DRUGS FOR DISORDERS OF

THE GASTROINTESTINAL
SYSTEM
NAUSEA AND VOMITING Kirsten Culver,
PhD
Science Lead
BScN Program
 VOMITING
 Forceful expulsion of stomach contents and the contents of the proximal small
intestine
 Associated with many conditions
 It is a symptom NOT a disease
 Regardless of cause, vomiting can have serious consequences
 Potassium deficiency  Esophageal and gastric injury (hemorrhage)
 Sodium depletion  Dental injury (erosions and caries)
 Alkalosis  Purpura (pin-prick red macules on face and neck)
 Malnutrition  Aspiration pneumonia
 DIFFERENTIAL DIAGNOSIS
 Gastroenteritis, constipation, obstruction
 Cortical (hydrocephalus, brain tumor, pain)
 Peripheral trigger areas (severe chest pain, pain from kidney stones)
 Systemic disease (malignancy)
 Vestibular (middle ear infections)
 Medications (chemotherapy, alcohol withdrawal)
 Pregnancy
 Upper GI disease (GERD, PUD, gastric cancer)
 Metabolic cause (uremia, diabetes)
 Psychogenic causes
 THE ACT OF VOMITING
Highly sequenced and tightly controlled biological response
 Nausea
 Retching (‘Dry Heaves’)
 Vomiting
 Projectile Vomiting
Does not include…
 Regurgitation
 Return of previously swallowed food or secretions into the mouth
(involuntary)
 Rumination
 Repetitive, effortless regurgitation of recently ingested food into the mouth
followed by re-chewing and re-swallowing (voluntary, purposeful)
 NAUSEA
 An unpleasant and difficult to describe “psychic” experience
 Sensation of unease and discomfort
 Physiologically, nausea is associated with…
 Decreased gastric motility
 Increased small intestinal tone
 Reverse proximal small intestinal peristalsis
 VOMITING
Propulsion of gastric and small intestinal contents up to and out of the mouth
A highly coordinated series of events…
 A deep breath,
 The glottis closes and the larynx is raised to open the upper esophageal
sphincter
 The soft palate is elevated to close off the posterior nares
 The diaphragm is contracted sharply downward
 Downward movement of the diaphragm, contraction of the muscles of the
abdominal walls
VOMITING REFLEX ILLUSTRATED

Direction of muscular
contractions

Flow of gastric contents

 CONTROL OF VOMITING
A complex, stereotypical, set of
activities that leads to vomiting
4th ventricle

 This suggests central neurologic

control Cerebellum

Brainstem; 3 anatomically and

functionally distinct units that Area postrema
Vomiting Centre

Nucleus of the
control vomiting: and CTZ
4 ventricle
th
solitary tract

 Vomiting Centres (VC)

 Nucleus tractus solitarius (NTS) Activate and coordinate
 Chemoreceptor Trigger Zones the vomiting reflex
(CTZ)
 VOMITING CENTRES
Bilateral vomiting centres
 Found in the reticular formation of the medulla
 Integrate signals from a large number of outlying sources
 Activation triggers vomiting
 Electric stimulation of the VC induces vomiting
 Destruction renders animals resistant to emetic drugs
 Receive afferent signals from:
 The chemoreceptor trigger zone & Nucleus Tractus Solitarius
 Visceral afferents from the GI tract
 Visceral afferents from outside the GI tract
 Afferents from extramedullary centres in the brain
 VOMITING CENTRES AFFERENTS
 CTZ & NTS
 Visceral afferents from GI Tract
 Vagus or sympathetic nerves
 GI distention (very potent), mucosal irritation
 Visceral afferents from outside GI Tract
 Bile ducts, peritoneum, heart and a variety of other organs
 Afferents from extramedullary centers in the brain
 Psychic stimuli (odors, fear)
 Vestibular disturbances (motion sickness)
 Cerebral trauma
 CHEMORECEPTOR TRIGGER ZONES
 Bilateral centres in the brainstem
 Located under the floor of the fourth ventricle
 Electrical stimulation does NOT cause vomiting
 Application of emetic drugs DOES cause vomiting
 CTZ acts as emetic chemoreceptor for the VC
 Detects chemical abnormalities (e.g., emetic drugs, hypoxia, diabetic
ketoacidosis)
 Sends excitatory signals to vomition centers
 Many antiemetic drugs act at the level of the CTZ
 VOMITING PATHWAYS
Absorbed toxic chemicals
and drugs in the blood (e.g. CTZ Vomiting Centre
morphine, chemotherapy)

Mechanical stimuli (e.g.

pharynx), pathology within Vagal afferents to
the GI tract (gastritis) or CTZ and NTS
other organs (e.g. MI)

Vestibular System Vestibular

(e.g. motion sickness) CTZ
nuclei

Stimuli within the CNS (e.g.

pain, unpleasant odors, Cerebral cortex,
psychological factors, such limbic system
as fear)
 CHEMOTHERAPY-INDUCED NAUSEA &
VOMITING
 Chemotherapeutic drugs directly stimulate the CTZ
 Chemotherapy also stimulates enterochromaffin cells in the GI tract to release
serotonin
 Serotonin activates 5-HT 3 receptors in 3 main areas
 Vagal afferents in the GI tract
 Nucleus Tractus Solitarius
 CTZ
 Dopamine D 2 , histamine, and neurokinin NK 1 receptors may also be
stimulated
 Impulses feed into the VC
 When threshold is reached in VC, efferent nerve impulses stimulate emesis
 5HT3 release:
Chemotherapy GI enterochromaffin cells

