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
Explain what will happen to steroids when ingested orally?
They are very lipophilic, as the hydroxyl groups are aliphatic, meaning they are unlikely to unionise due to having a pka of 16, hence, the LogD will be equivalent to LogP and will be able to passively absorb.
The hydrogen bonding exhibited should also aid in making it possible to passively absorb?
Steroids exhibit complementary binding at their receptors
What is lipinski’s rule of 5 and why does this matter?
It is believed that orally absorbed molecules are likely to observe factors in multiples of 5
- A molecular weight less than 500 da
- No more than 5 hydrogen bond donors
- No more than 10 hydrogen bond acceptors
- Calculated logP value less than 5
These rules are not exclusive for all molecules e.g Some antibiotics/ TB drugs, ciclosporin breach this rule but acts as a good rule of thumb in understanding drug action and drug design
How are steroids administered?
Administered orally or rectally
GR/ MR formulations or enaemae and foams
Due to chemical functionality i.e. non ionised and logP values between 0.5 and 1.2
Absorption therefore occurs in the stomach or colon
How does Kaolin work in diarrheoa?
It causes bulking up and reduces water output which is the symptom of diarrheoa
How does codeine work?
Gets converted to Morphine via phase 1 metabolism via CYP450 2D6 -formulated as a phosphate when orally administered
Once ingested and dissolved, should be ionised, but once it enters an area of higher pH, should be unionised, and therefore absorbed
How does atropine act on muscarinic acetylcholine receptors?
Atropine inversely agonises the mAchR
Why are drugs formulated as salts?
This makes it easier to dissolve
What form of reaction will occur in order to convert Racecadotril to Thiorphan?
Hydrolysis reactions via liver and plasma esterases
Where does loperamide become a salt?
At the tertiary aliphatic amine located at the centre of the molecule
How does linaclotide get absorbed?
It must be via some form of active transport due to molecular size and polarity - it is a circular peptide.
does not follow lipinski rule
Can be given in hard capsules
How does linaclotide work?
It is a guanylate cyclase activator - which is responsible for increasing water and electrolyte secretion.
How does lubiprostone work?
It is a CIC-2 calcium channel activator
It increases water and electrolyte secretion.
What is meant by malabsorption?
Inadequate absorption of nutrients from the GI tract - most absorption occurs via the smal, intestine walls
What are macronutrients?
Carbohydrates, fats and proteins
What are micronutrients?
Vitamins, minerals etc.
What is example of mucosal malabsorption conditions?
Crohn’s, Coeliac, and Surgery, which renders the intestine wall unable to absorb nutrients
What are examples of pre-mucosal malabsorption conditions?
Pancreatitits, Cystic Fibrosis, lactase deficiency - this is where macronutrients aren’t broken down and hence nothing available for absorption.
What is a rare, but possible condition which can cause both mucosal and pre-mucosal malabsorption?
Small Intestine bacterial overgrowth - this is where the damage to the mucosa as well as metabolism of bile salts via bacteria cause both forms of malabsorption
What complications can occur as a result of Crohn’s?
Deficiencies such as iron deficiency anaemia, B12/ folate deficiency, Vitamin D and calcium deficiency - N.B. Steroid usage in IBD cases can also cause additional issues.
What is Coeliac disease, and what deficiencies can it cause?
It is an autoimmune condition - whereby gluten activates an abnormal mucosal response - causing chronic inflammation and damage to the small intestine mucosa - villous atrophy
Symptoms include fatigue, GI symptoms, weight loss.
Diagnosed by serological testing.
Has to be treated via elimination of gluten.
What is short bowel syndrome?
This is usually secondary to surgery but can be congenital
May require parenteral nutrition - as less surface area available for absorption -
Osteoporosis and vitamin deficiencies are potential risks
Which medications may require higher dosing with short bowel syndrome?
Levothyroxine, warfarin, oral contraceptives, digoxin
What is chronic pancreatitits?
This is where chronic inflammation of pancreas leads to impaired function - less pancreatic enzymes
Affects men more than women and can happen at any age.
Strongly associated with alcohol consumption.
Test includes faecal elastase - and also tests for fat-soluble vitamin deficiencies.
What is cystic fibrosis?
It is an inherited genetic condition - causes decreased chloride secretion - and increased sodium absorption = thick mucus.
It is also strongly linked to pancreatic insufficiency (>85%).
Symptoms include Steatorrhoea, Osteoporosis, and Malnutrition, weight loss etc.
What forms of lactase deficiency exist?
Primary
Secondary
Congenital (Extremely rare)
Developmental (for premature babies but improves with age).
How to treat lactase deficiency?
Reduce or eliminate dietary lactose intake
Alternative calcium source required
Main causes of small intestine bacterial overgrowth?
Chronic Pancreatitis, motility disorders, surgery - most common causes - as it slows the passage of food and waste products in the digestive tract
Reduced gastric acid - restricts digestion: atrophic gastritis, drugs?
Impaired motility - diabetes, radiation enteritis, drugs, post surgery -loops?
What is the main reason for fat malabsorption?
Problem with digestion, insufficient enzymes, or absorption
Malabsorption more common in Coeliac, Crohn’s
Results in deficiencies of fat-soluble vitamins (A,D, E, K)
Symptom - steatorrhoea - fat in stools
Lack of which nutrient causes muscle wasting, malnutrition, oedema?
Protein
Lack of which nutrient causes night blindness?
Vitamin A
Which vitamins are water-soluble?
B and C
Where is Vitamin B12 mainly sourced from, in humans?
Meat, fish and dairy products.
What is the RDA of Vitamin B12?
1-2.5 mcg/ day
How is Vitamin B12 absorbed?
2 Mechanisms:
- Passive absorption
- Through buccal, duodenal and ileal mucosa
- Rapid but extremely inefficient
- less than 1% oral dose is absorbed. - Active transport
- Normal physiological mechanism is active transport
- occurs through the ileum
- mediated by gastric intrinsic factor - around 70% of ingested amount is absorbed
How is Vitamin B12 absorbed using intrinsic factor?
Vitamin B12 is released from food and bound to haptocorrin (transcobalamin I),
Intrinsic factor is secreted by parietal cells - on reaching the duodenum, haptocorrin is degraded by releasing vitamin B12.
Vitamin B12 is then captured by intrinsic factor, which then passes along intestine.
In the terminal ileum, intrinsic factor-bound Vitamin B12 is endocytosed by cubam.
