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Gastrointestinal > Pharamacological Basis of Treatment of GI disease > Flashcards

Pharamacological Basis of Treatment of GI disease Flashcards

1
Q

How much gastric acid is secreted a day?

A

Gastric acid secretion → 2.5L of gastric juice secreted/day

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2
Q

Describe the mechanism of action of acid secretion

A

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

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3
Q

List H₂ Receptor Antagonists used to inhibit acid secretion

A

Ranitidine
Cimetidine
Famotidine
Nizatidine

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4
Q

What are the clinical uses of H₂ Receptor Antagonists ?

A

Peptic ulcer and Reflex oesophagitis

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5
Q

Explain how H₂ Receptor Antagonists inhibit acid secretion

A

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

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6
Q

What potential side effects may occur when using H₂ Receptor Antagonists?

A

Generally rare but may be diarrhoea, muscle cramps, transient rashes, hypergastrinemia
Cimetidine → gynaecomastia in men (↓ sexual function, but this is rare)

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7
Q

What effect does cimetidine have on drug metabolism?

A

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.)

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8
Q

Compare the effects of cimetidine and ranitidine on acid secretion inhibition

A

Ranitidine is more potent than cimetidine:
IC50 for ranitidine = 0.07mcg/ml
IC50 for cimetidine = 0.44mcg/ml

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9
Q

What is the IC50 of a drug?

A

IC50 - [ ] that inhibits 50% of the drug

The lower the IC50, the more active the drug

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10
Q

What is the function of proton pump inhibitors?

A

treat gastric ulcers

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11
Q

Name some examples of proton pump inhibitors

A

omeprazole, lanzoprazole, pantoprazole, rabeprazole

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12
Q

What are the clinical uses of proton pump inhibitors?

A

Peptic ulcer, reflux oesophagitis; as a component of therapy for H. pylori
Can also be used in the treatment of Zollinger-Ellison syndrome

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13
Q

Explain the mechanism of proton pump inhibitor action

A

Weak bases; inactive at neutral pH and irreversibly inhibit the H+/K+-ATPase pump
Decreases basal and food-stimulated gastric acid secretion

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14
Q

What are the side effects of using proton pump inhibitors?

A

Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia; dizziness

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15
Q

What are gastroprotective drugs?

A

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

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16
Q

What is a stable analogue of PGE1?

A

Misoprostol (a stable analogue of PGE1)

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17
Q

Explain the mechanism of action of misoprostol

A

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

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18
Q

What cautions must be taken into considerations before using misoprostol?

A

Induces labour/abortion

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19
Q

What effect does metoclopramide have on gastric motility and emptying?

A

Metoclopramide inhibits pre- and postsynaptic dopamine (D2) receptors as well as 5-HT3 receptors (CNS) –
inhibits vomiting
Stimulates 5-HT4 (ENS) - prokinetic (promotes kinesis)

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20
Q

How does dopamine inhibit the release of ACh?

A

Dopamine inhibits the release of ACh from intrinsic myenteric cholinergic neurons by activating prejunctional D2 receptors

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21
Q

What effect does dopamine have on the gut?

A

Dopamine has relaxant effects on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum)

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22
Q

How does dopamine produce different effects in the gut?

A

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

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23
Q

What is the effect of inhibition of dopamine at D2 receptors?

A

↑ 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

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24
Q

What is the role of metoclopramide prokinetic effects?

A

It stimulates presynaptic excitatory 5-HT receptors and inhibitory nitrergic neurons → coordinated gastric motility

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25
Q

What other effects areas is metoclopramide useful in?

A

Metoclopramide has some antiemetic properties via centra effects
Metoclopramide relieves headache via central effects

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26
Q

What effects does metoclopramide have on gastric motility and emptying?

A

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

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27
Q

What is teh clinical utility of metoclopramide?

A

Symptoms of gastroparesis
Promotes gastric emptying
Antiemetic effects via central pathways
GORD; nausea due to surgery or cancer

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28
Q

Summarise how metoclopramide promotes gut motility

A

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

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29
Q

Name some antispasmodic agents

A

propantheline, dicloxerine (dicyclomine), mebeverine

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30
Q

What are the effects of antispasmodic agents?

A

↓ 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

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31
Q

What is the role of muscarinic receptor antagonists?

A

inhibit parasympathetic activity. This reduces spasm in the bowel

32
Q

What are the goals of pharmacological intervention in gastric ulcers?

A

Reduce acid secretion with H2 receptor antagonists
Neutralise secreted acid with antacids
Attempt to eradicate H. pylori

33
Q

What effect does inhibition of acid secretion have on gastric ulcers?

A

Inhibition of acid secretion, removes the constant irritation and allows the ulcer to heal

34
Q

Which conditions are drugs used to inhibit / neutralise gastric acid secretion for?

A

Peptic ulcer
Reflux oesophagitis: gastric acid secretion can damage oesophagus
Zollinger-Ellison syndrome: gastrin-producing tumour

35
Q

What is a major risk factor for gastric ulcer?

A

H. pylori infection is a risk factor

H. pylori: a Gram negative bacillus→ chronic gastritis → duodenal ulcer

36
Q

What antacids are used for heartburn?

A

Sodium alginate
Sodium bicarbonate
Calcium carbonate

37
Q

How do antacids work to neutralise gastric acid?

A

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.

38
Q

Which antacids have cytoprotective effects?

A 
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
39
Q

What is the side effects of bismuth chelate?

A

Blackens stool and tongue

Suspected GORD or heartburn must be investigated

40
Q

What is the pharmacological management of gastric ulcers?

