MP322 - MANAGEMENT OF DIARRHOEA AND CONSTIPATION Flashcards
diarrhoea
increased liquidity of the stool and/or increased loose or liquid stool frequency (>3 times/day)
classification of diarrhoea
acute <14 days
persistent >14 days
chronic >30 days
physiological classification of diarrhoea
inflammatory and non-inflammatory
inflammatory diarrhoea
- presence of an inflammatory process
- mucoid and bloody stool, tenesmus, fever cramp-like abdominal pain
- small frequent bowel movements
- histology of GI tract is abnormal
non-inflammatory diarrhoea
osmotic and secretory
- watery, large-volume, frequent stool (>10-20/day)
- volume depletion is possible due to frequency
- histology of GI tract is preserved
osmotic non-inflammatory diarrhoea
- presence of unabsorbed or poorly absorbed solute (e.g. Mg2+, mannitol)
- stool volume is small
- stops or improves with fasting
- due to maldigestion or malabsorption
secretory non-inflammatory diarrhoea
- altered transport of ions across the mucosa
- increased secretion and decreased absorption of fluids
- doesn’t improve with fasting
- stool volume larger than osmotic
bacteria that cause diarrhoea
E. Coli
Campylobacter
Salmonella
C. difficile
Listeria
V. Cholerae
viruses that cause diarrhoea
rotavirus
norovirus
adenovirus
astrovirus
parasites/protozoa that cause diarrhoea
Entamoeba Histoltica
Giardia Lamblia
Cryptosporidium
mechanisms causing diarrhoea
increased secretion or decreased absorption of fluids and electrolytes
absorption of water is passive and secondary to the absorption of solutes
Cl- transport in the intestine
- secreted Cl- is provided by the Na+/K+/2Cl- cotransporter
- activity is driven by low intracellular Na+
- Cl- is secreted through Cl- channels
- Na+ and water enter lumen by paracellular transport
infection - Vibrio Cholerae
- cholera toxin enters cells
- activates G protein, which activates adenylyl cyclase
- increases cellular cAMP and activation of protein kinase A (PKA)
- phosphorylation of Cl- channel
- increased efflux of Cl- (and water)
use of antibacterial
- disruption of normal intestinal microflora
- proliferation of opportunistic pathogens (C. Difficile)
- impaired fermentation of poorly absorbed carbohydrates and/or reduced production of short chain fatty acids
increased motility
- reduction in intestinal transit time results in inadequate absorption
- drugs with cholinergic activity (e.g. pilocarpine for dry mouth)
- drugs with anticholinesterase activity (e.g. donepezil for Alzheimer’s disease)
drug treatment of diarrhoea
antimotility drugs (stop excess water being secreted)
prolong the duration of intestinal transit
diphenoxylate drug
- opioid receptors on neuronal varicosities
- activation of opioid receptors decreases ACh release
- peristaltic activity decreased
- segmental contraction increase
- usually provided as a mixture with atropine (co-phenotrope)
codeine phosphate
POM
- symptomatic relief of chronic diarrhoea
- mechanism of action similar to diphenoxylate
adverse effects of opiates
rebound constipation
higher doses can have CNS effects
prolonged use can lead to opioid dependence
Racecadotril
PRO-DRUG
- activation of S opioid receptors decreases the cellular cAMP levels
- decreased secretion of Cl-
- decreased water secretion
- metabolised to thiorphan
thiorphan - enkephalinase inhibitor (prevents the breakdown of enkephalins)
Enkephalins are the endogenous activator of S opioid receptors
Constipation
heterogeneous disorder
symptoms:
- <3 bowel movements per week
- straining
- lumpy or hard stools
- sensation of anorectal obstruction
- sensation of incomplete defaecation
- manual manoeuvring required to defaecate
causes of primary constipation
- normal-transit constipation
- slow-transit constipation
- pelvic floor dysfunction
- IBS with constipation
causes of secondary constipation
- medications
- metabolic disorders
- endocrine disorders
- psychiatric (anxiety, depression)
drug induced constipation
drugs with anticholinergic activity
- antidepressants, antihistamines, antimuscarinics, antipsychotics, antiparkinsonian agents
- opioids
- drugs affecting electrolytes
- laxative misuse (atonic colon)
treatment of constipation
laxatives
- osmotic
- stimulant
- bulk-forming
- faecal softeners
Linaclotide
guanylate cyclase-C agonist
- 14 amino acid synthetic peptide
- increases cellular cAMP and activation of protein kinase G (PKG)
- phosphorylation of Cl- channels
- increased efflux of Cl- (and water)
- restricted use (SMC)
used to treat IBD with constipation
Lubiprostone
Prostone
- derived from functional fatty acids that occur naturally
- directly activates Cl- channel (CIC-2)
- increased efflux of Cl- (and water)
- may restore mucosal barrier function
adverse effects of linaclotide and lubiprostone
generally well tolerated
diarrhoea
nausea
vomiting
abdominal pain