Inside the enterocyte, intrinsic factor is degraded, releasing Vitamin B12
An ABC transporter releases Vitamin B12 in the blood - and is then bound to transcobalamin II although can be bound to I, II AND III, but II is most important for cellular uptake.
Internalisation occurs in complex with transcobalamin receptor CD320 via endocytosis.
Transcobalamin is degraded, yielding Vitamin B12.
Excess Vitamin B12 is sent to liver for storage.
How does Vitamin B12 act in the body?
It is an essential co-enzyme for 2 enzymes in the body:
It aids in the converstion of Homocysteine into Methionine
It also aids in the conversion of Methylmalonyl-CoA to Succinyl-CoA
What is the role of intrinsic factor in absorption?
Intrinsic factor is produced in the parietal cells and its secretion parrallels that of acid
In absence of intrinsic factor, inadequate amounts of Vitamin B12 are absorbed.
Causing megaloblastic anaemia - normal size of blood cells are 10 microns - megaloblastic means will be larger than this.
When it is due to absence of intrinsic factor, it is known as pernicious anaemia.
What does pernicious anaemia do?
It is known as autoimmune atrophic gastritis.
Causes destruction of parietal cells and associated lack of intrinsic factor.
Immune response directed against H+/K+/ ATPase
Also causes achlorhydria (low or no gastric acid production)
Can also be caused by antibodies directed against intrinsic factor.
Causes of Vitamin B12 Deficiency?
Inadequate dietary intake (rare)
Loss of gastric parietal cells or intrinsic factor
Functionally abnormal intrinsic factor.
Bacterial overgrowth in intesine
Disorders of ileal mucosa
Disorders of plasma transport
Dynfunctional uptake and use of Vitamin B12 by cells
Which drugs can induce Vitamin B12 deficiency?
- Proton pump inhibitors/ H2A’s - reduction in stomach
- Oral contraceptive and hormone replacement therapy - believed to reduce levels of transcobalamin
- Metformin - reduces vitamin B12 absorption
- Colchicine - impairs or inhibits receptors in the terminal ileum.
What is the normal serum concentration of Vitamin B12?
115-1000 pmol/L
What can Vitamin B12 deficiency be accompanied with?
Leucopaenia, thrombocytopaenia, hypersegmented neutrophils.
Consequences of vitamin B12 deficiency?
Neurological - Pins and needles in hands and feet
Sensory loss
Gait ataxia
Weakness in legs
Subacute combined degeneration of the spinal cord (also affects brain and peripheral nerves).
Can also get digestive effects such as Hunter’s glossitis
Can also get cardiovascular effects such as angina, Venous thromboembolic disease
Gynaecological effects such as infertility.
Composition of Vitamin B12 derivatives in human serum?
0-10% cyanocobalamin
8-15% hydroxycobalamin
22-39% Deoxyadenosylcobalamin
36-62% Methylcobalamin
Which forms of B12 are active in humans?
Deoxyadenosylcobalamin
and Methylcobalamin
RDA of Vitamin B9 (folate) in humans?
200 mcg/ day
400 mcg/ day in pregnancy
How does folate get absorbed?
Natural folates are conjugated to a polyglutamyl chain - folates are absorbed in monoglutamate form
Hydrolysed by folypoly-y-glutamate carboxypeptidase
5-MTHF is main form of dietary folate
Where does most of folate absorption occur?
Most absorption occurs in proximal small intestine (duodenum, jejunum) - some can happen in colon.
Folate absorbed from lumen by proton coupled folate transporter.
Absorption also occurs via redued folate carrier (RFC), with folate being exchanged for organic phosphate.
What do enterocytes do to folate?
Enterocytes also have folate receptors (binds folate and internalises it by receptor mediated endocytosis).
Folate can be exported without further metabolism - or reduced to 5-MTHF.
Both forms of folate are exported from enterocyte by an organic anion transporter.
How is most folate transported and uptaken by cells?
Most is transported as mono-glutamyl derivative - most folate circulates free in the blood - some is bound to albumin
Plasma conc is 10-30 nmol/l
In terms of cellular uptake, this is done by the same mechanisms as for enterocytes - PCFT, RFC, and folate receptor
How does intracellular folates exist?
75% exists as polyglutamate conjugates.
What is folate crucial for?
The transfer on one-carbon units to amino acids, nucleotides, and other biomolecules.
Causes of folate deficiency?
Inadequate dietary intake
Congenital defects in uptake systems
Intestinal disease
Drug interaction - cholestyramine, sulfasalazine, trimethoprim, methotrexate, metformin
Chronic alcohol use
Increased cellular requirement.
Symptoms of folate deficiency?
Sore tongue, pain upon swallowing, GI symptoms, Neurologic, and when severe, results in megaloblastic anaemia
What can happen as a result of folate deficiency?
Neural tube defects
Treatment for folate deficiency?
Oral folic acid - 1-4 months
Oral route sufficient even in malabsorption
Treated until haematological recovery occurs.
What is diabetes mellitus?
This is where there is either an insufficiency in the production or action of the pancreatic hormone insulin.
By far most common endocrine disorder.
Difference between Type 1 and type 2 diabetes?
Type 1 - loss of insulin production
Type 2 - Insulin resistance, insufficient secretion of insulin
What are main characteristics noted in diabetes?
Abnormal fuel metabolism is noted - which results most notably in hyperglycaemia and dyslipidaemia, due to defects in insulin production/ secretion, insulin action, or both.
What are the main characteristics in type 1 diabetes?
Referred to as insulin- dependent diabetes
only 5-10% people with diabetes have type 1
peak age of diagnosis is 10-14
pancreas produces little to no insulin - autoimmune reasons?
Main characteristics of type 2 diabetes?
Occurs when the body is in an insulin-resistant state and pancreatic beta cells cannot release sufficient insulin to compensate
Most common form of diabetes
Diagnosed later on in life
Lifestyle causes - primary reason
How can type 2 diabetes be reversed in just a matter of weeks?
600 calorie diet
What is gestational diabetes?
Can affect up to 25% women during preganancy
Usually develops in 2nd trimester and disappears after child is born.
Cause not clear, but thought to be due to hormonal changes that occur during pregnancy, many of which can block the action of insulin
Diagnosis of Diabetes?
There are 3 main tests conducted?
- Fasting glucose and random glucose
- Glucose tolerance test
- Hba1c
What should fasting glucose show?
