GI Flashcards
What coordinates emesis in the body and where is it located?
Nucleus Tractus Solitarus, it is located in the medulla
Where does NTS receive input from?
GI tract, vestibular system and the area postrema
How does Gi communicate with NTS
Communicates via vagal nerve, when GI gets irritated it releases mucosal serotonin which binds to the 5HT 3 receptors, this leads to signals being sent via afferent vagal nerve to NTS
How does NTS regulate emesis
It coordinates with the rest of the medulla to coordinate emesis response
How does vestibular system communicate with NTS?
Via CN VIII
What receptors are present in the vestibular system?
M1 and H1 receptors
What is Area Postrema and where is it located
Area Postrema is a chemoreceptor trigger zone, it responds to presence of emetogenic substances such as chemotherapy agents.It is located adjacent to NTS on the 4th ventricle outside the BBB
What part of the CNS is responsible for sea sickness or motion sickness?
Vestibular system
Ondanestron MOA and what is it used for?
Antagonist of 5HT-3 receptors on the vagal afferents in the GI tract. Ondanestron is good for treating chemo induced emesis or post op emesis
AE of Ondanestron
ConstipationHeadacheDizzinessQT prolongation so it can precipitate torsades and potentially serotonin syndrome
What is serotonin syndrome?
It is associated with systemic release of serotonin and leads to symptoms such as rigidity, tremor, hyperthermia, hyperreflexia, and confusion
What drugs can be used to treat motion sickness?
1st gen H1 receptor blockers can cross the BBB so they can be used to motion sickness, they also have anti muscarinic properties so they can block both H1 and M1 receptors
Name 1st gen H1 antagonists
Diphenhydramine, meclizine, hydroxyzine
Scopolamine
Anti muscarinic agent, used clinically to treat vestibular nausea/motion sickness/sea sickness via M1 receptor inhibition.
What kind of receptors does area postrema contain?
D2 receptors and neurokonin 1 receptors (NK 1)
MOA of metoclopramide
It has 2 principle MOA, it antagonizes D2 receptors in area prostrema to treat chemo induced emesis and it has a pro kinetic effect on GI as it promotes GI motility
What is another use of metoclopramide
Activates GI smooth muscles by antagonizing D2 receptors so it is used for treatment of delayed gastric emptying
Contraindications for metocloproamide
It can only be used for non obstructive GI obstruction, cannot be used in case of a small bowel obstruction as that can lead to GI perforation
What are the side effects of metoclopramide
- Prokinetic effects mean it induces diarrheaMost of the side effects of metoclopramide are due to D2 receptor blockade of the CNS and are more common andsevere in elderly patients
* Drowsiness
* Depression
* Extrapyramidal symptoms
* Tardive dyskinesia
* Myopathy and rhabdomyolysis Neuroleptic malignant syndrome
* QT prolongation
* Prolactinemia
What extrapyramidal symptoms are caused by metoclopramide
Dystonia, akathisia, and parkinsonian features.
Explain neuroleptic malignant syndrome
Caused directly by inhibiting D2 receptors in CNS fever, rigidity, mental status changes, autonomic instability, and rhabdomyolysis
Why is there elevated prolactin secretion due to metoclopramide? What can elevated prolactin cause?
Due to CNS D2 blockade, leads to gynecomastia, impotence, galactorrhea, and menstrual disorders.
What drugs discussed so far are contraindicated in torsades?
Onadnestrone and metoclopramide
What other drugs can be used to inhibit emesis?
Antipsychotics
What is the role of substance P in inducing emesis?
Substance P binds to NK1 receptors in Area Postrema, activating it to relay info into the NTS
Aprepitant MOA
Competitively inhibits the NK1 receptors in Area Postrema, often used in combination with 5HT-3 antagonists to inhibit emesis
Why is aprepitant often preferred over other anti emetics?
It lacks any effects on serotonin, dopamine and muscarinic receptors so it has a shorter side effects profile
What is the function of parietal cells?How do they achieve this?
Parietal cells are located on the fundus of the body and release acid into the lumen via the H+/K+ ATPase. K+ goes into the cell, H+ goes out of the cell using the energy from 1 ATP.
What regulates acid secretion by parietal cells?
- Histamine is released by the ECL (Enterochromaffin-like) cell, activating H2 receptors on the parietal cell on the basolateral membrane
- ECL cells in turn respond to gastrin released by G cells
- G cells are located in the antrum of the stomach and release G protein in the presence of intraluminal peptides into the circulation
- Gastrin binds to CCKB receptors on ECL and parietal cells
- Additionally vagus nerve releases gastrin releasing peptide (GRP instead of ACh) to directly stimulate parietal cells
Name H2 receptor blockers
Ranitidine, cimetidine, famotidine, nizatidine
MOA of H2 receptor antagonists, their effectiveness and clinical indications
Inhibit histamine regulated acid secretion however they are not 100% effective since parietal cells can be stimulated by gastrin and vagus nerveClinical uses:1. Nocturnal secretion of acid since this is largely histamine related2. Second line treatment for GERD, gastric and duodenal ulcers
What mostly controls post prandial acid secretion and what is a clinical concequence to this?
