ANTINAUSEANTS AND ANTIEMETICS:

Pathophysiology of emesis:

ANTINAUSEANTS AND ANTIEMETICS:

1- 5HT3 RECEPTOR ANTAGONISTS
First-generation antagonists Ondansetron (prototype), granisetron, dolasetron , and tropisetron.
Second-generation antagonist palonosetron: higher receptor affinity, a longer t1/2, and
demonstrated superiority over first-generation antagonists.
Mechanism of Action: selective 5-HT3 antagonists, peripherally in GIT (vagal afferents) and
central (STN and CTZ).
Pharmacokinetics: All Given orally or parenterally (except palonosetron iv only). Half-life of
4–9 hours (except palonosetron 40 hours). Metabolised by cytochrome P450 system in liver and
eliminated by renal and hepatic excretion. In hepatic insufficiency, dose reduction may be
required with ondansetron.
Uses: chemotherapy and Radiation-induced nausea and vomiting (most effective). They are also
effective in Postoperative nausea and vomiting and hyperemesis of pregnancy, but not against
motion sickness.
Adverse Effects: In general, they are very well tolerated.
Most common: constipation or diarrhea, headache, and lightheadedness.

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QT prolongation (most pronounced with dolasetron). No QT prolongation with Palonosetron.
Serotonin syndrome (if they are used with other serotonergic drugs such as SSRIs).
2- DOPAMINE RECEPTOR ANTAGONISTS:
Mechanism of Action: D2 receptor antagonism at the CTZ, reducing excitatory
neurotransmitter release.
A- PHENOTHIAZINES: Prochlorperazine, Chlorpromazine and promethazine.
- in addition to D2 receptor antagonism, they have antihistaminic and anticholinergic activities.
Also block α1-adrenoceptors.
- uses: most commonly used “general-purpose” antinauseants and antiemetics, chemotherapy
and Radiation-induced nausea and vomiting, Postoperative nausea and vomiting. Nausea and
vomiting im motion sickness and that of GI origin (due to antihistaminic and anticholinergic).
- Adverse Effects: extrapyramidal reactions, hypotension, Somnolence, cardiac effects,
Increased mortality in elderly patients with dementia-related psychosis.
B- BUTYROPHENONES: droperidol
- used in postoperative nausea and vomiting and in combination with the opioid fentanyl in
neuroleptanesthesia.
- it causes extrapyramidal reactions, hypotension, Q–T prolongation and torsade de pointes.
C- BENZAMIDES: prokinetic (metoclopramide), trimethobenzamide,
Metoclopramide: used in acute and delayed chemotherapy-induced emesis, nausea and
vomiting of GI dysmotility syndromes.
Trimethobenzamide is used for gastroenteritis and postoperative nausea and vomiting.
- Adverse Effects: restlessness, dystonias, and parkinsonian symptoms, elevate prolactin levels.
Domperidone: it does not readily cross the blood-brain barrier, no extrapyramidal side effects. It
increased risk of serious ventricular arrhythmias.
D- OLANZAPINE:
- its antiemetic due to inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors.
- used for prevention of chemotherapy-associated delayed nausea or vomiting (in combination
with a corticosteroid and 5HT3 antagonist) and refractory non–chemotherapy induced nausea
and vomiting.
3- ANTIHISTAMINES:
Cyclizine, meclizine, promethazine, and diphenhydramine, dimenhydrinate.
- they have also anticholinergic effects.
They are used in Nausea and vomiting, Motion sickness, vertigo. Nausea and vomiting
associated with pregnancy.