No food or drinks to be consumed for 8-10 hrs
Normal: 3.9 to 5.4 mmol/l
Prediabetes or impaired glucose tolerance: 5.5 to 6.9 mmol/l
Diabetic: >7 mmol/l
What should random glucose show?
Regardless of when person ate, random plasma glucose value of > 11.1 mmol/l
How does the oral glucose tolerance test show?
Subject must fast for atleast 8 hours - plasma glucose measured immediately before and 2 hours after giving 75g glucose dissolved in water.
Plasma glucose two hours after glucose administration:
> 11.1 mmol/l indicates diabetes
7.9 - 11.1 mmol/l indicates impaired glucose tolerance
HbA1c shows?
A measure of the average blood glucose levels over the previous 3-4 months.
What are the ranges for the HbA1c?
> 48 mmol/mol (6.5%) indicates Type 2 diabetes
42-48 mmol/mol (6.0-6.4%) indicates risk of developing diabetes
How is diabetes diagnosed?
diagnosis made by combination of symptoms and abnormal blood tests
In patients without classic symptoms, diagnosis can be made by 2 abnormal blood tests.
Type 2 can be diagnosed via opportunistic screening.
Early diagnosis is important because diabetes will otherwise get progressively worse
What are the acute symptoms of diabetes?
Excess urination, thirst, dehydration, weight loss, blurry vision
What is diabetic ketoacidosis?
Potentially life-threatening complication of type 1 diabetes
Caused by lack of insulin limiting glucose usage
Causing free fatty acids released from adipocytes
FFA’s converted to ketone bodies by liver, and said ketones cause pH of blood to become acidic.
Liver at the same time continues to synthesise glucose - blood glucose rises
High glucose in urine takes water and solutes such as potassium and sodium with it, resulting in dehydration.
How is diabetic ketoacidosis treated?
Fluid replacement, insulin, mineral replacement
What are the chronic complications of diabetes?
These develop gradually (over decades)
Chronic complications occur due to vascular damage. This can be either:
- Microvascular - damage to small blood vessels (capillaries)
- Macrovascular - damage to larger blood vessels (arteries and veins)
Hyperglycaemia associated with damage to blood vessels and atherosclerosis
Diabetes - increased risk of developing high blood pressure.
What is diabetic foot?
This is where nerve damage or poor blood flow increases risk of various complications.
Cuts and blisters become serious infections, which often heal poorly.
Diabetes is most common cause of lower limb amputations.
What is the link between diabetes and dementia?
People with diabetes are at 1.5-2.5 x greater risk of dementia.
Mechanisms not yet understood.
What complications can arise as a result of diabetes in pregnancy?
Increased risk of miscarriage, still birth, and birth defects when diabetes are not well-controlled.
For mother, diabetes increases risk of DKA, retinopathy, pregnancy-induced high blood pressure and pre-eclampsia.
Where is insulin secreted from?
The beta cells in the pancreas
How do blood glucose levels regulate insulin secretion?
An increased uptake and metabolism of glucose leads to an increase in ATP-ADP ratio
Said increased ratio leads to closure of ATP-sensitive Potassium channels and causes membrane depolarisation
Depolarisation leads to the opening of voltage gated of calcium channels
Increase in intracellular calcium promotes secretion of insulin
What is insulin supposed to do?
Increase:
- Glucose uptake
- Glycogen synthesis
- Fatty acid/ triglyceride synthesis
Decrease:
- Glycogen breakdown
- Gluconeogenesis
- Lipolysis
Where can insulin target?
It is able to travel through the blood - can target any cell in ther body
-Mainly targets, fats, liver, and skeletal muscle
How does insulin signalling lead to activation of Protein Kinase B?
- Insulin binds to Insulin receptor - leads to receptor autophosphorylation
- Phosphorylated residues on the IR acts as binding site for insulin receptor substrate proteins
- IR phosphorylates 4 tyrosine residues in IRS proteins
- Lipid kinase known as Phosphoinositide 3-kinase binds to phosphorylated residues on IRS proteins - and converts PIP 2 TO PIP 3.
- Binding to PIP3 activates PDK1, which then phosphorylates and activates protein kinase B.
- Activated PKB can then diffuse through the cell and activate processes such as glucose transport and glycogen synthesis.
Glucose is then able to transport into adipocytes and skeletal muscle.
How does insulin stimulate glucose transport into adipocytes and skeletal muscle?
Glucose transporter GLUT4 is contained in the cell in storage vesicles
Protein AS160 acts to hold these vesicles inside the cell
PKB phosphorylates AS160 and inactivates it.
This allows GLUT4 vesicles to fuse with the plasma membrane, leading to increased levels of the glucose transporter at the cell surface.
How does insulin repress gluconeogenesis?
Fox01 is synthesised in the cytosol but is targeted to the nucleus, where it regulates expression of genes, that mediate gluconeogenesis.
PKB phosphorylates Fox01, preventing it from entering the nucleus, leading to lack of expression of gluconeogenic genes, which leads to a loss of glucose production.
What is the complication of glucose levels with loss of insulin secretion or insulin resistance?
Loss of insulin secretion or resistance leads to hyperglycaemia due to:
- Loss of insulin-stimulated glucose uptake into target cells
- Loss of insulin-mediated repression of gluconeogenesis (and glycogen breakdown) in the liver.
What are the genetic risk factors for T1D?
Risk of T1D is 15x higher for first degree relatives of someone with the disease.
The HLA - region of chromosone 6 is linked to susceptibility to developing T1D
- This contains genes encoding components of major histocompatibility complex
- key component of the immune system
- Although HLA genes have strongest association with T1D, only 5% of people with disease- linked variants develop T1D.
How can autoantibodies play a role in T1D?
Presence of Autoantibodies against beta cell antigens is a significant risk factor.
Examples:
1. Glutamic acid decarboxylase-65
2. Insulin
3. IA-2
4. ZnT8
Upto 3-5% of the population may test positive for these or other antibodies against beta cell proteins - but only 20% will develop T1D.
Presence of two different antibodies increase risk of developing T1D within next 10 years to 75%
What Precipitating events can occur in the development of T1D?
This is difficult to identify as these triggers may occur years before onset of symptoms and there may be several events involved.
Enteroviruses (esp. coxsackie) have been implicated - could be due to similarity with 2c protein of virus and GAD65, which may suggest molecular mimicry might be involved.
How does Beta cells get destroyed via autoimmune factors?
