antiemetics

1. Four classes of agents:
1. Antidopaminergics – Phenothiazines and Metoclopramide
2. Antihistamines (HT1 antagonists) and Anticholinergics (M)
3. Serotonin 5-HT3 receptor antagonists
4. Misc. agents
Mechanisms of N/V and vertigo:
• Vomiting from drugs, radiation and metabolic disorders are
generally stimulated through the CNS chemotrigger zone (CTZ-
dopamine mediated) which further triggers the vomiting center
(VC-acetylcholine mediated) in the brain.
• Nausea of motion sickness is initiated by stimulation of the
labyrinthine mechanism of the ear which sends a signal to the
CTZ
• The VC may also be stimulated by GI irritation, motion sickness,
vestibular neuritis and others
Anti-emetic & Anti-vertigo Agents

2. Emetic Stimuli Fig 38-3 G&G, p1030

3. Prophylactic use in patients undergoing cancer chemotherapy is very
important so that they continue the regimen to the end. All
chemotherapy drugs vary in their emetic potential - some are
extremely severe.
Vertigo is a sensation of whirling or rotation accompanied by involuntary
swaying, weakness and lightheadedness.
Motion sickness is a functional disorder caused by repetitive angular,
linear or vertical motion - both are characterized by pallor, sweating,
hyperventilation and N/V.
Antidopaminergic agents are GENERAL PURPOSE anti-emetics
Antihistamines and Anticholinergics think motion sickness
Patient information:
• All of these agents cause drowsiness.
• Avoid alcohol and other CNS depressants due to an additive effect.
Anti-emetic & Anti-vertigo Agents

4. Antidopaminergic agents: Phenothiazines (also used as antipsychotic agents)
MOA: D2 – receptor antagonists at the CTZ (Chemotrigger Zone)
N
S
N
CH3
C
H3
Cl
Chlorpromazine HCl - Thorazine®
N
S
N
CH3
C
H3
CF3
Triflupromazine HCl - Vesprin®
Indications: control of N/V, relief of
intractable hiccups
Tablets 10-200 mg, SR capsules, syrup,
concentrate, suppositories, injection
Side effect: Thorazine shuffle
Do NOT use in children <6 months unless to
save a life
Indications: control of N/V
Injection 10 or 20 mg/mL
Do NOT use in children <2.5 years old, do
NOT use IV in children
Anti-emetic & Anti-vertigo Agents

5. Prochlorperazine maleate
- Compazine®
N
N
N
S
Cl
C
H3
Perphenazine - Trilafon®
N
N
N
S
Cl
O
H
Indications: Control of severe N/V including
during surgery
Tablets 5-25 mg, SR capsules, suppositories,
syrup, injection
Dosage must be individualized, can be
administered oral, IV, IM or SC
Use only in children >2 years of age
Indications: control of severe N/V, relief of
intractable hiccup
Tablets, concentrate, injection
Use only in children >12 years of age and use
IV only when needed to control violent
vomiting
Anti-emetic & Anti-vertigo Agents
Antidopaminergic agents: Phenothiazines
MOA: D2 – receptor antagonists at the CTZ (Chemotrigger Zone)

6. N
N
N
S
S
C
H3
CH3
Thiethylperazine maleate - Torecan®
N
S
CH3
(CH3)2N
Promethazine HCl - Phenergan®
Indications: Relief of N/V
Tablets and injection
Do NOT use this drug IV since it will
cause severe hypotension, IM preferred
route
Do NOT use in children <12 years old
Indications: prevention of N/V but
primary use is an an antihistamine
for type I hypersensitivity, sedation,
adjunct analgesia, motion sickness
Anti-emetic & Anti-vertigo Agents
Antidopaminergic agents: Phenothiazines
MOA: D2 – receptor antagonists at the CTZ (Chemotrigger Zone)

