes
- Identify causal organism and if possible treat with antibiotics e.g. erythromycin for Campylobacter jejuni
- Modify secretion/ absorption balance
Can be caused by:
- Infectious agents
- Toxins
- Anxiety
- Drugs
Effects:
- Rough, uncomfortable, and can lead to a medical emergency
- Acute diarrhoeal diseases;
- Diarrhoea → Increased GIT motility with increase secretion and decreased absorption of fluid → Decreased electrolyes (Na+) and H2O
How do antidiarrhoeal drugs differ from antispasmodic drugs?
Agents that ↑ motility without → purgation:
- Antidiarrhoeal drugs → ↓ movement
- Antispasmodic drugs → ↓ movement; relax smooth muscles in GIT
Describe the therapuetic strategies to treat diarrhoea, loperamide, the action of codeine and loperamide together, bismuth subsalicylate and traveller’s diarrhoea
- Maintain fluid and electrolyte: 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: abdsorbents and agents that modify fluid and elecrolyte transport
Loperamide - Selective on GIT, decreases passage of faeces, decreases duration of illness
Codeine and loperamide - Anti-secretory action; decrease intestinal motility
Bismuth subsalicylate - Decreases fluid secretion in bowel (not safe for children, Reye-like syndrome), may cause tinnitus and blackening of stool
Traveller’s diarrhoea:
- Gorbach, 1987: Travelling broadens the mind and loosens the bowel
- About 3 million people travel abroad/year & most will develop diarrhoea during their travel
- But some infections may be self-limiting
Describe the mechanism of action of loperamide
- Opioid receptor agonist
- Binds to the mu-opioid receptor of the myenteric plexus of the large intestine - inhibition of bowel function
- Myenteric plexus controls motility and secretion of GIT
- Stimulation of the mu-opiod receptor by loperamide inhibits gastric emptying, increases spinchter tone, induces stationary motor patterns and blocks peristalsis
- A spasmolytic agent which reduces smooth muscle activity in GIT, reducing passage of faeces
- Reduces force and speed of colonic movement by:
- Increases haustral mixing of the proximal colon
- Inhibits propulsive mass movement of distal colon
- DOESN’T cross blood-brain-barrier, no CNS effects
