7 - Common GI Drugs

Antacids

• Name in Thailand

• Composition/mechanism

• Use case

• ADRs(5)

• Alum milk

• 1:1 ratio of magnesium hydroxide and aluminum hydroxide, used to bind to already existing HCl in the stomach and reduce it to salt and water

• Mild cases of GERD, or cases of functional dyspepsia, all in all, as short-term relief

• Long-term use in renal dysfunction patients, impairs absorption of drugs like itraconazole, tetracycline, FQs, and FeSO4(So don’t take within 2 hours of other drugs)

Cimetidine/Ranitidine

• Mechanism

• Use case

• ADRs(5)

• These drugs are H2 receptor antagonists, blocking histamine binding to H2 receptors on the basolateral membrane of the basolateral cells → decreased H+K+ATPase activity → decreased HCl secretion

• At night, the H+K+ATPase pump depends a lot on the activity of H2 receptors, so it helps w reducing noctural gastric secretion, so it’s used in cases like patients with nighttime GERD

• Ranitidine: Taken off the market and not used in many countries due to a substance it has called NDMA which could cause cancer

• Cimetidine:

  • IV: Can cause mental status changes in elderly, and patients with renal/hepatic dysfunction

  • Oral: Anti-androgen effect → can cause gynecomastia and impotence

• Both: CYP450 inhibitors, leads to interactions with drugs like warfarin(Bleeding risk), and both reduce itraconazole absorption(requires gastric environment)

Omeprazole, -prazoles

• Administration and how long does it take to see effects

• Mechanism

• Use case

• ADRs(7)

• Can be IV or oral, if oral, take once a day before meal, and it requires 3-5 days to take full effect

• A prodrug that is absorbed into bloodstream then taken to parietal cells where they inhibit H+K+ATPase and reduce HCl secretion

• GERD, PUD from H. pylori or NSAID use, basically anything w that needs HCl inhibited for a long time

• Vulnerability to infections, decreased absorption of itraconazole, CYP2C19 inhibitor(Less clopidogrel effect → clotting), hypergastrinemia(ECL hyperplasia), interstitial nephritis, small gastric polyps, vitamin B12 deficiency

-prazans

• Mechanism

• Use case

• ADRs(6)

• Binds H+K+ATPase to inhibit K+ entry, which also stops H+ from being released

• GERD, PUD from H. pylori or NSAID use, basically anything w that needs HCl inhibited for a long time

• Vulnerability to infections, decreased absorption of itraconazole, hypergastrinemia(ECL hyperplasia), Intestinal nephritis, small gastric polyps, vitamin B12 deficiency

Antacids, H2 receptor antagonists, PPIs, P-CABs are part of what group?

Agents that reduce intragastric activity

Sucralfate

• Mechanism

• Use case

• ADRs(4)

• Works best in an acidic environment(like the stomach) and finds ulcers/erosions and binds to form a protective barrier

• Duodenal ulcers/stress ulcers

• Constipation, shouldn’t be used long term in patients w renal dysfunction, reduces absorption of thyroxine and FQs

Misoprostol

• Mechanism

• Use case

• ADRs(3)

• A PGE1 analogue, meaning it boosts mucus/bicarbonate production and inhibits acid release

• NSAID-induced ulcers + abortion

• Diarrhea, cramping, abortion(if patient doesn’t want one)

Bismuth

• Mechanism

• Use case

• ADRs(2)

• The drug splits into bismuth and salicylate. The bismuth has a wide range of effects(albeit mild), including coating erosions/ulcers, stimulating PGs to boost bicarb/mucus secretion, inactivates enterotoxins, and kills H. pylori. Meanwhile, the salicylate has antidiarrhea effects.

• Mild add-ons to other treatments, used for mild-moderate Traveler’s diarrhea

• Black stool, bismuth toxicity → encephalopathy

Main treatment of PUD

PPI or P-CAB with H2-RA เสริม

H. pylori treatment

10-14 days of PPI, amoxicillin(metronidazole if penicillin allergy), clarithromycin

Simple definition of a “prokinetic”

Boosts GI motility

What is a hormone that stimulates the ENS, and what is a hormone that inhibits it?