7. N
H
N CH3
O
CH3
OMe
Cl
NH2
Metoclopramide - Reglan®, Maxolan®
Indications: Prevention of N/V associated with emetogenic cancer
chemotherapy, possibly useful in N/V associated with pregnancy and labor
Available as a syrup, 5 and 10 mg tablets, and injection forms
If extrapyramidal symptoms occur administer 50 mg diphenhydramine IM.
For extremely emetogenic drugs such as cisplatin or dacarbazine use an IV
dose of 2 mg/kg
Anti-emetic & Anti-vertigo Agents
Antidopaminergic agents: Non-Phenothiazines
MOA:
1. D2 – receptor antagonists at the CTZ (Chemotrigger Zone)
2. Some HT3 Antagonist activity

8. Emetic Stimuli Fig 38-3 G&G, p1030

9. Antihistamines (H1 antagonists) - Piperazines
Meclizine HCl - Antivert®, Bonine®, Vergon®
N
N
Cl
CH3
Buclizine HCl - Bucladin-S®
N
N
CH3
C
H3
CH3
Cl
Indications: Prevention of N/V, and dizziness
of motion sickness, may be effective in
management of vertigo
12.5-50 mg tablets and capsules
Do NOT use morphine or other respiratory
depressants concurrently
Indications: Control of N/V and dizziness of
motion sickness
50 mg tablet that can be taken without water
by chewing, dissolving or swallowing whole
Dosage up to 150 mg/day
Not indicated for children
Anti-emetic & Anti-vertigo Agents

10. Cyclizine HCl - Marezine®
N
N
CH3
Indications: Control of N/V and dizziness of motion sickness
50 mg tablet that can be taken without water by chewing, dissolving or swallowing
whole
Dosage up to 200 mg/day, NOT recommended for children <12 years old
Anti-emetic & Anti-vertigo Agents
Antihistamines (H1 antagonists) - Piperazines

11. Diphenhydramine HCl - Benadryl®
O
N
CH3
CH3
Structural similarity?
Antihistamines (H1 antagonists)
N
S
CH3
(CH3)2N
Promethazine HCl - Phenergan®

12. Diphenhydramine theoclate or Dimenhydrinate - Dramamine®
O
N
CH3
CH3 N
N
N
N
H
Cl
CH3
O
O
CH3
Diphenhydramine HCl - Benadryl®
O
N
CH3
CH3
Indications: prevention and treatment of N/V, dizziness and vertigo of motion sickness
(Benadryl oral use only agent)
Available as tablets, injection and liquid
MOA: a depressant action on the hyperstimulated labyrinthine function of the middle ear
Anti-emetic & Anti-vertigo Agents
Antihistamines (H1 antagonists)

13. Others
N
H
OMe
OMe
OMe
O
O
N
C
H3
CH3
Trimethobenzamide HCl - Tigan®, Ticon®, Tebamide®
C
H3
N
O
H
O
OH
O
Scopolamine - Scopace®, Transderm-Scop®
Indications: Control of N/V
100 and 250 mg capsules, 100
(pediatric) and 200 (adult) mg
suppositories, injection
MOA: May inhibit CTZ but direct signals
to the VC NOT inhibited. Ex:.morphine
emesis relieved but not CuSO4
Indications: Motion sickness
prevention, some post-op utility
0.4 mg tablets, transdermal system
Do NOT use in children
Will cause a dry mouth, use caution in
spastic and Parkinsons patients
MOA: Anti-muscarinic
Anti-emetic & Anti-vertigo Agents

14. Emetic Stimuli Fig 38-3 G&G, p1030

15. Serotonergic Drugs
Receptor Action Drug Disorder
5-HT1A Partial Agonist Buspirone Anxiety, depression
5-HT1D Agonist Sumatriptan Migraine
5-HT2A/2C Antagonist Methysergide Migraine, depression
5-HT3 Antagonist Ondansetron Chemo-induced emesis
5-HT4 Agonist Cisapride GI disorders
5-HT
transporter
Inhibitor Fluoxetine,
sertraline
Depression, O/C, panic,
PTSD (Post traumatic)

