Clinical pharmacology

1. {
Drugs stimulating
gastrointestinal motility
Domina Petric, MD

2.  Prokinetic agents are drugs that selectively
stimulate gut motor function.
 Agents that increase lower esophageal
sphincter pressures may be useful for
GERD.
 Drugs that improve gastric emptying may
be helpful for gastroparesis and
postsurgical gastric emptying delay.
 Agents that stimulate the small intestine
may be useful for postoperative ileus or
chronic intestinal pseudo-obstruction.
 Agents that enhance colonic transit: for
constipation.
Introduction

3. {I.
Physiology of the
enteric nervous
system

4. The enteric nervous system is
composed of interconnected networks
of ganglion cells and nerve fibers
mainly located in the submucosa
(submucosal plexus) and between the
circular and longitudinal muscle
layers (myenteric plexus).
The enteric nervous system

5. Mucosa
Epithelium
Lamina
propria
Muscularis
mucosa
Submucosa
Meissner´s
(submucosal)
plexus
Muscularis propria
Circular
muscle
Auerbach´s
(myenteric)
plexus
Longitudinal
muscle
The enteric nervous system
Serosa/adventitia

6.  These plexuses give rise to nerve fibers
that connect with the mucosa and
muscle.
 Extrinsic sympathetic and
parasympathetic nerves project onto the
submucosal and myenteric plexuses.
 The enteric nervous system can
independently regulate gastrointestinal
motility and secretion.
The enteric nervous system

7.  Extrinsic primary afferent neurons
project via the dorsal root ganglia or
vagus nerve to the central nervous
system.
 Release of serotonin (5-HT) from
intestinal mucosa enterochromaffin
(EC) cells stimulates 5-HT3 receptors on
the extrinsic afferent nerves.
 Serotonin is stimulating nausea,
vomiting and abdominal pain.
The enteric nervous system

8.  Serotonin also stimulates submucosal 5-HT1P
receptors of the intrinsic primary afferent
nerves (IPANs).
 IPANs contain calcitonin gene-related peptide
(CGRP) and acetylcholine.
 IPANs project to myenteric plexus
interneurons.
 5-HT4 receptors on the presynaptic terminals
of the IPANs appear to enhance release of
CGRP or acetylcholine.
The enteric nervous system

9.  The myenteric interneurons are important in
controlling the peristaltic reflex, promoting
release of excitatory mediators proximally and
inhibitory mediators distally.
 Motilin may stimulate excitatory neurons or
muscle cells directly.
 Dopamine acts as an inhibitory
neurotransmitter in the gastrointestinal tract,
decreasing the intensity of esophageal and
gastric contractions.
The enteric nervous system

10. {II.
Cholinomimetic
agents

11.  Cholinomimetic agonists, like
bethanechol, stimulate muscarinic
M3 receptors on muscle cells and
at myenteric plexus synapses.
 Bethanechol is now seldom used.
 The acetylcholinesterase inhibitor
neostigmine can enhance gastric,
small intestine and colonic
emptying.
Cholinomimetics

12.  Intravenous neostigmine is sometimes
used for the treatment of hospitalized
patients with acute large bowel
distention: colonic pseudo-obstruction
(Ogilvie´s syndrome).
 Administration of 2 mg iv. results in
prompt colonic evacuation of flatus and
feces in the majority of patients.
 Cholinergic effects are excessive
salivation, nausea, vomiting, diarrhea
and bradycardia.
Cholinomimetics

13. Ogilvie˙s syndrome
Source: Wikipedia.org

14. {
Metoclopramide,
domperidone
III.

15.  Metoclopramide and
domperidone are dopamine D2
receptor antagonists.
 Activation of dopamine receptors
within the gastrointestinal tract
inhibits cholinergic smooth
muscle stimulation.
 Blockade of dopamine has
prokinetic effect.
Dopamine antagonists

16. These agents:
 increase esophageal peristaltic
amplitude
 increase lower esophageal
sphincter pressure
 enhance gastric emptying
 have no effect on small intestine
and colonic motility
Dopamine antagonists

17. Metoclopramide and
domperidone also block
dopamine D2 receptors in the
chemoreceptor trigger zone of the
medulla (area postrema),
resulting in potent antinausea
and antiemetic action.
Dopamine antagonists

18.  Metoclopramide and domperidone are
sometimes used in the treatment of
symptomatic GERD, but are not
effective in patients with erosive
esophagitis.
 Prokinetic agents are used mainly in
combination with antisecretory agents
in patients with regurgitation or
refractory heartburn.
Clinical use

19.  These agents are used in the treatment
of patients with delayed gastric
emptying due to postsurgical disorders
(vagotomy, antrectomy) and diabetic
gastroparesis.
 Metoclopramide is sometimes
administered in hospitalized patients to
promote advancement of nasoenteric
feeding tubes from the stomach into the
duodenum.
Clinical use

20.  These agents lead to symptomatic
improvement in a small number of
patients with chronic dyspepsia.
 Metoclopramide and domperidone are
used for the prevention and treatment
of emesis because of their potent
antiemetic action.
 Domperidone is sometimes
recommended to promote postpartum
lactation.
Clinical use

21.  The most common adverse effects
of metoclopramide involve the
central nervous system.
 Restlessness, drowsiness,
insomnia, anxiety and agitation
(10-20% of patients, especially
elderly).
Adverse effects,
metoclopramide

22.  Extrapyramidal effects are dystonias,
akathisia and parkinsonian features.
 Extrapyramidal effects are due to central
dopamine receptor blockade.
 Occur acutely in 25% of patients given
high doses and in 5% of patients
receiving long-term therapy.
Adverse effects,
metoclopramide

23.  Tardive dyskinesia, sometimes
irreversible, has developed in patients
treated for a prolonged period with
metoclopramide.
 Long-term use should be avoided unless
absolutely necessary.
 Elevated prolactin levels (both with
metoclopramide and domperidone) can
cause galactorhea, gynecomastia,
impotence and menstrual disorders.
Adverse effects,
metoclopramide

24.  Domperidone is well tolerated.
 It does not cross the blood-brain
barrier to a significant degree.
 Neuropsychiatric and
extrapyramidal effects are rare.
Adverse effects,
domperidone

25. {IV.
Macrolides

26.  Macrolide antibiotics such as erythromycin
directly stimulate motilin receptors on
gastrointestinal smooth muscle and promote
the onset of a migrating motor complex.
 Iv. erythromycin 3 mg/kg is beneficial in some
patients with gastroparesis, but tolerance
develops rapidly.
 It may be used in patients with acute upper
gastrointestinal hemorrhage to promote
gastric emptying of blood before endoscopy.
Macrolides

27. Katzung, Masters,
Trevor. Basic and
clinical pharmacology.
Wikipedia.org
Literature