Ex. 6 - GI Protection (61-62) Flashcards
Drugs affecting gastric secretion
Antacids
H2 histamine receptor antagonists
PPIs
Protectants
Drugs that increase GI motility
Laxatives
Prokinetic drugs
Reduce GI motility
Anti-diarrheals
Anti-emetics
Acid-peptic disease drugs used in tx of
Non-ulcer dyspepsia (indigestion)
Gastric and duodenal ulcers
GERD - Barrett’s Esophagus
Hypersecretory states such as Zollinger- Ellison syndrome
^Rare
Tumors that produce gastrin
Physiologic control of GI secretions
Parietal cell
in epithelium of stomach
Secretes acid into the lumen of stomach
**stimulated by activation of M3 receptors, AcH, histamine (H2 receptors) and gastrin
Conversion: Proton ATPase
-Moves protons into the stomach
-It does so by moving potassium into the parietal cell
Why do we have sensitivity to receptors in the parietal cell?
These are physiological modulators on the acid secretion of gastrin
Gastrin released in response to food intake
-Directly stimulates parietal cells
-Stimulates ECL cells
ECL Cells
Contain granules of histamine
Gastrin stimulation stimulates the release of histamine
Feedback loop
Lumen of the stomach = highly acidic: inhibitory signal for further acid secretion
-Achieved through activation of D cells which release Somatostatin
Inhibits release of gastrin
-Yellow in graphic
Make up the most of the endothelium of the stomach
Surface epithelial cells
Surface epithelial cells
Secrete mucus and bicarbonate within lumen of the stomach
-Protects underlying tissue from acid erosion
Mucus is a physical barrier - within mucus bicarbonate secreted by surface epithelial cells and creates a buffer within mucus to help neutralize and protect stomach
Prostaglandins (PGE2 and PGI2)
Persistent innovation of prostaglandin synthesis protects the stomach
-Protects through mucosa
Systemically absorbed Antacids
NaHCO3
Neutralizing capacity: High
Adverse: Systemic alkalosis, fluid retention; excess gas
(CO2)
CaCO2
Neutralizing capacity: Moderate
Adverse: Hypercalcemia, nephrolithhiasis, milk-alkali syndrome (CO2)
Minimally absorbed antacids
Al(OH)3
Neutralizing capacity:
High
Adverse:
Constipation, hypophosphatemia if absorbed; encephalopathy
Mg(OH)2
Neutralizing capacity:
High
Adverse:
Diarrhea
If absorbed: CNS toxicity
Commercial Antacids
AlternaGEL - AL(OH)3
Tums - CaCO3
Maalox, Mylanta - Al(OH3) and Mg(OH)2
Rolaids - CaCO3 & Mg(OH)2
Alka-Seltzer - ASA and NaHCO3
Gaviscon (sodium alginate + antacids) - Viscous, weak base
-Prevents reflux
Effective in GERD
Chewable tabs vs liquid suspension
-Liquid more popular but more expensive
H2 Histamine Receptor Antagonists - Cimetidine (Tagamet)
Competitive antagonist of H2 Histamine Receptor
-Reduce gastric acid secretion in response to histamine, gastrin, AcH
H2 Histamine Receptor Antagonists - second gen
Ranitidine
-No longer available
Nizatidine
Famotidine
Competitive antagonists of H2 histamine receptor
Reduce gastric acid secretion in response to histamine, AcH, gastrin
Longer half-life (Hs vs. BID dosing)
Fewer effects on CYP450 system
Greater potency
Absorbed quickly to reduce parietal cell function
PPIs
Main target for acid secretion in the stomach
-Red section on graphic
-inhibiting ultimate step of pathway
-Can suppress acid secretion of M2/3, Gastrin, and H2 receptors by blocking P
PPI types - Bezimidazoles
Esomeprazole (Nexium), omeprazole (prilosec)
-Same molecule, eso is purified S enantiomer - slightly more potent
Lansoprazole (Prevacid)
Raberprazole (Aciphex)
Panntoprazole (Protonix)
Dexlansoprazole (Dexilant)
PPI MOA
Have to be activated in the acidic environment of parietal cell
-essentially irreversible mechanism
-Why the drugs have such a long half-life
-You would have to replace the proton pumps to fix
*8Summary of PPI actions**
Must be absorbed in the SI (acidic), circulate and then be taken up by the parietal cells. This leads to slow onset
Prodrugs: Activated by acidic pH (IN the parietal cell)
Irreversible inhibitor of H+/K+-ATPase (Cys813)
Short plasma half-life (1hour) but long duration of action due to covalent inhibition (24hrs) and slow turnover of proton pumps
Hypergastrinemia occurs, and MAY result in rebound hypersecretion of gastric acid upon drug withdrawal
Main difference between PPIs and H2 antagonists
