MP322 - Management of GastroIntestinal and Endocrine systems Flashcards
Dyspepsia occurs in how many % of the population?
Around 40%, and leads to primary care consults in 5% and endoscopy in 1%
What findings are identified after a patient undergoes endoscopy?
- 40% - non-ulcer (functional dyspepsia)
- 40% - GORD confirmed
- 13% - ulcer disease
- 2% - Gastric Cancer
- 1% - oesophageal cancer
How is the lining of the stomach protected?
The upper mucosal layer releases alkaline mucus, keeping the layer safe from exposure to the stomach acid
There are tight junctions between epithelial cells
Damaged cells usually get replaced every few days
What factors cause/ contribute to Peptic Ulcer Disease?
- H.Pylori bacteria
- Smoking, alcohol, genetics, and stress raise the likelihood of developing ulcers
- Use of NSAID’s reduce the production of protective prostaglandins, again, rendering it more likely
- Hypersecretory states (but these are uncommon)
What are the symptoms of a Peptic Ulcer?
- Abdominal pain, discomfort and/or nausea
- Pain in the epigastrum and usually not radiating
- Burning, gnawing, and hunger pains?
- Gastric ulcer pain are aggravated by food, but duodenal ulcers are relieved upon food consumption
How is a peptic ulcer definitely diagnosed?
Usually GP’s likely to refer for endoscopy, those are cameras sent through the oesaphagus, to view stomach and duodenal area, to examine for ulcers.
Other methods are possible via lab work if believed to be caused by H.Pylori
What is H.Pylori and how is it related to peptic ulcers?
40% of individuals are believed to be infected with H.Pylori.
H.Pylori is a gram-negative bacterium responsible for 95% of gastric ulcer patients and 80% of dudodenal ulcer patients
Dr Marshall and Warren won Nobel Prize in 2005 for role in identifying H.Pylori in gastritis.
Where does H.Pylori target?
Lower part of the stomach, H.Pylori causes inflammation of gastric mucosa (leading to gastritis)
It can pass the mucus layer of the stomach and raise pH, causing mucin to de-gel.
Where H.Pylori is suspected, how can this be diagnosed?
Can do serologic evaluation for presence of H.Pylori antibodies but this may not be reliable as these can be present due to a previous infection
Urea Breath Test can be done based on the idea that H.Pylori contains large amount of the enzyme urease, which converts urea to NH3 and CO2 (carbon 13).
Can also use stool antigen test designed to detect an antigen released by organisms present in the stomach - this will prove an active infection.
If H.Pylori is not eradicated, what happens?
80% of H.Pylori infection-related ulcers can re-occur within a year.
What does the stomach body secrete?
Mucus via mucous cells - secrete bicarbonate
Parietal Cells - release stomach acid (HCl), and intrinsic factor
Enterochromaffin-Like cells (ECL), release histamine
Chief cells - Secrete pepsinogen
What different components act on the parietal cells?
- Acetylcholine acts on M3 receptors - promotes acid secretio
- Histamine acts on H2 receptors - promotes gastric acid secretion
- Gastrin acts on CCK receptors on parietal cells, which also promotes secretio of acid.
How is HCl produced for the stomach?
Carbonic anhydrase converts to Bicarbonate and Hydrogen ions
Bicarbonate is exchanged for Chloride ions and said chloride ions diffuse into the stomach lumen
Hydrogen ions are then pumped into the lumen by the Hydrogen/Potassium/ ATPase
How are peptic ulcers treated?
Antacids are used. These are antisecretory agents.
They can raise pH above 3 for few hours/ day and this promotes healing.
Duration of acid suppression determines how quickly stomach will heal
Rapid healing requires suppression for 18-20 hours a day.
What are H2 receptor antagonists?
These are products such as cimetidine, ranitidine, nizatidine, and famotidine
Act competitively on H2 Receptors on gastric acid parietal cells
Reduce basal acid secretion and prevent the increase that occurs in response to secretory stimuli.