16. Serotonin 5-HT3 receptor antagonists – improved treatment of severe N/V
Indications: Prevention of N/V under the following situations:
1. Initial and repeat course of chemotherapy especially high dose cisplatin
2. Postoperative N/V (ondansetron and dolasetron)
3. Radiotherapy in patients receiving total body irradiation, single high dose
fraction or daily fraction to the abdomen (ondansetron and granisetron)
4. Irritable bowel syndrome (IBS) in women (alosetron only)
MOA: Selective inhibition of 5-HT3 receptors that are located peripherally on
vagal nerve terminals, enteric neurons in the GI tract and centrally in the CTZ:
Mucosal enterochromaffin cells in the small intestine when subjected to chemo-
or radiotherapy release serotonin evoking a vagal discharge and vomiting. In
IBS it is believed that the pain, distension and exaggerated motor response are
caused by serotonin.
Metabolism: CYP 450 enzymes
Anti-emetic & Anti-vertigo Agents

17. Serotonin 5-HT3 receptor antagonists
N
N
N
O
CH3
C
H3
Ondansetron HCl - Zofran®
Dolasetron mesylate - Anzemet®
N
N
N
CH3
O
O
H
Indications: N/V; Unlabeled uses: N/V due to APAP poisoning,
treatment of acute levodopa-induced visual hallucinations,
prostacyclin induced N/V, reduction in bulimic episodes in
bulimia nervosa patients, social anxiety disorders, spinal or
epidural morphine-induced pruritus
4,8,24 mg tablets, 4 and 8 mg oral disintegrating tablets,
injection
Indications: N/V
50 and 100 mg tablets, injection
Use with caution in patients with QT abnormalities, taking
diuretics
Do NOT mix injection with other drugs - be sure to flush the IV
line before injecting
Can be mixed with apple or apple-grape juice for children
Anti-emetic & Anti-vertigo Agents

18. Serotonin 5-HT3 receptor antagonists
Granisetron HCl - Kytril®
N CH3
N
N
CH3
O
Alosetron HCl - Lotronex®
N
NH
N
N
CH3
O
C
H3
Indications: N/V
1 mg tablets and injection
Metabolism hepatic via N-demethylation, aromatic
ring hydroxylation and conjugation---metabolites
appear to be active - Liver cancer patients should
be watched carefully
Recommended for re-released May 2002 by the
FDA following withdrawl from the market
Indications: Irritable bowel syndrome (IBS) in
women only (safety in males has not been
demonstrated), carcinoid diarrhea
1 mg tablets, side-effect is severe constipation
that can lead to perforated colon
Anti-emetic & Anti-vertigo Agents

19. A NEW class of drug: Serotonin 5-HT4 receptor partial agonist
• this stimulates the peristaltic reflex, increases intestinal secretions and inhibits
visceral sensitivity
Indications: Short-term treatment of irritable
bowel syndrome in women only (safety in males
has not been demonstrated) - specifically where
the primary symptom is constipation
Not indicated for diarrhea-prominenet IBS
Side-effects are headaches and usually of
diarrhea is possible
No affinity for 5-HT3 or dopamine receptors
Elimination: 66% excreted unchanged in the urine
and the balance oxidized hepatically followed by
glucuronidation
Contraindicated in patients with severe renal
impairment and moderate/severe hepatic failure
Take before meals
N
H
O
CH3
N N
H
N
H
N
H
CH3
Tegaserod maleate - ZelnormTM
Anti-emetic & Anti-vertigo Agents

20. Misc. Agents
O CH3
C
H3
C
H3
CH3
OH
Dronabinol or THC - Marinol®
Phosphorylated Carbohydrate solution - Emetrol®
Indications: Antiemetic in cancer chemotherapy
Unlabeled uses: appetite stimulation in treating
anorexia associated with weight loss in AIDS
patients
2.5, 5 and 10 mg gelatin capsules containing
sesame oil
MOA: Complex CNS effects including central
sympathomimetic activity that appear to be
mediated by CNS cannabinoid receptors in
neural tissues
Avoid alcohol and barbiturates, patients should
remain under the supervision of a responsible
adult
Indications: relief of N/V caused by upset stomach from intestinal flu, stomach flu
and food and drink indiscretions
Contains dextrose, fructose and phosphoric acid
Anti-emetic & Anti-vertigo Agents