Vagus nerve, H2 blockers are not effective for inhibiting post prandial acid production
AE of H2 blockers?
Generally safe drugs with little adverse effects:1. Cimetidine inhibits CYP4502. Cimetidine inhibits binding of DHT to androgen receptor, together with inhibitng estrogen metabolism it can lead to gynacomastia, impotence and prolactinomia
MOA of PPIs
Proton Pump Inhibitors (PPIs) irreversibly inhibit the H+/K+ ATPase by covalently binding to them
Indications of PPIs
Effectively inhibit and shut down acid production, much more effectively than H2 blockers
- GERD, gastric and duodenal ulcers
- NSAIDs induced gastric ulcers
- Gastrinoma/Zollinger Ellison syndrome
- H. pylori infection
What are the side effects of PPIs
- Increased risk of infections especially C. Diff
- Increased risk of respiratory infections such as pneumonia
- Decreased absorption of Ca, Fe and Mg
- Osteoporosis and hypomagnesia
What other drug can be used to inhibit gastric acid production?
Octeotride
What are osmotic laxatives?
Nonabsorbale substances taht draw water into the intestinal lumen, lead to distention and eventual peristalsis
Name osmotic laxatives
Mg compounds such as MgOH and mg citrateLactulosePolyethylene glycol (PEG)
AE of Mg compounds?
Prolong use can cause hypermagenesia
What is PEG and how is it administered?
Non absorbable sugar, acts as an osmotic diuretic, administered with electrolytes
Lactulose MOAand what is its useother than a laxative?
Lactulose is metabolised by colonic bacteria, producing severe flatulence and cramps in the process, it can also be used to treat hepatic encephalopathy
Explain hepatic encephalopathy
Hepatic encephalopathy is a neurologic complication of cirrhosis due to the buildup of ammonia (inability to convert it into urea) and other toxins. A primary source of ammonia comes from intestinal bacteria degrading Nitrogen products. In patients with cirrhosis, GI bleeding can percipitate hepatic encephalopathy as intestinal bacteria break down hemoglobin, creating nitrogen products and ammonia; excess dietary protein intake is another potential trigger
How does lactulose help with hepatic encephalopathy?
Intestinal bacteria metabolize lactulose into acidic metabolites, lowering the pH of the intestinal lumen. The acidic environment created turns toxic ammonia (NH3) into ammonium (NH4+), which gets trapped in the lumen and secreted.
Rifaximin indications and MOA
Rifaximin (a poorly absorbed antibiotic)can also help treat hepatic encephalopathy by killing the intestinal bacteria responsible for toxic ammonia (NH3) production.
AE of laxatives.
Laxatives can cause diarrhea and dehydration.
What are bulk forming fibers?
Indigestible hydrophilic colloid -> absorbs water -> distention -> peristalsis
Name bulk forming laxatives
Psyllium, methylcellulose, and synthetic fibers
Name stool softners
Oral enema, docusate, and glycerine sopository.
MOA of stool surfactants (softners)?
Facilitate penetration of stool by water and lipids, can be administered orally or rectally
What are stimulant laxatives?
Stimulant laxatives/ Cathartics stimulate bowel movement through the enteric nervous system
Senna MOA and AE
Senna is a stimulant laxative (aka cathartic), which means it stimulates the enteric nervous system and colonic secretions.Chronic use of senna causes melanosis coli (brown pigmentation of the colon).
How does opioids treat diarrhea?
Activating mu receptors in the GI tract, these exist in high density in the GI tract and their action leads to significant GI side effects
Loperamide
Loperamide is an opioid agonist that does not cross the BBB and therefore has no analgesic properties or potential for addiction. Opioid agonists (e.g. loperamide and diphenoxylate) increase the colonic phasic segmenting activity of the colon, increasing the colonic transit time
Diphenoxylate
Diphenoxylate is an opioid agonist used to treat diarrhea that has some ability to cross the BBB -> combine with small doses of atropine to prevent abuse (gives the user adverse symptoms in order to combat euphoria)
What are the AE of diphenoxylate and loperamide?
Causes constipation
What is a VIPoma?
VIPoma’s are pancreatic endocrine tumors that secrete vasoactive-intestinal-peptide which can cause systemic symptoms such as flushing, wheezing, and a secretory diarrhea
What is a carcinoid syndrome?
Carcinoid syndrome is usually due to an ileal tumor with hepatic metastasis that is secreting a number of substances, including serotonin which can cause secretory diarrhea.
How do you treat VIPoma and carcinoid tumor pharmacologically?
Octreotide
