Lecture 8 - Diarrhoea and Constipation Flashcards
What is diarrhoea?
Increased liquidity of the stool and/or increased loose or liquid stool frequency (>3 times a day)
Classifications of diarrhoea?
acute (<14 days)
persistent (>14 days)
chronic (>30 days)
How many people a year suffer from one or more episodes of acute diarrhoea?
1 billion
What % of acute cases are caused by infectious agents?
90%
what are the two catagories of diarrhoea?
Inflammatory and non-inflammatory
What is inflammatory diarrhoea?
Presence of an inflammatory process (can be due to viral, bacterial or parasitic infection, radiation injury or inflammatory bowel disease
Symptoms of inflammatory diarrhoea?
mucoid and bloody stool, tenesmus, fever, crampy abdominal pain
small frequent bowel movements
Histology of GI tract in inflammatory diarrhoea?
abnormal
What is diarrhoea the main cause of?
death or disability in the world today
death is due to decreased blood volume
What is non-inflammatory diarrhoea?
watery, large volume frequent stool (>10 to 20 per day)
volume depletion is possible due to high volume and frequency of bowel movements
Symptoms of non-inflammatory diarrhoea?
No tenesmus, blood in the stool, fever or faecal leucocytes
Histology of GI tract in non-inflammatory diarrhoea?
Preserved
2 types of non-inflammatory diarrhoea?
Osmotic diarrhoea and secretory diarrhoea
Osmotic diarrhoea?
Presence of unabsorbed or poorly absorbed solute (eg Mg2+, mannitol and sortbitol - these promote water into the GI tract)
due to maldigestion or malabsorption
Stool volume of osmotic diarrhoea?
Small (compared to secretory diarrhoea)
Osmotic diarrhoea stops due to?
Stops or improves with fasting
Secretory diarrhoea?
altered transport of ions across the mucosa
increased secretion and decreased absorption of fluids
Secretory diarrhoea does not improve with?
Fasting
What is maldigestion?
when there is impaired digestion of nutrients in the GI lumen or the border of the mucosal epithelial cells
What is the most common cause of acute diarrhoea?
Infectious agents such as bacteria, viruses and parasites/protozoa
Bacteria causing diarrhoea?
E. coli, campylobacter, salmonella, C difficile, listeria, vibrio cholerae
E coli?
most common in developing countries, also a common cause of travellers diarrhoea
Campylobacter?
comes from contaminated poultry in developed countries
Salmonella?
ingestion of contaminated poultry (eggs and milk products)
C difficile?
one of the most common HAI, frequent cause of morbidity and mortality among older hospitalised patients
Viruses that cause diarrhoea?
Rotavirus, norovirus, adenovirus, astrovirus
Rotavirus?
leading cause of viral gastroenteritis and diarrhoeal deaths worldwide
it is vaccine preventable and causes diarrhoea that results in volume decrease
Norovirus?
major cause of epidemic gastroenteritis
Parasites/protozoa that cause diarrhoea?
Entamoeba histoltica, giardia lamblia, cryptosporidium
E. histoltica?
40-50 million develop colitis or extraintestinal disease annually
~40,000 deaths
is asymptomatic
Giardia lamblia?
causes epidemic and sporadic diseases, important cause of water and food borne diarrhoea
Cryptosporidium
has become more prevalent with increase of HIV and increased use of immunosuppressants in transplant patients
What is the most common non-infectious cause of diarrhoea?
medication
What % of adverse drug reactions does diarrhoea account for?
~10%
CV drugs that cause diarrhoea?
digoxin, quinidine, propranolol, ACE inhibitors
GI drugs that cause diarrhoea?
antacids (magnesium salts), laxatives, H2 antagonists
Endocrine system drugs that cause diarrhoea?
oral hypoglycaemic agents, thyroxine
Antibacterials that cause diarrhoea?
amoxicillin, cephalosporins, erythromycin
What type of diarrhoea do most drugs cause?
secretory
What are the 4 main processes of the GI tract?
digestion, absorption, secretion and motility
How much fluid enters GI tract every day?
Normally ~10L
How much fluid is reabsorbed?