Each form of cell (alpha, beta, delta), secrete distinct hormones. Each cell expresses different tissue-specific proteins.
In T1D, an effector T cell recognises peptides from a beta-cell specific protein and kills the beta cell.
Hence no insulin is produced.
What are the mechanisms underpinning the reason for insulin signalling being inhibited?
Protein Tyrosine Phosphatase 1B is able to dephosphorylate the Insulin receptor, leading to a loss of IRS binding.
IRS proteins can also be inactivated by phosphorylation of Serine residues by PKC, which prevents IR from phosphorylating tyrosine residues on IRS.
How does obesity contribute to insulin resistance?
It is possible the amount of triacylglycerols exceeds the storage capacity of adipose cells… as a result, fat starts to accumulate in other tissues such as liver and muscle.
Also, excess fat leads to increased levels of the intracellular lipid signalling intermediates Diacylglycerol and Ceramide (a component of sphingolipids) in the cytoplasm of cells. Both are formed from fatty acids.
These both cause the inhibition of PKB activation and phosphorylation of Serine residues on IRS. Leading to insulin resistance.
What do adipocytes do which can increase insulin sensitivity as well as contribute to insulin resistance?
Obesity is a pro-inflammatory condition associated with increased circulating levels of pro-inflammatory cytokines
Adipose tissue from lean individuals secrete anti-inflammatory and insulin- sensitising adipokines such as adiponectin.
In obesity, more pro-inflammatory cytokines are released such as TNF-a and less adiponectin.
How does increased TNF levels contribute to insulin resistance?
TNF-a has many different effects that may contribute to insulin resistance, including:
Expression of PTP1B, which can dephosphorylate the insulin receptor.
How does adiponectin levels affect insulin resistance?
Adiponectin is secreted from adipocytes and promotes insulin sensitivity.
Insulin-sensitising effects of adiponectin are related to its effects on sphingolipid metabolism.
Adiponectin secretion is decreased in obesity , which contributes to insulin resistance.
Why are insulin levels reduced in Type 2 diabetes?
Beta cell destruction and loss of insulin secretory pathway also contribute to Type 2 diabetes.
Dysregulation of insulin secretion is linked to accumulation of fat in pancreas.
What is the genetics of Type 2 diabetes?
Type 2 diabetes is a complex polygenic disorder (caused by lack of combination of genetic and lifestyle factors).
Recent GWAS studies identified many gene polymorphisms that occur more frequently in Type 2 diabetes than in controls (>75 risk genetic loci have been identified)
What medicine is typically first line for T2DM?
Metformin - a biguanide - Rx’d to approx 80% of people with T2DM
Doesn’t cause weight gain.
Does not cause hypoglycaemia.
First used clinically 1953
How does metformin work in the body?
Metformin’s main effect is it reduces hepatic glucose production
Mechanism of action is not clear, but metformin is known to affect multiple cellular processes… most widely accepted model is linked to inhibition of mitochondrial respiratory-chain complex 1.
This chain complex is involved in oxidative phosphorylation.
What is the suggested mechanism of action for glucose production in the liver being blocked?
Metformin entetrs via OCT1
Then binds and inhibits mitochondrial respiratory-chain complex 1
results in less ATP synthesis
Increase in AMP
Activation of AMPK
Phosphorylation and inhibition of CRTC2
Inhibition of gluconeogenic gene expression.
Side effects of metformin
GI side effects - Diarrheoa, nausea, vomiting, bloating, reduced appeptite. Leads to discontinuation in 5% of patients.
Vitamin B12 deficiency - reduces intestinal absorption of vit. b12 in up to 30% of patients and lowers serum levels in a dose dependant manner in 5-10% of patients.
Can lead to symptoms such as tiredness and tingling in hands and feet
Can rarely cause lactic acidosis.
What are sulphonylureas and how do they work?
Examples include gliclazide or glipizide
They stimulate insulin secretion from pancreatic beta cells via mimicking high glucose level conditions via closing the ATP sensitive potassium channels being closed.
How do SGLT2 inhibitors work?
These act on the proximal tubule in the kidneys. SGLT2 act as glucose transporters
These inhibitors prevent glucose from being reabsorbed in the kidney, resulting in glucose secretion.
Examples of SGLT2 inhibitors?
empagliflozin (Jardiance®) dapagliflozin (Forxiga®) canagliflozin (lnvokana®)
How do GLP-1 analogues work?
These act as incretin mimics which stimulate insulin secretion and inhibit glucagon release.
Normally, GLP1 and GIP are released in response to an increased concentration of glucose in the digestive tract lumen. And DPP4 can degrade incretins.
Examples of GLP-1 analogues?
Liraglutide, semgalutide, exanatide, dulaglutide
How does DPP-4 inhibitors work?
DPP-4 inhibitors prevent the degredation of incretin, which subsequently allows for insulin secretion and inhibit glucagon release.
Examples of DPP-4 medicines?
Sitagliptin, saxagliptin, alogliptin, linagliptin, viladagliptin
How does thiazolidinediones work?
Increases insulin sensitivity by stimulating expression of insulin- sensitising genes via acting on nuclear receptors such as PPARy - these
Examples of Thiazolidinediones?
Pioglitazone is only drug in this class.
How do meglitinides work?
They have a similar action to sulphonylureas but have a rapid onset and short duration
Should be taken before meals
Repaglinide
Nateglinide
How should T2D be treated?
Should follow healthy diet and regular exercise
T2DM is progressive disorder, oral medications may be required.
If glucose control not adequate, insulin may be prescribed.
Can surgery assist with T2DM?
Weight loss surgery can be effective in putting T2DM in remission in the long term.
This involves bypassing or reducing the size of the stomach - people feel much fuller sooner, less calories consumed = weight loss.
Bariatric surgery is a treatment for people with type 2 diabetes - it is a treatment irrespective of weight loss - blood sugar levels drop soon after surgery and diabetes medications can be stopped soon after
NICE recommends all patients in the uk with BMI of more than 35 with recent onset T2DM should be assessed for surgery.
Initial cost of weight loss surgery is £6000
Can a calorie deficit be shown to reverse T2DM?
YES - studies have shown maintaining a 600 calorie diet for 3/4 weeks can reverse T2DM - success was closely correlated with weight loss.
How should treatment be optimised for Type 2 diabetes?
In general, you start with one agent unless very symptomatic
If not controlled, other agents can be added in.