CTZ
5HT3, D2, H1, NK1, M
Nucleus Tractus
Cortex Solitarius
Vomiting Centre 5HT3, D2, H1, NK1, M

CNS Centres
Salivary, Respiratory, Vasomotor

Abdominal muscles, Diaphragm, Receptors

Stomach, Esophagus 5HT3 = serotonin
H1 = histamine
Chemotherapy-Induced D2 = dopamine
Nausea & Vomiting
(CINV)
Vomiting NK1 = neurokinin
M = muscarinic
 CHEMOTHERAPY AND RADIATION
THERAPY INDUCED NAUSEA
Anticipatory nausea and vomiting
 Occurs before or during therapy in individuals who have had severe symptoms
with previous therapy
 Triggered by specific odors, tastes, or objects that a patient associates with
treatment
Acute nausea and vomiting
 Occurs within 24 hours after cancer treatment
Delayed (late onset) nausea and vomiting
 Occurs more than 24 hours after cancer treatment and may continue for several
days
 ANTIEMETIC DRUG CLASSES

Anticholinergic Drugs
 Muscarinic receptor antagonists in the NTS and CTZ
 Dry mouth, constipation, urinary retention
 Scopolamine
Antihistamine Drugs
 Antagonists at H 1 receptors in the NTS and CTZ
 Sedation
 Diphenhydramine
Cannabinoids
 Agonists at CB 1 receptor in the cortex and VC
 ANTIEMETIC DRUG CLASSES
Dopamine antagonists
 D 2 receptors in the CTZ and NTS
 Olanzapine
 Atypical antipsychotic drug
 Sedation, blurred vision, dry mouth, constipation, urinary retention
 Metoclopramide (also an antagonist at 5HT 3 receptors)
 Domperidone Gastric prokinetics

 Sedation, diarrhea, galactorrhea, extrapyramidal signs

 Haloperidol & Prochlorperazine
 Typical neuroleptic drugs
 Sedation, hypotension, extrapyramidal signs, etc..
 ANTIEMETIC DRUG CLASSES
Serotonin antagonists
 5HT 3 receptors in the CTZ and NTS
 Generally, well tolerated
 Ondansetron
 QTc prolongation and cardiac arrhythmias with IV dosing
 Palonosetron
 Headache, malaise, constipation
 ANTIEMETIC DRUG CLASSES
Glucocorticoids
 Mechanism of action related to…
 Anti-inflammatory & analgesic effects
 Inhibition of serotonergic tone (5HT release & receptor density)
 Reversal of chemotherapy induced HPA hypofunction
 Direct central action within the NTS
 Commonly combined with 5HT antagonists and NK1antagonists
 Dexamethasone
 ANTIEMETIC DRUG CLASSES
Neurokinin receptor antagonists
 NK 1 receptors in the CTZ and NTS
 Block the binding of Substance P at the NK 1 receptor
 Aprepitant & Rolapitant; highly selective for NK 1 receptor
 Commonly co-prescribed with 5HT receptor antagonists and glucocorticoids,
generally well tolerated
 Adverse effects
 Aprepitant inhibits of CYP3A4 enzymes, therefore glucocorticoid dose should
be reduced if co-administered as an antiemetic drug
 ANTIEMETIC DRUG CLASSES
 Adults who receive highly emetogenic chemotherapy should be offered
primary prophylaxis with a four-drug regimen consisting of:
 A neurokinin-1 receptor antagonist (e.g. Aprepitant)
 A serotonin receptor antagonist (e.g. Ondansetron)
 Dexamethasone, a glucocorticoid drug
 Olanzapine, a dopamine receptor antagonist (atypical neuroleptic drug)
 ANTIEMETIC THERAPY
Treatment approach
Sensory input (pain, smell, sight) Higher cortical Memory, fear, anticipation
1. Assess likely cause centres
NK1 Antagonists

 GI/central Histamine antagonists

Muscarinic antagonists Benzodiazepines
Dopamine antagonists

2. Assess consequences Cannabinoids

Chemotherapy Chemoreceptor
 Dehydration, etc.. Anaesthetics Trigger Zone Vomiting Centre
(area prostrema, (medulla)
Opioids
4th ventricle)
3. Treat consequences 5HT3
Vomiting Reflex
antagonists
 IV, NG, antiemetics Histamine antagonists
Muscarinic antagonists
Sphincter modulators
4. Confirm the cause
Chemotherapy
5. Treat the cause Surgery Stomach
Labyrinths Surgery

Small intestine Neuronal pathways

Radiotherapy
Factors which can
cause nausea & vomiting
Gastroprokinetic
agents Sites of action of drugs
 Evaluation: H & P, Labs;
Patient with
Rx: Fluids & Electrolytes,
Nausea / Vomiting Antiemetics

Underlying disorder
Unknown Known Treat

Abdominal X-rays
Surgery
No obstruction Obstruction
Consult
Endo + Barium Studies
No lesion Lesion Treat

Gastric Emptying Test PK Rx,

Normal Abnormal Manometry,
EGG
CT, Psychiatric consult,
Antiemetic Rx, Non-pharm Rx