Upper GI Pharmacology

Question 1

What causes emesis (vomiting)

Answer 1

Vomiting (emesis) is a holdover mechanism to protect us from ingested toxins. It sometimes occurs as a result of excessive vestibular stimulation (motion sickness) or psychological stimuli such as fear, dread, or obnoxious sights and odors.

Question 2

Areas of the brain associated with vomiting

Answer 2

Nucleus Tractus Solitarius (NTS)

Vestibular System

Area Postrema or Chemoreceptor Trigger Zone (CTZ)

Question 3

Role of nucleus tractus solitarius in vomiting

Answer 3

Located in the medulla, it receives input from the GI tract, vestibular system and area postrema

Vagal afferents work here

• Mechanical stimulation
• Chemical stimulation: acetylcholine, dopamine, serotonin, histamine and neurokinins

Projects to the other medullary nuclei and coordinates vomiting response

Question 4

Role of vestibular system in vomiting

Answer 4

CN VIII (vestibulococclear nerve) responsible for vertigo induced nausea

Rich in muscarinic M1 and histamine H1 receptors

Question 5

Role of Area Postrema or Chemoreceptor Trigger Zone (CTZ) in vomiting

Answer 5

Next to NTS but outside the BBB in the 4th ventricle; so responds to many substances that may not cross the BBB.

Substance P - activates many NK1 receptors

Dopamine2 receptors, opioid, serotonin 5-HT3 and others

Question 6

Mechanism of emesis

Answer 6

Afferents include the vagus, spinal and phrenic nerves.They may be directly irritated from infection/medication/radiation therapy or distention like gastroparesis. When these afferents are stimulated, they relax the fundus and body of the stomach and the lower esophageal sphincter and retrograde giant contractions occur in the small intestine. Diaphragmatic and abdominal muscle contractions compress the stomach, and together these factors produce vomiting.

Question 7

SEROTONIN 5HT3 ANTAGONISTS mechanism and use

Answer 7

Mechanism: Antagonize 5HT3 receptors on peripheral vagal afferents in the GI tract and in the CTZ.

Uses: Great for chemotherapy-induced, post-operative or gastroenteritis-induced nausea/emesis. Often used with steroids + prochlorperazine for post-chemo nausea prevention. Not as awesome for motion sickness-derived nausea.

Question 8

Adverse effects of serotonin 5HT3 antagonists

Answer 8

The most serious (and hence most commonly asked) adverse effect includes QTc prolongation which can lead to torsades de pointes. This is really only an issue when patients are on multiple medications that prolong the QTc interval - and most anti-emetics do, so pay attention when combining or schdeduling them. Headache, dizziness and constipation are other common adverse effects. USMLE questions note that it can contribute to serotonin syndrome: rigidity, tremor, hyperthermia (however it is under debate scientifically). Typically this happens with only with multiple SSRIs or other serotoninergic agents

Question 9

Examples of SEROTONIN 5HT3 ANTAGONISTS

Answer 9

Ondansetron (Zofran) - the most commonly used of this class. It comes as an intravenous, sublingual and oral form.

Granisetron (Kytril) - pretty expensive so restricted even in-hospital

Dolasetron

Palonosetron

Question 10

Mechanism and uses of SUBSTANCE P / NEUROKININ ANTAGONISTS

Answer 10

Mechanism: Antagonists at neurokinin1 (NK1) receptors in the CNS, inhibiting the action of substance P in the CTZ.

Uses: Prevention of acute/delayed chemotherapy-associated nausea. Used in combo with steroids/ serotonin antagonists.

Question 11

Adverse effects of Neurokinin inhibitors

Answer 11

Adverse Effects: These are pricey and getting prior authorization from insurance can be tricky. Metabolized by the liver through CYP3A4 so may have drug-drug interactions with warfarin as well as some chemo agents.

Question 12

Examples of SUBSTANCE P / NEUROKININ ANTAGONISTS

Answer 12

Aprepitant (Emend) - oral

Fosaprepitant - IV prodrug of aprepitant.