It is not recommended stopping a treatment unless you are at triple therapy or an injectable has been added - unless intolerant or no change in HbA1c in 6 months.
How should metformin be dosaged?
Increase dosing gradually to minimise GI side effects
Increase weekly by 500mg - aim to get 1-2g daily can make it bd, can increase to tds, do not do qds - better to do 2 bd.
Take with food.
Caution - renal impairment
Side effects - diarrheoa, anorexia, n&v
N.B. BNF may be contradictory to local guidelines - BNF says no more than 2g, but manufacturers can recommend more
Also possible to get 850mg tabs.
How to help with side effects of Metformin?
Could try offering M/R version - may improve pt compliance.
Advantages of metformin?
Can reduce HbA1c by 1-2%
Not associated with weight gain
Not associated with hypoglycaemia when given alone.
Beneficial effects on lipid profile
No Blood glucose monitoring required.
Good evidence base.
How effective are sulphonylureas?
Gliclazide, Glimeprimide, Glipizide, Glibenclamide
Decreases HbA1c by 1-2%
First line if metofrmin intolerant.
Advantages:
-good evidence base
-Inexpensive
- Good to bring back glycaemic control within 2 weeks.
- Good for helping fatigue symptoms of T2DM
Disadvantages:
- Weight gain
- Increased risk of hypoglycaemia (1/100)
- Glibenclamide - has too high half life
How effective are thiazolidinediones? (Pioglitazone)
Decreases HbA1c by 1%, do cause sodium retention though, will increase urination a releasing more glucose via urine hence it may be problematic if prone to UTI’s.
Advantages:
Useful in renal failure as substitute for Metformin
Low risk of Hypo
Disadvantages:
Contraindicated in heart failure
Fractures - can increase risk
Haematuria
How do DPP-4 inhibitors function (gliptins)?
Can be used in mono, dual and triple therapy
Not believed to cause weight gain and not potent either.
Take time to exert effect (2 months).
Less incidence of hypo compared to sulfonylureas
Alternative to use in place of TZD’s (such as Pioglitazone) if weight gain a problem or glitazone is contraindicated/ poorly tolerated.
Reduce HbA1c by approx 0.7%
Good to use if no renal function.
How effective are SGLT2 inhibitors?
Can decrease HbA1c by 5mmol/mol
Weight loss
BP reduction
No hypos
BUT:
Does however take time to observe effect (6 WEEKS)
Polyurea
Genital infections more likely (as peeing more)
Care with hypovolemia/ loop diuretics
Cannot be given to >85 years
Can cause renal impairment
How effective are meglitinides?
Not commonly used due to cost
Can be used as mono or with metformin
Disadvantage:
- weight gain
- increased risk of hypoglycaemia (but less than sulfonylureas)
- expensive
How are GLP-1 agonists administered?
Albiglutide, dulaglutide, Exanatide MR, semaglutide - weekly
Exenatide, Liraglutide, Lixisenatide - daily or twice daily.
Under what circumstances are GLP-1’s used?
3rd line with Met and SU or TZD
BMI >35
HbA1c > 58mmol/mol
Diagnosis < 10 years
OR
BMI <35 but unable to tolerate insulin.
What is hypoglycaemia?
This is where blood glucose is 4 mmol/
symptoms:
- Sweaty, hungry, cold, pounding heartbeat, tingling lips
- Neuroglycopenic - can lose consciousness, dizzy, faint, tired, confused irritability.
How to manage Hypoglycaemia?
Eat or drink something which has sugar - sweets, glucose tabs, sugar drink
Followed up by longer acting CHO - sandwich, fruit, biscuits, milk
Should feel better after 5-10 min
Eat normal meal soon as possible.
What should diabetic patients also be offered?
Annual CV risk assessment unless literally no risk factors such as BP, Weight, smoking, lipid profile
Foot care should be monitored - Abnormal ACR tests should warrant checks.
Should diabetic patients be using aspirin?
It should be avoided unless they have serious cardiovascular issues.
What are the symptoms of Hypothyroidism?
No energy, depressed/ low mood, dry skin, high TSH and low free T4 levels
What is the treatment for Hypothyroidism?
Levothyroxine, and Liothyronine
Increase dosing by 25mcg every 2-4 weeks, and monitor for symptom improvement.
Is possible to take overdose if wrong strength is consumed?
Pt should be advised to take in morning.
How to treat hyperthyroidism?
Should use Carbimazole and Propylthiouracil
Mainly use carbimazole - but can add propranolol if they have palpitations.
Side effect of carbimazole - agranulocytosis - must make sure to be aware of cold-like symptoms, sore throats, bruising.
How to treat any rashes which occur due to usage of carbimazole?
Use antihistamine
How is insulin packaged in the body?
Insulin is first formed as its pre-sequence form. This takes it to the endoplasmic reticulum - from where it is packaged into secretory vesicles.
Signal sequence is cleaved off by a protease in the endoplasmic reticulum, generating pro-insulin.
Then, disulphide bonds are formed between Chain A and B.
Then, proteases cleave at either end of chain C.
This gives Insulin and ‘C peptide’.
How is insulin stored in the body?
Insulin is stored as an inactive hexamer - which has 6 subunits.
Has 2 A and 2 B chains
Has Zinc ion in the middle of the hexamer - stabilises hexamer.
What happens to the hexamer when insulin is released?
It disassembles upon release to bloodstream.
Describe the groups of insulin?
1 - Animal - not widely used but some people find it works better for them.
2 - Human - synthetically made via recombinant DNA
3 - Analogues - Human insulin is altered to make it work quicker and longer.
Describe the classifications of Insulin preparations?
Rapid acting - soluble insulin - e.g. insulin aspart, insulin glulisine, insulin lispro
Intermediate action - isophane insulin.
Long acting - insulin detemir and insulin glargine.
What are biphasic insulins?
They are pre- mixed insulin preparations containing various combinations of short-acting insulin or rapid-acting insulin analogue together with an intermediate acting insulin
% of short acting can vary from 10-50%
How does the size of insulin molecules affect uptake?
Insulin and it’s analogues are injected subcutaneously, they have to diffuse across capillary walls to enter general circulation.
Diffusion is limited by size of insulin - ie. monomer > dimer > hexamer/aggregates
How can insulin be modified to alter kinetics?
Humulin S (soluble) is short acting.
Humulin I (isophane) is medium- acting.
These both have the same form of insulin but have different profiles due to the I version adding on protamine
What does protamine do to insulin?