A

Prostaglandins protect the stomach mucus against damage by:
Stimulating bicarbonate secretion
Reducing H+ secretion
Promoting vasodilation

41
Q

What is the advantage of PGs?

A

PGs protect the stomach against damage

42
Q

Why do NSAIDS (e.g. aspirin) cause gastric bleeding?

A

Inhibit PG synthesis

Celecoxib, rofecoxib (selective COX-2 inhibitors) → less bleeding

43
Q

Which antibiotics can be used to treat a H.Pylori infection?

A

Omeprazole, amoxicillin and metronidazole, clarythromycin, tetracycline,bismuth chelates

44
Q

What cytoprotective effects do bismuth chelates have?

A

Provide physical barrier (coat) over surface/base of ulcer
Enhances local synthesis of PGs
Promote bicarbonate secretion

45
Q

What are the toxic effects of bismuth chelate?

A

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

46
Q

What caution must be taken before administering bismuth chelate to patients with renal failure?

A

If patient has renal impairment, [bismuth chelate]plasma may rise causing encephalopathy

47
Q

What are the unwanted side effects of bismuth chelate?

A

nausea, vomiting, blackening of tongue and faeces

48
Q

What advice is given to patients when taking bismuth chelate?

A

Adhere to treatment
Resistance to metronidazole
Do not give metronidazole in first trimester
Disulfiram-like reaction results if metronidazole is taken with alcohol

49
Q

Which proton pump inhibitors treat gastric ulcers?

A

omeprazole, lanzoprazole, rabeprazole

50
Q

What are the consequences of constipation upon rectal distension?

A

Headache
Loss of appetite
Nausea
Abdominal distension and stomach pain

51
Q

What is constipation?

A

Holding of faecal matter → ↑ water loss and dryer faeces (*painful and harder to defecate)

Causes of Constipation

52
Q

What are the causes of constipation?

A 
↓ motility of large intestine
Old age
Damage to enteric nervous system of colon
Diet
Inactivity 
Drugs (polypharmacy)
53
Q

Which factors increase colon motility?

A

(↑ 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

54
Q

What signs indicate chronic constipation?

A

Acute onset constipation in older individuals
Weight loss (10lb)
Blood in the stool
Anaemia
Family history of colon cancer or inflammatory bowel disease

55
Q

How do we manage constipation?

A

Lifestyle changes
Diet, fluid intake and exercise and their effects on constipation (appealing?)
↑ fibre intake → bloating and flatulence (not appealing)
↑ water intake??

56
Q

What are purgatives?

A

laxatives, faecal softeners & stimulant purgatives can modulate/hasten food transit in the intestine

57
Q

Name examples of bulk laxatives

A 
Bulk laxatives: methylcellulose, 
Plant gums (e.g. sterculia, agar, linseed, bran, ispaghula husk- are polysaccharide polymers)
58
Q

What is the function of bulk-forming and osmotic laxatives ?

A

They retain water in gut lumen → promotion of peristalsis, but take a few days to work
Increase the stool’s solid content

59
Q

What is the side effect of bulk-forming use?

A

Bloating and flatulence

60
Q

How does the osmotic laxative (lactulose) maintain water in faeces?

A

↑s and maintains volume of fluid in the lumen of bowel by osmosis

61
Q

How does lactulose aid the movement of contents through the gut?

A

↑s transfer of gut contents into the intestine

62
Q

WHat effect does lactulose (osmotic laxative) have on defecation?

A

Increases volume of gut content entering the colon → distension and purgation in 1hr

63
Q

What is the consequence of taking high doses of osmotic laxatives?

A

High doses → flatulence, cramps, diarrhoea, vomiting and tolerance

64
Q

What is the role of anti-diarrhoeal agents?

A

Maintain body fluids and electrolytes
Identify causal organism and if possible treat with antibiotics e.g. erythromycin for Campylobacter jejuni
Modify secretion/ absorption balance

65
Q

What are the causes of diarrhoea?

A

Infectious agents
Toxins
Anxiety
Drugs

66
Q

What are the consequences of diarrhoea?

A

↑ motility of GIT, with ↑ secretion and ↓ absorption of fluid → ↓ electrolyte (Na+) and H2O

67
Q

What is the effect of diarrhoea due to cholera?

A

loss of gut contents

68
Q

How can we maintain fluid and electrolyte balance in patients with diarrhoea?

A

Maintain fluid and electrolyte balance: Oral rehydration therapy

69
Q

Why may anti-infectives be used to tackle diarrhoea?

A

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

70
Q

What drugs are used to decrease motility through the gut?

A

Use of anti-motility drugs: adsorbents and agents that modify fluid and electrolyte transport

71
Q

How can we mediate the movement of substances in the gut?

A

The movement of substances in the gut can be modulated by:

Purgatives: ↑ passage of food through the intestine

72
Q

Which agents increase motility without leading to purgation?

A

Antidiarrhoeal drugs → ↓ movement

Antispasmodic drugs → ↓ movement; relax smooth muscles in GIT

73
Q

Explain the effects pf loperamide on travellers diarrhoea

A 
Selective on GIT, decreases passage of faeces; 
Decreases duration of illness
Anti-secretory action; 
↓ intestinal motility
 *codeine has same effects
74
Q

What are the effects of bismuth subsalicylate on travellers diarrhoea?

A

Decreases fluid secretion in bowel;
Safe for young children;
May cause tinnitus and blackening of stool

75
Q

Describe the mechanism of action of loperamide?

A

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

76
Q

Explain the advantage of using loperamide to treat diarrhoea?

A

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

Gastrointestinal (18 decks)

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