Drugs Affecting Gut Motility

Question 1

How is gastric motility controlled?

Answer 1

Myogenic

Neuronal

Hormonal

Question 2

Tell me about myogenic control.

Answer 2

Rhythmic contraction
Slow waves of depolarisation throughout the smooth muscle.

Passive current spread through gap junction

Interstitial cells of Cajal act as pacemaker to drive electrical activity

Question 3

Tell me about the neural control of gut motility.

Answer 3

Intrinsic and extrinsic control

Stimulation of the post-ganglionic cholinergic enteric nerves increases force of contraction of gut

Stimulation of non-adrenergic inhibitory nerves inhibits contractions

Question 4

What are the different extrinsic nerves controlling gut motility?

Answer 4

Intestino-intestinal inhibitory reflex
Distension of one intestinal segment causes complete intestinal inhibition

Anointestinal inhibitory reflex
Distension of the anus causes intestinal inhibition

Gastrocolic and duodenocolic reflexes
Stimulates motility after material has entered the stomach

Question 5

What neurotransmitters are used in gut motility?

Answer 5

All endocrine hormones effective in GI tract are peptides produced in endocrine cells of mucosa

Gastrin promotes acid secretion
Secretin - duodenum
Cholecystokinin - small intestine
Motilin - small intestine
Paracrine transmitters - histamine, Somatostatin and prostaglandins

Question 6

What is emesis?

Answer 6

Vomiting

The pyloric sphincter closes while the cardia and oesophagus relax

Gastric contents propelled by contraction of abdominal wall and diaphragm

Glottis closes with elevation of the soft palate preventing entry of vomitus unto the trachea and nasopharynx

Question 7

What things cause vomiting?

Answer 7

Pregnancy
Medications, toxins, pain, irradiation
Smell, touch
Intercranial pressure
Stomach - stretching and inflammation
Rotational movement

Question 8

How is emesis controlled and what are the neurotransmitters involved?

Answer 8

Vestibular apparatus
Acetylcholine, H1 (histamine)

AND

Postrema on the floor of the 4th ventricle
Dopamine

Feed into the Medullary Centre
Acetylcholine
H1
5-Hydroxytryptiamine (HT)3

Question 9

What are the different classes of anti-emesis drugs?

Answer 9

Dopamine D2 receptor antagonists

• Domperidone
• Metoclopramide
• (Phenothiazine’s)

5-HT - receptor antagonist
- Ondansetron

Anti-muscarinics
- Hyoscine

Histamine H1 receptor antagonists
- Cyclizine & Promethazine

Other agents

• Cannabinoids - nabilone
• Benzodiazepines - Lorazepam

Question 10

Tell me a little about Domperidone (D2 antagonist)

Answer 10

Treats mild nausea

Acts:

• Postrema on the floor of the 4th ventricle
• Stomach: increase rate of gastric emptying

Route: Oral or PR(extensive first pass metabolism)

But does not cross blood-brain barrier

ADR: Stimulates prolactin release (galactorrhoea) but rare dystonia

Question 11

Tell me about Ondansetron (5-HT(3) antagonist).

Answer 11

For severe or those on chemo

5-HT released into gut causes vagal stimulation

Acts:

• Postrema on the floor of the 4th ventricle
• Against vagal afferent nerves in GI

Indicated:
high doses of radiation sickness and Chemo/postoperative

Route: IV/IM or orally

The anti-emetic effect can be enhanced by single dose of corticosteroid

ADRs:
Headaches
Constipation
Flushing (IV)

Question 12

Tell me about metoclopramide.

Answer 12

In addition to D2 antagonism (4th ventricle and gastric emptying)

• Anticholinergic effects (GI)
• Blocks vagal afferent 5-HT(3)R (GI)

Indications:
GI cause for N&V; Migraine; Post-op

Routes: oral, IM, IV
Short t1/2 ~ 4hrs

ADRs:
Extrapyramidal reactions (dystonia) occur in 1%
(Therefore avoid Parkinson’s disease
Galactorrhoea)

Question 13

Tell me about Hyoscine (ACh antagonist)

Answer 13

Also known as scopolamine

Direct antagonist of muscarinic cholinergic receptors

Used to treat motion sickness (oral or patch)

Effects usually short lived (2 hours)

ADRs:
systemic anti-cholinergic effects
Bradycardia

Question 14

Tell me about Cyclizine (H1 antagonist)

Answer 14

Has additional anti-muscarinic effects

Used in acute nausea and vomiting

Can be given oral, IV or IM
But can cause QT prolongation and therefore Cl in myocardial ischaemia etc.

Crosses blood-brain barrier - sedative effect

Question 15

What are the different classes of laxatives?

Answer 15

Non-pharmacological

Bulk
- Fybogel
Faecal softeners
- Glycerol (also acts as a stimulant)
Osmotic
- Lactulose/macrogols/phosphate enemas
Irritant/Stimulants
- Castor Oil
- Senna
- Sodium picusulfate

Question 16

What are some non-pharmacological laxatives?