Netupitant - oral; lasts longer than aprepitant

Rolapitant - oral; lasts longer than aprepitant

Question 13

ANTIPSYCHOTIC / ANTIDOPAMINERGIC AGENTS mechanism and uses

Answer 13

Mechanism: D2 receptor antagonist in CTZ; inhibits dopaminergic stimulation of the CTZ. Anti-psychotics dosed for nausea are typically 1/3 of the dose required for psychosis.I won’t ask you to separate these by classes (but recognize them all as antipsychotic/antidopaminergic agents).

Uses: Nausea from drugs or surgery. Gastroparesis (metoclopramide). Not as often used for chemo-associated nausea (except olanzapine). Can be an extreme solution to hiccups.

Question 14

ANTIPSYCHOTIC / ANTIDOPAMINERGIC AGENTS adverse effects

Answer 14

Mirror those caused by antipsychotics: extrapyramidal symptoms like dystonia, akathesia, tardive dyskinesia.

QTc interval prolongation

Sedation, depression, increased prolactin (leading to galactorrhea/gynecomastia)

Anticholinergic agents, so can lead to neuroleptic malignant syndrome (NMS); fever, rigidity, mental status change, autonomic instability, rhabdomyolysis. Less common in metoclopramide vs. higher-potency antipsychotics.

Question 15

Substituted benzamides example, use, adverse effect

Answer 15

Question 16

Phenothiazines examples and use

Answer 16

Prochlorperazine (Compazine)

Extra Uses: Posesses anti-muscarinic activity so is helpful with vestibular disorders. Also used to abort migraines.

Promethazine (Phenergan) - very commonly used for nausea but with more side effects than ondansetron.

Question 17

Butyrophenone example and use

Answer 17

Haloperidol (Haldol) -

Extra Uses: Traditionally used as a first gen antipsychotic, but also great for severe nausea - often used as part of a palliative care regimen for cancer-related nausea(sometimes with steroids + ondansetron).

Question 18

Olanzapine (Zyprexa), adverse effect, and use

Answer 18

Anti psychotic

Extra Uses: Second-gen antipsychotic; prevention of chemo-induced nausea as part of a regimen

Adverse Effects: Weight gain, hyperglycemia, hyperlipidemia

Question 19

Role of serotonin in digestion

Answer 19

Serotonin is also a big player in treating GI motility issues: it is naturally produced by enterochromaffin cells in the gut (not completely known). It increases tone and facilitates peristalsis through direct action of serotonin on 5-HT2 smooth muscle receptors and 5HT4 receptors activation releasing acetylcholine

Question 20

Prokinetics examples and uses

Answer 20

Metoclopramide (Reglan) - It generates increased tone in the esophagus and stomach - creating a propulsion machine. This helps with gastroparesis by accelerating gastric emptying. It is also sometimes used for GERD, refractory constipation due to decreased motility as well as emesis.

Erythromycin - a macrolide antibiotic which can be used for the adverse effect that leads to increased motility. Recall that it is a CYP inhibitor.

Question 21

Anticholinergic agents example, uses, mechanism

Answer 21

promethazine (antihistamine), prochlorperazine.

Scopolamine (Hyoscine)

Mechanism: Antimuscarinic that works on the vestibular system via M1 receptors. Muscarinic receptors are involved in the visceral afferent input from the gut to the vomiting centre and in the tract that CN VIII takes from the labyrinth to the CTZ via the vestibular nucleus.

Uses: Motion sickness, will occasionally add a patch on to an existing regimen

Question 22

Anticholinergic agents side effects

Answer 22

Adverse Effects: Typical anticholinergic; dry mouth, blurred vision, drowsiness.Available orally, transdermally and parentally.

Question 23

Antihistamines mechanism and use and side effects

Answer 23

Mechanism: These are first-generation antihistamines so they will easily cross into the CNS and all have weak antiemetic properties in addition to sedation.