~99%, 0.1ml is excreted normally
What is the major site of reabsorption?
the small intestine
What is diarrhoea caused by?
a decreased absorption of fluids and/or increased secretion of fluid
can also be caused by an increase in bowel motility
What does water follow?
the movement of electrolytes and glucose
follows the osmotic gradient
What do epithelial cells do?
form a boundary between the external environment and internal environment
they also transport material across cells
What is absorption?
transporting material from the lumen to the internal environment
What is secretion?
process of transporting material from the internal environment to the lumen
What are enterocytes?
the intestinal absorption cells
they are similar to columnar epithelial cells
Where are enterocytes found?
all the way along the large and small intestine, they are the most abundant cell in the GI tract
What do microvilli do?
increase the surface area for digestion and transport of molecules from the lumen
What membrane faces the GI lumen?
apical membrane
What membrane faces the interstitial fluid?
the basolateral membrane
Why is transport across enterocytes possible?
the membrane on one side has different transport systems to the membrane on the other side, meaning that they are polarised cells
Give examples of mechanisms that can cause diarrhoea?
increased Cl- secretion
reduced Na+ absorption
increased paracellular permeability
reduced Cl- absorption
reduced H2O absorption
reduced Na+ and glucose absorption
How does water move across cell membranes?
It is not actively transported
active transport of sodium results in a decrease concentration of sodium on one side the the epithelial later and an increase on the other side, these changes are accompanied by changes in water concentration, which causes water to move by osmosis
What diarrhoea does vibrio cholerae cause?
acute diarrhoea that does not cause enteritis
What does adenelyl cyclase do?
converts ATP to cAMP
what does an increase in cAMP in the cell do?
activates protein kinases
it also inhibits the Na+/H+ exchanger, which prevents absorption of sodium from the GI lumen (attracts water to the GI lumen)
What does the use of antibacterials cause?
a distruption of normal intestinal microflora and proliferation of opportunistic pathogens (C difficile)
What does C difficile produce?
2 different toxins
What % of cases of drug induced diarrhoea are due to antibacterials?
~25%
What % does C difficile account for?
> 20% of antibacterial associated diarrhoea and almost all causes of pseudomembranous colitis
What is the disease spectrum of antibacterial associated diarrhoea?
from benign to pseudomembranous colitis
most frequently it is benign, appearing within the first days of treatment and disappearing when treatment is stopped
What else can antibacterials cause?
impaired fermentation of poorly absorbed carbohydrate and/or reduced production of short chain fatty acids - resulting in diarrhoea
Frequency of diarrhoea caused by antibiotics?
~40%
What does reduction in intestinal transit time cause?
inadequate absorption of nutrients
What do drugs with cholinergic activity do?
mimic the parasympathetic effects of acetylcholine by directly acting on the acetylcholine receptors on smooth muscle cells
How does pilocarpine work?
Has cholinergic activity
(usually used for dry mouth)
excites smooth muscle cells in the GI tract causing an increase in the motility and leading to diarrhoea as an adverse effect
Drugs with anticholinesterase activity?
Donepezil (for Alzheimer’s disease)
drug prevents the breakdown of acetylcholine, allowing it to accumulate in the synaptic and neuromuscular junctions, prolonging its effect
this enhances contractile effects and produces diarrhoea in up to 14% of patients
Drug treatment of diarrhoea?
antimotility drugs such as loperamide
these prolong the duration of intestinal transit by binding to opioid receptors in the GI trat
when to use antimotility drugs?
in uncomplicated acute diarrhoea in adults, not good for use in young children
What is important in all forms of acute diarrhoea?
fluid and electrolyte replacement
Symptomatic treatment of diarrhoea?
diet and oral rehydration therapy
Treatment of severe diarrhoea?
hospitalisation may be necessary for parenteral rehydration therapy and correction of hypokalaemia
How does most diarrhoea resolve?
Most are self limiting and resolve themselves without treatment
What does diphenoxylate work on?
Mu opioid receptors on neuronal varicosities
What does diphenoxylate cause?
a decrease in acetylcholine release, which results in a decrease in peristaltic activity and increased segmental contraction
How is diphenoxylate usually provided?
as a mixture with atropine (co-phenotrope)
What is codeine phosphate used for?
symptomatic relief of chronic diarrhoea
POM medicine
Mechanism of codeine phosphate ?
similar to that of diphenoxylate
Adverse effects of opiates?
rebound constipation
higher doses can have CNS effects
prolonged use can lead to opioid dependence
What side effects can patients taking medication that contains atropine experience?
nausea and dry mouth
What receptors does racecadotril activate?
delta opioid receptors
What does activation of delta opioid receptors cause?
decreased cAMP, causing a decrease secretion of Cl-, and therefore decreased secretion of water
What are the endogenous activator of delta opioid receptors?
enkephalins
What is racecadotril metabolised to?