Protamine causes clustering of insulin, limiting diffusion through capillary walls.
Protamine is basic protein (+ve charge), which binds to negatively charged insulin and clusters insulin hexamers.
How can the insulin protein be altered to modify its kinetics in the case of Novorapid?
Insulin aspart (Novorapid) has a proline to aspartate substitution in the B chain, which reduces the tendency to form hexamers. As a result, it is more rapidly transferred from the sub-cutaneous injection site to the bloodstream.
How can the insulin protein be altered to modify its kinetics in the case of Humalog?
Insulin lispro has two substitutions in the B chain, which also diminish the tendency of insulin molecules to self - associate.
How can the insulin protein be altered to modify its kinetics in the case of Insulin glulisine?
Insulin glulisine has two substitutions in the B chain - Asparagine is replaced with a lysine, and a lysine is replaced with a glutamic acid. These changes also reduce insulin self-association.
How can the insulin protein be altered to modify its kinetics in the case of Insulin glargine (lantus)?
It contains an aspargine to glycine substitution in A chain and also has two arginines added to the carboxy terminal end of the B chain - these changes make insulin analogue less soluble at physiological pH, which limits absorption from the site of injection.
Half life ~18-26 hrs
How can the insulin protein be altered to modify its kinetics in the case of Insulin detemir (levemir)?
Insulin detemir has a covalently attached fatty acid (myristic acid) that causes the molecule to bind to albumin in the blood serum.
Albumin competes with the insulin receptor for binding to insulin detemir, prolonging its action.
Albumin binding also protects insulin detemir from circulating peptidases, increasing its stability.
Half life ~18-26 hrs
How can the insulin protein be altered to modify its kinetics in the case of Insulin degludec (Tresiba)?
It has a hexadecaneodioic acid group added to B chain - this mediates albumin binding but also causes formation of multi-hexamers when injected.
Monomers are slowly released from these multi-hexamers, extending duration of action beyond 40 hours.
Why does insulin need to be injected?
If orally administered, it would be degraded by proteases in the stomach and small intestine.
Injection is sub-cutaneous.
Once injected, insulin diffuses into small blood vessels and enters the bloodstream.
Why are injection sites for insulin alternated?
Injection site is typically the stomach, buttocks, or thighs.
Rotated to avoid lipohypertrophy, accumulation of lumps under the skin. This can lead to problems with absorption of insulin.
How should insulin be stored?
Below 25 degrees celcius and ideally in the fridge.
What is the dosage regimen for insulin for type 1 diabetics, according to NICE?
Multiple daily injection basal-bolus insulin regimens.
Injections of short action insulin analogue before meals, together with 1 or more separate daily injections of intermediate-acting insulin or long acting insulin analogue.
Can use continuous subcutaneous insulin infusion; a programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually rapid acting insulin analogue or short acting insulin).
How should insulin be used in the treatment of type 2 diabetes?
Insulin should be used in combination with oral-antidiabetic drugs
Basal insulin is usually a suitable first step with once- or twice daily intermediate or long acting insulin.
Biphasic insulin can be used if diabetic control is particularly poor.
Basal-bolus regimen can be introduced if blood glucose remains inadequate.
What is the artificial pancreas?
It is a closed loop system that continuously monitors glucose levels and uses the information to adjust the levels of insulin being administered by an insulin pump
What is islet cell transplantation?
Islet cell transplantation takes the approach of implanting islet cells from a deceased donor or using stem cell-derived beta cells.
Simple procedure where these are injected into the hepatic portal vein
But body’s immune system can attack these cells - need immunosuppressants
Recently islet cells have been encapsulated in biocompatible material, which blocks the immune response to transplanted islet cells and negates the need for immunosuppressive drugs.
What other methods are being explored in relation to insulin therapy with diabetes?
Beta cell regeneration - using chemical/genetic approaches that stimulate beta cell growth and regeneration and prevent immune system attack.
Immunotherapy - these drugs are given to at-risk individuals and can delay the onset of T1D by up to 3 years. Hopes that similar drugs might reverse and permanently stop beta cell destruction.
Also hoping to create insulin spray which is absorbed by mouth - attach insulin to carriers that protect from degredation and allow oral delivery.
Non protein insulin subs that are able to bind to the insulin receptor and activate intracellular signalling pathways.
What are the properties of Biguanides from a physicochemical point of view?
Log P are all negative, Pka’s of 12 approx, likely due to resonance forms of biguanide which stabilise the conjugate acid. Hence will always be ionised in physiological pH.
Therefore can never be passively absorbed.
How does metformin work throughout the body?
Metformin does not get metabolised so is unchanged throughout the body.
What are the properties of sulphonylureas?
Oldest form of oral hypoglycaemic agents. Pka’s approx 5.4-5.9
Stimulate insulin secretion by binding to sulfonylurea receptor 1 subunit of ATP sensitive K-channels in the beta cell plasma membrane.
Can be used with metformin if required.
How does Meglitinides work physicochemically?
Nateglinide has Log P 3.8, Pka of 3.6 (refers to carboxylic acid)
Repaglinide has log P 5.2, Pka of 4.1 (aromatic carboxylic acid) and 6.0 (aromatic tertiary amine)
These work similarly to sulfonylureas
But has weaker binding and dissociation from the SUR-1 binding site of ATP sensitive potassium channel.
How do Glitazones (TZD’s) work physicochemically?
Possess the TDZ moiety
Activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR-Gamma)
Helps improve insulin sensitivity.
How do DPP-4 inhibitors work physicochemically?
DPP4 normally acts on GLP1 AND GIP
Released after food intake in the intestine and stimulate insulin production
DPP-4 inactivates GLP-1 AND GIP so inhibition results in insulin stimulation.
How are thyroid hormones synthesised?
Thyroid follicles have epithelial cells arranged in spheres
Colloid - proteinaceous depot of thyroid hormone precursors.
Iodine is brought into follicle cells via the Na/I co-transporters.
Iodine then diffuses across and is transported to the colloid via pendrin transporters - oxidised, and attached to rings of tyrosines in thyroglobulin (forming MIT and DIT).
The iodinated ring of one MIT or DIT is added to another DIT at another spot - giving t3 and t4 structures in thyroglobulin.
This structure is endocytosed back into follicle cells.
Lysosomal enzymes release t3 and t4 from their thyroglobulin structures. Then t3 and t4 are secreted.