Uses: Motion sickness / vestibular nausea more so than most other kinds of nausea

Adverse Effects: sedation and muscarinic receptor blocking (dry mouth, blurred vision, urinary rentention, constipation).

Question 24

Antihistamines examples

Answer 24

Diphenhydramine (Benadryl) - pretty sedating, but can take advantage of that and combo with other antiemetics to help acutely for chemotherapy-associated nausea and migraines

Dimenhydrindate (Dramamine) - classic over the counter med for motion sickness

Meclizine (Anivert) - prescription med for vestibular nausea/vertigo

Question 25

Corticosteroids use and examples

Answer 25

Not approved for nausea/vomiting but commonly used for chemotherapy-induced vomiting both alone; although, they work better in combination with other anti-emetics.

Methylprednisolone (Solu-medrol) - IV formulation

Prednisone - oral

Dexamethosone (Decadron) - longer-lasting steroid, both oral and IV

Question 26

Benzodiazapines uses and examples

Answer 26

These have no intrinsic anti-emetic properies but will sometimes help with amnesia during an emetogeneic period (chemo administration) or with anticipatory nausea (from the next treatment). Can cause sedation and amnesia of vertiginous episodes so may be paired with meclizine.

Lorazepam (Ativan)

Diazepam (Valium) - longer acting than lorazepam

Question 27

Cannabanoids mechanism, use, adverse effects

Answer 27

Mechanism: Synthetic derivatives of tetrahydrocannabinol or THC, (a psychoactive substance in cannabis); unclear mechanism of action - possibly inhibition of cortical activity and anxiolysis.

Uses: preventing chemotherapy-induced vomiting, but uncommonly used now with so many other agents available

Adverse Effects: Uncertain about potential for abuse. Possibly from inhibition of neuronal serotonin release): euphoria, dysphoria, sedation, hallucinations, vertigo, ataxia, dry mouth.

Question 28

Cannabanoids examples

Answer 28

Dronabinol (Marinol)

Nabilone (Cesamet)

Question 29

Treatment for pregnancy-induced emesis

Answer 29

Eating modifications, ginger and other non-pharmacologic means are attempted prior to medications for morning sickness (this includes accupuncture and wrist bands) and treating any contributing symptoms like GERD.

Pyridoxine (or vitamine B6) is commonly combined with doxylamine (see anti-histamine lecture).

Antihistamines: Diphenhydramine, dimenhydramine and meclizine may be used.

Dopamine antagonists: Metoclopramide, promethazine, prochlorperazine.

Serotonin antagonists: Ondansetron and granisetron (unclear whether this has an effect on the fetus - studies are underway but used with risk/benefit discussions, particularly in hyperemesis gravidarum).

Question 30

Drugs for motion sickness

Answer 30

Scopolamine, promethazine, prochlorperazine, meclizine, lorazepam & diazepam (helpful adjuncts)

Question 31

Postoperative vomiting drugs

Answer 31

Ondansetron, Scopolamine, metoclopramide, prochlorperazine, promethazine

Question 32

Drug-induced vomiting drugs

Answer 32

Prochlorperazine, metoclopramide, ondansetron

Question 33

Cytotoxic/chemo drug-induced vomiting drugs

Answer 33

Prochlorperazine, metoclopramide, dronabinol, nabilone, ondansetron, aprepitant. 
Adjunctive treatments (e.g. dexamethasone, solumedrol, lorazepam, diazepam)

Often in combinations

Question 34

Pregnancy induced vomiting drugs

Answer 34

Promethazine, metoclopramide, prochlorperazine, pyridoxine +/- doxylamine, diphenhydramine, dimenhydramine, meclizine

Question 35

Non-drug treatments for stomach

Answer 35

dietary and postional changes as well as smoking cessation.

Question 36

Pathophys of GERD

Answer 36

The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3) which modify the gastric acid production. When these are bound, they cause increased cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+-ATPase (the proton pump).