H2 receptor antagonists = not as efficient at suppressing nocturnal acid as PPI
Bypassing H2 receptor blocker are good at suppressing response toward food, but not so much in general
Acid rebound
Increased gastric acid secretion upon withdrawal of acid-suppressing meds
Reduced gastric acid removes somatostatin’s inhibition of gastrin secretion - Hypergastrinemia
Tolerance to H2 antagonists can occur
Risk associated with suppressing acid secretion
Potentially increase risk of infections:
-Primary role of acid in stomach is to kill of bacteria
-Suppress too much acid - nothing to kill bacteria
Vitamin B12 deficiency:
-No acidity = Vitamin B12 does not efficiently unbind from enzymes and then it is poorly absorbed
Decreased Ca2+ absorption/increased bone fractures:
-Ca salts absorption need acidic environment to be absorbed properly = decrease in plasma calcium conc
Hypergastrinemia
-Simulate PTH
-Simulate bone resorption
-Decreases bone strength
PPI - Vonoprazan
Potassium-competitive acid blocker (P-CAB)
Approved 2023
Advantages:
-Faster acid suppression
-NOT prodrug
-Not influenced by meals
-Very stable in low pH
“ATP-driven H+ export into the gastric lumen an uptake of K+ into the cytoplasm thought to vary from 2H/2K to 1H/1K per ATP as the luminal pH decreases
Mucosal Protective Agents - Sucralfate (Carafate)
Aluminum hydroxide complex of sucrose
-Polymerizes and forms protective barrier at ulcer site
-Acidic pH activates complex
-Poorly absorbed
-Used in conjunction w/other drugs
-Given for a long period of time - lumen toxicity
Mucosal Protective Agents - Misoprostol (Cytotec)
Semi-synthetic prostaglandin E1 derivative
-Reduced acid secretion (parietal cell)
-Cytoprotectant effects - enhanced mucus and bicarbonate secretion
-Used in combination with chronic NSAIDs
AE: Diarrhea, Abortifacient
H. Pylori and Peptic Ulcers
Many peptic ulcers are associated w/ infection of the gastric mucosa by the gram-negative bacilli, Helicobacter Pylori
Noble Prize in 2005 - Barry Marshall and Robin Warren
H. Pylori infection detected by:
13/14 -labelled urea
H2N-CO-NH2
(detects urease activity)
PCR stool sample
H. pylori eradication: Bismuth Subsalicyclate (Pepto-Bismol)
Converted to bismuth salts and salicylic acid in the GI tract
-Antibacterial, Antiviral, and antisecretory activity
Uses: Nausea, heartburn, indigestion, upset stomach, diarrhea
-Part of multi-drug therapy for H. Pylori eradication
H Pylori Eradication - Other drugs
Therapy consists of tx with various combinations of:
-Bismuth Salt (Pepto)
-Antibiotic - Metronidazole, Tetracycline, Amoxicillin
-H2 blocker or PPI
Laxatives
Prokinetic drugs that can stimulate GI motility
Most common: Bulk laxatives
NOT absorbed - form a hydrophilic acid in the GI tract - causes fluid to be retained in the tract, causes contractions
Bulk and osmotic laxatives
Fiber laxatives; Psylium (Metamucil), Methylcellulose, (Citrucel), calcium polycarbophil (fiberCon)
Peg 3350 (MiraLax) aka Macrogol (Movicol)
Isosmotic electrolyte solutions w/PEG 3350 (GoLytely) produce similar effects
(PEG 3350)
Lactulose (duphalac) a non-absorbable sugar has an osmotyic affect. Also, fermented by bacteria in the gut producing acetate which stimulates peristalsis
-Sugar free gummies have a non-absorbable sugar alcohol called malitol. This also forms hydrophilic mass in the presence of water
-Increase water in the intestinal lumen by osmotic force, leading to distention and an increase in peristalsis
Laxatives - Stool Softeners
Docusate Sodium (colace), mineral oil, glycerin
-Surfactants and lubricants
-Incorporate into stool to make passage easier and decrease water absorption
-Lubricate lower bowel to reduce fecal impaction
-Can decrease absorption of fat-soluble vitamins
Secretory or Stimulant Laxatives
Poorly understood mechanism
Castor oil: hydrolyzed in the upper small intestine to ricinoleic acid
Diphenylmethane Derivatives: Bisacodyl (Dulcolax)
Anthraquinones: Cascara, senna, and aloes
Irritation of the mucosa affects fluid secretion/absorption balance and induces peristalsis
Common GI Hypomotility Disorders
Gastroparesis
-Neuropathy during diabetes or Parkinson’s disease
Ileus
-Small bowels don’t recover after surgery
Opioid induced constipation
-Peripheral activation of opioid receptors slows down the G.I system
Prokinetic Drugs