1. Stimulates: Motilin

2. Inhibits: Dopamine(Upper GI only, no effect on small and large intestines)

4 uses of prokinetics

1. Boosts LES pressure → GERD

2. Boosts gastric emptying → Gastroparesis

3. Boosts small intestine motility(NOT D2 RA) → Postoperative ileus

4. Enhances colonic transit(NOT D2 RA) → Constipation

Metoclopramide

• Mechanism

• Use case

• ADRs(6)

• D2 receptor antagonist which blocks dopamine’s inhibitory effect on the upper GI, and also crosses the BBB to inhibit vomiting

• GERD, gastroparesis

• General CNS effects, especially in the elderly like insomnia, drowsiness, restlessness

• More concerning effects like dystonia(เกร็ง), akathisia(ผุดลุกผุดนั่ง), parkinsonism(tremors, bradykinesia, ataxia, rigidity), tardive dyskinesia(involuntary movements)

• Hyperproloactinemia → gynecomastia, impotence, galactorrhea, amenorrhea

Domperidone

• Mechanism

• Use case

• ADRs

• D2 receptor antagonist which blocks dopamine’s inhibitory effect on the upper GI, but doesn’t cross BBB but can still be anti-emetic

• GERD, gastroparesis

• QT Prolongation

“-pride” drugs

• Names

• Mechanism

• Use case

• ADRs

• Prucalopride, cisapride(Banned due to QT prolongation)

• Binds 5-HT4 receptors at presynaptic terminal to boost ACh release and boost ENS activity in the lower GI only

• Chronic constipation

• None, get in there

Erythromycin

• What’s it doing here?

• Erythromycin, despite being a macrolide, stimulates the motilin receptor to boost upper GI activity

GERD treatment

1. PPIs

2. H2-RAs

3. Prokinetics(Usually in combination w the first 2)

• Antacids for acute symptoms

Why are these drugs avoided in GERD patients?

• -ozins

• Salbutamol

• -dipines

• atropine

• -ozins: Alpha one antagonists block alpha one receptors → relaxation of smooth muscle

• Salbutamol: Beta 2 agonists → relaxes smooth muscle

• -dipines: DHP CCBs → Blocks Ca2+ channels → Smooth muscle can’t contract → relaxation

• atropine: Blocks M3 receptors → Smooth muscle relaxation

Functional dyspepsia drug use

1. If it causes epigastric pain: PPI/H2-RAs

2. If it causes postprandial fullness: Prokinetics

Simethicone

• Full name

• Purpose

• Air-X

• Anti-flatulent

Peppermint oil

• Purpose

• Anti-flatulent

Psyllium

• Other name

• Similar thing

• Mechanism

• ADRs(2)

• Ispaghula husk

• Methylcellulose

• Acts like a fiber that uses water in the lumen, helping make stool more voluminous, distending the colon and boosting peristalsis

• Flatulence, bloating

Senna

• Mechanism

• ADR(4)

• A stimulant laxative called an anthraquinone, boosts the ENS to contract more

• Abdominal pain, dependence, myenteric plexus destruction, melanosis coli

Bisacodyl

• Mechanism

• ADR(2)

• Another stimulant laxative, but not an anthraquinone

• Abdominal pain, dependence

Glycerol

• Mechanism

• ADRs(2)

• Another stimulant laxative, but not an anthraquinone. Glycerol also helps lubricate the colon

• Abdominal pain, dependence

Lactulose

• Mechanism

• Use case

• ADRs

• An osmotic laxative, aka it stays in the lumen and draws out water which makes stool more voluminous and distends the gut to trigger peristalsis. Not only that, the gut bacteria will ferment it, forming lactic acid, which reduces pH and allows for NH3 to bind H+ and form NH4+ and get excreted

• Constipation, hepatic encephalopathy from hyperammonia

• Flatulence, abdominal cramp

Mg(OH)2, MgSO4, Sodium phosphate

• Mechanism

• Use case

• ADRs(2)

• Osmotic laxatives that use their positive charges to draw water into lumen

• Constipation

• Renal dysfunction + elderly(in sodium phosphate)

Polyethylene glycol/macrogol

• Mechanism

• Use cases

• Taken with water, and binds to that water to stop it from being reabsorbed, and uses the power of that water to cleanse the colon without having to draw out fluid or force the body to reabsorb any fluid