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- side effects: sedation and dry mouth and other anticholinergic side effects.
Doxylamine succinate and pyridoxine: (H1 receptor antagonist and vitamin B6)
- Nausea and vomiting of pregnancy (first line).
4- ANTICHOLINERGIC AGENTS: scopolamine : muscarinic receptor antagonist
- uses: prevention and treatment of motion sickness (best) in postoperative nausea and vomiting.
- side effects are Constipation, drowsiness, dry mouth, blurred vision dry mouth and other
- better tolerated as a transdermal patch.
5- NEUROKININ RECEPTOR ANTAGONISTS:
Aprepitant (Its IV prodrug fosaprepitant), Rolapitant, netupitant.
Mechanism of Action: central blockade of Neurokinin 1 (NK1)-receptor in CNS.
Uses: used in combination with 5-HT3- receptor antagonists and corticosteroids for the
prevention of acute and delayed chemotherapy induced-nausea and vomiting.
- Netupitant is available only in combination with palonesetron to help prevent
delayed phase chemotherapy-induced nausea and vomiting.
- they are metabolized by CYP3A4 and, therefore, may inhibit the metabolism of other drugs.
- Contraindicated in patients on cisapride, pimozide (due to life-threatening QT prolongation).
- half life: Aprepitant (9–13 h.), Rolapitant (180 h), netupitant (80 h).
- Side effects: Fatigue, constipation, hiccups.
6- CANNABINOIDS:
Dronabinol is Δ9-tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana.
Mechanism of Action: stimulation of Cannabinoid 1 (CB1) receptor on neurons in
and around the CTZ and emetic center.
Uses: chemotherapy induced nausea/vomiting when other antiemetic medications are
not effective and as an appetite stimulant in AIDs-related anorexia and wasting.
Side effects: euphoria, dysphoria, sedation, hallucinations, dry mouth, increased
appetite and autonomic effects (tachycardia, conjunctival injection, and orthostatic
hypotension). Nabilone is a synthetic cannabinoid.
7- GLUCOCORTICOIDS: dexamethasone, methylprednisolone
Mechanism of Action: they have antiemetic properties suppressing peritumoral
inflammation and prostaglandin production.
They are used in combination with other antiemetics for acute and delayed
chemotherapy induced nausea and vomiting (to enhance the efficacy).
8- BENZODIAZEPINES: lorazepam and alprazolam (sedative, amnesic, and antianxiety
effects). They are used to reduce anticipatory vomiting or vomiting caused by anxiety.

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9- PHOSPHORATED CARBOHYDRATE SOLUTIONS:
- Aqueous OTC solutions of glucose, fructose, and orthophosphoric are available to
relieve nausea.
- Their mechanisms of action are unclear.
- safe for pregnancy.

Dr. Hamad Alshabi

PROKINETIC AGENTS
Prokinetic agents are medications that enhance coordinated GI motility and transit of
material in the GI tract.
1- DOPAMINE RECEPTOR ANTAGONISTS:
- Dopamine in GIT acts at D2-receptor→ suppression of ACh release → inhibits
cholinergic smooth muscle stimulation) → inhibitory effects on motility, including
reduction of lower esophageal sphincter and intragastric pressures.
- Blockade of this effect is the primary prokinetic mechanism of action of dopamine
receptor antagonists.
- They blocks dopamine D2-receptors within the CTZ→ antinauseants and
antiemetics.
a- Metoclopramide:
Mechanism of Action: in addition to dopamine D2-receptor antagonism,
metoclopramide have 5HT4 receptor agonism, vagal and central 5HT3 antagonism,
and possible sensitization of muscarinic receptors on smooth muscle.
Effects: increases lower esophageal sphincter tone and stimulates gastric and small
intestinal contractions (enhance gastric emptying). It has no effects on large-bowel
motility.
Uses: gastroparesis, nausea and vomiting due to GI dysmotility syndromes and
Chemotherapy. Other uses: GERD, adjunctive in medical or diagnostic procedures
such as upper endoscopy or contrast radiography of the GI tract.
Adverse Effects: extrapyramidal effects (Dystonias, Parkinsonian-like symptoms,
Tardive dyskinesia, Elevated prolactin levels (galactorrhea, gynecomastia, impotence,
and menstrual disorders). Methemoglobinemia (in premature and full-term neonates).
b- Domperidone:
Mechanism of action: same metoclopramide except that domperidone
predominantly antagonizes the d2 receptor without effect on other receptors.
Uses: prevention and treatment of nausea and vomiting, Postpartum lactation
stimulation.
Adverse Effects: it does not readily cross the blood-brain barrier → no
extrapyramidal side effects.
It has effects in the parts of the CNS that lack BBP SO It elevates prolactin levels
(galactorrhea, gynecomastia, impotence, and menstrual disorders).