This can reduce secretion by around 60%
Can be used for ulcers but relapse is common after treatment stops.
Side effects of H2 antagonists?
Diarrheoa,
Headache,
Confusion in elderly,
Gynaecomastia with Cimetidine (because of anti-androgen effect)
Cimetidine inhibits cytochrome P450 system (interacts with warfarin, phenytoin, and theophylline)
What are proton pump inhibitors?
Products such as Omeprazole, lansoprazole, pantoprazole, and esomeprazole
These inhibit the pump - almost completely block acid secretion
Proton Pump Inhibitors are irreversible, and acid secretion can only return with synthesis of new enzymes (H+, k+ ATPase)
Acid secretion inhibited by 90% for 24 hours with single dose
Adverse effects of PPI’s?
GI upset (discomfort, nausea, diarrheoa)
Headache
Skin Rashes
Omeprazole has both stimuatory and inhibitory effects on cytochrome p450
Long term use may cause Gastric Atrophy
Osteoprosis
Treatment regimen to eradicate H.Pylori infection
Triple therapy:
PPI
Amoxicillin
Clarithromycin OR metronidazole
For patients allergic to penicillin:
PPI
Clarithromycin
Metronidazole
Example of cytoprotective agents which can reduce acid secretion?
Misoprostol - it’s a metyl analogue of prostaglandin E1, and enhances duodenal bicarb secretion
Weakly inhibits gastric secretion by activating prostaglandin receptor on parietal cells.
Causes increased blood flow
Must NOT be used in pregnancy, as it can cause intrauterine contractions to be induced, which can lead to abortions etc.
What is Zollinger- Ellison Syndrome?
Rare disorder which can cause gastric or duodenal ulcers (usually multiple), as well as in the jejunum
Massive gastric acid hypersecretion
Due to gastrin secreting tumour in the pancreas or duodenum (gastrinoma), that stimulates acid secretion in stomach
Patient likely to have intractable ulcer disease
Treatment must control the hypersecretion and the gastrinoma
What is the situation with GORD?
Amount of acid secretion
Functionally incompetent LOWER oesophageal sphincter
Allows reflux of gastric contents (containing acid and pepsin into oesophagus
Symptoms - restrosternal burning
What medications can assist with GORD?
Antacids and antacid/alginate combinations
Drugs which inhibit gastric acid secretion (H2 receptor antagonists and proton pump inhibitors)
Drugs which act on Oesaphageal and/or gastric motility.
What is Barrett’s Oesaphagus?
This is commonly diagnosed in patients with long term GORD
Caused by the replacement of normal stratified squamous epithelium by columnar epithelium with goblet cells
Can lead to oesophageal adenocarcinoma (>85% mortality)
What is Inflammatory Bowel Disease?
This is a broad term consisting of 2 diseases - Ulcerative Colitis and Crohn’s disease
Both are characterised by inflammation, swelling, and ulceration of intestinal tissue - chronic periods of remission
Symptoms include stomach pain, weight loss, diarrheoa (blood/ mucus), and tiredness
Can also cause joint pain, inflamed eyes and rashes.
What is the main difference between Crohn’s and Ulcerative Colitis?
UC only affects the large bowel and inflammation is on the inner lining.
Crohn’s can affect any area of the GI system and all layers of tissue can be inflamed.
How is IBD diagnosed?
Symptoms presented in Primary care,
Blood tests conducted for anaemia, vitamin deficiencies, and inflammatory markers
Can also get an X-Ray or MRI
Sigmoidoscopy and Colonoscopy
For Chron’s disease, small bowel enema and small capsule endoscopy can be used.
Causes of IBD?
Genetics,
Autoimmune Disease
Environmental
Previous infection
Prevalence of IBD?
Most common in late teens or early 20’s, more common with white ethnic folk, is slightly more common in women than men,
can affect 1 in 350 in the UK.
What is the main aim of treatment?
Induce and maintain remission
Reduce symptoms and improve quality of life
Reduce inflammation - steroid, aminosalicylates, and cytokine modulators
Reduce autoimmune response - immunosuppressant drugs
How are Corticosteroids administered and examples?