Question 37

Most common causes of stomach ulcers

Answer 37

H. Pylori and NSAIDs

Question 38

Role of Vagus nerve in GERD

Answer 38

releases acetylcholine which binds to M3 receptors to power the proton pump

releases gastrin release peptide (GRP) which activates G-cells

GRP activation releases gastrin which causes enterochromaffin-like cells (ECLs) to release histamine.

Question 39

Targets for pharmacotherapy for GERD

Answer 39

Acid Suppressor - working at the level of the parietal cell (to decrease the acid from being made in the first place).

Antacid - to increase the pH in the gastric lumen. Think of it as a buffering or neutralizing agent.

Question 40

Antacids mechanism and uses

Answer 40

Mechanism: weak bases that reach with gastric HCl to form a salt and water, thereby lowering intragastric acidity quickly.

Uses: In the moment treatment of heart burn (p.r.n = as needed = pro re nata in Latin). Over the counter so many patients have tried these before they make it to us, important to ask specficially in your history as they often neglect to mention them.

Question 41

Antacids adverse effects

Answer 41

Adverse Effects: As they all change the gastric pH and can even bind directly to other medications, they can impact other medication’s absorption. Often need 2 hours between antacids and some meds (clasically iron + antibiotic/antifungals).

Question 42

Examples of antacids and special uses/adverse effects (4)

Answer 42

Calcium carbonate (Tums)

Uses: antacid, hypocalcemia, osteopenia, hyperphosphatemia - calcium can bind phosphate in patents with chronic kidney disease (I won’t ask about anything other than antacid during this block)

Adverse Effects: constipation, belching, gastric distention; large doses can lead to rebound acid secretion and Milk-Alkalai syndrome (hypercalcemia, renal insufficiency, metabolic alkalosis).

Sodium Bicarbonate (Alka Seltzer / baking soda)

Adverse Effects: gastric distention (from carbon dioxide formation) and increased sodium load can impact those with heart failure, hypertension, chronic kidney disease.

Aluminum hydroxide - no gas, so no belching; can cause constipation

Magnesium hydroxide - no gas, so no belching; can cause osmotic diarrhea

Often aluminum/mag combo allows these GI side effects to be balance each other (Mylanta/Maalox)

Question 43

What is Milk-Alkalai syndrome

Answer 43

Hypercalcemia from overuse of antacids/ingestion oif milk

Question 44

H2 blockers (antihistamines) uses and mechanism

Answer 44

Mechanism: reversible, competitive, yet selective block of only histamine H2-receptors leading to decreased hydrogen ion secretion by parietal cells in a dose-dependent manner and decreasing gastrin’s effect on acid secretion.

Uses: GERD, dyspepsia (not really used for peptic ulcers anymore). Sometimes used for an allergic reaction to provide some excess histamine antagonism (in addition to H1-antihistamine and if anaphylaxis, also need steroid + epinephrine). These really help with nighttime secretion but only offer moderate relief during the meal-time surge. They also decrease the pepsin.

Question 45

H2 blocker antihistamine adverse effects

Answer 45

Adverse Effects: pretty safe meds

Question 46

H2 blocker antihistamines examples

Answer 46

Randitine (Zantac)

Famotidine (Pepcid)

Cimetidine (Tagamet) - has anti-androgenic side effects: impotence, gynecomastia, galactorrhea. It’s also a CYP inhibitor so can have medication side effect

Nizatidine

Question 47

Proton Pump Inhibitors mechanism and uses

Answer 47

Mechanism: inactive prodrugs (protected by delayed release capsules/tablets) that difuse into parietal cell canniliculi before becoming active (bonus points for remembering it’s by the Henderson-Hasselbalch reaction). The active form blocks the protein pump by forming a covalent disulfide bond. These are delayed-release, and have once daily dosing, making patient adherence more likely. Although, they are best taken an hour before a meal and take a few days to reach full effect.