Prucalopride
Erthyromycin
Bethanechol
Metoclopramide - D2 receptor
Neostigmine
Prokinetic - Metoclopramide (Reglan)
D2 Dopamine receptor antagonist
-Blockade of D2 receptors in the myenteric plexus leads to increase acetylcholine release
-D2 receptor blockade also produces anti-emetic effects
-Clinical Uses: Promotes gastric emptying to facilitate small bowel intubation, post op and diabetic gastroparesis, gastro-esophageal reflux disease (GERD)
-Can lead to acute dystonic reactions
Opioid receptor antagonists
Centrally acting: anit-addictive agents
-Naloxone (Narcan)
-Naltrexone
-Nalmefene
Peripherally acting (cannot cross BBB)
-Naloxegol (Movantik)
-Albimopan (Entereg)
-Naldemedine (SYMPROIC)
Prokinetic Drugs - Prucalopride (Motegrity)
5HT4 receptor agonist
5HT4 serotonin receptor, GPCR, GaS coupled, activation leads to increased cAMP, PKA activation and release of ACH
-Indicated for the tx of chronic idiopathic constipation (CIC) in adults
Tegaserod (Zelnorm)
5HT4 agonist
5HT4: Serotonin receptor, GPCR, GaS coupled activation leads to increased cAMP, PKA activation and release of ACH
Indicated for the tx of IBS with constipation in women under 65
Increased _ in the gut will lead to increased Na+, and therefore Increased H2O
Cl-
Downregulation of cytokines = Decreased Pain
Chloride Channel Activators
Increase Cl- rich fluid secretion into intestine
For treatment of IBS + constipation
Not absorbed systemically
Lubprostone (Amatiza)
-Stimulation of type 2 cl channel (ClC-2) activator in small intestine
**Linaclotide (Linzenss) - Plecanatide (Trulance)
-A peptide activator of guanylate cyclase C (GC-C)
Prokinetic drugs - Tenapanor
Sodium/hydrogen exchanger inhibition
-Sodium/Hydrogen exchanger (NHE3) is expressed on the luminal side of small bowel and colonic epithelial cells
-NHE3 functions to absorb sodium from the luminal contents
-Increased Na+ in the gut leads to increased water in the gut accelerating transit of intestinal contents
-This affect can also be achieved through direct treatment with a sodium phosphate (Fleet) enema
Anti-Diarrheals - Opiates
Slow peristalsis to increase water and electrolyte absorption
Opiates = inhibition of presynaptic cholinergic nerves
Diphenoxylate (Diphenoxylate + atropine = Lomotil)
-Active in the CNS
Loperamide (Imodium)
-Poorly traverse the BBB
-Act locally to delay gastric emptying
Reduce Gi motility - 5HT3 receptor antagonist
Alosetron (Lotronex
Blocks visceral afferent pain sensation and decreases colon motility
-GI Se - constipation, ischemic colits
Don’t confuse IBS with IBD
GI drugs - the enteric nervous system
Intrinsic primary afferent neuron
-Submucosal PAN
Extrinsic primary afferent - nausea, vomiting, pain
-Dorsal root or cranial nerve afferent
Enteric Nervous System Neuron increased peristalsis
Emetic response
Acute irritation of gastrointestinal mucosa
-Mechanoreceptors, Chemoreceptors
5HT3- receptors
Chemoreceptor trigger zone (area postrema)
-D2 receptor
-NK receptor?
-5-HT3 receptor
Vomiting center (nucleus of tractus solitarius
-H1 receptor
-M1 receptor
-NK receptor?
(5-HT3 receptor)
Anti-Emetics: 5-HT3 Receptor antagonists
Ondansetron (Zofran), Grainsetron (Kytril), Dolasetron, palonosetron
-Block activity of afferent nerves from stomach and small intestine which activate the trigger center in the CNS
-Clinical use: Nausea and vomiting associated w/chemotherapy
SE: Constipation
Anti-Emetics: NK1 antagonists
Aprepitant, Netupitant, Rolapitant - receptors in chemoreceptor trigger zone
-Combined with 5HT3 receptor antagonits; Akynzeo is combination of Netupitant and palonsetron
Anti-Emetics: Antihistmaines/Anitcholinergics
Dimenhydrinate (Dramamine) = Diphenhydramine - H1 antagonist + the stimulant 8-chlorotheophylline
-Meclizine (Antivert)-H1 antagonist
-Promethazine -H1 antagonist
-Scopolamine - Muscarinic receptor antagonist
Used to prevent MOTION SICKNESS
Anti-Emetics: D2 dopamine receptor antagonists
-Anti-emetic and sedative properties
-Also has antimuscarinic and anthistamine effects
-Can cause acute disotonic reactions
-metoclopramide = Reglan
-Prochlorperazine = Compazine
-Droperidol = Inapsine
Activation of opioid receptors in the myenteric plexus:
- Decrease smooth muscle contraction
- Increases rectal sphincter tone
- Decreases colonic mucosa secretion