Administered Orally and rectally - should use GR/ MR forms or enemas and foams etc.
Hydrocortisone
Beclomethasone
Budesonide
Prednisolone
How does Steroids work in terms of their pharmacology?
Reduce inflammatory mediators directly, and also have effects on expression of genes associated with inflammatory and anti-inflammatory proteins
What are the cautions of Corticosteriods?
Avoid in congestive heart failure, hypothyroidism, osteoprosis, and untreated infection
Side effects of Corticosteroids?
Insomnia, dyspepsia, Cushing’s syndrome, impaired healing, adrenal suppression with long term use.
Interactions of corticosteroids?
Grapefruit juice increases plasma concentration or oral budesonide, corticosteroids antagonise diuretic effect.
Examples of Aminosalicylates and how they’re administered?
Administered orally or rectally - Can be MR tabs/ caps/ granules, suspensions, or foam, suppository, enema’s
Balsalazide
Mesalazine
Olsalazine
Sulfalazine
Side effects of Aminosalicylates?
Blood disorders - unexplained bleeding, brusing, purpura, sore throat, fever, or malaise during treatment?
Renal function should be checked before starting oral therapy then 3 months later, then annually
Salicylate sensitivity?
If you are diagnosed with Ulcerative colitis….
Aminosalicylates are likely to be recommended:
- As an initial treatment for people who have mild to moderate flare-ups of Colitis.
- To maintain a period of recovery (remission), and help prevent flare-ups of colitis in longer term
If you are diagnosed with Crohn’s…
Aminosalicylates are not commonly prescribed unless:
- To get your symptoms under control, if your symptoms are mild, and you cannot, or decide against usage of steroids
- If it is not clear whether you have Crohn’s or colitis?
- To help maintain remission if you have had surgery for Crohn’s
What are the predominant interactions and side effects of Sulfasalazine?
Urine and contact lenses are coloured orange - hence contact lenses may be discouraged
Sulfasalazine decreases concentration of digoxin (moderate) and absorption of folates (moderate).
What is the function of cytokine modulators?
These are monoclonal antibodies which inhibit pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-a)
Administered subcutaneously
Examples - infliximab, adalimumab, golimumab, vedolizumab
These stop the expansion of activated T-cells by interrupting the calmodulin-calcineruin cascade.
How does immunosuppressants work in the treatment of IBD?
Mainly T-cell effects, administered orally or by injection, care required when handling in pharmacy
Azathioprine, Ciclosporin, mercaptopurine
Methotrexate
Anticancer drugs with blood toxicity and liver toxicity so require regular monitoring of blood counts and organ function for safe use
How is methotrexate administered?
Weekly dosage, usually orally but can be done via subcutaneous and intramuscular injection
2.5mg tablets normally used
Can get sore throats, bleeding, bruising, and mouth ulcers.
Regular monitoring - FBC, renal and liver
Keep safety card
High risk drug for MCR
In what manner are IBD drugs used?
In mild cases of disease in rectum and rectosigmoid is treated via local steroid or aminosalicylate
Diffuse or unresponsive IBD is treated orally as above
Parenteral administration is used in severe cases (steroid, immunosuppression and antibody therapy)
Non-drug treatment for IBD?
Smoking cessation
Attention to diet
- low residue diet
- trigger foods?
Surgery
- Stoma operations
- resection operations
Examples of alginates?
Peptac, gaviscon (rafting agents)
Examples of antacids?
Co-magaldrox, magnesium trisilicate
Examples of PPI’s and strengths?
Omeprazole - 10, 20, 40mg
Lansoprazole - 15, 30mg
Esomeprazole - 20, 40 mg
Rabeprazole - 10, 20mg
Examples of PPI dosage forms?
Tabs, caps, granules - gastro-resistant
Dispersible, oro-dispersible tabs
Oral Liquids/ suspensions from specials
Injections
What are the cautions associated with PPI use?
