Antinauseants & Antiemetic

Agents
Brian J. Piper, Ph.D., M.S.

October 16, 2012

 Learning objectives
Pharmacy students should be able to:
1. Explain emesis pathway(s)
2. Identify drug targets for antiemetic agents
3. Describe mechanism of action of antiemetic agents
4. Recognize adverse effects of antiemetic agents

Ibn Bultan (1531)

 Emesis
A protective reflex that serves to rid the stomach
and intestine of toxic substances and prevent their
further ingestion.

Vomiting is a complex process that consists of:

Pre-ejection phase: gastric relaxation & retroperistalsis
Retching: rhythmic action of respiratory muscles
preceding vomiting and consisting of contraction of
abdominal and intercostal muscles and diaphragm against
a closed glottis
Ejection: intense contraction of the abdominal muscles
and relaxation of the upper esophageal sphincter
 Importance
Vomiting is an adverse effect of many clinically
useful drugs:
cancer chemotherapy & radiation
opioids
general anesthetics
Nausea may be a component of:
migraines
pregnancy
 Area Postrema
surrounds 4th ventricle
outside blood brain barrier & monitors blood

Miller & Leslie (1994). Frontiers in Neuroendocrinology, 15(4), 301-320.

 Activity of Area Postrema Following
Chemotherapy

Neuronal activation (c-fos, arrowheads) in the area postrema (AP)

following cisplatin administration (10 mg/kg) to an adult ferret. CC:
Central Canal (4th ventricle); NTS: nucleus of the solitary tract; DMX
dorsal motor nucleus of vagus nerve.

Miller & Leslie (1994). Frontiers in Neuroendocrinology, 15(4), 301-320.

 Area Postrema & Nausea

Rats (non-retching) got saccharine, injection (saline or lithium chloride), then

two-bottle choice

Bernstein et al. (1992). Brain Research, 575, 132-137.

 Area Postrema & Nausea

Rats (non-retching) got saccharine, injection (saline or lithium chloride), then

two-bottle choice
Lesion of the area postrema eliminated this response.

Bernstein et al. (1992). Brain Research, 575, 132-137.

 Area Postrema (AP) & Nausea
*
*

Rats (+AP lesioned) got saccharine, injection (saline or lithium chloride)

Behavioral ratings of response to lithium (Lieing on Belly) were made
Pre-inections, a meal was consumed. Stomach contents were examined.
Area Postrema = chemoreceptor trigger zone

Bernstein et al. (1992). Brain Research, 575, 132-137.

 Anatomy of Emesis
Chemoreceptor trigger zone (CTZ) in the area postrema
(AP) at the bottom of the fourth ventricle has high
concentration of:
5-HT3 (?)
D2
M1
NK1
opioid
The CTZ has connections to the Nucleus of the Tractus
Solitarius (NTS) & Reticular Formation (aka vomiting
center) which contains:
5-HT3 (?)
M1
NK1
 M1

D2

Krakauer et al. (2005). New England Journal of Medicine, 352, 817.

 Classification of antiemetics

some peripheral activity at 5-HT3 receptor;

some antihistamine and anticholinergic activity
 Ondansetron
MOA: 5-HT3 antagonist
Indications:
radiation, chemotherapy, postoperapative
Dosing: 1x/day
Adverse Effects: constipation & headache
 5-HT3 Antagonists (-etron) Compared
Granisetron Ondansetron Dolasetron

Brand name Kytril, Sancuso Zofran Anzemet

FDA Approval 1988 1991G 1997
Indications chemotherapy chemotherapy chemotherapy
radiation radiation radiation
Half-life (hours) 9 4 8
Routes of oral, iv, transdermal oral, iv oral, iv
administration
Adverse effects constipation & constipation & headache
headaches headaches tachy/bradycardia

Ggeneric form available

 5-HT3 Antagonists (-etron) Compared
Granisetron Ondansetron Palonosetron

Brand name Kytril, Sancuso Zofran Aloxi

FDA Approval 1988 1991G 2003 (delayed nausea)
Indications chemotherapy chemotherapy chemotherapy
radiation radiation post-operative
Half-life (hours) 10 4 40
Routes of oral, iv, transderm oral, iv oral, iv
administration
Adverse effects constipation & constipation & headache, constipation,
headaches headaches QT
 5-HT3 Antagonists Compared: Efficacy
Chemotherapy patients (N = 563) randomized to
receive ondansetron versus palonosetron
Treatment failure = emetic response or rescue
medication

% of Patients

Gralla et al. (2003). Annals of Oncology, 14, 1570-1577.

 5-HT3 Antagonists Compared: Safety
Chemotherapy patients (N = 563) randomized to
receive ondansetron versus palonosetron

Gralla et al. (2003). Annals of Oncology, 14, 1570-1577.

Pathway of Emesis

4
3
1

2
 Pavlovs Experiments
During conditioning, the neutral stimulus (tone)
and the US (food) are paired, resulting in
salivation (UR).
After conditioning, the neutral stimulus (now
Conditioned Stimulus, CS) elicits salivation (now
Conditioned Response, CR)

19
 Classical Conditioning & Nausea
Pre-Conditioning
Neutral Stimulus: hospital environment
Unconditioned Stimulus: chemotherapy
Unconditioned Response: nausea & vomiting
Post-Conditioning
Conditioned Stimulus: hospital environment
Conditioned Response: nausea & vomiting
 Metoclopramide
MOA: D2 antagonist, 5-HT3 antagonist
Indications: chemotherapy, post-operative
Adverse Effects: restlessness, Parkinsonian
symptoms

1 min: http://www.youtube.com/watch?v=dum81RdFrhM
Pronunciation: http://dictionary.reference.com/browse/metoclopramide?s=t
 Olanzapine
MOA: D2 antagonist + others
Indications: acute & delayed CINV
Adverse Effects:

Stahl (2008). Essential Psychopharmacology, p. 411.

 Dronabinol
Synthetic delta-9-tetrahydrocannabinol (9-THC)
Schedule: III
MOA: Cannabinoid receptors?
AE: dysphoria, postural hypotension
Density of Cannabinoid Receptor 1 (Increased
Darkness = more receptors labeled with [3H]CP-55,940)

Hekenham et al. (1991) J Neurosci, 11, 563-583.

 Aprepitant
MOA:
substance P binds to NeurokininA receptors
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met
NeurokininA antagonist
Indications: CINV, PONV
Adverse Effects: asthenia, constipation, hiccups
 NeurokininA Antagonist: Efficacy
Abdominal surgery patients (N=750) randomized
to receive oral Aprepitant or Ondansetron
Hours until vomiting or rescue medication

Gan et al. (2007). Anesthesia & Analgesia, 104(5), 1082-1089.

 NeurokininA Antagonist: Safety
Abdominal surgery patients (N=750) randomized
to receive oral Aprepitant or Ondansetron

Gan et al. (2007). Anesthesia & Analgesia, 104(5), 1082-1089.

 Summary
High Therapeutic Index Low Therapeutic Index
5-HT3 antagonists cannabinoids
NK1 antagonists dopamine antagonists
corticosteroids (combo) benzodiazepines

Hesketh (2008). New England Journal of Medicine, 358, 2482-2494.

 Abbreviations
CB1 Cannabinoid 1
CINV Chemotherapy-induced nausea and vomiting
CTZ Chemoreceptor trigger zone
DA Dopamine
NK1 Neurokinin 1
PONV Post-operative nausea and vomiting
STN Solitary tract nucleus
VC Vomiting center