Uses: GERD, first-line for PUD and gastritis, Gastrinomas (Zollinger-Ellison), H.pyloritherapy, stress ulcer prophylaxis in ICU patient

Question 48

PPI adverse effects

Answer 48

Adverse Effects: lots of unknowns

Can impact absorption of drugs that require acidic environment for uptake (some concern over clopidigrel).

C.difficile colitis? Decreased acidic environment can lead to maybe lead risk for C.diff (especially if during treatment with abx for H.pylori), but no strong evidence.

Pneumonias? Theoretically, patients on stress ulcer prophylaxis in the ICU with PPIs are at increased risk of nosocomial pneumonias. However, large randomized trialsshow that short-term use very rarely (<1%) leads to complications and likely isn’t a thing.

My take: ensuring that only those with true indications (typically those with the most severe illnesses) are placed on PPIs and that they are discontinued if no longer needed after transfer out of the ICU.

Osteoporosis, hypomagnesemia, iron-deficiency? There are concerns of decreased absorption of food-bound materials due to hypochlorhydia. This can theoretically lead to decreased absorption of calcium, magnesium airon and vitamin B12 with prolonged use. There are some obesrvational studies but not strong evidence to support this.

Question 49

PPI Examples

Answer 49

Omeprazole (Prilosec)

Esomeprazole (Nexium) - IV/PO

Lansoprazole (Prevacid)

Pantoprazole (Protonix) - IV/PO

Dexlansoprazole (Dexilant)

Rapebrazole (Aciphex)

Question 50

Somatostatin example and use

Answer 50

Octreotide (Sandostatin) - great for gastrinomas. Will inhibit the release of gastrin (however, gastrinomas release enough to overwhelm this) and subsequently histamine by ECL. Helps with diarrhea in VIPomas and carcinoid tumors We will revisit this again when we discuss the liver as it is also used for acute esophageal variceal bleeds (as an IV formulation).

Question 51

Misoprostol (Cytotec) mechanism, use, and adverse effects

Answer 51

Mechanism: Prostaglandin E1 agonist that inhibits gastric acid secretion and stimulates secretion of mucus and bicarbonate by epithelial cells.

Uses: PUD, prevention of gastric ulcers for patients that are on long-term NSAIDs.

Adverse Effects: Dosed four times daily so not very well tolerated; also causes diarrhea and cramping.

Question 52

Sulcrafate (Carafate) mechanism, use, and adverse effects

Answer 52

Mechanism: viscous polymer of sucrose octasulfate and aluminum hydroxide; usually a suspension. Can coat the stomach adhering to ulcers and it inhibits pepsin-catalyzed hydrolysis of mucosal proteins.

Uses: Peptic ulcer disease or stress-related ulcer prevention (less effective than H2/PPI for prevention)

Adverse Effects: No systemic effects as it’s not absorbed. It can reduce absorption of other drugs so timing can be tricky.

Question 53

Bismuth subsalicylate (Pepto-Bismol, Kaopectate) mechanism, use, adverse effects

Answer 53

Mechanism: Rapid dissociation allows salicyclate to absorb for mainly enteric exposure. Coats ulcers and may stimulate prostaglandin, mucus, bicarbonate. However, inhibition of intestinal prostaglandin/chloride secretion can help with slowing down diarrhea and it can directly bind to enterotoxins in bacterial diarrhea (and helps against H.pylori too) so is a real multipurpose medication.

Uses: Nausea, heartburn, indigestion, upset stomach, diarrhea! Used for many reasons by patients as it is over the counter. Also, H.pylori eradicationtreatments.

Adverse Effects: Pretty safe for short periods of time, but can lead to black stool or darkened tongue. Prolonged usage can cause toxicity including encephalopathy.

Question 54

H. Pylori diagnosis methods

Answer 54

gastric biopsy with CLOtest, stool test, breath urea test; the least desirable is the serum test. Stool test is usually easiest to obtain and most cost-effective.