Increased risk of bone fracture on prolonged use in susceptible patients
Increase of C.dif infection
Masks symptoms of cancer
Rebound hyper secretion of acid on cessation
What common interactions occur with PPI’s?
Esomeprazole and Omeprazole reduce the antiplatlet effect of clopidigrel
Pantoprazole may increase anticoagulant effect of warfarin.
Examples of side effects of PPI’s?
Abdominal Pain, headaches - common
Arthralgia, parasthesia - uncommon
Confusion, gynaecomastia - Rare
Examples of H2-receptor antagonists?
Ranitidine (150, 300mg)
Cimetidine (200, 400, 800mg)
Famotidine (20mg, 40mg)
Nizatidine (150, 300mg)
Side effects of H2R antagonists?
- Masks symptoms of cancer
- Diarrheoa, dizziness (common)
- erythema - multiform (uncommon)
- Hepatitis, confusion (rare).
Interactions of H2R antagonists?
Cimetidine increases blood conc of erythromycin
Famotine and ranitidine reduce plasma conc or atazanavir
What other drugs can be used in disorders of gastric acid and ulceration?
Chelates and complexes:
Sucralfate - 1000mg
Tripotassium dicitratobismuthate (120mg)
Prostaglandin analogue:
Misoprostol (200 mcg)
Pro-kinetic drugs:
Domperidone, metoclopramide
How should drugs like antacids and PPI’s be used?
Should use lowest effective dose for shortest period, move from treatment doses to maintenance dose after period of time dependent upon the indication
Can be used in combination with antibacterials for H.Pylori eradication
What is Omeprazole’s mechanism of action?
Omeprazole is usually in gastro-resistant form when administered - hence, it passes the stomach and evades being ionised at this point - it enters the bloodstream once absorbed in the small intestine, and then, once going through the bloodstream, it reaches the parietal cells and diffuses through the fatty secretory canals of the parietal cells.
The pH of the parietal cells is very low (approx 1)
Because of this, and the presence of the pyridinic groups, becomes ionised, and is thereafter trapped in the parietal cells as it cannot diffuse back out
This results in a build up of omeprazole and causes chemical conversion
Omeprazole converts to sulphenic acid and then sulphenamide (Which is omeprazole’s active form). There is maximal conversion to sulphenamide due to steep proton gradient due to the proton pump enzyme
Omeprazole and Sulphenamide are ion-trapped (sulphenamide is a permanently charged quarternary ammonium salt
Sulphenamide reacts with thiol groups in the proton pump enzyme, which forms a stable disulphide complex.
No more acid is produced until new enzyme is made, which results in long term inhibition of gastric acid production.
How is Omeprazole designed fairly well?
- formulated in hard gelatine capsules - prevents conversion to sulphenamide in stomach
-if sulphenamide was formed, it would react with thiols in food and gastric mucus and be charged, rendering it unavailable.
How well does Omeprazole work?
High doses (80mg) are able to eliminate gastric acid production for atleast 4 hours
Single 40mg does can still affect acid secretion 72 hours later with effects taking 3-5 days to disappear.
Patients are given 20mg doses daily for 2-4 weeks (duodenal ulcer) or upto 8 weeks (gastric ulcer)
What is noted about Omeprazole and how it can be further improved?
Improvement was sought but omeprazole is effective as a chiral molecule
R-enantiomer was noted to give 15% gastric acid inhibition whereas the S-enantiomer gives 90% inhibition.
Hence, Esomeprazole is now manufactured which is simply omeprazole but only the s-enantiomer form.
How do H2 receptor antagonists work?
Ranitidine has a tertiary aliphatic amine, and 2 x Secondary alipathic amine, a thio-ether and nitro group.
The sulfur can be converted to suloxides etc.
There is likely complementary binding with the receptor and the antagonists, preventing the binding of other agonists etc. and therefore, inhibiting the activation of H2 receptors.
What is the name of the group of drugs which are typically used for treating GIT inflammation?
