(21) Drugs for motility disorders I: prokinetic agents

What increases and decreases GI motility?

Parasympathetic → ↑ GI motility

Sympathetic → ↓ GI motility

Normal movement of food

Behind the food = contraction

In front of the food = relaxation

→ creates pressure

→ pushes food forward

Important neurotransmitters

• ACh = ↑ contraction/motility

• Dopamine = ↓ motility → “brake”

• Motilin = ↑ motility / migrating motor complex

• 5-HT = helps control GI reflexes

SEROTONIN RECEPTORS

overview

• 5-HT3

• 5-HT4

SEROTONIN RECEPTORS

5-HT3

• 5-HT3 activation → nausea/vomiting

• Therefore: 5-HT3 antagonist → ↓ nausea/vomiting

• 3 = nausea → BLOCK

SEROTONIN RECEPTORS

5-HT4

• 5-HT4 activation

  • → ↑ ACh release

  • → ↑ GI motility

• Therefore: 5-HT4 agonist = pro-motility

• 4 = motility → ACTIVATE

3 main prokinetic drug types/classes?

• Cholinomimetic agents

  • Bethanechol

  • Neostigmine / Pyridostigmine

• Dopamine D2 antagonists

  • Metoclopramide

  • Domperidone

• Motilin receptor agonists

  • Azithromycin/Erythromycin

Bethanechol

topic overview

• main idea

• mechanism

• use

• ADR

Bethanechol

main idea

direct M3 muscarinic agonist

Bethanechol

Mechanism

Bethanechol

→ activates M3

→ acts like ACh

→ ↑ GI contraction/motility

Bethanechol

Use

• Historically used for:

  • GERD

  • gastroparesis

• But now rarely used because of side effects.

Bethanechol

ADRs

too much cholinergic activity

• bradycardia

• abdominal cramping

• salivation

• nausea/vomiting

• diarrhea

NEOSTIGMINE

topic overview

• main idea

• mechanism

• use

• ADR

NEOSTIGMINE

main idea

• Bethanechol acts directly on M3.

• Neostigmine acts indirectly.

NEOSTIGMINE

Mechanism

Neostigmine blocks acetylcholinesterase (AChE)

→ ACh is not broken down

→ ↑ ACh

→ ↑ contraction

→ ↑ GI motility

NEOSTIGMINE

Use

• Ogilvie syndrome / acute colonic pseudo-obstruction → IV neostigmine

• Ogilvie = Colon looks obstructed, but the major problem is failure of the colon to contract, rather than something physically blocking it.

NEOSTIGMINE

ADR

• same as Bethanechol :)

Metoclopramide

topic overview

• mechanism and its effects

• use

• ADR

Metoclopramide

mechanism

• Dopamine = brake on GI motility

• So: Block D2

  • → remove dopamine brake

  • → ↑ ACh effect

  • → ↑ GI motility

Metoclopramide

effects

Effects mainly in UPPER GI

• ↑ esophageal contractions

• ↑ lower esophageal sphincter pressure

• ↑ gastric emptying

• little/no major effect on small intestine or colon

• D2 blockade in vomiting center → antiemetic

Metoclopramide

uses - overview

• MAIN USE: GASTROPARESIS

• GERD

Metoclopramide

uses - GASTROPARESIS

• Metoclopramide → used for gastroparesis

• Especially:

  • diabetic gastroparesis

  • postsurgical delayed gastric emptying

Metoclopramide

uses - GERD

• Metoclopramide has a limited role.

• Think: refractory regurgitation + delayed gastric emptying → may add a prokinetic

• It is not used to treat erosive esophagitis itself.

Metoclopramide

ADR - overview

• CNS

• Extrapyramidal symptoms (EPS) = abnormal movement effects

• Dopamine normally ↓ prolactin, but D2 blockade → ↑ prolactin

Metoclopramide

ADR - CNS

• restlessness

• anxiety

• agitation

• drowsiness/insomnia

Metoclopramide

ADR - EPS

• Know:

  • acute dystonia - twisted muscles

  • akathisia - ants in your pants

  • parkinsonism - stiff/shaky/slow

  • tardive dyskinesia - repetitive abnormal movements

• Most important

  • Long-term use → tardive dyskinesia risk and it may be irreversible.

• Therefore: avoid unnecessary long-term use

Metoclopramide

ADR - Dopamine normally ↓ prolactin, but D2 blockade → ↑ prolac

can cause:

• galactorrhea

• gynecomastia

• menstrual problems

• impotence

DOMPERIDONE

topics discussed

• how it different than Metoclopramide

DOMPERIDONE

how it different than Metoclopramide

• Does not significantly cross BBB → fewer CNS/EPS effects.

• But it is not FDA-approved in the lecture.

Azithromycin / erythromycin

topic overview

• Mechanism

• Use

• Major limitation

Azithromycin / erythromycin

Mechanism

Motilin receptor stimulation

→ activates motor complex

→ ↑ upper-GI motility

Azithromycin / erythromycin

Use

• Can be used for acute gastroparesis, especially when D2 therapy is not working/tolerated.

• example when used - clearing the stomach before endoscopy in acute upper-GI bleeding.

Azithromycin / erythromycin

Major limitation

Tolerance develops rapidly

→ effect decreases

→ not good for chronic treatment

→ mainly short-term/acute use

PROKINETIC CONDITION → DRUG

Condition	Know
Ogilvie syndrome	IV neostigmine
Gastroparesis	Metoclopramide
Gastroparesis not responding/tolerating D2 drug	Short-term motilin agonist
Regurgitation + delayed gastric emptying	Prokinetic may be added
Nausea/vomiting + motility issue	Metoclopramide