Which form of thyroid hormone is active?
T3 is the active one
Most circulating t3 derived from t4 (via deiodination)
T3 and T4 are extensively protein bound in the plasma.
Bound to thyroxine- binding globulin (TBG) and Transthyretin thyroxine-binding prealbumin.
Describe the sequence for the process of thyroid hormone secretion?
Hypothalamus releases TRH targeting the anterior pituitary.
Anterior pituitary then releases TSH.
TSH targets the thyroid gland - releases thyroid hormone - target cell response.
What is the euthyroid state?
This is where thyroid secretion is normal.
What is the hypothyroid state?
Thyroid hormone secretion is subnormal
(also known as myxoedema)
What is the hyperthyroid state?
Thyroid hormone secretion is excessive (also referred to as thyrotoxicosis)
What other effects does TSH have apart from stimulating t3 and t4 production?
Increasing protein synthesis in follicular epithelial cells, increases DNA replication, and cell division
Increases rough endoplasmic reticulum and cell machinery required for protein synthesis
Thyroid will undergo hypertrophy if exposed to greater TSH concentration. Results in Goitre
How does thyroid hormones affect tissues and nervous system?
Increased BMR
Heat production
Responsiveness to parasympathetic stimuli
Permits normal growth and development
Permits maintenance of normal activity.
What is iodine deficiency disease?
- Cretinism is the most extreme manifestation of iodine deficiency
- Can cause mental retardation
- Reduction in physical growth
- Deaf-mutism
- Can be caused by inadequate dietary iodine intake
- Can also be due to maternal iodine deficiency during pregnancy
Salt is now fortified with iodine
From thyroid function tests, what would you note from hyperthyroidism?
High T4, low TSH
From thyroid function tests, what would you note from primary hypothyroidism?
High TSH, low T4
From thyroid function tests, what would you note from SECONDARY hypothyroidism?
low TSH, low T4
What are the symptoms of hypothyroidism?
- Cold intolerance
- Modest weight gain
- Bradycardia
- Unexplained tiredness
- Constipation
- Forgetfulness
- Pale, coarse skin
- Puffiness of face
How do most cases of hypothyroidism occur?
Damage or loss of thyroid tissue
But can also be due to low iodine consumption
How does Hashimoto’s thyroiditis?
Autoimmune condition whereby CD4 T cells recruit CD8 T cells and B cells.
Antibodies to thyroid peroxidase and Cytotoxic T cells attack thyroid cells, leading to necrosis/ apoptosis of thyroid cells, resulting in hypothyroidism. Can also result in goitre.
How is primary hypothyroidism treated?
Levothyroxine, which is the synthetic form of thyroxine (t4)
Dose adjusted until TSH levels in mid range, patients should be monitored atleast annually, but more frequently for kids.
How should pregnant women be monitored for hypothyroidism?
Monthly monitoring, and require 50-100% increase in normal dose
Early treatment needed in neonates to prevent mental defect.
What are the known adverse effects of levothyroxine?
Hair loss first few months of treatment
Headaches
Insomnia
Nervousness
Fever, hot flashes and/or sweating
Pounding heart beat or fluttering in chest
Appetite changes
What other treatment can be used for treatment of hypothyroidism?
Liothyronine, is a synthetic form of T3,
Controversy surrounds its use in treatment of hypothyroidism
Not supported in Royal College of Physicians
Risks from t3 therapy on bone, and heart
Differences in medicinal properties between Levothyroxine and liothyronine?
Levothyroxine:
1. Single dose, max effect in 10 days, passes off in 2-3 weeks
2. Half life is 7 days in euthyroid, 14 days in hypothyroidism
Liothyronine:
1. 5 times as biologically potent as t4
2. Single dose reaches max effect in 24 hrs and passes off in 1 week
3. Half life is 2 days in euthyroid
What is secondary hypothyroidism?
This is uncommon, as it suggests that the pituitary does not produce TSH or the hypothalamus doesn’t produce sufficient TRH (tertiary)
Both t3, t4, and TSH are low, treatment similar to primary hypothyroidism
What is myxoedema coma?
This is end result of untreated hypothyroidism
Progessive weakness leading to unconsciousness
Extreme hypothermia
Areflexia, seizures, and respiratory depression
Precipitating factors - illness, infection, trauma, drugs which suppress CNS
Medical emergency requiring urgent treatment
Which other drugs can affect thyroid function?
Corticosteroids
- Can decrease basal production of TRH and TSH, consequently decreasing thyroid hormone levels
Lithium
- inhibits release of thyroid hormone and interferes with their peripheral deiodination
Amiodarone
- Contains iodine and can cause both hypothyroidism and hyperthyroidism
Cholestyramine
- Reduces absorption of thyroxine
Signs of hyperthyroidism?
Heat intolerance
Palpitations
Weight loss - decreased appetite
Restlessness and Nervousness
Fatigue
Increased sweating
Frequent bowel movements
Goitre may be present
What does hyperthyroidism look like biochemically?
Thyroid produces excess of t4
Reduction of TSH due to negative feedback loop
T3 usually elevated as well.
What is graves’ disease?
Most common cause of hyperthyroidism
Signs include goiter and Exopthalmos
How does Graves’ disease occur?
This is also an autoimmune disease
Caused by thyroid stimulating immunoglobulin (TSI)
Activates TSH receptor on thyroid follicular cells
Results in increased secretion of thyroid hormones
How is hyperthyroidism treated?
Surgery
Radioactive iodine (131 iodine)
Administered orally - solution or capsule
Taken up by thyroid gland
Emits gamma and beta radiation (half life 8.1 days)
Treatment usually has its maximum effect around 3 months; but may be as long as 6 months.
Examples of antithyroid drugs?
Thioamides such as carbimazole , propylthiouracil
Accumulated by thyroid
Inhibit thyroid peroxidase, which is responsible for the iodination of tyrosine, and prevent hormone synthesis.
Propylthiouracil also inhibits peripheral deiodination
Effect is slow in onset - 4-6 weeks.
Generally safe but may cause agranulocytosis, thereby increasing risk of infection.
What hormones are secreted by the adrenal cortex?
Adrenocorticoids - such as:
- mineralocorticoids - mainly aldosterone - released from zona glomerulosa - responsible for sodium resorption and potassium excretion in kidneys
- glucocorticoids - mainly cortisol - released from zona fasciculata - regulate the body’s response to stress.