Aminosalicylates
What is the drug which is also referred as 5-Aminosalicylic acid?
Mesalazine
How are balsalazide and Olsalazine formulated?
Typically formulated as sodium salts due to the presence of carboxylic acids - the di-sodium salt makes the molecule more water soluble for formulation
What is sulfalazine?
It is a pro-drug, which is responsible for breaking down to the active 5-aminosalisilic acid (Mesalazine)
Where is the site of action for mesalazine?
The colon
What is the mechanism of action for aminosalicylates?
Not completely clear but believed to inhibit prostaglandin and leukotriene biosynthesis amongst others.
How is sulfalazine broken down?
Broken due to bacterial cleavage. The resulting sulfapyridine has no anti-inflammatory effect but can possibly give side effects hence balsalazide and olsalazine are designed.
Describe the colon environment?
Colonic microflora contains many species of bacteria
It is low in oxygen and pH is between 6-7
Gives rise to reductive environment
Hence bacterial azo-reductases cleave the sulfalzaine azo bond
How is aminosalicylates formulated?
They typically are formed as oral coated tablets which disintegrate at pH 7 in the intestine or suspension
Administered by the rectum in suppository and enemae form
How to work out fraction unionised for an acid?
1/(1+10^Ph-pka)
How to work out fraction unionised for a base?
1/(1+10^pka-ph)
In the stomach, describe how each functional group of aminosalicylates would act?
Carboxylic acid has pka 2.5
Aromatic hydroxyl (phenol) has pka 11.5 and is acidic.
Azo group acts fairly neutral in all circumstances
Sulphonamide group has pka 6.5 and is also acidic
Pyridine has pka of 4 and is basic so will be ionised.
Because pH of stomach is roughly 2, carboxylic acid, phenol and sulphonamide will remain unionised.
But pyridine will be fully ionised hence wouldn’t absorb across stomach membrane. Log D = 0
In the ileum, describe how each functional group of aminosalicylates would act?
In ileum, pH is roughly 7-8.
Pyridine won’t be ionised as it’s pka is 4 and it’s a base
Sulphonamide will be dissociated as it has a pka of 6.5
Carboxylic acid will be ionised fully (pka 2.5)
Phenol not ionised as it acts as acid and pka is 11.5.
Furthermore, due to molecule size, it’s able to pass through to colon where it is cleaved to 5-ASA
In the colon, describe how each functional group of aminosalicylates would act? N.B colon pH 5.5-7.8
Carboxylic acid will be ionised fully (pka 2.5) and therefore can’t passively absorb.
Sulphonamide will be dissociated as it has a pka of 6.5 and therefore not fully ionised. Pyridine also may be partially ionised as it’s pka is 4.
Phenol not ionised as it acts as acid and pka is 11.5.
Hence still has inability to passively be absorbed.
BUT, is broken down to 5-ASA
How does 5-ASA get absorbed in the colon?
With 5-ASA, the carboxylic acid is still fully ionised, and Aromatic amine and hydroxyl are not ionised, hence would still not passively absorb, but, because of the size of molecule being smaller, it is able to absorb through aqeuous gaps in between epithelial cells as it is a small molecule.
What is the advantage of using Olsalazine and Balasalazide ?
It does cleave but does not cause sulfa pyridyl toxicity.
What things can particle size affect?
Bioavailability
Settling rate
Possibility of obtaining homogenous mixtrues (and maintaining it)
Flowability
Other properties important for transformation of powders into tablets, capsules
How can particle size be increased?
Granulation
How can particle size be reduced?
Milling
Attrition
Examples of mills used and purpose?
Pin and ball mills - combined impact and attrition methods
vibration mills and hammer mills - Impact methods
End runners mills roller mills - compression methods
Cutting methods
Cutter mill can be used so the material is cut by one or more blade
Compression methods
Designed to apply pressure -
can use Mortar and Pestle or use Roller mills
Impact methods
designed to cause particles to be hit by a moving surface and Moving particles to hit a surface
Attrition methods
pressure and fiction principle
can use Roller mills, but ones which rotate at different speeds.
