Drugs and the GI tract Flashcards
What is GORD?
- GORD; recurrent episodes of heartburn, inflammation of the oesophagus, oesophagits, predisposition to oesophageal cancer, BM, Stricture
- Due to ACID REFLUX
How might be suppress acid?
- PPI’s (Omeprazole)
- H2 blockers (Ranitidine) Blocks histamine release
- Antacids increase pH
- Alginates (Gaviscon)
Alginates (Sodium alginate)
- Two sugars, fibre, binds calcium, polymerises, thick gelatinous structure in the presence of calcium.
- Forms a physical barrier that stops the acid from refluxing up into oesophageas
- Neutralises stomach acid
- Sits on top of stomach acid, Contains bicarbonate, reacts with stomach acid to form Co2 bubbles, these bubbles become trapped within the gel to form a boyant raft
- Floats to top of stomach
- Protective barrier to stop heart burn
- Co2 gets trapped in hydro gel, sits on top of stomach juice so that acid can’t reflux
- Antacid within the formulation neutralises the stomach acid.
- Can reside in stomach for up to four hours
HP
Helicobacter pylori
• Class 1 carcinogen, colonises the stomach of 40% of humans
• Microaerophillic bacterium
• The leading cause of peptic ulceration
o Acid production
o Barrier damage
• Flagella: Motile
• Adhesion substances of surface: adhere to mucosa
• Evolved a number of mechanisms which allow it to colonise the stomach
• HP can cause:
o Gastritis
o Gastritis + Duodenal Ulcers
o Gastric Cancer (WHO) class 1 carcinogen
• HP Posesses urease; This breaks down the urea into NH3+ CO2+H2O NH4+ + HCO3-
• HCO3- neutralises the stomach acid and allows the bacteria to colonise
• Allows bacteria to colonise very close to the epithelia
• Hypochlorhydria: Loss of stomach acid; occurs in body of the stomach (CORPUS) largely associated with gastric ulcers
• ANTRUM: Hypergastrinaemia; too much acid secretion (hypersecretion by G-cells); Decrease antral D-cell somotastatin release
• Hypergastrinaemia duodenal ulcers
- Most recent data suggests that IL-1B does this through the down regulation of gastrin!
- CagA (cytotoxin-associated gene A)
Treatment of HP
• Treatment: Triple therapy consisting of the antibiotics amoxicillin, clarithromycin and a PPI.
CREON
- CREON:- delayed release capsules
- CREON is a prescription medicine used to treat EPI e.g where the pancreas does not make enough enzymes due to CF, swelling of the pancreas that lasts a long time (chronic pancreaitis), removal of some or all of the pancreas (pancreatectomy), or other conditions.
- Delayed release: so they don’t become deactivated by stomach juice
- Taken as prescribed, CREON replaces the enzymes that your pancreas isn’t producing, helping you to digest fats, proteins and carbohydrates.
- Exocrine pancreatic insufficiency (Enzymes don’t work properly anymore)
- Creon: Combination of the synthetic enzymes, encapsulated within a delayed release system so that they are protected from the stomach juice, only activated in the small bowel.
IBD
- Made up of two conditions: Chrons disease, ulcerative colitis
- Chrone’s disease far more aggressive
Aminosalicylates
- 5-aminoalicyclic acid (5-ASA) also known as mesalazine, is effective for both induction and maintenance of remission in patients with UC.
- Sulfasalazine, which is sulfapyridine molecule linked to 5-ASA, was originally used to treat UC. It is associated with many intolerable and life-threatening adverse reactions (fever, angioedema, liver damage)
- 5-ASA exerts its therapeutic effects topically on the inflamed mucosa of the colon by interacting with the damaged epithelium
- The exact mechanism of action is unknown, but 5-ASA is a known scavenger of oxygen-free radicals, and it blocks production and chemotaxis of leukotrienes, in addition to many other actions aimed at modifying the immune response and inflammation.
- 5-ASA have many different effects(multi-factorial), first line therapy for IBD.
- Treating, ensures patients remain in remission and don’t have a flare up of their disease.
- Mediates apoptosis
Immunomodulators
- Azathioprine: Purine analogue, interferes with the synthesis of DNA.