Thoirphan
What is thiorphan?
an enkephalinase inhibitor (prevents the breakdown of enkephalins)
What does thiorphan cause?
enkephalins to be present for longer and stimulate delta opioid receptors, causing a longer inhibitory effects on the chloride ion channels and iproves diarrhoea
What does racecadotril act as?
an anti-secretory drug and is less likely to cause rebound constipation
What is constipation?
it is a symptom rather than a disease itself
a heterogenous disorder
What do patients with constipation report?
One of more of -
fewer than 3 bowel movements per week
straining
lumpy or hard stools
sensation of anorectal obstruction
sensation of incomplete defaecation
manual manoeuvring required to defaecate
What causes primary constipation?
intrinsic defects in colonic function
Subtypes of primary constipation?
normal transit constipation
slow transit constipation
pelvic floor dysfunction
irritable bowel syndrome with constipation
Normal transit constipation?
most common subtype, stool passes through the colon at a normal rate but patient finds it difficult to evacuate the bowels
Slow transit constipation?
decreased frequency, decreased urgency or straining
more common in females - have impaired phasic colonic motility
Pelvic floor dysfunction?
patients report prolonged/excessive straining, feeling of incomplete evacuation, difficult meals to evacuate
irritable bowel syndrome?
many reasons - genetic, environmental, psychological
Secondary constipation?
medications, metabolic disorders (hypercalcaemia, hypothyroidism), endocrine disorders, psychiatric (anxiety, depression, spinal cord diseases)
Drugs causing constipation?
drugs with anticholinergic activity, opioids, drugs effecting electrolytes, laxative misuse
Drugs with anticholinergic activity?
antidepressants, antihistamines, antimuscarinics, antipsychotics, antiparkinsonian agents
lead to a decreased motility which results in constipation
Antimuscarinics have …?
an inhibitory effect on the GI tract
Opioids causing constipation?
mechanism of action to treat diarrhoea will cause constipation by suppressing peristalsis, raise sphincter tone which delays passage time of faeces through GI tract
What does a delayed passage time through GI tract cause?
increased absorption of water and electrolytes
What does laxative misuse lead to?
atonic colon
Treatment of constipation
Laxatives
drug treatment is commonly used in constipation associated with IBS and chronic idiopathic constipation
Osmotic laxatives?
drawing fluid into the body or retaining fluid
macrogols, saline purgatives (milk of magnesium)
can take up to 48 hours to work
Stimulant laxatives?
increase motility and can cause stomach cramps
should be avoided if there is intestinal obstruction
excessive use can cause diarrhoea
rapid acting (8-12 hours)
Examples of stimulant laxatives?
glycerol and senna
Bulk forming laxatives?
Increase faecal mass which stimulated peristalsis
good for patients with hard stools and adequate fluid must be maintained to avoid intestinal obstruction
Examples of bulk forming laxatives?
methylcellulose, isphagula husk
Faecal softeners?
liquid paraffin
What is linaclotide?
14 amino acid synthetic peptide
What does linaclotide activate?
guanylate cyclase C (GC-C)
What does activation of GC-C cause?
increase cGMP and activation of PKG
what does increase cGMP and activation of PKG cause?
phosphorylation on Cl- channel, resulting in increased efflux of Cl- (and water)
What is GC-C?
a membrane protein which is also an enzyme
located on the apical membrane of the enterocytes
What is use of linaclotide restricted to?
restricted to use in patients with moderate to severe IBS with constipation who have not responded to other suitable treatments
How is linaclotide taken?
it is orally active
What is lubiprostone?
member of a class of agents called prostones
What are prostones derived from?
functional fatty acids that occur naturally
What does lubiprostone activate?
it directly activates the Cl- channel (CIC-2)
What happens upon activation of the Cl- channel
there is an efflux of Cl- into the GI lumen, which water follows
this relieves symptoms of constipation
What does drawing water into the GI lumen do?
helps facilitate movement of the stool to the colon
What is lubiprostone used to treat?
chronic idiopathic constipation in the adult population
What else might lubiprostone do?
restore mucosal barrier function
What are the adverse effects of linaclotide and lubiprostone?
They are generally well tolerated
diarrhoea
nausea
vomiting
abdominal pain
What has lubiprostone not been approved for?
SMC has not approved it for treatment of chronic idiopathic constipation (due to cost/benefit analysis)
