Drugs Affecting Gut Motility Flashcards
How is gastric motility controlled?
Myogenic
Neuronal
Hormonal
Tell me about myogenic control.
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
Tell me about the neural control of gut motility.
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
What are the different extrinsic nerves controlling gut motility?
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
What neurotransmitters are used in gut motility?
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
What is emesis?
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
What things cause vomiting?
Pregnancy Medications, toxins, pain, irradiation Smell, touch Intercranial pressure Stomach - stretching and inflammation Rotational movement
How is emesis controlled and what are the neurotransmitters involved?
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
What are the different classes of anti-emesis drugs?
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
Tell me a little about Domperidone (D2 antagonist)
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
Tell me about Ondansetron (5-HT(3) antagonist).
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)
Tell me about metoclopramide.
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)
Tell me about Hyoscine (ACh antagonist)
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
Tell me about Cyclizine (H1 antagonist)
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
What are the different classes of laxatives?
Non-pharmacological
Bulk - Fybogel Faecal softeners - Glycerol (also acts as a stimulant) Osmotic - Lactulose/macrogols/phosphate enemas Irritant/Stimulants - Castor Oil - Senna - Sodium picusulfate
What are some non-pharmacological laxatives?
Consider underlying medical cause - Diabetes, Parkinson's disease, dehydration, pregnancy or mechanical obstruction - Cancer!! Increase fluid intake High fibre diet Exercise
List some drugs that cause constipation. (5 will do)
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
Tell me about bulk laxatives.
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
Tell me about faecal softeners.
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
Tell me about osmotically active laxatives. (magnesium and sodium salts)
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
Tell me about osmotically active laxatives. (Lactulose)
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)
Tell me about osmotically active laxatives. (Macrogols)
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
How do irritant/stimulant laxatives work?
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
Give some example of irritant/stimulant laxatives.
Cator oil - powerful given orally 3hrs later watery discharge stool - but obsolete in clinical practice
Bisacodyl (phenylmethane) Anthraquinones: - Danthron - Senna plant - Rhubarb roots
How do you decide on what laxatives to use?
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)
What are important points to think of in diarrhoea
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
Tell me about anti-motility drugs.
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
Tell me about Bulk forming drugs.
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
Tell me about fluid adsorbents.
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
How is IBS treated?
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