- Inhibits the proliferation of quickly rapidly dividing cells, especially cells of the immune system.
- Bioactivity determined by the downstream metabolites
- Cells which are avidly proliferating are stunted in the presence of immunomodulators.
Biologics
- Infliximab: Blocks TNF-a mediated signalling
- TNF-a is an inflammatory cytokine that is involved in host defence inflammation, apoptosis, and activation of immune cell functions.
- TNF-a is the most important cytokine that mediates intestinal tract inflammation and the expression of TNF-a increases in IBD
- Monoclonal antibody against TNF-a are commonly used to treat IBD- Infliximab, Adamilmumab, Golimumab
- Lymphocyte migration and recruitment within the intestinal mucosa is an important process in initiation/maintenance of inflammation mediated by adhesion molecules.
- Inhibitors to these molecules interfere with the adhesive interactions of endothelial cells and circulating immune cells, reducing the mobility of the immune cells- Vendolizumab.
- Inhibits lymphocytes from rolling and getting into mucosa
- Infliximab: Cytokine increase massively in IBD, initiates inflammatory response, neutralises the TNF-a effect.
- ‘mab’ means a monoclonal antibody
Corticosteroids
- Used in IBD
- Steroids
- Inflammation is typically characterised by increased expression of multiple inflammatory proteins, some of which are common to all inflammatory diseases.
- The increases expression of most of these inflammatory proteins is regulated at the level of gene transcription through the activation of proinflammatory transcription factors, such as nuclear factor- kB (NF-kB) and activator protein-1 (AP-1).
- These proinflammatory transcription factors are activated in all inflammatory diseases and play a critical role in amplifying and perpetuating the inflammatory process.
- Corticosteroids regulate this gene expression
- They bind to glucorticoid receptor (GR) in the cytoplasm that translocates to the nucleus and bind to glucorticoid response elements (GRE) in the promotor region of steroid-sensitive genes, which may encode anti-inflammatory proteins suppress activation of proinflammatory transcription factors.
- Can induce genes which have glutiocortcoid genes within them
- Either get induction or inhibition of the gene
- Antinflammatory effect
Constipation and laxatives
• Stimulant laxatives: (Act by increasing motility through chemoreceptor activation and the myenteric nerve plexus) stimulate myenteric plexus, stimulate motility
o Senna, cascara
o Castor oil that contains ricinoleic acid (inhibitor of Na transport)
• Saline (osmotic) laxatives: Act by drawing water into the bowel through osmosis due to high concentration of osmotic particles.
o Mg, sulfate or phosphate, non-absorbable sugar
• Emollient (fecal softner) laxatives
o Non-absorbable lubricants
• Bulk-forming laxatives (dietary fibre, and products based on fibre i.e psyllium (Metamucil), methyl cellulose (Citrucel)
o Bran, methylcellulose
o The safest and generally prescribed laxatives
Loperamide
- LOPERAMIDE
- Prolongs the transit time of the intestinal contents
- Reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes.
- Loperamide: Acts through opiod receptor, inhibits the myenteric plexus and therefore inhibits motility within the gut, allows the contents of gut to be there for longer, allows water be adsorbed.
- Gives the gut as much time as possible to try and absorb the water.
- Also decrease colonic mass movements and suppresses the gastrocolic reflex (distenstion of the stomach which causes colon to be more motile)
Na+/Glucose transporter
- Need Na+ to absorb water
- One of the 4 mechanisms needed to do this: sodium, glucose link transporter, requires glucose to transport Na+ in, draws glucose in against its concentration gradient.
- Na+ imported via Electrical gradient set up by Na+/K+ ATPase pump.
Secretory diarrhoels
- Secretory diarrhoea due to over activity of secondary messenger
- The enterotoxin induces intracellular concentrations of cAMP which increases Cl and K secretion and inhibits electroneutral absorption.
- Because the second messengers do not alter the function of nutrient-coupled Na+ absorption, administration of oral rehydration solution containing glucose and Na+ is effective in the treatment of enterotoxin-mediated diarrhoea.
- Secretory diarrehoas are largely attributed to poor action of secondary messenegers