Sex hormones - androgens - released from zona reticularis - regulate reproductive function
What is released from the adrenal medulla?
Mainly catecholamines
80% adrenaline, 20% noradrenaline
How is hormonal secretion regulated by the adrenal cortex?
Hypothalamus releases CRH
Anterior pituitary then releases ACTH, which targets the adrenal cortex, which then causes the production of cortisol.
What is noticed about serum cortisol levels?
Cortisol shows daily fluctuation - spikes when time to get up, shows diurnal variation
What are the cellular actions of cortisol?
Receptors for cortisol are found in many tissues
Increases circulating glucose level
Maintain normal responsiveness of blood vessels to vasoconstrictive stimuli
Effects on immune system, nervous system, and kidneys
How does cortisol act on target tissues?
Inhibits glucose and amino acid uptake by many tissues
Increases lipolysis of adipocytes
Increases protein breakdown and reduced protein synthesis in muscle tissues etc.
Increases gluconeogenesis in the liver.
What can cortisol do in cells?
Cortisol can easily pass the plasma membrane and does not require transporters etc.
Alters gene expression - takes some time for proteins etc. to be formed or lack thereof.
What is Addison’s disease?
This is due to dysfunction or destruction of the entire adrenal cortex
Affects both glucocorticoid and mineralocorticoid function
Onset of disease occurs when 90% or more of both adrenal cortices are destroyed.
40-60 cases per 1 mil population
Most common in adults 30-50 years.
Symptoms of Addison’s disease?
Darkened areas of skin
Extreme fatigue
Unintentional weight loss
Low BP - light headedness and faintaing
GI disturbance - nausea, vomiting
Salt craving
Low blood glucose (hypoglycaemia)
How does Addison’s disease occur?
Primary adrenal insufficiency
Autoimmune destruction of gland
Can be triggered via infections - TB, HIV, sphilis, Cryptococci
Invasion - neoplastic, fibrosis, sarcoidosis, amyloidosis
Haemorrhage
What does Addision’s disease show for biochemical testing?
Decreased cortisol due to lack of negative feedback
Increased CRH and ACTH
How is Addison’s disease treated?-
Hydrocorisone, prednisolone, dexamethasone
fludrocortisone (mineralocoritcoid)
Daily adult dose HC is 15-30mg
Given as divided dose e.g. 10mg waking, 5mg noon, 5mg evening
Intercurrent illnesses might require increased glucocorticoid dose - life long treatment
How does secondary Adrenal insufficiency occur?
Lack of ACTH secretion from pituitary
Lack of CRH release from hypothalamus
Patients don’t typically show hyperpigmentation or have cravings for salt
Can also be due to glucocorticoid drug therapy
Can occur if glucocorticoid meds stopped abruptly.
Treatment is glucocorticoid - mineralocorticoid is unnecessary
Other therapeutic uses of glucocorticoids?
Bronchial asthma, anaphylaxsis and angioedema
Acute fibrosing alveolitis
Chronic inflammatoryn diseases such as IBD, chronic active hepatitis, glomerulonephritis, systemic lupus
Neoplastic disease such as myeloma, lymphomas, lymphocytic leukaemias
Effect of Glucocorticoids on Hypothalamus and anterior pituitary?
Glucocorticoids suppress hypothalamus and anterior pituitary
How to withdraw a patient from glucocorticoids?
No single regime as depends on patient response, disease being treated, and duration of treatment
Short courses of less than 3 weeks can be stopped abruptly
Gradual for:
- those who received >3 weeks treatment
- repeated courses
- >40mg prednisolone daily for a week
What is adrenal crisis?
This is where you have sudden, severe pain in the lower back, abdomen or legs
Severe vomiting and diarrhoea,
dehydration,
low BP
loss of consciousness
Can result in death if not treated immediately.
What is cushing’s syndrome?
-Hypersecretion of cortisol
- linked to metabolic complications - T2DM, Dyslipidaemia, excessive bone resorption, hypertension
Aetiology of cushing’s syndrome?
Pituitary tumour leading to excess secretion of ACTH - 65-70% of cases
Adrenocorticol tumours - benign or malignant - or bilateral hyperplasia or dysplasia - 15-20% of cases
Tumours external to HPA axis - 10-15% of cases.
How is Cushing’s syndrome classified?
ACTH dependant - body making too much ACTH - Due to pituitary or ectopic tumour
ACTH independent - ACTH levels are low - adrenal glands making too much cortisol - adrenal tumour or hyperplasia.
How can Cushing’s syndrome be drug induced?
Iatrogenic (drug related) Cushing Syndrome is commonly seen in clinical practice
Glucocorticoid treatment e.g. prednisolone, dexamethasone, hydrocortisone, beclomethasone
Occurs irrespective of route of admin
If treatment is prolonged,and drug is potent, then Cushing’s can occur
What drug interactions can be linked with Cushing’s syndrome?
Glucocorticoids - metabolised by cyp p450 enzymes
cyp3a4 important for metabolism
Drugs which inhibit cyp p450 enzymes can prolong action of glucocorticoids - itraconazole, ritonavir, number of antidepressants.
How is Cushing’s syndrome treated?
Surgery - to remove pituitary gland or adrenal glands
When drug induced - gradual withdrawal of the causative drug - aim to discontinue causative drug if possible
Mifepristone
- glucocorticoid receptor antagonist
- Restore glucose tolerance and low blood pressure
- doesn’t reduce cortisol level
What is Metyrapone?
It is an 11B - hydroxylase inhibitor
recent studies show effective for short and long term treatment of cushing’s
requires dose titration and careful clinical and biochemical monitoring
How is thyroid hormone transported?
Blood bound to proteins - active in unbound form - have function in almost all cells
Describe physicochemical properties of Levothyroxine and liothyronine?
Log P 7.4 for levo and 6 for liothyronine and pka’s of 10, 9, and 4
Halogens add more molecular weight and increase lipophilicity
How is hypothyroidism treatment administered?
Can simply be given orally but can be given by IM injection too.
How does carbimazole function?
It is a prodrug, which converts to methimazole - which inhibits thyroid peroxidases, preventing conversion of tyrosine into MIT and DIT, which means T3 and T4 won’t absorb.
How does Propythiouracil work?
inhibits thyroid peroxidases, preventing conversion of tyrosine into MIT and DIT, which means T3 and T4 won’t absorb. But also inhibits 5’ deiodinase enzymes helping to stop T3 biosynthesis.