Answer 16

Consider underlying medical cause
- Diabetes, Parkinson's disease, dehydration, pregnancy or mechanical obstruction
- Cancer!!
Increase fluid intake
High fibre diet
Exercise

Question 17

List some drugs that cause constipation. (5 will do)

Answer 17

Anti-cholinergics
Aluminium antacids
Antidepressants (TCAs and SSRIs)
Antiepileptics (carbamazepine)
Antipsychotics (clozapine, quetiapine)
Antispasmodics (dicycloverine, Hyoscine)
Calcium supplements
Diuretics (indapamide)
Iron supplements
Opioids (codeine, buprenorphine)
Verapamil

Question 18

Tell me about bulk laxatives.

Answer 18

Ispaghula

Insoluble and non-absorbable substances which distend the gut

This then activates stretch receptors to make muscle contract behind the mass, and relax in front o f the mass

Vegetable fibre, resistant to digestive enzymes
Takes a few days to work
Attempt to re-establish normal bowel habit
Normal fluid intake essential

ADR: flatulence

Contraindications:
- Adhesions/ulceration - may cause intestinal obstruction

Question 19

Tell me about faecal softeners.

Answer 19

Arachis oil (enema and glycerol (supp.) act by lubricating and softening stool

• Safe!
• But not always effective

Indicated as per bulk laxatives but also:
Adhesions etc. as no risk of obstruction
- Anal fissures/haemorrhoids

Question 20

Tell me about osmotically active laxatives. (magnesium and sodium salts)

Answer 20

Magnesium and sodium salts

Cause water retention in small/large bowel to increase peristalsis
Act quickly and are severe
Usually PR
Would reserve for ‘resistant’ constipation and if urgent relief required

Question 21

Tell me about osmotically active laxatives. (Lactulose)

Answer 21

Lactulose - disaccharide (galactose/fructose)

Cannot be hydrolysed by digestive enzymes
Fermentation of lactulose by colon bacteria leads to acetic and lactic acid (osmotic effect)

Oral
Takes 48hrs to work
Used in liver failure (reduced production of ammonia)

Question 22

Tell me about osmotically active laxatives. (Macrogols)

Answer 22

Movicol (polyethylene glycol)

Powder (oral)
May prevent dehydration
Initial effects within hours
Takes 2-4days to get full relief

Caution required to prevent intestinal obstruction

Question 23

How do irritant/stimulant laxatives work?

Answer 23

They irritate the mucosa
Excitation of sensory nerve ending leads to water and electrolyte retention and thus peristalsis

Used for rapid treatment
- e.g. faecal impaction or surgical prep.
Can act 6-8hrs (orally) so bedtime Rx
Repeated use:
- Colonic atony (and thus constipation)
- Hypokalaemia

Question 24

Give some example of irritant/stimulant laxatives.

Answer 24

Cator oil - powerful given orally 3hrs later watery discharge stool - but obsolete in clinical practice

Bisacodyl (phenylmethane)
Anthraquinones:
- Danthron
- Senna plant
- Rhubarb roots

Question 25

How do you decide on what laxatives to use?

Answer 25

If history and examination reveals soft faeces:
- Stimulant laxatives (e.g. senna, bisacodyl, glycerol)

If history and digital rectal examination reveals hard faeces:

• Osmotic laxatives (e.g. Movicol)
• Bulk-forming laxatives (e.g. ispaghula)

Question 26

What are important points to think of in diarrhoea

Answer 26

Think cause!!!

May represent overflow constipation
Anti-diarrhoeal drugs treat symptoms NOT the cause
Appropriate fluid/electrolyte management is important

Three key types:

• Anti motility
• Bulk forming
• fluid absorbents
• Fluid adsorbents

Question 27

Tell me about anti-motility drugs.

Answer 27

Opiate analgesics (codeine)
Opiate analogue - Loperamide (Imodium)
(40 times more potent then morphine as anti-diarrheal agent and penetrates CNS poorly)

Act via opioid receptors in bowel:
Reduce bowel motility - increase time for fluid to reabsorb
Increase anal tone and reduce sensory defecation reflex

Good for chronic diarrhoea
Avoid in IBD - toxic megacolon

Question 28

Tell me about Bulk forming drugs.

Answer 28

A relatively small amount of faecal fluid (10-20ml) influences composition
Drugs such as ispaghula act via water absorption

Particular useful for patients with IBS (constipation and diarrhoea) and those with an ileostomy

Question 29

Tell me about fluid adsorbents.

Answer 29

A relatively small amount of faecal fluid (10-20ml) influences composition

Kaolin acts as a fluid absorbent, therefore producing a more formed stool
Very little use

Question 30

How is IBS treated?

Answer 30

Mebeverine - reserpine derivative
It has direct effects on colonic hypermotility
It relieves spasm of intestinal muscle
It does not have troublesome systemic anti-muscarinic side effects

Useful when combined with bulk forming agent
Other smooth muscle relaxants - peppermint oil and alverine