What is important for a ball mill?
The speed of rotation
Need to use 2/3 of the angular velocity where centrifugal force occurs to ensure that the balls are lifted on the rising side of the drum, until their dynamic angel of repose is exceeded. At this point, they fall back or roll back and cascade back to base of drum - rendering most effective size reduction
How to select appropriate form of mill?
consider Particle size to obtain
Consider characteristics of the material:
1 - Cutter mills for elastic, fibrous, materials like roots and woods.
2 - Attrition methods are used for ointments, solid in suspensions and pastes
3. impact methods used for brittle materials
Other factors such as cost,time, product stability should be considered.
What is the area diameter?
The diameter of the area of space taken by particle surface, assuming it is fully circular
What is the perimeter diameter?
The diameter of of the complete area of space taken by particle, regardless of circularity or lack thereof.
What is feret’s diameter?
The mean distance between 2 parallel tangents of the projected outline of a particle
How to analyse particle size??
Direct methods are sieving and microscopy
Indirect methods include sedimentation rate and permeability
What is the size range for using light microscopy?
1-1000 micrometers for particles - provides 2D images and very diluted suspension used.
What is the size range for using electron microscopy?
Size as low as 0.001 micrometers
Can give 3D images, and info on shapes
Disadvantages would be - expensive, high level of operator exercise.
How does Coulter Counter work?
Measure the volume of particles 0.1 to 1000 micrometres.
The aperture creates a sensing zone. As the particle moves through the aperture there is a change in impedance and the change can be correlated to the volume of the particle.
How does laser light scattering work?
Laser lights react with particles
Light is diffracted by particles by an angle which is inversely proportional to the volume of the actual particle
Detector analyses the radiation diffracted by the laser.
He and Ne laser are more widely used laser.
How does Sieve methods work?
Sieve’s seaparate varying sizes of particles, they are classified based on the sieve aperture diameter (expressed in Micrometres).
Sieve 1000 means the sieve aperture diameter is 1000 micrometer (1mm).
Sieve aperture diameter - distance between 2 consecutive wires.
What is sedimentation methods?
It is another method of particle seperation and the idea is the diameter of particles are estimated based on their sedimentation rate.
Stokes equation is also used for this.
What is cyclone separation?
This is where particles suspended in medium are introduced at high fluid velocity.
This results in vortex drawing them down due to fluid flow (gravity interactions are relatively minor).
A tip of cyclone fluid flow is above the critical velocity where it can escape through narrow opening.
This forms in inner vortex that travels up the cyclon and out of the outlet.
coarser particles separate from fluid stream and fall out.
What is elutriation and how does this work?
This is where fluid direction is opposite to sedimentation direction.
Separatiom is dependent on veolcity of fluid flow
Vectors are velocities
If settling velocity is less than the fluid flow velocity particles get moved into direction of fluid flow.
What is mixing?
Where two or more components are mixed together with the aim to obtain a homogenous distribution (without physical or chemical changes occurring).
What is a positive mixture?
Materials that mix sponteneously and irreversibly.
What is a negative mixture?
The components tend to separate
What is a neutral mixture?
Components neither tend to separate nor mix.
What is the definition of a random mixture?
Where the probability of selecting a particular type of particle is the same at all positions in the mix and is equal to the proportion of such particles in the total mix.
Observation about particles?
The more particles are present in a dose, ther more likely it is that the content will mirror the ratio in the mixture.
Lower the proportion of a component in the mixture, the more difficult it is to achieve the same correct amount in each sample.
What other parameters affect mixing?
Particle size
Shape
Density
Flowability
Ratio between different components
Mixing time
Electrostatic interactions
Total volume of powders being mixed
Friability of material
Humidity
What is segregation?
The opposite process of mixing (i.e. de-mixing)
Due to powders having different densities, shapes, and sizes
Equipment used for mixing?
Tumbling mixers (mixing franuels and free flowing powders - at correct speed, tumbling action and powder bed dilates, resulting in shear mixing).