Dr. Hamad Alshabi

increased risk of serious ventricular arrhythmias, including sudden cardiac death
(especially in older persons (>60 years) and at doses above 30 mg/d.).
2- SEROTONIN RECEPTOR AGONISTS:
a- Cisapride:
Mechanism of Action: it is a 5HT4 agonist, weak 5HT3 antagonist, may directly
stimulate smooth muscle.
Uses: it was used as prokinetic agent because it induces serious and occasionally fatal
cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and
torsades de pointes (due to effect on K+ channel).
b- Prucalopride:
Mechanism of Action: it is a specific 5HT4 receptor agonist. No effect on K+
channel
Uses: use in women with chronic constipation in whom laxatives fail to provide
adequate relief.
Adverse effects: Nausea, diarrhea, abdominal pain, and headaches.
3- MOTILIN AND MACROLIDE ANTIBIOTICS (erythromycin)
Motilin, a 22–amino acid peptide hormone secreted by enteroendocrine M cells and
by some enterochromaffin cells of the upper small bowel, is a potent contractile agent
of the upper GI tract.
Erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle.
It also causes cholinergic facilitation. It has multiple effects on upper GI motility,
increasing lower esophageal pressure and stimulating gastric and small-bowel
contractility. By contrast, it has little or no effect on colonic motility.
At doses higher than 3 mg/kg, it can produce a spastic type of contraction in the small
bowel, resulting in cramps, impairment of transit, and vomiting.
Uses: Gastroparesis for Short-term use only (due to Tachyphylaxis and side effects).
It may be used in patients with acute upper gastrointestinal hemorrhage to promote
gastric emptying of blood before endoscopy.
Adverse effects: GI toxicity, Ototoxicity, Pseudomembranous colitis, QT
prolongation, and sudden death, particularly when used in patients taking medications
that inhibit CYP3A4.
4- CCK peptide analogue: Sincalide (C-terminal octapeptide of CCK):

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The hormone CCK is released from the intestine in response to meals and delays
gastric emptying, causes contraction of the gallbladder, stimulates pancreatic enzyme
secretion, increases intestinal motility, and promotes satiety.
Uses: The C-terminal octapeptide of CCK, sincalide, is useful for stimulating the
gallbladder or pancreas and for accelerating barium transit through the small bowel
for diagnostic testing of these organs. It is given by intravenous injection.
Adverse effects: Nausea, vomiting, diarrhea, Sweating, Light-headed, Headache and
May cause serious allergic reactions.

DRUGS USED IN THE TREATMENT OF IRRITABLE BOWEL

SYNDROME:
1- Alosetron:
It is a 5-HT3 antagonist. It Reduces smooth muscle activity in gut.
Uses: used for severe diarrhea-predominant IBS in women (rarely used due to side
effects).
side effects: most serious are constipation and ischemic colitis. Other adverse
reactions include nausea and vomiting, GI discomfort and pain, diarrhea, flatulence,
hemorrhoids.
2- Eluxadoline:
Eluxadoline is a mixed MOR agonist, DOR antagonist, and κ-opioid receptor agonist.
It acts locally to reduce abdominal pain and diarrhea
It is used for the treatment of diarrhea-predominant IBS in adults.
side effects: are constipation, nausea, and abdominal pain.
3- Rifaximin:
It is bacterial RNA synthesis inhibitor. Used for diarrhea-predominant IBS.
Adverse reactions include nausea, peripheral edema, dizziness, fatigue, and the
development of ascites and elevation in serum alanine aminotransferase.
4- Antispasmodics:
Anticholinergic agents (“spasmolytics” or “antispasmodics”):
Tertiary amines dicyclomine and hyoscyamine and the quaternary ammonium
compounds glycopyrrolate and methscopolamine.
They are nonspecific antagonists of the muscarinic receptor.
These agents typically are given on either an as-needed basis or before meals to
prevent the pain and fecal urgency that occur in some patients with IBS.

Dr. Hamad Alshabi

Cimetropium and acotiamide are also muscarinic antagonists that are effective in
patients with IBS.
Other Drugs:
Otilonium bromide is a quaternary ammonium salt with antimuscarinic effects that
also appears to block Ca2+ channels and neurokinin NK2 receptors.
Mebeverine hydrochloride, a derivative of hydroxybenzamide, appears to have a
direct effect on the smooth muscle cell, blocking K+, Na+, and Ca2+ channels.

Dr. Hamad Alshabi