• Short and long term relief of constipation and colonic cleansing before endoscopy or surgery

Lubiprostone

• Mechanism

• Use case

• Activates Cl- channel to excrete Cl-, Na+ follows, and water follows them, allowing the water to soften stool, boost volume and trigger peristalsis

• Chronic constipation

Laxatives general use case

Short-term/intermittent cases

Safest laxative

Bulk-forming

Drugs of choice in pregnancy induced constipation

1. Bulk forming laxatives

2. Lactulose

Drugs of choice for chronic constipation

1. PEG

2. New laxatives(Prucalopride, lubiprostone)

Diphenoxylate/Loperamide

• Mechanism

• Use case

• ADRs(5)

• Both are opioid agonists that weakly(so that none of the analgesic effects are induced) bind Mu receptors which are found in the ENS and reduce activity → Slows down gut motility and allows for more water to be reabsorbed, making the stool harder

• Diarrhea

• CNS depression, paralytic ileus, avoid in children under 12, addiction(In diphenoxylate which crosses the BBB), bloody/mucous stool

Racecadotril

• Mechanism

• Use case

• ADRs

• A drug that inhibits enkephalinase which reduces breakdown of enkephalins(an opioid peptide). This allows enkephalins to bind delta opioid receptors at mucosal cells, which reduces cAMP and reduces amount of secretion of water into intestinal lumen(antisecretory effect) → This makes stool less watery without affecting motility, which is good because it can be used in infectious diarrhea(which we can’t use dipheno./loperamide in, because those decrease motility and doesn’t push out bacteria)

• Diarrhea, specifically infectious diarrhea

• Few!

Activated charcoal(Activated carbon)

• Mechanism

• Use case

• ADR(1)

• Adsorbs drugs and chemicals to itself to block absorption into GI tract

• Poisoning and drug overdose

• Black stool

Dicycloverine

• Mechanism

• Use case

• ADR(1)

• Muscarinic antagonist that blocks ACh from binding to muscarinic receptors which decreases smooth muscle contractions

• Antispasmodic

• Antimuscarinic effects: Dry mouth, blurred vision, constipation, urinary retention, tachycardia

Buscopan

• Other name

• Mechanism

• Use case

• ADR(1)

• Hyoscine

• Muscarinic antagonist that blocks ACh from binding to muscarinic receptors which decreases smooth muscle contractions

• Antispasmodic

• Antimuscarinic effects: Dry mouth, blurred vision, constipation, urinary retention, tachycardia

Mebeverine

• Mechanism

• Use case

• Musculotropic antispasmodic(Doesn’t need to block muscarinic receptors and just acts on the muscle itself, focusing on stopping the spasm-type contractions w/o affecting normal motility)

• Antispasmodic

IBS and types and treatment

IBS, or irritable bowel syndrome, is a functional GI disorder that can cause abdominal pain and discomfort, along with other symptoms depending on type

• IBS C: Constipation, use laxatives like bulk forming, PEG, new agents

• IBS D: Diarrhea, use anti diarrheal drugs like Loperamide or Ramosetron

• Note: Use antispasmodics for the general pain

“-setrons”

• Mechanisms

• Use cases

• ADRs

• Bind 5HT_3 receptors in the GI wall which help reduce motility and pain signals, making it good for treating IBS-D. However, one of them, Alosetron is very dangerous.

• IBS-D, Alosetron is only for women with IBS-D when all other treatments failed but Ramosetron can be used in both genders

• Ischemic colitis(Alosetron), constipation(Alosetron and Ramosetron)

How is vomiting controlled by the body?