Agitator mixers (motion of blade or paddle due to convection),
mixer- granulators (impeller blade at high speed forces material up before it drops. Overall high shear forces and good mixing. Once mixed, granulation liquid can be added, chopper blade to break down products.
What are the practical considerations for mixing?
- Initially mixing active ingredients with equal amount of diluent. Mix and then add more diluent
- Not overflow mixing unit.
What is granulation?
The process in which homogenous mixtures of primary powder particles form larger, still homogenous particles called granules.
What does granulation do?
Improve powder flow,
Patient segregation
improve compaction
What is wet granulation?
The powders are mixed with granulating fluid, and the mass is then forced through a sieve.
Mechanism of wet granulation?
- adheshion and cohesion forces in immobile films
- Interfacial forces in mobile liquid films.
- Solid bridges (hardening binders or crystallization of dissolved substances).
- Attractive forces between particles.
What machines can you use for wet granulation?
High speed mixer/ granulator - mixing, massing, and granulation all in one piece of equipment.
OR
fluidized - bed granulator - all granulation processes done in one equipment, but requires optimisation.
How does dry granulation work?
This is where a pressure is applied,
intermediate product is broken,
Sieving.
Dry granulation mechanisms?
- use of attractive forces between solid particles
- solid bridges (by partial melting)
Granules formed via applied pressure, formation of sheet, milling and sieving etc.
What form of compaction can dry granulation utilise?
Roller compaction.
What is diarrhoea?
Increased liquidity of stool and/or
Increased loose or liquid stool frequency (>3 times/day)
What are the classifications of diarrhoea?
Acute (less than or around 14 days)
Persistent (more than 14 days)
Chronic (more than 30 days)
Categories of diarrhoea?
Inflammatory
- Presence of inflammatory process
- mucoid and bloody stool, tenesmus, fever, crampy abdominal pain
- small, frequent bowel movements
- Histology of GI tract - abnormal
Non-inflammatory
- watery, large-volume, frequent stool (>10-20/day)
- volume depletion is possible due to high volume and frequency of bowel movements
- no tenesmus, blood in stool, fever or faecal matter
- histology of GI tract is normal
What are the different forms of non-inflammatory diarrhoea?
Osmotic diarrhoea:
- presence of unabsorbed or poorly absorbed solute
- stool volume is small
-stops or improves with fasting - mainly occurs down to maldigestion or malabsorption
Secretory Diarrhoea:
- Altered transport of ions across the mucosa
- Increased secretion and decreased absorption of fluids
- doesn’t improve by fasting
What is the main cause of acute diarrheoa?
Most common cause is infectious diseases
- Bacteria such as e.coli, campylobacter, salmonella, c.diff
- Viruses such as Rotavirus, norovirus
- Parasites/ protozoa such as Entamoeba histoltica, giardia lambia,
What is the main cause of diarrhoea with non-infectious causes?
Most common cause is medications:
- Cardiovascular drugs, such as digoxin, quinidine, propranolol, ACE inhibitors
- GI drugs such as magnesium based antacids, laxatives, H2 Antagonists
- Endocrine drugs such as Oral hypoglycaemic agents, thyroxine
- Antibacterials such as amoxicillin, cephlasphorins, erythromycin
What is important to note about water flow?
Water follows the movement of electrolytes and glucose
How is water absorbed via the GI tract?
Normally absorbed passively and is secondary to the absorption of solutes
How is Chloride secreted in the intestine?
The secreted chloride comes from the Na/K/2Cl cotransporter
This activity is driven by the low intracellular Na+
Once in the cells, chloride is secreted via chloride channels
Na+ and water enter lumen by paracellular transport
How does the Vibrio cholera toxin work?
The toxin from the cholerae enters the cell - activates the G protein, which activates adenylyl cyclase
This causes increased intracellular cAMP and activation of protein kinase A (PKA)
Leading to phosphorylation of chloride channels
Hence causing increased efflux of Cl- (and water) and diarrhoeal like symptoms
How does use of anti-bacterials contribute to diarrheoa?
