Drugs affecting GI tract and kidneys

Question 1

Action of osmotic diuretics

Answer 1

• Involves mannitol being filtered by glomerulus but not readily reabsorbed, presence of mannitol increases osmolarity
• Increases osmolarity means less water being take back from tubular fluid to body
• Excess glucose also has similar actions to mannitol as it is osmotic reactive causing lose of urine (increased urination) as water is not being taken back into body
• Deliberate use of mannitol parallels a similar situation seen in someone with hyperglycaemia
• Osmotic diuretics are used therapeutically to reduce fluid in tissues or organs e.g glaucoma where fluid is being drawn away from the eye to relive excess pressure built up in the eye
• Diuretics cannot be used in situations where there just appears to be too much fluid in the systemic circulation as this gives the heart a lot more work to do in pumping that fluid and so by giving osmotic diuretics, the extra fluid being drawn out tissues will end up in the blood circulation

Question 2

Diuretics acting on tubular reabsorption

Answer 2

• All readily able to enter the nephron by secretion in the proximal tubule by transporter (cannot be filtered as they are bound to plasma proteins)
  1. Loop diuretics, e.g furosemide
• work by blocking Na/K/Cl transport in ascending loop of Henle, by inhibiting this transport, the molecules remain in the nephron lumen
• Molecule absorption allows for highly concentrated region in kidney, high osmotic potential is important for water to draw out of collecting ducts and back into body, so blocking transport causes effect on ability of concentrated environment to pull water back
• There can be resistance to drug action, possibly due to genetic difference that leads to changes in transporter protein which the diuretics target
  2. Thiazides e.g Bendroflumethiazide
• Has action in distal convoluted tubule, targets NaCl transport (inhibit this transport)
• Not as efficient as diuretics overall but more effective than loop diuretics at treating hypertension, shows simplistic view of mechanism of reducing blood volume cannot be sufficient explanation of mechanism
• Dose for reducing blood pressure is less than that used to produce significant diuresis
  3. Potassium-sparring diuretics, e.g spironolactone
• Receptor antagonist that inhibits aldosterone action and works on distal convoluted tubule/collecting ducts
• Blocks Na reabsorption, has small effect on reuptake of water which impacts how these drugs are used
• In general, it is used with another diuretic
  e. g amiloride/triamterene
• Work by blocking Na channels (collecting duct)
• More active Na-K ATPase, the more K will enter cells as the cells of collecting duct have K channels
• These drugs block Na channel, any sodium in the lumen remains in the lumen, leading to less Na-K ATPase activity, so less K in the cells that can be lost

Question 3

Drugs in IBD

Answer 3

1. Aminosalicylates
   - 5-aminosalicyclic acid effects both induction and maintenance of remission of patients with ulcerative colitis
   - 5-ASA is poorly absorbed so remains in luminal and exerts its therapeutic effects topically on inflamed mucosa of colon by interacting with damaged epithelium
2. Immunomodulators
   - Azathioprine interferes with DNA synthesis, inhibits proliferation of rapidly dividing cells
   - During metabolism. hypoxanthine guanine phosphoribosyl converts 6-mercaptopurine to cytotoxic 6-thioguanine (can lead to bone marrow toxicity and myelosuppression)
3. Biologics
   - TNF-α most important cytokine, mediates intestinal tract inflammation expression of TNF-α increases in IBD
   - Monoclonal antibodies against TNF-α used to treat IBD including: infliximab, adalimumab, and golimumab
   - Lymphocyte migration and recruitment in intestinal mucosa is an important process in initiation/maintenance of inflammation mediated by adhesion molecules
   - Inhibitors of molecules interfere with adhesive interaction of endothelial cells and circulating immune cells, reducing mobility of the immune cells (vedolizumab drug)
4. Corticosteroids
   - Inflammation characterised by increased expression of multiple inflammatory proteins, some are common to all inflammatory diseases
   - Increased expression inflammatory proteins is regulated at level of gene transcription through activation of proinflammatory transcription factors, e.g nuclear factor-kB and activator protein-1
   - Proinflammatory transcription factors are activated in all inflammatory disease have critical role in amplifying and perpetuating inflammatory process
   - Corticosteroids regulate gene expression, bind to glucocorticoid receptor in cytoplasm that translocate to nucleus and bind to glucocorticoid response elements in promoter region of steroid-sensitive genes, encode anti-inflammatory proteins, supress activation of proinflammatory transcription factors

Question 4

Laxatives and anti-diarrhoeal

Answer 4

• Stimulant laxative: increasing motility through chemoreceptor activation and myenteric nerve plexus
• Include: senna, cascara, ad castor oil that contains ricinoleic acid (inhibitor of Na transport)
• Saline (osmotic) laxative: draw water into bowel by osmosis due to high concentration of osmotic particles, include: Mg, sulfate/phosphate, and non-absorbable sugar
• Emollient = faecal softener laxative: non-absorbable lubricant
• Bulk-forming laxative =dietary fibre/products based on fibre (psyllium and methyl cellulose), include: bran (methylcellulose), safest/preferred laxative
• Loperamide anti-diarrhoeal: prolong transit time of intestinal contents, reduces daily faecal volume, increases viscosity/bulk/density, diminishes loss of fluid + electrolytes
• Loperamide = opioid receptor agonist, acts on the μ-opioid receptors in the myenteric plexus large intestines, works by decreasing activity of myenteric plexus, decreases motility of circular + longitudinal smooth muscles of intestinal wall, increases amount of time substance stay in intestine, allowing more water to be absorbed out of faecal matter
• Loperamide decreases colonic mass movements + suppresses gastrocolic reflex
• Na/glucose transport or Na/amino acid transport causes secretory diarrhoea as enterotoxin induces intracellular concentrations of cAMP, increases Cl and K secretions and inhibits electroneutral NaCl absorption
• Second messengers do not alter function of nutrient-coupled Na+ absorption, administration of an oral rehydration solution containing glucose and Na+ is effective in treatment of enterotoxin-mediated diarrhoea (also inhibits electroneutral Na transport