The vomiting center does the work, but it has sensors

1. Nucleus Tractus Solitaris: Receives from the GI, has H1, D2, M, NK, 5HT3, and CB1 receptors

2. Area postrema/Chemoreceptor trigger zone: Receives from the blood, has D2, M, 5HT3, CB1 receptors

3. Cerebellum: Receives from the inner ear, has H1 and M receptors

Scopolamine

• Mechanism

• Use case

• ADRs(1)

• A specialized anti-emetic focused on inhibiting muscarinic receptors, often used as a transdermal patch

• Motion sickness

• Antimuscarinic effects: Dry mouth, constipation, urinary retention, blurry vision

Dimenhydrinate

• Mechanism

• Use case

• ADRs(2)

• A H1 anti-histamine that blocks H1 receptors to reduce effects of motion sickness also with anti muscadine effect

• Motion sickness

• Sedation, antimuscarinic effects(Dry mouth, constipation, urinary retention, blurry vision)

Cinnarizine

• Mechanism

• Use case

• ADRs(3)

• A H1 anti-histamine that blocks H1 receptors to reduce effects of motion sickness but also blocks D2 receptors and is a CCB and has mild anti muscarinic effect

• Motion sickness

• Sedation, antimuscarinic effects(Dry mouth, constipation, urinary retention, blurry vision), parkinsonism

Prochlorperazine

• Mechanism

• Use case

• ADRs(A lot)

• An anti-emetic drug that works by inhibiting D2 receptors, M receptors, and H1 receptors

• A broad spectrum antiemetic

• General CNS effects, especially in the elderly like insomnia, drowsiness, restlessness

• More concerning effects like dystonia(เกร็ง), akathisia(ผุดลุกผุดนั่ง), parkinsonism(tremors, bradykinesia, ataxia, rigidity), tardive dyskinesia(involuntary movements)

• Hyperproloactinemia → gynecomastia, impotence, galactorrhea, amenorrhea

• Antimuscarinic effects: Dry mouth, constipation, urinary retention, blurred vision)

Droperidol

• Mechanism

• Use case

• ADRs(A lot)

• An anti-emetic drug that inhibits D2 receptors

• Medication-induced, post-operative, gastroenteritis emesis

• General CNS effects, especially in the elderly like insomnia, drowsiness, restlessness

• More concerning effects like dystonia(เกร็ง), akathisia(ผุดลุกผุดนั่ง), parkinsonism(tremors, bradykinesia, ataxia, rigidity), tardive dyskinesia(involuntary movements)

• Hyperproloactinemia → gynecomastia, impotence, galactorrhea, amenorrhea

• QT prolongation

D2 receptor antagonist use cases in emesis

• Medication-induced, post-operative, gastroenteritis emesis

Odansetron, granisetron, palonosetron

• Mechanism

• Use case

• ADRs

• 5HT3 receptor antagonists

• Non motion sickness vomiting(Chemo/radiotherapy, postoperative, gastroenteritis)

• Few, safe and high efficacy

“-prepitant”

• NK1 receptor antagonists, NK1 only found at the NTS

• Chemo/radiotherapy induced emesis

• Few, safe and high efficacy

Dronabinol/nabilone

• Mechanism

• Use case

• ADRs

• CB1 receptor agonists, which inhibits GI activity

• Add-on to other antiemetic drugs for non motion sickness cases

• Euphoria/sedation/hallucination

Motion sickness, vertigo, labryinthitis anti-emetic treatment

H1 antihistamines: Dimenhydrinate, cinnarizine

Muscarinic: Scopolamine

Because the motion sickness pathway only has H1 and M receptors

Gastroenteritis, food intoxication anti-emetic treatment

D2 receptor antagonists: Metoclopramide, domperidone

5A3 receptor antagonists: Ondansetron, Granisetron, Palonosetron

D2 receptors exist at the NTS where this takes place, and also are prokinetics, and we have 5A3 as an alternative

Medication-induced emesis anti-emetic treatment

D2 receptor antagonists: Metoclopramide, domperidone

D2 receptors exist at the NTS and CRTZ

Post-operative emesis anti-emetic treatment

D2 receptor antagonists: Metoclopramide(No domperidone since there’s no IV)

5HT3 receptor antagonists: Ondansetron

Both D2 and 5HT3 receptors exist at CRTZ and NTS which are both involved here since a surgery causes drugs to be in blood and GI(CRTZ and NTS)

Chemotherapy and radiotherapy emesis anti-emetic treatment

5HT3 receptor antagonists: Ondansetron

NK1 receptor antagonists: Aprepitant, fosaprepitant

5HT3 because these exist at the NTS and will block any signals from serotonin released from damage to cells, while NK1 inhibitors blocks delayed response from substance P(released by neurons when there’s damage) because substance P binds to NK1