Disruption of normal intestinal microflora
Proliferation of opportunistic pathogens occurs (C.diff for example)
Leading to impaired fermentation of poorly absorbed carbohydrate and/or reduced production of short chain fatty acids.
How can motility issues lead to diarrheoa?
This occurs due to a reduction in intestinal transit time and will result in inadequate absorption
- drugs with cholinergic activity - e.g. pilocarpine (for dry mouth)
- drugs with anticholinesterase activity e.g. donepezil (for Alzheimer’s disease)
How can loperamide help treat diarrheoa?
Loperamide is an anti-motility drug, which aims to prolong intestinal transit - can be used in uncomplicated diarrhoea in adults?
How does Diphenoxylate work in diarrhoea?
Acts on Mu opioid receptors on neuronal varicosities - causes decreased acetylcholine release
Causes the reduction of peristaltic activity and increase segmental contraction
Diphenoxylate is usually provided as a combination with atropine - co-phenotrope
Codeine also has similar mechanism of action
What are the adverse effects of opiates?
Rebound Constipation, higher doses can have CNS effects
Prolonged use can lead to opioid dependence.
What is the mechanism of action of racecadotril?
Causes the activation of delta opioid receptors, which decrease the cellular cAMP
Leads to the decreased secretion of Chloride and water
Note: Enkephalins are the endogenous activator of delta opioid receptors
Racecadotril (pro- drug) is metabolised to thiorphan and thiorphan acts as an enkephalinase inhibitor (i.e. prevents the breakdown of enkephalins)
What is constipation?
Heterogeneous disorder
Patients typically report 3 or more:
- fewer than 3 bowel movements a wee
- straining
- Lumpy/ hard stools
- Sensation of anorectal obstruction
- Sensation of incomplete defecation
- Manual manoeuvring required to defecate
What does the bristol stool chart show?
Level of stool liquidity - grade 1 being rock solid and grade 7 being pure liquid
Most common causes of constipation?
Primary:
1. Normal transit
2. Slow transit
3. Pelvic floor dysfunction
4. IBS with constipation
Secondary:
1. Medications
2. Metabolic disorders
3. Endocrine disorders
4. Psychiatric (anxiety, depression)
Mechanisms of drug-induced constipation?
- Anticholinergics
- Antidepressants, antihistamines, antimuscarinics, antipsychotics, antiparkinsonian agents - Opioids
- Drugs affecting electrolytes
- Laxative misuse - leads to atonic colon
Examples of laxatives?
- Osmotic
- Stimulant
- Bulk-forming
- Faecal softeners
Drug treatment:
- Predominantly used in constipation associated with irritable bowel syndrome and chronic idiopathic constipation
How does Linaclotide work?
Linaclotide is a 14 amino acid synthetic peptide
Linaclotide activates Guanylate Cyclase C (GC-C)
Increased cellular cGMP and activation of protein kinase G (PKG)
Phosphorylation of Cl- channel
Increased efflux of Cl- and water.
What is lubiprostone?
Member of a class of agents called prostones - derived from functional fatty acids that occur naturally
How does lubiprostone work?
Lubiprostone acts directly on Cl- channels (CLC-2)
This leads to efflux of Cl- (and water)
MAY also restore mucosal barrier function
What are the known adverse effects of linaclotide and lubiprostone?
Whilst both tend to be well tolerated;
- Diarrhoea
- Nausea
- Vomiting
- Abdominal Pain
What are steroids and how are they formed?
Steroids are hormones which control many biological events
They are derived from lanosterol in animals
Produced in human adrenal glands
Glucocorticosteroids are important in controlling inflammation - ALL share same 4 membered ring backbone
What properties does hydrocortisone have?
Has primary aliphatic hydroxyls, ketones and methyl groups.
How does beclometasone compare to hydrocortisone?
It has an extra double bond - which is useful in improving specificity
Chlorine is also added in place of a hydrogen and this makes the molecule more lipophilic
